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P04-05

SYMPATHETIC MODULATION OF CARDIOVASCULAR ACTIVITY IN NORMAL AND STRESSED FEMALE AND MALE RATS

Glushkovskaya-Semyachkina O., Anishchenko T.

The aim of study was to investigate the sex particularities in cardiovascular responses to adrenaline (Ad) and propranolol (P) in normal and stressed rats.

The rats of both sexes (n=40) was instrumented with catheters for measuring of arterial pressure (AP), heart rate (HR) and for P (0.1 mg/1000g) and Ad (10mg/1000g) administration. The study of AP, HR was performed during: 1) control conditions; 2) 60-min immobilization stress (IS); 3) Ad or P injection; 4) IS+Ad or P.

In females compared with males IS resulted in more significant tachycardia (32% against 24%, P<0.05) but less significant hypertension (11% against 18%, P<0.05). The short-lasting hypertensive effect of Ad didn’t differ between females and males (39% and 31%, respectively). However, females vs. males demonstrated higher compensatory decrease in HR (74% against 30%, P<0.001). Ad caused the increase in AP and decrease in HR responses to IS, more pronounced in females than in males. The usual gender difference in HR and AP responses to IS were reversed. So during IS+Ad females vs. males exhibited lesser tachycardia (11% against 18%, P<0.05), but more significant hypertension (45% against 31%, P<0.05). P injection caused bradycardia that was exspressed in a greater degree and in the greater number of females vs. males (by 58% in 67% of females and 10% in 58% of males). The decrease in HR induced by P was accompanied by compensatory increase in AP (21% in females and 15% in males). The IS of rats injected by P was accompanied by bradicardic response in females and small tachycardic response in males. P didn’t depress stress-induced elevation in AP that was similar in males and females. Our data suggest that sympathetic modulation of cardiovascular activity is more pronounced in females than in males both under normal and stress conditions. Partly supported by grand CRDF (REC-006) and Grand of Ministry of Education of Russia RD 02-1.4-261.

State University of Saratov- Russia

P04-06

INTESTINAL BLOOD FLOW IN RATS KEPT ON LOW SODIUM DIET: ROLE OF NO, ALPHA-1 AND AT1 RECEPTORS

Sipos A., Bartha J., *Vág J., *Keremi B., *Csillag M., Hably Cs.

Background: According to our previous studies low sodium diet results in elevation of intestinal blood flow. The question is if activation of vasodilator mechanisms and/or decrease of vasoconstrictor effects result in the increase of blood flow? Method: In rats kept on low (LS) or normal (NS) sodium diet for six weeks the blood pressure (BP), the cardiac output (CO) and the intestinal blood flow (IBF) were measured (by 86Rb-accumulation technique) in anaesthesia. NO synthesis was inhibited by L-NAME (15 mg/kg), angiotensin II type 1 (AT1) receptors were blocked by Candesartan (1,0 mg/kg), and alpha1-adrenergic receptors by Prazosin (0,5 mg/kg).

Results (x+/-S.D.): Sodium depletion failed to influence the CO, but IBF (ml/min/100g tissue) increased (219 +/- 66 vs. 174 +/- 49 p<0.01). L-NAME increased the BP and decreased the CO both in NS and LS rats, and IBF decreased both in NS (117 +/- 38 vs. 174 +/- 49, p<0.001) and LS (106 +/- 42 vs. 219 +/- 66, p<0.001) rats; the decrease was higher in LS rats than in NS ones (p<0.05). Candesartan decreased the BP and CO both in NS and LS rats, but IBF decreased only in LS rats (126 +/- 35 vs. 219 +/- 66, p<0.001). Prazosin decreased the BP and CO both in NS and LS rats, but had no effect on IBF either in NS or LS rats. Conclusion: In case of decreased sodium intake the vasoconstrictor effect of angiotensin II is partially counterbalanced by increased NO production.

Semmelweis University, Faculty of Medicine, Dept of Physiology and *Dept of Conservative Dentistry, Budapest, Hungary

P04-07

THE ROLE OF ALPHA ADRENERGIC RECEPTORS IN VASOCONSTRICTOR EFFECT OF EPINEPHRINE IN RAT GINGIVA

*Keremi B., **Sipos A., **Hably C., *Vág J., *Fazekas Á.

Background: Epinephrine is widely used in dental practice. However the role of adrenergic receptor subtypes in the mediation of vasoconstrictor effect is not well-known. Thus, the aim of the present study was to investigate the effect of alpha1 or/and alpha2 adrenergic receptor blockade on the gingival vasoconstriction evoked by locally applied epinephrine (0,01%). Method: Experiments were carried out on anaesthetized female Wistar rats. Prior to locally applied epinephrine animals received iv. injection of physiological saline (Group A, n=9); prazosin (0.5mg/kg, group B, n=12); yohimbine (10mg/kg, group C, n=12); prazosin + yohimbine (group D, n=9). Gingival blood flow was measured by laser doppler flowmetry. Blood pressure (mmHg), heart rate (1/min), gingival blood flow (BPU) were registered continuously and gingival vascular resistance was calculated (GVR, mmHg/BPU). Results: Epinephrine did not influence blood pressure (102+/-8 vs. 98+/-8) and heart rate (369+/-17 vs. 368+/-18). Epinephrine produced GVR elevation in group A (0.52+/-0.05 vs. 0.22+/-0.02, p<0.001), in group B (0.28+/-0.02 vs. 0.24+/-0.02, p<0.01) and in group C (0.25+/-0.03 vs. 0.22+/-0.02, p<0.05), but not in group D (0.19+/-0.02 vs. 0.18+/-0.02). The increment of GVR in group B and C was practically the same (17% vs. 17%). In contrary the alteration in group A was significantly higher (139%, p<0.001). Conclusion: The vasocontrictor effect of locally applied epinephrine is mediated by both alpha1- and alpha2-adrenerg receptors.

Support: ETT 30/2000

Semmelweis Univ.*Dept.of Conservative Dentistry,** Dept.of Physiology - P.O.Box 259, 1444, Budapest, Hungary

P04-08

IS BARORECEPTOR REFLEX HEART RATE CONTROL CHANGED IN BORDERLINE HYPERTENSION?

Voita D., Vitols A.

It is showed that baroreceptor (BR) heart rate (HR) control is diminished in mild hypertension, but there are contradictory data about BR function at borderline hypertension (BH). The aim of the present study is to analyze the BR reflex bradycardic reaction in BH at rest and during pressor reaction accompanying static muscular exercise.

In 56 patients with BH (men, aged 18-24 yrs) and 27 age and gender matched controls ( C ) were studied at rest and during static muscular exercise with force 50% MVC and duration 60s. Beat-to- beat HR and finger mean arterial pressure (MAP) were monitored non-invasively. Carotid baroreceptors were stimulated applying neck suction (-60 mmHg for 5s) at rest and during handgrip. The obtained data showed that BR reflex bradycardic reaction revealed high variability in the patients group - from 2 to 20 bpm, but in C the bradycardic reaction to BR activation was relatively stable - it varied from 16 to 22 bpm. HR at rest was increased (p<0.05) in patients comparing to C and the correlation between HR and BR bradycardic reaction was found (p<0.01). In BH whom HR didn’t differ significantly from the same aged healthy C, the bradycardic reaction to BR activation and its dynamics during the static exercise also was not different. The bradycardic reaction at rest and decrease of the bradycardic reaction amplitude during the pressor response accompanying static exercise was faster and more expressed in patients with significantly (p>0.01) higher HR at rest comparing to C. Although MAP didn’t differ significantly in comparing patients groups. The present data showed that BR reflex control is changed only in those patients with BH which have elevated HR at rest comparing to controls. We hypothesis that these patients, probably, may develop the more stable hypertension. Further study will be performed in future.

Latvian Institute of Cardiology – Riga, Latvia

P04-09

RAT RETINAL TISSUE RELEASES A VASORELAXING FACTOR

Van de Voorde J., Boussery K., Delaey C.

The present study aimed to investigate whether the retina of the rat exerts a vasodilatory influence by the release of a relaxing factor (as was previously observed with bovine retina) and to characterise the retinal relaxing factor (RRF). The relaxing influence of the rat retina was investigated by placing the retina in close proximity of a precontracted isolated rat carotid artery ring segment, mounted for isometric tension measurements. Application of rat retina relaxed the precontracted artery in a reliable and reproducible way (33.3 + 1.7 % relaxation). The NO-synthase inhibitor nitro-L-arginine (0.1 mM), the soluble guanylyl cyclase inhibitor ODQ (1 µM) and removal of the endothelium of the artery all failed to affect the RRF-response. The RRF-response was not decreased, in contrast rather increased, after treatment with a cyclooxygenase-inhibitor (indomethacin or sodium diclofenac). Acute hypoxia largely enhanced retina-induced relaxation. Several potential mediators of hypoxia-induced vasodilation (glutamic acid, GABA, aspartic acid, taurine, glycine, adenosine, lactic acid) were excluded from being the RRF, and from mediating the enhanced response to RRF in hypoxia. Inhibition of the plasma membrane Ca2+-ATPase with vanadate (1 mM) significantly affected the RRF-response. It is concluded that (an) as yet unidentified relaxing factor(s) is (are) continuously released from the rat retina. Acute hypoxia profoundly enhances the RRF-response. None of the known mediators of hypoxia-induced vasodilation, nor NO, prostanoids or endothelial factors mediates the RRF-response. Activation of the plasma membrane Ca2+-ATPase seems to be involved in the RRF-response.

Department of Physiology and Pathophysiology, Ghent University, De Pintelaan 185 - Blok B, 9000 Gent, Belgium.

P04-10

CHRONIC TREATMENT OF INTERFERON-ALPHA REDUCED THE ENDOTHELIUM-DEPENDENT RELAXATION

Yao H., Cao C.M., Jin H.F., Shan Q.X., Wang L.L., Xia Q.

Objective: To investigate the vascular effect of acute and chronic treatment of interferon-alpha (IFN-alpha) in rat aortic rings.

Methods: The isolated thoracic aortic rings were mounted on the organ bath and the tension of the vessel was recorded.

Results: IFN-alpha (100~10000 U/ml) caused concentration-dependent relaxation of aorta rings preconstricted with PE (1 microM) in endothelium-intact rings. Removal of the endothelium, or pretreatment with L-NAME (100 microM) or methylene blue (10 microM) or AMG (100 microM) inhibited the relaxation of IFN-alpha, respectively. Pretreatment with IFN-alpha (1,000,000 U/d, i.p.) for five days markedly inhibited the endothelium-dependent relaxation of the aortic rings to acetylcholine. But the endothelium-dependent relaxation to acetylcholine was not changed by pretreatment of IFN-alpha (10000 U/ml) with the isolated aorta rings for 2 h.

Conclusion: The results indicate that the vasorelaxation induced by IFN-alpha in rat aorta rings is endothelium dependent and possibly mediated by inducible nitric oxide synthase. Chronic treatment of IFN-alpha may impair the enodothelium or NO-sGC pathway.

Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China

P04-11

THE BENEFIT OF ANTICOAGULANT TREATMENT IN PROLONGUED IMMOBILIZATED PATIENTS FOR HIP FRACTURES

Ion I., Ceamitru N., Adumitresi C.

The objective of our study is to emphasize the advantage of using low molecular anticoagulant treatment in patients with limb fractures who underwent orthopedic surgery.

In this study, were examined patients with fractured hips, hospitalized in the Orthopedic surgery department of the County Hospital – Constanta, between November 16th and December 7th, 2001. During the whole period of hospitalization, have been administrated to the patients, subcutaneously, once daily, low molecular weight heparin’s (LMWH). The blood tests were performed before surgery, immediately after it and 7 days latter. From plasma obtained after blood centrifugation, collected on sodium citrate, were determined Fibrinogen (FIB), Activated Partial Prothrombin Time (APTT), Prothrombin Time (PT), and Thrombin Time (TT). From the whole blood collected on EDTA, thrombocyte number was counted.The obtained data were statistically analyzed and values of P < 0.05 were considered significant.

There was observed the increase of thrombocytes number and fibrinogen values in patients with hips fractures as a reactive response to the inflammation and surgical intervention. Also, under LMWH treatment APTT was maintained in the normal range and prolongation of PT and TT were noticed.

Because LMWH administered subcutaneously (SC) once daily are at least as effective and safe as low dose unfactionated heparin (UFH) administered SC two or three times daily, LMWH has become the anticoagulant of choice for the prevention of venous thrombosis following major orthopedic surgery.

Faculty of Medicine, Constanta, Romania

P04-12

ROLE OF NITRIC OXIDE IN REFLEX SELF-REGULATION OF BLOOD PRESSURE

Datsenko V., Moybenko А., Pavlyuchenko V., Maisky V.

The main goal of the present study was to elucidate the possible nitric oxide participation in the reflex self-regulation of circulation.

Experiments (n=20) was carried out on the anaesthetized closed-chest dogs. We used the unique method of double-lumen catheterization and autoperfusion of the left coronary artery in the dogs and stimulation of cardiac receptors in order to reproduction cardiogenic reflexes. Excitation of cardiac receptors were reproduced by intracoronary injection of veratrine and catecholamines. In order to estimate reflex vasomotor reactions in the peripheral vessels, performed autoperfusion of the hindlimb arterial vessels by a constant flow pump. Other part of experiments (n=9) was performed on the anaesthetized rats under similar conditions. We carried out the especial series of experiments with NADPH-d-staining to evaluate the distribution of NOS-containing neurons in the medulla of dogs and rats.

Veratrine and cahecholamines injections resulted in a reflex decrease of mean arterial pressure and relaxation of coronary and peripheral vessels.

After NOS inhibition by L-NNA (30 mg/kg i.v.) reflex coronary and peripheral vessels vasodilatation and depressor reaction decreased or disappeared, while reflex cardiogenic vasoconstrictor responses significantly intensified. Species differences were shown: the depressor reflexes decreased after NOS inhibition in dogs, but they increased or were not changed in rats.

Morphological analysis showed species differences in the distribution of NOS-containing neurons in the medulla. In comparison to rats, the rostral and caudal ventrolateral medulla and subdivision of nucleus tractus solitarius in dog contained more NO-generated neurons.

Our data suggest that NO-dependent mechanisms play an important role in the realization of cardiogenic reflexes, predominantly related to n.vagus. These NO-dependent reflex reactions decrease a cardiac afterload, therefore they could be admitted as compensatory reactions.

Bogomoletz Institute of Physiology NAS, Kiev, Ukraine.

P04-13

INCREASE OF BAROREFLEX AND HRV WITH TRAINING IN THE ELDERLY

Pichot V., Roche F., Denis C., Garet M., Costes F., Barthélémy J-C

Purpose: Autonomic nervous system activity decreases continuously with age and appears as a powerful predictor of disease and death. Thus, in the intent of improving health, attempts are made to reincrease autonomic nervous systemactivity. Methods: We assessed autonomic nervous system activity by heart rate variability and cardiac spontaneous baroreflex sensitivity in eleven elderly men (73.5±4.2 years) before and after a 14 weeks of cycloergometer sustained interval training program. Heart rate variability indices were calculated using time domain, Fourier and wavelet analysis over 24-hour Holter recordings. Baroreflex sensitivity was calculated from 15-minute recordings of blood pressure and RR interval spontaneous variations using sequences and cross spectral methods. Results: After the training period, VO2peak increased by 18.6% (26.8±4.4 to 31.8±5.2 ml.kg-1.min-1, p<0.01). Total power and high frequencies of heart rate variability increased up to +73.8% (p<0.05) and the BRS indices increased up to +52.5% (6.9±2.2 to 10.5±3.7 mmHg.ms-1, p<0.05). Conclusion: Intensive endurance training in the elderly increased the spontaneous cardiac spontaneous baroreflex sensitivity and more generally the parasympathetic activity. Physiological mechanisms and long-term clinical benefits on health status should be further investigated.

Laboratoire de Physiologie - GIP E2S - CHU de Saint-Etienne, Saint-Etienne, France.

P04-14

NEW CARDIAC HORMONE ASSAYS FOR THE ASSESSMENT OF HEART FUNCTION

Hirvinen M., Ruskoaho H., Vuolteenaho O.

Natriuretic peptides are cardiac hormones regulating blood pressure and fluid homeostasis. A- and B-type natriuretic peptides (ANP and BNP) and their N-terminal prohormones (NT-ANP and NT-BNP) are upregulated in heart failure and they appear to serve as excellent markers of the cardiac performance. In this study we prepared recombinant peptides, raised antisera and set up several specific immunoassays for N-terminal prohormones. We tested these assays in healthy persons and cardiac patients.

We set up two competitive immunoassays for NT-ANP (epitope specificities 1-20 and 46-79) and five for NT-BNP (1-22, 5-24, 10-29, 52-70, 57-76). Recombinant human NT-ANP1-98 and NT-BNP1-76 were used as tracers and calibrators. The sensitivities of the assays allowed direct measurement from plasma or serum. The normal values of NT-ANP (250 pmol/l) and NT-BNP (85 pmol/l) increased parallelly with the NYHA classification (6-fold and 17-fold, respectively at NYHA4). The two NT-ANP assays (1-20 and 46-79) showed good correlation (n = 230, r2 = 0.8) indicating that these assays recognize the same peptide. RP-HPLC analyses from human plasma and serum samples revealed a single immunoreactive peak corresponding to NT-ANP1-98. On the other hand, immunoreactive NT-BNP in human blood consisted of several components. The NT-BNP concentrations obtained by different assays (5-24, 10-29, 57-76) correlated extremely well (r2 = 0.75-0.83), although the absolute levels varied between the assays. Apparently the different antisera recognize circulating fragments of NT-BNP with varying lengths and half-lives.

In conclusion, we set up sensitive immunoassays for NT-ANP and NT-BNP. The assays utilize native calibrators and can measure the various circulating forms of the N-terminal prohormones. The assays can be used to monitor the cardiac status in physiological and pathophysiological situations.

Departments of Physiology and Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland

P04-15

EFFECTS OF ENDOTHELIN-1 IN SALMON CARDIAC PEPTIDE SECRETION AND CARDIAC CONTRACTILE FUNCTION

Vierimaa H., Ronkainen J., Ruskoaho H., Vuolteenaho O.

We have recently cloned from salmon (Salmo salar) a novel heart-specific hormone, salmon cardiac peptide (sCP), related to mammalian natriuretic peptides. sCP has natriuretic, diuretic and vasodilatory effects. sCP has turned out to be an useful model for studying general biology of natriuretic peptides. We have previously shown that major stimulant for sCP secretion is mechanical load of the heart. Now, we have studied effects of endothelin-1 (ET-1) in sCP secretion and characterized its inotropic effects to salmon myocardium. We have set up specific radioimmunoassays for sCP and its aminoterminal fragment (NT-pro-sCP) and used them to characterize their secretion patterns.

Human ET-1 injection to the dorsal aorta of salmon caused a clear (1.5-fold) increase in serum NT-pro-sCP levels in vivo. The increase was abolished by pre-treatment with the endothelin type A receptor antagonist (BQ-123 and BQ-610). In vitro ET-1 caused a moderate increase in sCP release from isolated salmon ventricle (p < 0.01). The ET type A receptor antagonist attenuated the response induced by load (p < 0.001). ET-1 exerted a positive inotropic effect in salmon myocardium preparation which could be inhibited by ET type A receptor antagonist.

Thus, endogenous ET-1 appears to play a significant role in the maintenance of salmon cardiac endocrine and contractile function. The effects are mediated by ET type A receptors. ET-1 may have a paracrine role in regulating the release of the sCP peptides. The effects of ET-1 in vivo may be both direct and indirect (ET-1-induced increase in blood pressure). The role of ET-1 in salmon is therefore similar as in mammals. Thus, the regulation of the cardiac endocrine and contractile function appears to be highly conserved over the great phylogenetic distance between fish and mammals.

Departments of Physiology and Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland

P04-16

COMPARISON OF PATHOPHYSIOLOGICAL SYMPTOMS IN ATHEROSCLEROTIC HEART DISEASES IN DURING OF LIFETIME

Nobahar M., Vafaei AA.

Atherosclerotic Heart Diseases (AHD), [Unstable angina (UA) and Acute myocardial infarction (AMI)] are very prevalence in aging and are mainly factor for create mortality in elderly (>65 years old). Although many studies have described symptoms associated with AHD, few, if any, have examined symptom predictors of AHD and whether they differ by patients' age. Aim of this study to compare of pathophysiological symptom predictors of AHD in younger (< 45 years), 46-65 and older (> 66 years) patients. This research was a retrospective cross-sectional descriptive study that analysis of observational data gathered by checklist (demographic data, history, sign and symptom) on 570 patients hospitalized in coronary care unit during one year in Fatemiah hospital in Semnan. Data indicated that UA more prevalence in women and AMI more prevalence in men. Diaphoresis and Pain (presence, spread and sort) have more prevalence in younger patient than older (P<0.05). Don’t significantly different between another symptoms and age. In compare symptoms between UA patient and AMI, result indicated that pain, diaphoresis, nausea and vomiting in AMI more prevalence than UA (P<0.05). Finding above shown that typical AHD symptoms are lower predictive in older age. Therefore early and correct diagnosis of sign and symptom in elderly are very helpful for control of AHD.

University of Medical Sciences, Faculty of Nursing and Paramedical, Semnan, Iran

P04-17

COMPARISON OF PATHOPHYSIOLOGICAL RISK FACTORS THAT INDUCED OF AHD IN DURING OF LIFETIME

Nobahar M., Vafaei AA.

The main cause of Atherosclerotic Heart Diseases (AHD), [Unstable angina (UA) and acute myocardial infarction (AMI)] is risk factors (Smoking, Hypercholesterolemia, and Hypertension, Diabetes, Obesity, History of heart diseases and family history). Evidence indicated that presence of this factors dependent of age that differentially in younger and older patient. The aim of this study to compare of pathophysiological risk factors that may be induced AHD in younger (< 45 years), 46-65 and older (> 66 years) patients. This research was a retrospective cross-sectional descriptive study that analysis of observational data gathered by checklist (demographic data and risk factors) on 570 patients hospitalized in coronary care unit during one year in Semnan Fatemiah hospital. Data indicated that hypertension is more prevalence in older (P<0.05). But hypercholesterolemia, smoking, diabetes and history of heart diseases more prevalence in moderate age but less prevalence in younger and older. Family history was more prevalence in younger (P<0.05). Don’t significantly different between another risk factor and age. In compare of risk factors between UA and AMI, result indicated that smoking and diabetes more prevalence in AMI and history of heart diseases and hypercholesterolemia more prevalence in UA than the AMI (P<0.05). Finding above shown that the risk factors that may be induced of AHD are differs in during of life time. Therefore early diagnosis of risk factors and modulating those are very helpful for prevention of AHD.

University of Medical Sciences, Faculty of Nursing and Paramedical, Semnan, Iran

P04-18

HEART RATE AND BLOOD PRESSURE VARIABILITIES IN YOUNG DIABETICS

Javorka M., Javorka K., Javorková J.

The primary aim of the study was to compare the parameters of the heart rate and blood pressure variabilities quantified by application of the Poincaré and sequence plots and sample entropy parameter in the group of young subjects with diabetes mellitus type 1 (DM1) and in healthy controls. The patients included 17 subjects (10 females, 7 males, mean age 22.4 ± 1.0 years) with an average duration of DM1 of 12.4 ± 1.2 years. Controls (17 subjects) were matched for age, sex and BMI. RR intervals were telemetrically transmitted through the VariaCardio TF4 system (Sima Media,Olomouc,Czech republic) to a receiver and PC, peripheral beat-to beat blood pressure values were registered by the volume-clamp method (Finapres, Ohmeda, USA) and PC.

Conventional parameters of the heart rate variability (HRV) in high and low frequency bands obtained by spectral analysis (FFT) were lower in diabetics in comparison to controls. In DM1 group, the length and widths of the Poincaré plot constructed from resampled RR intervals were significantly shorter; the percentage of the points in the 3rd quadrant of the sequence plot was decreased; the number of the RR interval sequences with a minimal RR length changes was higher. Complexity of the heart rate evaluated by the sample entropy parameter (SampEnRR) was not different between the groups. HRV parameters correlated neither with the DM1 duration nor with the values of glycated hemoglobin. Blood pressure variability at rest in the young patients with DM1 was not different from controls.

The results using non-conventional mathematical methods confirm the heart rate dysregulation in young diabetics primary by the insufficient parasympathetic regulatory output without a disorder of the BP regulation at rest.

Dept.of Physiology,Comenius University, Jess.Med.Faculty and Paediatric Clinic,University Hospital, Martin, Slovakia

P04-19

EFFECTIVENESS OF OVERALL BAROREFLEX REGULATION: ITS MEASUREMENT BY A TWO-POINT METHOD

Burattini R., Borgdorff P., Westerhof N.

The aim of the study is to quantify the overall baroreflex effectiveness, which results from the combined action of baroreflex regulation and the counteracting effect of short-term (minutes) total systemic autoregulation, by means of the effective overall open-loop gain, Goe. This gain is estimated by a method which requires two measurements of cardiac output, CO, and mean systemic arterial pressure, MAP: one in the reference state (set-point) and the other in a steady-state reached 1 to 3 minutes after a small CO perturbation. Defining ΔP and ΔPi as the steady state changes in MAP, with and without resistance regulation, respectively, Goe is computed as ΔPi/ΔP-1. A small decrease of CO by partial occlusion of the inferior vena cava in anaesthetised cats and by cardiac pacing in anaesthetised dogs yielded mean (±SEM) Goe values of 1.4±0.2 in the cat (n=8) and 1.5±0.4 in the dog (n=5). The real baroreflex open-loop gain, Gor, was calculated by correction for total systemic autoregulation, which was quantified using the relation between autoregulation resistance gain and initial (control) peripheral resistance, normalised for body weight (Burattini et al., Am. J. Physiol. 1994;267:R1182-9). Mean Gor was 3.3±0.4 in the cat and 2.8±0.8 in the dog. The ratio of Goe to Gor indicated that total systemic autoregulation masks ~55% of the baroreflex open-loop gain. A model based analysis showed that without autoregulation, i.e. with Goe larger than 2 to 3 units, the transient response of MAP to a stepwise perturbation in CO may result in sustained and, eventually, undamped oscillations with a ~0.1 Hz rhythm, most likely caused by characteristics of the resistance vessels. We conclude that autoregulation reduces the effectiveness of the baroreflex gain and prevents baroregulation from instability. Our two-point method for estimation of Goe in closed-loop conditions might become a practical tool for quantifying baroreflex effectiveness.

Polytechnic University of Marches, 60131 Ancona, Italy; VU University Medical Center, 1081 BT Amsterdam, The Netherlands.

P04-20

THE EFFECTS OF EXERCISE ON CARDIOCIRCULATORY AND ENDOCRINE PARAMETERS IN ELDERLY PATIENTS WITH EAHT

Revnic C.R., Revnic F., Teleki N., Voiculescu V.

The lack of physical activity in elderly represents a major risk factor in the onset of cardiovascular pathology.Cardiovascular disases and esspecialy arterial hypertension occupy the first place among pathologies found in the elderly.

The aim of our study was related with the evaluation of a 30 minutes standard physical effort of moderate intensity upon cardiovascular parameters(heart rate and systolic and diastolic blood pressure and upon metabolical and clinicofunctional parameters in elderly male patients.24 patients aged between 46-78 years old admitted in the Rehabilitation Clinique for osteoarticular and posttraumatic pathologies divided into two groups of 21 patients each:group A of adults patients with normal physical activity and group B sedentary and obese patients with EAHT.Before and after training program, cardiocirculatory parameters and EKG have been determined , as well as the levels of CK,CKMB .HGH , hTSH,T3, T4 and Cortisol have been determined with a DELFIA 1234 Research Spectrofluorimeter.After each day of training,the EMG of biceps and triceps muscle have been evaluated with an EMG Schwartzer-Picker 2000. Results:Our data have pointed out that after standard physical effort of moderate intensity the sedentary and hypertensive subjects have adapted very well to the effort as the clinicofunctional parameters of cardiorespiratory apparatus have shown. The subjects were able to perform movements with a better neuromuscular coordination. Conclusion:The decrease of blood pressure values after the standard physical effort in sedentary patients with hypertension accaunts for a good degree of their adaptability to physical effort of moderate intensity being well tolerated constituting as an alternative to the classical drug treatment with increased risk by its nephrotoxic effects.

UMF”Carol Davila”,*N.I.G.G.”Ana Aslan”, Physical Medicine and Rehabilitation Institute,Bucharest, Romania.

P04-21

DIFFERENT PATTERN OF CONDUIT ARTERIES OF ADULT RATS AND THEIR NEWBORNS AFTER NITRIC OXIDE INHIBITION

Kristek F., Gerova M., Lehotsky M.

We studied morphological characteristics of thoracic aorta (TA) and carotid artery (CA) of adult nitric oxide deficient (NODH) rats and their newborns. Adult rats were administered NG-nitro-L-arginine methyl ester (L-NAME) in drinking water (40 mg/kg/day) for 6 weeks. The newborns were 4 weeks old born from these NO deficient parents (parents were administered L-NAME for 5 weeks before fertilization and females continued 7 weeks during pregnancy and breast feeding). Both groups had own age matched controls. Blood pressure (BP) was measured weekly noninvasively on tail artery, using the plethysmographic method. At the end of the experiment the cardiovascular system was perfused with glutaraldehyde fixative under the pressure 120 mm Hg. TA and CA were processed according to standard electron microscopic procedure. Geometry of the arteries was measured on semithin sections in light microscopy. Volume densities of smooth muscle cells (SMC) and extracellular matrix (ECM) in the arterial wall (tunica intima + tunica media) of CA were determined in electron microscopy. Adult rats: BP of NODH rats (172±1.7 mmHg) was higher then in controls (102.8±1.1 mmHg). The inner diameter (ID) in TA was increased, not in CA. Increased wall thickness (WT) of both arteries was due to increase of both SMC but mainly ECM. WT/ID was higher in NODH rats then in controls. Newborns: in spite of increased BP of NODH newborns (150±2.3 mmHg vs. 105±2.1 mmHg in controls) the ID increased in TA only, not in CA. Surprising was decline of WT of both TA and CA comparing to control arteries. The decline of WT was accounted for by the pronounce decline of volume density of SMC. WT/ID ratio in vessels from NODH newborns was lower too. In conclusion: The known WT and WT/ID ratio increase in NODH adult rats was contradictory to decrease of both these parameters in NODH newborns.

Institute of Normal and Pathological Physiology, Bratislava, Slovakofarma, J.S.C. Hlohovec,Slovakia

P04-22

PENTOXIFYLLINE REDUCES ENDOTHELAEMIA, VWF AND HPA-AXIS ACTIVATION IN RATS IN IMMOBILIZATION STRESS

Kristová V., Mlynárik M.*., Slámová J., Kiss A.*., Kriska M., Jezová D.*

Stress is generally considered to be a risk factor of several diseases including cardiovascular diseases. The direct evidence on stress-induced damage to the endothelium is still lacking. Therefore, the model of immobilization stress used in previous studies was exploited as a suitable model for neuroendocrine activation and possibly for endothelial damage.

The aim of present study was to verify the following hypotheses: (1) a single exposure to an intensive stressor is followed by a damage to the endothelium, (2) potential stress-induced endothelial cell damage is reduced by repeated administration of pentoxifylline (PTX) and (3) PTX treatment modifies neuroendocrine activation under stress conditions through changes in hypothalamic-pituitary-adrenocortical (HPA) axis activation.

Rats were treated with saline or PTX (20 mg/kg, s. c.) once daily for 7 days. In saline pretreated rats, a single exposure to immobilization stress for 120 min was followed by an increase in endothelaemia, von Willebrand factor (vWf) concentrations, adrenocorticotropic hormone (ACTH) and corticosterone release, as well as by enhanced gene expression of hypothalamic corticotropin releasing factor (CRH). Pretreatment with PTX significantly reduced endothelaemia, plasma ACTH and corticosterone concentration in the adrenals.

The obtained results have shown that a single exposure to an intensive stressor associated with significant HPA-axis activation caused damage to the endothelium. PTX pretreatment reduced markers of endothelial injury as well as stress-induced rise of hormone levels. These data provide the evidence on protective action of pentoxifylline under stress conditions.

This study was supported by grants of EC ICA1-CT-2000-70008, VEGA 2/20007 and 1/9302/02.

Dept. of Pharmacol., Fac. of Med., Comenius Univ., *Inst. of Exp. Endocrinol., Slovak Acad. Sciences, Bratislava, Slovakia

P04-23

ENDOTHELIUM-PROTECTIVE EFFECTS OF POLYPHENOLIC COMPOUNDS FROM RED WINE

Kristová V., Vojtko R., Kurtanský A.*., Cerná A.**., Slámová J., Kriska M., Babál P.**

Protective effects of red wine polyphenols (RWP) on cardiovascular system have been documented in numerous human as well as animal experimental studies. These effects involve improvement of vascular relaxation mediated by increased production of nitric oxide (NO) by vascular endothelium. In the present work, the model of endothelial damage by chronic administration of carbon tetrachloride (CCl4) was used for evaluation of endothelium-protective effect of RWP.

The aim of this study was to investigate the effect of RWP and CCl4 on vascular responses and endothelaemia as the marker of endothelial cell injury in vivo in rats. The polyphenolic extract was administered orally 40 mg/kg/day for 8 weeks, CCl4 parallel 0.5 mg/kg intraperitoneally twice a week. After 8 weeks animals were sacrificed, leaving 2 groups of animals with spontaneous regression and regression with polyphenols administration during 3 weeks.

It was found that CCl4-pretreatment did not change vasoconstrictor responses of isolated renal arteries to standard doses of noradrenaline (0.1; 1; 10 μg) but relaxations to acetylcholine (at dose 20 μg) were diminished if compared to controls. Combination of RWP with CCl4 decreased vasoconstrictor responses to noradrenaline and opposed unfavorable effect of CCl4 itself on vascular relaxation.

CCl4-pretreatment increased 3-fold endothelaemia when compared with controls (2.47±0.28 cells/10 μl). Polyphenolic compounds themselves did not lead to significant changes, but pretreatment with them decreased significantly CCl4-induced rise in endothelaemia. Spontaneous regression did not affect significantly elevated endothelaemia. Administration of polyphenols during 3-week regression significantly decreased the number of cells in blood. These findings supported histologically suggest protective effects of red wine polyphenols on vascular endothelium.

This study was supported by grants VEGA 1/9302/02 & 1/9303/02.

Depts. of Pharmacology, *Physiology & **Pathology, Fac. of Medicine, Comenius Univ., Bratislava, Slovakia

P04-24

CONTRIBUTION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE 2 AND 4 IN ANGIOGENESIS

Favot L., Keravis T., Holl V., Lugnier C.

The proliferation and migration of endothelial cells induced by play a major role in angiogenesis. Physiological angiogenesis is tightly regulated by growth factors such as vascular endothelial cell growth factor (VEGF) which stimulates endothelial cells to migrate, proliferate and differentiate to form new vessels. Several pathological conditions such as atherosclerosis and tumor growth are associated to an excessive angiogenesis in which vessels develop in an uncontrolled or disorganized manner. Elevation of cAMP in endothelial cells has been shown to inhibit cell proliferation and migration. Our hypothesis was that inactivation of cAMP-specific phosphodiesterases (PDEs) would inhibit angiogenesis. The effect of PDE inhibitors on in vitro and in vivo angiogenesis, using human umbilical vein endothelial cell (HUVEC) and chick chorioallantoic membrane (CAM) models, were studied. Treatment of HUVEC by VEGF increased the global cAMP-PDE activity and PDE2 and PDE4 activities. VEGF acts at the transcriptional level since it increased the expression of PDE2, PDE4A, PDE4B and PDE4D at mRNA level. Treatment of VEGF-stimulated HUVEC by EHNA (PDE2 selective inhibitor) and RP73401 (PDE4 selective inhibitor), resulted in an increase of intracellular cAMP level and an inhibition of proliferation and migration. PDE2 inhibition merely decreased the S to G2/M phase transition, whereas PDE4 inhibition prevented the G0/G1 to S phase transition. Western blot analysis indicated that treatment of VEGF-stimulated HUVEC by EHNA and RP73401 was modulating the expression of MAP kinases, cyclin A, cyclin D1, p21waf1, and p27kip1. Moreover, the effect of PDE inhibitors were investigated on in vivo angiogenesis. Treatment of CAM with PDE2 and PDE4 inhibitors reduced dose-dependently the density of capillary vessels. Altogether, these results indicate that PDE2 and PDE4 represent new potential therapeutic targets for angiogenesis and that PDE2 and PDE4 are implicated in angiogenesis.

CNRS UMR 7034, ULP, Strasbourg, France

P04-25

LACK OF DYSTROPHIN REDUCES NO-DEPENDENT VASCULAR FUNCTION: TOTAL RECOVERY AFTER GENTAMICIN TREATMENT

Loufrani L., Dubroca c., Li Z., Levy bi., Paulin D., Henrion D.

Mutations in the dystrophin gene causing Duchenne’s muscular dystrophy (DMD), lead to pre-mature stop codons. In mdx mice, a model for DMD, they can be suppressed by aminoglycosides such as gentamicin. Dystrophin is likely to play a role in flow (shear stress) mediated endothelium-dependent dilation (FMD) in arteries. Thus we investigated the effect of gentamicin on vascular, structure and function in mdx mice.

Mice carotid and mesenteric resistance arteries (450 and 85µm diameter, respectively) were mounted in vitro in arteriographs allowing continuous diameter measurements. In mdx mice, NO-dependent FMD and endothelial NO-synthase expression were lower than in control mice. In mdx mice treated with gentamicin, dystrophin was recovered in vascular cells, FMD and NO-synthase expression were identical to control in mdx mice treated with gentamicin. Smooth muscle-dependent contractions as well as dilation to acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were not affected by the absence of dystrophin and/or by gentamicin. FMD, attenuated in vimentin-null mice, was not restored by gentamicin.

These findings open important perspectives in the mechanism involved in the pathophysiology of genetic diseases related to pre-mature stop codons such as DMD.

INSERM U541, PARIS, FRANCE

P04-26

COMPARISON BETWEEN THE EFFECTS OF ICV OR IV INFUSION OF HYPERTONIC NaCl DURING HAEMORRHAGE

Hjelmqvist H., Frithiof R., Ullman, J., Eriksson, S., Rundgren, M.

Effects of treatment with intravenous infusion of hypertonic (1.2 M, 4 mL / kg) NaCl (IHTNa) or intracerebroventricular (ICV) administration of (0.5 M 0.02 mL / min) NaCl (CHTNa) on tolerance to haemorrhage were investigated in conscious or anaesthetized sheep. All treatments were started 30 min before commencement of a slow (0.7 mL / kg / min) venous heamorrhage, which was continued until the mean systemic arterial pressure (MSAP) suddenly dropped to < 50 mm Hg. Corresponding bleeding during ICV infusion of artificial cerebrospinal fluid (aCSF) served as control.

To reach the distinct fall in MSAP the following amount of blood had to be withdrawn in a) conscious animals: aCSF 13.9 ± 0.5 mL / kg (n = 7), CHTNa 24.0 ± 1.8 mL / kg (n = 6), IHTNa 22.4 ± 1.4 mL / kg (n = 6) and b) anaesthetized animals: aCSF 10.2 ± 0.9 mL / kg (n = 7), CHTNa 10.4 ± 0.9 mL / kg (n = 6), IHTNa 15.1 ± 0.2 mL / kg (n = 5). Significantly more blood (p < 0.001) had to be removed from conscious CHTNa than in anaesthestized CHTNa compared to the much lower difference between conscious IHTNa and anaesthetized IHTNa.

In conclusion, CHTNa as well as IHTNa treatment were found to improve the tolerance to haemorrhage in conscious animals. However, the effect of CHTNa was abolished during iso-flurane-anaesthesia, suggesting that the mechanism for the beneficial effect of ICV infusion of hypertonic saline is different from the peripheral effect of hypertonic saline.

Depts of Anaestesiology and Physiology, Karolinska Institutet, Stockholm, Sweden

P04-27

THE EFFECT OF CYSTATIN C ON ADP-INDUCED PLATELET AGGREGATION

Karaorman G., Yakaryılmaz A., Basbay Y., Genc Y., Ersoz G.

Cystatins are natural inhibitors of cycteine proteinases. Cystatin C is an inhibitor of cathepsin B, L and H. Because of the widespread extracellular distrubution there is a growing interest about the physiological effects of cyctatin C and its roles on several pathological processes. The aim of the present study was to investigate the effect of cystatin C on ADP-induced platelet aggregation in whole blood.

Venous blood samples were obtained from healthy, non-smoker, male volunteers who did not take any medication preceeding two weeks (n=16). Samples were collected in siliconized tubes containing 3.8% sodium citrate. 1, 1.75 and 3µg/ml of cystatin C was added into the blood samples and incubated 2 minutes at 370C. ADP (10µM) induced platelet aggregation was evaluated by impedance technique in whole blood. Maximal intensity of platelet aggregation (MIA) was calculated. The data was analysed statistically by using Friedman test.

Cystatin C reduced maximal intensity of ADP-induced platelet aggregation 30.9 % in concentration of 1 µg/ml, 73.2 % in concentration of 1.75µg/ml (p=0.06). 3µg/ml of cystatin C caused a 55.6 % decrease in platelet aggregation.

It was shown that cystatin C inhibited platelet aggregation in concentration-dependent manner. Its effect may due to the inhibition of cathepsins. Further researches are needed to clear the underlying mechanisms.

Ankara University Medical School Department of Physiology and Statistics - TURKEY

P04-28

INTRAVITAL MICROSCOPY OF A TUMOR-DRAINING LYMPH NODE

Carrière V., Colisson R., Girard J-P., Amalric F., M'Rini C.

Homing of the whole naive lymphocyte pool into secondary lymphoid organ is a physiological process that is critical to ensure encounter between antigen-presenting cells (APCs) and the unique or few T cell(s) specific to presented antigens. In peripheral lymph nodes (PLNs), this process is initiated by a multi-step sequence of interactions between lymphocytes and endothelial cells lining the node High Endothelial Venules (HEVs). We used intravital microscopy (technic allowing in vivo analysis of circulation blood cells into tissues of an anaesthetized mouse)to study tumor-induced modifications of lymphocyte and other circulating blood cell behaviors into HEVs of inguinal node draining a B16-F10 melanoma at different stages of development. Intravital microscopy studies indicate that proximity of melanoma tumor deeply modifies the behaviors of blood cell when circulating inside the node venular tree. In venules flowing in regard to the node medulla, tumor proximity triggers unusual phenomena of polynuclear cell rolling and firm adhesion whereas in venules flowing in regard to the node paracortex, it decreases the physiological firm adhesion of naive lymphocyte. These tumor-induced modifications are very early starting less than 24 hours after tumor implementation and are sustained as long as last the tumor and the animal survey. Another mechanism set up by tumor to escape the immune surveillance seems to have been identified, mechanism that targets one of the earliest phases of the immune response, the homing of naive lymphocytes inside secondary lymphoid organs.

IPBS/CNRS et Laboratoire de Physiologie de la Faculté de Médecine de Rangueil, route de Narbonne, 31 Toulouse, France

P04-29

INFLUENCE OF AGE ON ADRENOCEPTORS AND CATECHOLAMINES IN WOMEN

Litschauer B.

The incidence of cardiovascular diseases is lower in premenopausal women compared to men but this difference is no longer apparent after menopause. This has been ascribed to protective effects of estrogen, involving besides metabolic, vascular and cardiac mechanisms direct influences on the autonomic nervous system.

The aim of our study was to assess sympathetic nervous system activity by measuring adrenoceptors and catecholamines in young and middle-aged women in relation to the estradiol concentration.

In 20 healthy middle-aged women, aged 48 - 64 years, without hormon replacement therapy during the preceding 6 months and 38 healthy female students, aged 19 to 27 years, baseline plasma concentrations of adrenaline and noradrenaline, blood pressure, heart rate and platelet alpha2-adrenoceptor- and lymphocyt beta2-adrenoceptor densities and estradiol concentration were measured.

Middle-aged women had significantly higher noradrenaline plasma concentrations and lower platelet alpha2-adrenoceptor densities compared to values observed for young women, whereas lymphocyt beta2-adrenoceptor density and adrenaline plasma concentrations were similar in both groups. A significant positive correlation between estradiol and noradrenaline and a negative one with alpha2-adrenoceptor densities was found. Blood pressure was significantly higher and heart rate was significantly lower in middle-aged women combared to young women. Blood pressure was positively related to noradrenaline, beta2-adrenoceptor density and negatively to alpha2-adrenoceptor density.

To the extent that platelet alpha2-adrenoceptors reflect the behavior of alpha2-adrenoceptors in other tissues, the findings of the present study indicate that estradiol may modulate sympathetic activity by increasing presynaptic inhibitory alpha2-adrenoceptors.

Department of Physiology, Vienna, Austria



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