Session 11 : Pharmacologie cardiovasculaire

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Session 11 : Pharmacologie cardiovasculaire

119

CARDIAC PERFORMANCE IS MAINTAINED IN A RAT MODEL OF AORTIC STIFFNESS

S. Hubert, I. Lartaud-Idjouadiene, A.M. Lompré1 and J. Atkinson

Laboratoire de Pharmacologie Cardiovasculaire, UHP-Nancy 1, 54000 Nancy and 1 CNRS ERS 570, Université Paris-Sud, 91405 Orsay, France.

Aortic stiffness can lower left ventricular (LV) performance in man (Nichols et al. Am J Cardiol 1985; 55: 1179-1184). However, we did not observe this in a rat model of aortic stiffness induced by elastocalcinosis (VDN model, vitamin D3-nicotine treatment, Lartaud-Idjouadiene et al. Am J Physiol 1997; 272: H2211-H2218). The aim of the present study was to evaluate whether intrinsic cardiac adaptation could explain the maintainance of LV performance in this model. For this, we studied in control rats (n=8) and VDN rats (n=10) LV mass (LV weight/body weight) and LV content of myosin heavy chain (MHC) isoforms 3 months after induction of aortic stiffness. Cardiac performance under baseline conditions and following volume overload was evaluated by measurement of stroke volume in awake unrestrained rats by an electromagnetic flow probe. Aortic elastic modulus (EM) was calculated from pulse wave velocity and histomorphometric parameters according to the Moens-Korteweg equation. Results are means

± s.e.m. and were compared with Student’s t-test (* P < 0.05). In spite of an increase in EM in VDN rats (controls, 6± 1; VDN, 16± 3*, 106 dynes.cm-2), stroke volume under baseline conditions (controls, 222± 18; VDN, 211± 13, µ1) and following volume overload (controls, 378± 14; VDN, 338± 15, µl) was not altered. However, LV mass increased (controls, 1.54± 0.06; VDN, 1.73± 0.05*, g.kg-1) and the MHC-distribution was modified with a shift from a-MHC (controls, 82± 2; VDN, 69± 3*, %) to b -MHc (controls, 18± 2; VDN, 31± 3*, %).We conclude that three months’ exposure to aortic stiffness induced intrinsic cardiac adaptation with LV hypertrophy and alteration of the MHC-distribution leading to an increase in inotropism so explaining the maintainance of LV performance in VDN rats.

120

EFFECT OF FASIDOTRIL, A MIXED INHIBITOR OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN I-CONVERTING ENZYME, ON SURVIVAL OF RATS WITH MYOCARDIAL INFARCTION

C. Marie*, C. Mossiat*, C. Gros**, J-C. Schwartz**, J.M. Lecomte***, and J. Bralet*.

* Laboratoire de Pharmacodynamie, Faculté de Pharmacie, 21033 Dijon Cédex; ** INSERM U 109 Centre Paul Broca, 75014 Paris; *** Laboratoire Bioprojet, 9 rue Rameau, 75002 Paris.

Two hormonal systems with opposite effects are activated in congestive heart failure. The renin-angiotensin system that promotes vasoconstriction, sodium retention and cardiac hypertrophy, and the atrial natriuretic factor (ANF) with vasorelaxant and natriuretic effects. In congestive heart failure, it could be of interest to associate prevention of angiotensin II formation by inhibition of angiotensin I-converting enzyme (ACE), with potentiation of ANF effects by inhibition of neutral endopeptidase (NEP). The effects of long-term therapy (40 weeks) with fasidotril, a mixed NEP/ACE inhibitor were assessed in rats submitted to coronary artery ligation. 24 hours after ligation, 172 rats were assigned to either placebo or fasidotril therapy (180 mg/kg/day, orally). Rats were classified as having small, moderate or large infarcts. In rats with moderate infarcts, fasidotril prolonged survival, 50 % of the untreated rats dying during the 40 week-observation period compared with 30 % of treated rats (P