ASSESSMENT OF THE ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN CARDIAC CONTRACTILITY UTILIZING THE RENIN INHIBITOR REMIKIREN

1 The role of the renin-angiotensin system in the regulation of myocar dial contractility is still debated. In order to investigate whether r enin inhibition affects myocardial contractility and whether this acti on depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c .) infusions of the renin inhibitor remikiren, were compared and relat ed to the effects on systemic haemodynamics and circulating angiotensi n II in open-chest anaesthetized pigs (25-30 kg). The specificity of t he remikiren-induced effects was tested (1) by studying its i.c. effec ts after administration of the AT(1)-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2 Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min(-1). Mean arterial pressure (MAP) , cardiac output (CO), heart rate (HR), sytemic vascular resistance (S VR), myocardial oxygen consumption (MVO(2)) and left ventricular (LV) dP/dt(max) were not affected by remikiren at 2 and 5 mg min(-1), and w ere lowered at higher doses. At the highest dose, MAP decreased by 48% , CO by 13%, HR by 14%, SVR by 40%, MVO(2) by 28% and LV dp/dt(max) by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO(2) was accompanied by a decrease in myocardial work (M AP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) impli es a reduced myocardial efficiency ((MAP x CO)/MVO(2)). 3 Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min(-1). MAP, CO, MVO, and LV dP/dt(max) were not affected by r emikiren at 0.2, 0.5 and 1 mg min(-1), and were reduced at higher dose s. At the highest dose, MAP decreased by 31%, CO by 26%, MVO(2) by 46% and LV dP/dt(max) by 43% (mean values; P < 0.05 for difference from b aseline, n = 6). HR and SVR did not change at any dose. 4 Thirty minut es after a 10 min i.v. infusion of the AT(1) receptor antagonist, L-15 8,809 at 1 mg min(-1), consecutive 10 min i.c. infusions (n = 5) of re mikiren at 2, 5 and 10 mg min(-1) no longer affected CO and MVO(2), an d decreased LV dP/dt(max) by maximally 27% (P < 0.05) and MAP by 14% ( P < 0.05), which was less than without AT(1)-receptor blockade (P < 0. 05). HR and SVR remained unaffected. 5 Plasma renin activity and angio tensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic ha emodynamics or regional myocardial function, both after i.v, and i.c. infusion. 6 Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with norad renaline. In trabeculae that were not precontracted no decrease in bas eline contractility was observed with remikiren in concentrations up t o 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19 % (P < 0.05). 7 Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilatation and with remikiren i.c. by cardiac depression. The blood levels of remikiren r equired for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin I I does not appear to be the sole explanation for these haemodynamic re sponses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.