ATTENUATION OF CORONARY AUTOREGULATION IN THE ISOLATED RABBIT HEART BY ENDOTHELIUM-DERIVED NITRIC-OXIDE

Objective: The aim was to investigate the role of endothelium derived nitric oxide (EDNO/EDRF) in the control of coronary autoregulation. Me thods: In isolated saline perfused rabbit hearts coronary flow respons es to stepwise increases in perfusion pressure were studied under cont rol conditions, during maximum dilatation with sodium nitroprusside, a nd in the presence of the inhibitor of EDNO synthesis, N-G-nitro-L-arg inine (L-NNA), or the vasoconstrictors endothelin-1 and arginine vasop ressin. Results: At a constant perfusion pressure of 60 mm Hg, infusio n of L-NNA (30 mu M), but not D-NNA, reduced the coronary flow from 24 .7(SEM 2) to 13.6(2.2) ml.min(-1) and abolished flow increases induced by the EDRF stimulator acetylcholine. Under these conditions, pressur e induced coronary flow increases were reduced (p<0.05 compared to con trol) over the whole range of perfusion pressures studied (45 to 120 m m Hg). Arginine vasopressin [2(0.6) nM] and endothelin-1 [1.5(1) nM] i nduced similar reductions of coronary resting flow but the pressure in duced how increases were significantly greater than in the presence of L-NNA. Moreover, inhibition of EDRF synthesis reduced the peak reacti ve hyperaemia after a 30 s interruption of coronary flow from 47(2) to 32(2) ml.min(-1). These changes occurred in spite of a decrease in th e myocardial oxygen uptake from 5.1(0.6) to 3.3(0.5) ml.100 g(-1).min( -1) (p<0.01) and a concomitant increase in the lactate release from 46 (7) to 95(54) mu mol.min.100 g(-1) (p<0.01), indicating myocardial isc haemia. Conclusions: EDNO attenuates coronary autoregulatory responses which, if unopposed, potentially impair a functionally adequate myoca rdial perfusion. It is suggested that the modulator role of EDNO is, a t least in part, specific and most likely to be due to shear dependent alterations of EDNO release.