INHIBITION OF CALCIUM-RELEASE FROM THE SARCOPLASMIC-RETICULUM OF RABBIT AORTA BY HYDRALAZINE

1 The mechanism of hydralazine-induced vasorelaxation was investigated in rabbit isolated aorta, by determining its ability to interfere with force development under a variety of conditions. 2 Hydralazine relaxed phenylephrine-contracted aorta with half maximal relaxation at 17 mu M and maximal relaxation above 100 mu M. At 200 mu M, hydralazine had little effect on contractions induced by 25 mM or 50 mM K+. 3 Hydralazine was equally effective at inhibiting contractile responses to phenylephrine in the absence or presence of extracellular Ca2+. Responses to phenylephrine in Ca2+-free solution were blocked to the same degree whether hydralazine was applied during filling of the sarcoplasmic reticulum (SR) Ca2+ stores or after filling was complete. Caffeine-induced contractions were less sensitive to block by hydralazine. 4 Thapsigargin, cyclopiazonic acid, ryanodine, nifedipine and diltiazem all failed to block the inhibitory effect of hydralazine on tonic contractions to phenylephrine in the presence of extracellular Ca2+. However, when cyclopiazonic acid was applied either with diltiazem or ryanodine, substantial inhibition of the hydralazine response was observed. 5 We propose that tonic contractions to phenylephrine are largely maintained by Ca2+ cycling through the SR, with Ca2+ entering the smooth muscle cell bring sequestered by the SR eventually to leak out through IP3-activated channels close to the contractile proteins. Sequestration of Ca2+ would employ two pathways, one sensitive to inhibitors of the SR Ca2+-ATPase and the other to Ca antagonists. We further suggest that, in the presence of extracellular Ca2+ and phenylephrine, the leakage of Ca2+ through IP3-activated channels is significantly reduced only if both routes for SR Ca2+ accumulation blocked or the Ca2+-ATPase is blocked while the SR is made leaky with ryanodine. 6 We conclude that the main action of hydralazine is to block the IP3-dependent release of Ca2+ from the sarcoplasmic reticulum. Thus conditions that diminish the contribution of IP3-induced Ca2+ release to tension can inhibit the hydralazine-induced vasorelaxation.