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 microM and maximal relaxation above 100 microM. At 200 microM, 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 Ca(2+)-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 being 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 Ca(2+)-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 are 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.
Gurney
A M
AM
Department of Pharmacology, United Medical School, St. Thomas's Hospital, London.
Allam
M
M
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006830:Hydralazine / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects*
D012433:Ryanodine; D010656:Phenylephrine; D006830:Hydralazine; D002118:Calcium