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.

Hydralazine relaxed phenylephrine‐contracted aorta with half maximal relaxation at 17 μm and maximal relaxation above 100 μm. At 200 μm, hydralazine had little effect on contractions induced by 25 mm or 50 mm K⁺.

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.

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.

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 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 are blocked or the Ca²⁺‐ATPase is blocked while the SR is made leaky with ryanodine.

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.