In search of the hyperpolarizing factor(s): summary of progress.

In the isolated, perfused kidney of the rat, arachidonic acid (AA) elicits prostaglandin endoperoxide-dependent vasoconstriction that is blocked by inhibition of cyclooxygenase, uncovering an endothelium-dependent vasodilation that is susceptible to inhibitors of cytochrome P450 monooxygenases (P450), suggesting the formation of a dilator P450-AA metabolite. A natural progression was to determine the contribution of P450-AA to the vasodilator effect of a hormone, bradykinin (BK), that stimulates phospholipases to release of AA. Although the vasodilator action of BK is generally attributed to release of NO, this is not the sole mechanism and release of a hyperpolarizing factor has been invoked. In the rat perfused kidney we demonstrated 3 components to the vasodilator action of BK, two major components subserved by NO and P450 and a minor component mediated by prostaglandins. As the coronary vasodilator effect of BK in the rat was reported to be independent of NO, we also used the rat perfused heart to characterize the vasodilator activity of BK. We confirmed that the response was independent of NO and showed, using inhibitors, a dependency on P450, presumably via AA metabolism as BK stimulates phospholipases. Subsequently, we showed that the coronary vasodilator effect of BK was dependent on phospholipase C and A2 activity but not diacylglycerol lipase activity. Finally, we investigated the role of K+ channels in the coronary and renal vasodilator effects of BK and showed the response was dependent on Ca2+-activated K+ channels. We conclude that NO-independent vasodilation to BK is mediated by a hyperpolarizing factor that is generated via P450-AA metabolism subsequent to the sequential activation of phospholipase C and A2.