Vascular cytochrome P450 in the regulation of renal function and vascular tone: EDHF, superoxide anions and blood pressure

Renal cytochrome P450 (CYP)‐dependent arachidonic acid metabolites have a wide and contrasting spectrum of biological effects. The profile and relative rates of eicosanoid production not only influence renal haemodynamics and tubular ion and water transport but may also play a determinant role in mechanisms associated with the development of hypertension. The eicosanoids generally thought to play major roles in regulating these functions are the epoxyeicosatrienoic acids (EETs) and their derivatives which activate Ca2+‐dependent K+ (KCa) channels in endothelial and smooth‐muscle cells, as well as 20‐hydroxyeicosatetraenoic acid (20‐HETE) which exerts an antagonistic effect on KCa channel activity. There are also reactive oxygen species (e.g. superoxide anions) generated during the enzymatic conversion of arachidonic acid by CYP within the vascular wall, which have both acute and chronic effects on vascular homeostasis. Nitric oxide (NO) and prostacyclin (PGI2) are the best‐characterized vasodilatory endothelium‐derived autacoids; however, a third type of agonist‐induced, endothelium‐dependent relaxation can be evidenced in the presence of a combination of nitric oxide synthase and cyclo‐oxygenase inhibitors. Since this NO/PGI2‐independent relaxation was not observed in the presence of depolarizing concentrations of K+ and was co‐incident with vascular smooth‐muscle hyperpolarization, the relaxation was assumed to be mediated by an endothelium‐derived hyperpolarizing factor (EDHF). The relative importance of NO and EDHF in mediating endothelium‐dependent vasodilatation alter on descending the vascular tree, such that EDHF becomes the predominant endothelium‐derived modulator of arteriolar dilatation. Most resistance‐sized arteries are thought to be hybrids which express both the NO and the EDHF synthases. It is in these vessels that the loss of one vasodilator system can be compensated for by an increase in the output of the other (for review see [1]).