A study of potassium channel activation as a pharmacological principle for vasodilation of cerebral blood vessels

Sammanfattning: Increasing [K+]o is intimately coupled to progressive ischemia and reduced CBF. In isolated cerebral and mesenteric arteries, it was found that significant differences in the vascular responses to [K+]o exist. Among the species studied, human cerebral arteries were the most sensitive artery to increasing [K+]o. Rabbit basilar arteries, denuded from the endothelium, showed increased sensitivity to [K+]o which may reflect a reduced influence of EDHF as a result of the endothelial damage. This increased sensitivity could be restored with the KATP channel opener pinacidil. It was found that the effect of pinacidil in human and rabbit cerebral but not in mesenteric arteries, on K+-induced contractions, was stronger in endothelium-denuded cerebral arteries than in arteries with intact endothelium. In rabbit basilar arteries KRN2391 induced a consistent relaxation in arteries pre-contracted with endothelin-1. The nitrate-like effect of KRN2391 demonstrated in other preparations was not seen in the present study. It was concluded that in rabbit basilar arteries, KRN2391 induced a cGMP-independent relaxation, which is mediated mainly by opening of KATP channels. KRN2391 was found to be an equally effective vasodilator in both human pial and omental arteries. Similar to rabbit basilar arteries the KRN2391- induced relaxation in human pial arteries was mediated entirely by activation of the KATP channel. This relaxation appeared to be independent of both KATP channel activation and guanylate cyclase in the omental artery. KATP channel opening resulted in a more effective vasodilation of human pial than of omental arteries. The opposite was true for stimulation of guanylate cyclase with the NO-donor SIN-1. It is concluded that KATP channel activation may be a promising therapeutic principle for cerebral vasodilation and for preventing cerebral ischemia.