Distinct effects of intravascular and extravascular angiotensin II on cerebrovascular circulation of newborn pigs

Abstract

Angiotensin II (AngII) is important in regulation of vascular resistance and control of blood flow among organs and tissues. The effect of AngII on the cerebral microvasculature may be mediated or altered by endothelial-derived signals. The aim of this study was to test the hypothesis that blood AngII dilates neonatal pial arterioles via an endothelial-dependent mechanism but brain AngII can constrict pial arterioles by activating smooth muscle AT1 receptors. Studies used anesthetized newborn pigs with surgically implanted closed cranial windows. AngII was given either by infusion into the carotid artery ipsilateral to the cranial window or topically. Intracarotid infusion of AngII dilated pial arterioles. The dilation was blocked by systemic administration of the AT1-receptor antagonist, losartan, but unaffected by topical losartan. Topical AngII also caused dilation, but this dilation was converted to constriction by topical losartan. In piglets pretreated with the angiotensin-converting enzyme (ACE) inhibitor, enalapril, topical AngII constricted, rather than dilated, pial arterioles. In enalapril-treated piglets, light/dye endothelial injury blocked dilation to intracarotid AngII but did not affect constriction to topical AngII. Either indomethacin or l-nitroarginine methyl ester blocked the dilation to intraluminal AngII, but neither affected constriction to topical AngII. Chromium mesoporphyrin, that inhibits heme oxygenase, did not affect responses to either topical or intravascular AngII. These data are consistent with the hypotheses that: (a) circulating AngII dilates pial arterioles via endothelial AT1 receptor-derived relaxing factors, notably prostanoids and nitric oxide; (b) direct AT1 receptor activation on the brain side of the blood–brain barrier by AngII causes AT1 receptor-mediated constriction that can mask underlying AT1 receptor-independent dilation when ACE is inhibited. Clinical manipulation of the renin–angiotensin system will have disparate actions on cerebral circulation depending on the functional integrity of the intima and ACE.