Abstract
Background: Phenylephrine is an alpha 1-adrenergic receptor (α1R) agonist. Evidence indicates activation of α1Rs can initiate both vasoconstrictor and dilator signaling. How phenylephrine affects cerebrovascular regulation remains unclear. Methods: A retrospective analysis of data examining cerebral perfusion and blood pressure during systemic phenylephrine infusion in humans and swine was completed. Follow-up experiments examining cerebral hemodynamics during intracarotid arterial infusion of phenylephrine in anesthetized swine were performed. Ex vivo experiments were conducted on isolated porcine cerebral arteries. Results: Systemic phenylephrine infusion increased indices of cerebrovascular resistance in both humans (P=0.0423) and swine (P<0.0001) but did not decrease perfusion. Intracarotid phenylephrine infusion did not alter cerebrovascular resistance, but increased perfusion in control conditions (P=0.0045), whereas resistance increased (P≤0.0155) without altered perfusion during NOS (nitric oxide synthase) inhibition conditions. α1Rs were detected on both extraluminal and intraluminal aspects of cerebral arteries, reflecting a population of vascular smooth muscle and endothelial α1Rs, respectively. Extraluminal phenylephrine caused vasoconstriction whereas intraluminal phenylephrine elicited an endothelium-dependent NO-mediated dilation. NOS inhibition enhanced phenylephrine-induced vasoconstriction in third-order branch of the middle cerebral artery, but not the first-order or second-order pial arteries (P=0.0267), and this corresponded with an increased ratio of phosphorylated to total endothelial NOS protein content in third-order versus first-order and second-order arteries (P≤0.0022). Phenylephrine-induced constriction was greatest in first-order arteries (P=0.0419), and this corresponded with increased perivascular adrenergic innervation and α1R protein content in first-order versus second-order and third-order arteries (P≤0.0054). Conclusions: Neither systemic nor intracarotid phenylephrine infusion compromised cerebral perfusion, possibly related to increased endothelial NO signaling and reduced α1R density in downstream pial arteries.