Effect of Phenylephrine on Cerebrovascular Regulation: A Translational Perspective

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.

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.

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).

Neither systemic nor intracarotid phenylephrine infusion compromised cerebral perfusion, possibly related to increased endothelial NO signaling and reduced α1R density in downstream pial arteries.