Metoprolol impairs b1-adrenergic receptor-mediated vasodilation in rat_ cerebral arteries: Implications for b-blocker therapy

Abstract

The practice of prescribing b-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of b-blocker therapy primarily relies on preventing activation of cardiac b1-adrenergic receptors (ARs). However, we reported that b1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that b-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed b1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1–10 mmol/l) prevented b1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The b1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted b1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent b1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on b-blockers relates in part to adrenergic dysregulation of cerebrovascular tone.