Abstract
The practice of prescribing beta blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned due to reports of an increased risk of stroke. The benefit of beta blocker therapy primarily relies on preventing activation of cardiac β1-adrenergic receptors (β1AR). However, we reported that β1ARs also mediate vasodilator responses of rat cerebral arteries (CA), implying that beta blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed β1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CA ex vivo and in vivo. MET (1-10 µmol/L) prevented β1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CA. The β1AR-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 β1AR-mediated dilation of CA. In the same animals, NE-induced dilation of CA was reversed to sustained constriction. Administration of MET for two weeks in drinking water (2 mg/mL) or subcutaneously (15 mg/kg/day) also resulted in NE-induced constriction of CA in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent β1AR-mediated dilation of CA and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on beta blockers relates in part to adrenergic dysregulation of cerebrovascular tone.
Significance Statement Beta-blocker therapy using second-generation, cardio-selective beta-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardio-selective beta-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.
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