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Metoprolol impairs resistance artery function in mice
Mostafa H El Beheiry1, Scott P Heximer, Julia Voigtlaender-Bolz
1Department of Anesthesia, St. Michael's Hospital, Keenan Research Centre of the Li Ka Shing Knowledge Institute, University of Toronto, Canada.
Abstract:
Acute β-blockade with metoprolol has been associated with increased mortality by undefined mechanisms. Since metoprolol is a relatively high affinity blocker of β(2)-adrenoreceptors, we hypothesized that some of the increased mortality associated with its use may be due to its abrogation of β(2)-adrenoreceptor-mediated vasodilation of microvessels in different vascular beds. Cardiac output (CO; pressure volume loops), mean arterial pressure (MAP), relative cerebral blood flow (rCBF; laser Doppler), and microvascular brain tissue Po(2) (G2 oxyphor) were measured in anesthetized mice before and after acute treatment with metoprolol (3 mg/kg iv). The vasodilatory dose responses to β-adrenergic agonists (isoproterenol and clenbuterol), and the myogenic response, were assessed in isolated mesenteric resistance arteries (MRAs; ∼200-μm diameter) and posterior cerebral arteries (PCAs ∼150-μm diameter). Data are presented as means ± SE with statistical significance applied at P < 0.05. Metoprolol treatment did not effect MAP but reduced heart rate and stroke volume, CO, rCBF, and brain microvascular Po(2), while concurrently increasing systemic vascular resistance (P < 0.05 for all). In isolated MRAs, metoprolol did not affect basal artery tone or the myogenic response, but it did cause a dose-dependent impairment of isoproterenol- and clenbuterol-induced vasodilation. In isolated PCAs, metoprolol (50 μM) impaired maximal vasodilation in response to isoproterenol. These data support the hypothesis that acute administration of metoprolol can reduce tissue oxygen delivery by impairing the vasodilatory response to β(2)-adrenergic agonists. This mechanism may contribute to the observed increase in mortality associated with acute administration of metoprolol in perioperative patients.
Insights
Acute metoprolol treatment may increase mortality by blocking beta-2 receptors, impairing blood vessel dilation and reducing oxygen delivery. This beta-blockade effect impacts cerebral blood flow and microvascular function.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Neuroscience
Background:
- Acute beta-blockade with metoprolol is linked to increased mortality through unknown mechanisms.
- Metoprolol's high affinity for beta-2 adrenoreceptors suggests a potential role in its adverse effects.
Purpose of the Study:
- To investigate if metoprolol-induced blockade of beta-2 adrenoreceptors impairs microvessel vasodilation, contributing to increased mortality.
- To assess the impact of metoprolol on cardiovascular function and tissue oxygen delivery.
Main Methods:
- Measurements in anesthetized mice included cardiac output, mean arterial pressure, cerebral blood flow, and brain tissue oxygenation.
- Vasodilatory responses to beta-adrenergic agonists were tested in isolated mesenteric and cerebral arteries.
- Myogenic responses of isolated arteries were also assessed.
Main Results:
- Metoprolol reduced heart rate, stroke volume, cardiac output, cerebral blood flow, and brain oxygenation, while increasing systemic vascular resistance.
- In isolated arteries, metoprolol impaired vasodilation induced by beta-adrenergic agonists.
- Metoprolol did not affect basal tone or myogenic responses in mesenteric arteries.
Conclusions:
- Acute metoprolol administration impairs beta-2 adrenergic agonist-mediated vasodilation.
- This impairment reduces tissue oxygen delivery and may contribute to increased perioperative mortality.
- The findings support the hypothesis that beta-2 adrenoreceptor blockade is a mechanism for metoprolol's adverse effects.
