Metoprolol impairs resistance artery function in mice

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.

Fig. 1.

Changes in cardiovascular function after metoprolol administration in mice. Heart rate (A), stroke volume (B), and cardiac output (C) are significantly reduced while systemic vascular resistance (SVR; D) is increased following metoprolol injection (3 mg/kg). Average end-systolic and diastolic pressures and volumes (E–H) were not affected by metoprolol treatment (n = 6; *P < 0.05). bpm, Beats/min.

Fig. 2.

Representative pressure-volume loop before and after metoprolol administration in mice. An example of a tracing of steady state pressure-volume loops recorded in a representative mouse (n = 6). Steady-state loops were acquired 10 min after intravenous saline bolus and 10 min after intravenous metoprolol bolus. In this case, there is a clear increase in the end diastolic and systolic volumes and a reduction in stroke volume and ejection fraction after metoprolol administration.

Fig. 3.

Relative changes in heart rate (HR), mean arterial pressure (MAP), and relative cerebral blood flow (rCBF) before and after metoprolol administration in mice. Metoprolol resulted in a ∼10% reduction in HR (A) from baseline, without affecting MAP (B). C: rCBF was decreased by ∼20% within the first hour of treatment with metoprolol (n = 6; *P < 0.05 vs. baseline; #P < 0.05 between groups).

Fig. 4.

Mean HR, MAP, and microvascular brain oxygen tension (PBr_mvO₂) before and after metoprolol administration in mice. Within 60 min, administration of metoprolol 3 mg/kg resulted in a decrease in HR (A) and microvascular brain Po₂ (C), while MAP remained unchanged (B). *P < 0.05 vs. baseline; #P < 0.05 between groups; n = 6.

Fig. 5.

Effect of metoprolol on the myogenic response in isolated mesenteric arteries. There is no effect of metoprolol (50 μM) on the myogenic response kinetic (A), reversal of distension (B), or vessel diameter (C).

Fig. 6.

Effect of metoprolol (MET) on isoproterenol dose-response curves in mesenteric resistance arteries. Isoproterenol dose-response curves were generated before (control) and after incubation with metoprolol in mesenteric resistance arteries (A). Isoproterenol dose-response curve was unaffected by both time (0 μM metoprolol; B) and 5 or 10 μM of metoprolol (C and D). There is a significant rightward shift in the isoproterenol (β^1/2-nonspecific agonist) and clenbuterol (β₂-specific agonist) dose-response curves with 50-μM metoprolol treatment (E and F). *P < 0.05; n = 3 to 7.

Fig. 7.

Effect of metoprolol on isoproterenol dose response in posterior cerebral arteries. Isoproterenol dose-response curve was unaffected by time in control vessels (A). As with MRAs, there is a significant rightward shift in the isoproterenol dose-response curve with 50 μM metoprolol treatment (B). *P < 0.05; n = 7.