Chronic administration of the beta-blockers propranolol and metoprolol increased ventricular sympathetic axon density by 48% and 44%, respectively, compared to saline in rats.
Does beta-adrenoceptor blockade increase cardiac sympathetic innervation in rats and sympathetic neuronal cell cultures?
Chronic beta-blockade increases ventricular sympathetic axon proliferation by disrupting beta1-autoreceptor negative feedback, providing a potential mechanism for beta-blocker withdrawal syndrome.
p-value: p=<0.05
β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β(1)-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β(2)-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β(1)-adrenoceptors. Immunohistochemistry revealed β(1)-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β(1)-autoreceptors that negatively regulate axon outgrowth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.
Clarke et al. (Wed,) conducted a other in Healthy and myocardial infarction (animal model). Propranolol or Metoprolol vs. Saline was evaluated on Ventricular sympathetic axon density (p=<0.05). Chronic administration of the beta-blockers propranolol and metoprolol increased ventricular sympathetic axon density by 48% and 44%, respectively, compared to saline in rats.