β-Adrenoceptor Blockers Increase Cardiac Sympathetic Innervation by Inhibiting Autoreceptor Suppression of Axon Growth

Abstract

␤-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 ␤-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective ␤-blocker propranolol and the ␤ 1 -antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, ␤-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramineinduced 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 ␤ 2 -blocker ICI 118551 did not. Norepinephrine synthesis suppression by ␣-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via ␤ 1 -adrenoceptors. Immunohistochemistry revealed ␤ 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 ␤ 1 -autoreceptors that negatively regulate axon outgrowth. Chronic ␤-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to ␤-blocker withdrawal syndrome.

Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons

“…We also sought to determine if NGF synthesis by cardiac ganglion neurons was promoted by a direct effect of sympathetic agonists. To examine these questions, we utilized a well-established model of chronic coronary artery ligation for induction of myocardial infarction and CHF that we have previously characterized (Clarke et al, 2010; Donohue et al, 2009; Hasan et al, 2006). Previous studies (Clarke et al, 2010; Hasan et al, 2006) show post-infarction morphological changes in ligated animals, including fibrosis and scarring, ventricular wall thinning, and ventricular enlargement.…”

“…To examine these questions, we utilized a well-established model of chronic coronary artery ligation for induction of myocardial infarction and CHF that we have previously characterized (Clarke et al, 2010; Donohue et al, 2009; Hasan et al, 2006). Previous studies (Clarke et al, 2010; Hasan et al, 2006) show post-infarction morphological changes in ligated animals, including fibrosis and scarring, ventricular wall thinning, and ventricular enlargement. In our model we observed significant decreases in mean arterial pressure, pulse pressure, and systolic pressure, as well as reduced ventricular ejection fraction similar to those reported previously (Henze et al, 2008; Henze et al, 2013; Kruger et al, 1997; Liu et al, 1997; Mulder et al, 2004).…”

Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease

“…Alterations in neuronal excitability can create variable gates for signal processing in autonomic ganglia (3). Such an effect may represent an ongoing compensation to the increased sympathetic output, reduced central drive from Stimulus Frequency (Hz) 5 1 . There was no difference in the frequencies recorded from sham and MI tissues, but there was a significant increase in output frequency in neurons derived from PO animals at the higher frequency (**P Ͻ 0.01 by ANOVA).…”

“…Suprathreshold stimuli were then given in 2-s trains at frequencies of 10, 20, and 30 Hz, and the number of APs produced by the neuron of interest was determined. Subthreshold EPSPs were analyzed by averaging individual events (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The average trace was used to determine the amplitude and time constant of the decay determined from a single exponential fit.…”

The Expression Level of Ecto-NTP Diphosphohydrolase1/CD39 Modulates Exocytotic and Ischemic Release of Neurotransmitters in a Cellular Model of Sympathetic Neurons

“…␤-Blockers have been extensively used to alleviate ischemic arrhythmias, preserve left ventricular ejection fraction, and normalize blood pressure (Böhm and Maack, 2000;Lindholm et al, 2005;Zicha et al, 2006). Yet, ␤-blockers are not without disabling side effects (e.g., fatigue, muscle weakness, cold extremities, nightmares, and impotence) (Böhm and Maack, 2000) and have been shown to increase cardiac sympathetic innervation (Clarke et al, 2010). Thus, a prejunctional inhibition of abnormal NE release may offer advantages over blockade of NE effects at postsynaptic sites.…”