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

Abstract

Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg(-1)·day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.

Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

“…Additionally, there was no change in the baseline excitability in neurons from control, MI, and MI with drug treatments. Previous studies demonstrated that chronic MI induces an increased sensitivity to NE in the F/I curves (14). This result was confirmed in the present study ( Fig.…”

“…Previous studies (14) showed that implantation of empty pumps, in either control or sham MI surgery, had no effect on neuronal responses. Intracellular voltage recordings were obtained from individual neurons in whole-mount preparations of the cardiac plexus.…”

“…A subset of control animals were surgically implanted with pumps containing either captopril, losartan, or CGP 42112A (n ϭ 6 for each condition), as described above, and maintained for 3 or 4 wk. Previous studies (14) found no effect of sham MI surgery coupled with pump implantation (no drug) on intrinsic neuronal properties or responses to modulators, such as NE, bethanechol, or ANG II, so these experiments were not repeated.…”

“…Remodeling of this network with disease exerts profound effects on beat-to-beat modulation of regional cardiac function (3). Remodeling of the IC plexus with chronic MI includes an enhanced sensitivity to NE and a reduced response to ANG II (14). Prior research from our group has also shown that ANG II mediates direct effects on these neurons via AT 2 receptors to potentiate both adrenergic and muscarinic responses (9).…”

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM‐HFpEF study

“…In that study, stimulation was delivered at a moderate intensity (2.0 ± 0.6 mA) and a frequency of 5–10 Hz (near the natural frequency of discharge of vagal fibres during physiological reflex activation24, 25). The device used in the ANTHEM‐HF study (VITARIA, LivaNova PLC, London, UK) received Conformité Europeénne Mark approval in 2015 for the treatment of HFrEF 26…”