Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a ß-adrenoceptor blocker (propranolol) to determine the role of ß-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n = 10, ∆: +2.1 ± 1.4 beats min-1 , P = 0.002) and CO (n = 8, ∆: +100 ± 150 mL min-1 , P = 0.002) was elevated, followed by an increase in CoBF (n = 9, ∆: +0.76 mL min-1 , P = 0.001) and CVC (n = 8, ∆: +0.0038 mL min-1  mmHg-1 , P = 0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on ß-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by ß-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by ß-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P=2.5×10-7), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure.

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

Activation of the carotid body increases directly recorded cardiac sympathetic nerve activity and coronary blood flow in conscious sheep.

Activation of the carotid body (CB) using intracarotid potassium cyanide (KCN) injection increases coronary blood flow (CoBF). This increase in CoBF is considered to be mediated by co-activation of both the sympathetic and parasympathetic nerves to the heart. However, whether cardiac sympathetic nerve activity (cardiac SNA) actually increases during CB activation has not been determined previously. We hypothesized that activation of the CB would increase directly recorded cardiac SNA, which would cause coronary vasodilatation. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA and diaphragmatic electromyography (dEMG), flow probes to record CoBF and cardiac output, and a catheter to record arterial pressure. Intracarotid KCN injection was used to activate the CB. To eliminate the contribution of metabolic demand on coronary flow, the heart was paced at a constant rate during CB chemoreflex stimulation. Intracarotid KCN injection resulted in a significant increase in directly recorded cardiac SNA frequency (from 24 ± 2 to 40 ± 4 bursts/min; P < 0.05) as well as a dose-dependent increase in mean arterial pressure (79 ± 15 to 88 ± 14 mmHg; P < 0.01) and CoBF (75 ± 37 vs. 86 ± 42 mL/min; P < 0.05). The increase in CoBF and coronary vascular conductance to intracarotid KCN injection was abolished after propranolol infusion, suggesting that the increased cardiac SNA mediates coronary vasodilatation. The pressor response to activation of the CB was abolished by pretreatment with intravenous atropine, but there was no change in the coronary flow response. Our results indicate that CB activation increases directly recorded cardiac SNA, which mediates vasodilatation of the coronary vasculature.

Impaired Baroreflex Function in an Ovine Model of Chronic Heart Failure Induced by Multiple Coronary Microembolizations.

Testing new therapies in heart failure (HF) requires a chronic stable model of HF in large animals. Microembolization of the coronary arteries has been used to model HF previously; however, neural control has not been previously explored in this model. Thus the aim of this study was to further characterize neural control in this model of HF. HF was induced by infusion of microspheres (45 micron; 1.3 ml) into the proximal left coronary artery or left descending coronary arteries, with three sequential embolizations over 3 weeks. Twelve to 14 weeks after the final embolization, and when ejection fraction had decreased below 45%, animals were instrumented to record blood pressure and heart rate. Baroreflex control of heart rate was investigated in conscious animals. Additionally, pressure-volume loops were constructed under anesthesia. Embolization-induced HF was associated with a decrease in mean arterial pressure (67 ± 2 vs. 85 ± 4 mmHg, p < 0.05), an increase in heart rate (108 ± 4 vs. 94 ± 4 bpm, p < 0.05), and a significant increase in left ventricular end-diastolic pressure (11.4 ± 2 vs. 6.2 ± 1 mmHg, p < 0.01). Under conscious conditions, there was a significant decrease in the gain (-8.2 ± 2 vs. -4.1 ± 1 beats/min/mmHg, p < 0.05) as well as the lower plateau of the baroreflex in HF compared to control animals. HF was also associated with significantly increased respiratory rate (107 ± 4 vs. 87 ± 4 breaths/min, p < 0.01) and incidence of apneas (520 ± 24 vs. 191 ± 8 apnea periods >4 s, p < 0.05), compared to control sheep. The microembolization model of heart failure is associated with an increase in left ventricular end-diastolic pressure, impaired cardiac function, and altered baroreflex control of the heart. These findings suggest this chronic model of HF is appropriate to use for investigating interventions aimed at improving neural control in HF.