Carol T. Bussey

Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes.

Elevated sympathetic nerve activity (SNA) coupled with dysregulated β-adrenoceptor (β-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the β-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to β-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular β1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial β2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac β-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart.

Chronic bilateral renal denervation reduces cardiac hypertrophic remodelling but not β-adrenergic responsiveness in hypertensive type 1 diabetic rats.

What is the central question of this study? Can bilateral renal denervation, an effective antihypertensive treatment in clinical and experimental studies, improve cardiac β‐adrenoceptor responsiveness in a diabetic model with underlying hypertension? What is the main finding and its importance? Bilateral renal denervation did not affect β‐adrenergic responsiveness in the diabetic hypertensive rat heart, but denervation reduced the hypertension‐induced concentric hypertrophic remodelling. This suggests that the positive haemodynamic changes induced by renal denervation are most likely to reflect an attenuation of sympathetic effects on the systemic vasculature and/or the renal function rather than direct sympathetic modulation of the heart.

Dual implantation of a radio-telemeter and vascular access port allows repeated hemodynamic and pharmacological measures in conscious lean and obese rats.

Expansion of physiological knowledge increasingly requires examination of processes in the normal, conscious state. The current study describes a novel approach combining surgical implantation of radio-telemeters with vascular access ports (VAPs) to allow repeated hemodynamic and pharmacological measures in conscious rats. Dual implantation was conducted on 16-week-old male lean and obese Zucker rats. Continued viability one month after surgery was observed in 67% of lean and 44% of obese animals, giving an overall 54% completion rate. Over the five-week measurement period, reliable and reproducible basal mean arterial pressure and heart rate measures were observed. VAP patency and receptor-independent vascular reactivity were confirmed by consistent hemodynamic responses to sodium nitroprusside (6.25 µg/kg). Acutely, minimal hemodynamic responses to repeated bolus administration of 0.2 mL saline indicated no significant effect of increased blood volume or administration stress, making repeated acute measures viable. Similarly, repeated administration of the β-adrenoceptor agonist dobutamine (30 µg/kg) at 10 min intervals resulted in reproducible hemodynamic changes in both lean and obese animals. Therefore, our study demonstrates that this new approach is viable for the acute and chronic assessment of hemodynamic and pharmacological responses in both lean and obese conscious rats. This technique reduces the demand for animal numbers and allows hemodynamic measures with minimal disruption to animals’ welfare, while providing reliable and reproducible results over several weeks. In conclusion, dual implantation of a radio-telemeter and VAP introduces a valuable technique for undertaking comprehensive studies involving repeated pharmacological tests in conscious animals to address important physiological questions.

Chamber-specific changes in calcium-handling proteins in the type 2 diabetic human heart with preserved ejection fraction

a Department of Physiology — HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand b Department of Cardiothoracic Surgery, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand c Department of Medicine — HeartOtago, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand d NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom

β1‐Adrenoceptor, but not β2‐adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo

What is the central question of the study? The sympathetic system regulates heart rate via β‐adrenoceptors; this is impaired during diabetes. However, the specific β‐adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non‐diabetic and type 2 diabetic rats demonstrated that the β1‐adrenoceptor subtype, and not the β2‐adrenoceptor, regulated the lower resting heart rate and increased β‐adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence.

Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

What is the central question of the study? Is the reduced signalling of AMP‐activated protein kinase (AMPK), a key regulator of energy homeostasis in the heart, responsible for the reduced β‐adrenergic responsiveness of the heart in obesity? What is the main finding and its importance? Inhibition of AMPK in isolated hearts prevented the reduced cardiac β‐adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between β‐adrenergic responsiveness and AMPK signalling in the heart, and it suggests that AMPK might be an important target to restore the β‐adrenergic responsiveness in the heart in obesity.

Effect of type 2 diabetes, surgical incision, and volatile anesthesia on hemodynamics in the rat

Diabetic patients have increased cardiac complications during surgery, possibly due to impaired autonomic regulation. Anesthesia lowers blood pressure and heart rate (HR), whereas surgical intervention has opposing effects. The interaction of anesthesia and surgical intervention on hemodynamics in diabetes is unknown, despite being a potential perioperative risk factor. We aimed to determine the effect of diabetes on the integrative interaction between hemodynamics, anesthesia, and surgical incision. Zucker type 2 diabetic rats (DM) and their nondiabetic littermates (ND) were implanted with an intravenous port for drug delivery, and a radiotelemeter to measure mean arterial blood pressure (MAP) and derive HR (total n = 50). Hemodynamic pharmacological responses were assessed under conscious, isoflurane anesthesia (~2–2.5%), and anesthesia–surgical conditions; the latter performed as a laparotomy. MAP was not different between groups under conscious conditions (ND 120 ± 6 vs. DM 131 ± 4 mmHg, P > 0.05). Anesthesia reduced MAP, but not differently in DM (ND −30 ± 6 vs. DM −38 ± 4 ΔmmHg, P > 0.05). Despite adequate anesthesia, surgical incision increased MAP, which tended to be less in DM (ND +21 ± 4 vs. DM +13 ± 2 ΔmmHg, P = 0.052). Anesthesia disrupted central baroreflex HR responses to sympathetic activation (sodium nitroprusside 10 μg·kg−1, ND conscious 83 ± 13 vs. anesthetized 16 ± 5 Δbpm; P < 0.05) or to sympathetic withdrawal (phenylephrine 10 μg·kg−1, ND conscious −168 ± 37 vs. anesthetized −20 ± 6 Δbpm; P < 0.05) with no additional changes observed after surgical incision or during diabetes. During perioperative conditions, type 2 diabetes did not impact on short‐term hemodynamic regulation. Anesthesia had the largest hemodynamic impact, whereas surgical effects were limited to modulation of baseline blood pressure.