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NEW FINDINGS What is the central question of this study? Are there specific contributions of β1 - and β2 -adrenoceptor subtypes to the impaired β-adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance? In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the β1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the β2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. ABSTRACT Impaired β-adrenoceptor (β-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of β1 - and β2 -AR subtypes to β-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific β1 - and β2 -AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff-perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the β-AR agonist isoprenaline (1 × 10-11 to 3 × 10-8 mol l-1 ) with or without the selective β1 -AR antagonist CGP20712A (3 × 10-8 mol l-1 ) or the β2 -AR antagonist ICI-118,551 (5 × 10-8 mol l-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216 ± 17 beats min-1 versus diabetic 151 ± 23 beats min-1 , P

Increased cardiac sympathetic nerve activity in type 2 diabetes mellitus (DM) suggests impaired autonomic control of the heart. However, the central regions that contribute to the autonomic cardiac pathologies in type 2 DM are unknown. Therefore, we tested the hypothesis that neuronal activation would be increased in central sympathoregulatory areas in a pre-clinical type 2 DM animal model. Immunohistochemistry in 20-week-old male Zucker diabetic fatty (ZDF) rats revealed an increased number of neurones expressing ΔFosB (a marker of chronic neuronal activation) in the intermediolateral column (IML) of the spinal cord in DM compared to non-diabetic (non-DM) rats (P < 0.05). Rostral ventrolateral medulla (RVLM) neurones activate IML neurones and receive inputs from the hypothalamic paraventricular nucleus (PVN), as well as the nucleus tractus solitarius (NTS) and area postrema (AP), in the brainstem. We observed more ΔFosB-positive noradrenergic RVLM neurones (P < 0.001) and corticotrophin-releasing hormone PVN neurones (P < 0.05) in DM compared to non-DM rats. More ΔFosB-positive neurones were also observed in the NTS (P < 0.05) and AP (P < 0.01) of DM rats compared to non-DM rats. Finally, because DM ZDF rats are obese, we also expected increased activation of pro-opiomelanocortin (POMC) arcuate nucleus (ARC) neurones in DM rats; however, fewer ΔFosB-positive POMC ARC neurones were observed in DM compared to non-DM rats (P < 0.01). In conclusion, increased neuronal activation in the IML of type 2 DM ZDF rats might be driven by RVLM neurones that are possibly activated by PVN, NTS and AP inputs. Elucidating the contribution of central sympathoexcitatory drive in type 2 DM might improve the effectiveness of pharmacotherapies for diabetic heart disease.

New Findings 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. β-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of β1- and β2-adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (β1- and β2-adrenoceptor agonist, 0.1–300 μg kg−1) in the presence of atenolol (β1-adrenoceptor antagonist, 2000 μg kg−1) or nadolol (β1- and β2-adrenoceptor agonist, 4000 μg kg−1) to determine the chronotropic contributions of the β-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min−1 non-diabetic versus diabetic, P

New Findings 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. Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and experimental studies of hypertension by reducing systemic sympathetic output. This study determined the effect of BRD on cardiac β-adrenoceptor (AR) responsiveness in a diabetic model with underlying hypertension using the transgenic (mRen-2)27 rats. Bilateral renal denervation or sham surgeries were conducted repeatedly at 3, 6 and 9 weeks in Ren-2 rats with or without streptozotocin (STZ)-induced diabetes (4 × n = 7); Sprague–Dawley rats (n = 6) served as control animals. Cardiac function was determined in isolated hearts at 18 weeks of age. Normalised left ventricular developed pressure and relaxation was recorded in response to incremental concentrations of the β-AR agonist isoprenaline (from 10−10 to 10−7 m) or the β3-AR agonist BRL37344 (from 10−13 to 10−6 m). Expression levels of β1-AR were determined by Western blot. Both inotropic and lusitropic β-AR responsiveness was reduced in the hypertensive diabetic hearts, but these responses were unaltered after BRD. Expression levels of β1-AR were increased after BRD (Sham, 0.85 ± 0.11 versus 1.01 ± 0.05 a.u.; BRD, 1.45 ± 0.11 versus 1.46 ± 0.07 a.u.; Ren-2 versus Ren-2 STZ, P

Cardiac muscle functions as a molecular machine that converts an electrical stimulus into a Ca2+-dependent mechanical contraction. This article is protected by copyright. All rights reserved

The positive force-frequency relation, one of the key factors modulating performance of healthy myocardium, has been attributed to an increased Ca(2+) influx per unit of time. In failing hearts, a blunted, flat or negative force-frequency relation has been found. In healthy and failing hearts frequency-dependent alterations in Ca(2+) sensitivity of the myofilaments, related to different phosphorylation levels of contractile proteins, could contribute to this process. Therefore, the frequency dependency of force, intracellular free Ca(2+) ([Ca(2+)](i)), Ca(2+) sensitivity and contractile protein phosphorylation were determined in control and monocrotaline-treated, failing rat hearts. An increase in frequency from 0.5 to 6 Hz resulted in an increase in force in control (14.3 +/- 3.0 mN mm(-2)) and a decrease in force in failing trabeculae (9.4 +/- 3.2 mN mm(-2)), whereas in both groups the amplitude of [Ca(2+)](i) transient increased. In permeabilized cardiomyocytes, isolated from control hearts paced at 0 and 9 Hz, Ca(2+) sensitivity remained constant with frequency (pCa(50): 5.55 +/- 0.02 and 5.58 +/- 0.01, respectively, P>0.05), whereas in cardiomyocytes from failing hearts Ca(2+) sensitivity decreased with frequency (pCa(50): 5.62 +/- 0.01 and 5.57 +/- 0.01, respectively, P

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

Diabetes reduces heart rate (HR) reserve during maximal exercise. We measured HR during a low- and high-dose (0.1 and 0.4 mg·kg-1) atropine bolus followed by incremental dobutamine infusions (5 - 40 μg·kg-1·min-1) up to 85% maximal HR to determine the roles of the parasympathetic and sympathetic nervous system in the diabetic HR response. Five 18 – 30 year old individuals with type 1 diabetes (T1D), but without cardiovascular disease or hypertension and four age-, sex- and training-matched non-diabetic subjects (CON) performed a VO2max test (with ECG) on a cycle ergometer. On a second day, parasympathetic control was determined by comparing the change in HR during atropine doses using ANOVA. Sympathetic responsiveness was compared using the slope of the change in HR (after high-dose atropine) across dobutamine infusion rates. VO2max and maximal HR during the exercise test were the same between groups (P > 0.05). Resting HR was greater in the T1D vs. CON (75 ± 4 vs. 62 ± 6 beats·min-1; P < 0.05). Heart rat...