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

Abstract

New Findings r 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? r 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 β 3 -AR agonist BRL37344 (from 10 −13 to 10 −6 m). Expression levels of β 1 -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 β 1 -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 < 0.05 versus Sham). No effect of β 3 -AR agonist stimulation with BRL37344 was observed. Interestingly, BRD increased left ventricular diastolic volume in both the Ren-2 and the Ren-2 STZ groups. Bilateral renal denervation did not restore the attenuated cardiac β-AR responsiveness in the diabetic hypertensive rats, but it reduced the extent of hypertension-induced concentric hypertrophic remodelling. Thus, the haemodynamic

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

“…The hearts from the lean and obese animals of the Time‐Controls revealed that basal LVP dev declined over the 90 min between the start of the first and the start of the second ISO dose–response curve, but to a similar extent in both groups (lean −21 ± 5% versus obese −22 ± 6%, P > 0.05, Student's unpaired t test, n = 6 per group), which is comparable to previous reports (Bouwman et al., ; Thaung, Yao et al., ). The difference in normalized ISO dose–response curve between the hearts from the lean and obese rats remained in the Time‐Control group (data not shown).…”

“…Maximal LV developed pressure ( P max ) was determined with a postextrasystolic rest potentiation protocol, which consists of interposing trains of 20 Hz stimulation for 1, 2 or 4 s, followed by a 3 s rest period, after which normal 5 Hz pacing is resumed. The largest contraction immediately after the 3 s rest period reflects P max (Schouten, Allaart, & Westerhof, ; Thaung, Yao et al., ). At the end of the experiment, the isolated hearts of both groups were frozen in the presence or absence of CC.…”

Renal denervation attenuates cardiac hypertrophy in spontaneously hypertensive rats via regulation of autophagy

“…In a previous study with SHRs, Jiang et al found that RD can significantly delay the progression of left ventricular hypertrophy, possibly not only through the suppression of sympathetic activity and attenuation of pressure load, but also due to the reduction in myocardial inflammation, as reflected by significantly reduced myocardial levels of Toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrotic factor alpha (TNF-α) and interleukin 6 (IL-6) after RD ( 22 , 31 ). In a subsequent study in hypertensive type 1 diabetic rats, Thaung et al found that bilateral RD reduces cardiac hypertrophic remodeling in these rats without restoring the attenuated cardiac β-AR responsiveness ( 32 ). Instead, they proposed that indirect cardiac effects, such as attenuation of sympathetic innervation of the systemic vasculature and/or kidney may be involved ( 32 ).…”

A Clinically Relevant Functional Model of Type-2 Cardio-Renal Syndrome with Paraventricular Changes consequent to Chronic Ischaemic Heart Failure

“…release inflammatory cytokines into the systemic circulation, provoking myocardial damage. Renal injury is also indicated to increase sympathetic activity within the cardiovascular regulatory centres of the midbrain via the renal somatic afferent nerves, altering cardiac structure and function 16,17 . However, the existence of a clinical correlation between co-morbidities does not imply causality.…”