Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy

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

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“…), with a moderate reduction in SBP, although the animals clearly remained hypertensive (Dias et al . ; Yao et al . ).…”

Section: Discussionmentioning

confidence: 99%

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

Thaung

Yao

Bussey

et al. 2015

Experimental Physiology

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“…Diabetic animals display reduced heart rate variability, hypertension, and elevated plasma and tissue levels of NE [16-20]. These animals develop systolic and diastolic cardiac dysfunction over time [4,18,19,21].…”

Section: Introductionmentioning

confidence: 99%

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

Thackeray

Radziuk

Harper

et al. 2011

Cardiovasc Diabetol

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BackgroundDiabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.MethodsCardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.ResultsThe animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.ConclusionsTaken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.

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“…The role of renal nerves and renal denervation in hypertension, heart failure and chronic kidney disease has been widely studied in many species, including rats, mice, miniature swine, sheep and dogs [44,65,97,98,99,100,101,102,103]. The experiments utilize several methodological approaches to renal denervation.…”

Section: Basic Science Support For Renal Denervationmentioning

confidence: 99%

“…The experiments utilize several methodological approaches to renal denervation. The most common is surgical exposure of renal arteries and chemical coagulation of renal nerves with solution of phenol in absolute ethanol [101,103]. Intrarenal delivery of guanethidine or 6-hydroxydopamine [104,105], and electrical denervation has also been used [106].…”

Section: Basic Science Support For Renal Denervationmentioning

confidence: 99%

Drug Resistant Hypertension - No SIMPLE Way Out

Skrzypecki

Ufnal

2015

Kidney Blood Press Res

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Hypertension poses growing challenge for health policy-makers and doctors worldwide. Recently published results of Symplicity-III trial (HTN-3), the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal-artery denervation, as compared with controls. In this paper we review clinical and experimental studies on renal denervation. In order to identify causes of inconsistent results in renal denervation studies we look at basic science support for renal denervation and at designs of clinical trials.

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Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy

Cited by 21 publications

References 46 publications

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

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

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

Drug Resistant Hypertension - No SIMPLE Way Out

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