Sympathoactivation and rho-kinase-dependent baroreflex function in experimental renovascular hypertension with reduced kidney mass

Abstract

BackgroundDysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. The contribution of different forms of renovascular hypertension and the mechanisms contributing to autonomic dysfunction in hypertension are incompletely understood. Here, murine models of renovascular hypertension with preserved (2-kidneys-1 clip, 2K1C) and reduced (1-kidney-1 clip, 1K1C) kidney mass were studied with regard to autonomic nervous system regulation (sympathetic tone: power-spectral analysis of systolic blood pressure; parasympathetic tone: power-spectral analysis of heart rate) and baroreflex sensitivity of heart rate by spontaneous, concomitant changes of systolic blood pressure and pulse interval. Involvement of the renin-angiotensin system and the rho-kinase pathway were determined by application of inhibitors.ResultsC57BL6N mice (6 to 11) with reduced kidney mass (1K1C) or with preserved kidney mass (2K1C) developed a similar degree of hypertension. In comparison to control mice, both models presented with a significantly increased sympathetic tone and lower baroreflex sensitivity of heart rate. However, only 2K1C animals had a lower parasympathetic tone, whereas urinary norepinephrine excretion was reduced in the 1K1C model. Rho kinase inhibition given to a subset of 1K1C and 2K1C animals improved baroreflex sensitivity of heart rate selectively in the 1K1C model. Rho kinase inhibition had no additional effects on autonomic nervous system in either model of renovascular hypertension and did not change the blood pressure. Blockade of AT1 receptors (in 2K1C animals) normalized the sympathetic tone, decreased resting heart rate, improved baroreflex sensitivity of heart rate and parasympathetic tone.ConclusionsRegardless of residual renal mass, blood pressure and sympathetic tone are increased, whereas baroreflex sensitivity is depressed in murine models of renovascular hypertension. Reduced norepinephrine excretion and/or degradation might contribute to sympathoactivation in renovascular hypertension with reduced renal mass (1K1C). Overall, the study helps to direct research to optimize medical therapy of hypertension.

Loss of Prolyl Carboxypeptidase in Two-Kidney, One-Clip Goldblatt Hypertensive Mice

“…Previous studies described a gradual increase and full development of hypertension in mice over two weeks and sustained hypertension until week four post-clipping [ 60 – 63 ]. Gradual and sustained hypertension was also observed in rats after clip placement [ 64 , 65 ].…”

Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats

“…The 2K1C method that Goldblatt et al originally developed in 1934 was used to induce renovascular hypertension, as previously described (30). Briefly, a retroperi-toneal flank incision was performed in rats under anesthesia with sodium pentobarbital (50 mg/kg ip) (7,41). The right renal artery was exposed and partly occluded by placing a U-shaped silver clip of 0.2-mm internal diameter on the artery to induce renovascular hypertension.…”

“…Angiography. Four weeks after the 2K1C method was used to induce renovascular hypertension, the rats were catheterized via the femoral artery using PE50 polyethylene catheters under anesthesia with sodium pentobarbital (50 mg/kg ip) (7,41). The contrast medium ioversol (5 ml) (Jiangsu Hengrui Medicine, Lianyungang, China) was injected, and images of the left and right kidneys and renal arteries were obtained using a C-arm X-ray machine (Siemens, Erlangen, Germany).…”

“…RSD or sham surgery was performed at the end of the fourth week after clipping. A retroperitoneal flank incision was performed under anesthesia with sodium pentobarbital administration (50 mg/kg ip) (7,41). The left renal artery was exposed and treated with 95% alcohol containing 10% phenol for denervation (34,37,43).…”

Glycopenia - induced sympathoadrenal activation in diabetes mellitus and uncontrolled arterial hypertension: an observational study

“…Long-term studies are needed to address the question, whether fear of or repeated hypoglycemic events lead to higher sugar intake as a contributing factor to obesity [ 20 ]. Besides obesity, a more advanced chronic kidney disease found in Group-1 patients may further contribute to the evolution of arterial hypertension either via a renoparenchymal or renovascular mechanism [ 21 ]. Either way, the resulting poorer arterial hypertension may lead to vascular calcification and a faster decline of kidney function [ 22 ].…”