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.
Highlights
Dysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease
Angiotensin II-subtype-1 (AT1) receptor blockers [5] or angiotensin-converting enzyme (ACE) inhibitors [6] slow the progression of chronic kidney disease (CKD), yet they are contraindicated in bilateral renal artery stenosis or in unilateral renal artery stenosis and single kidney situation
To gauge autonomic nervous system effects of an AT1 blockade, Irb treatment was performed in 2K1C animals
Summary
Dysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. 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. On the basis of the effect of propranolol and atropine methyl nitrate on resting heart rate, an elevated sympathetic tone in models of renovascular hypertension with (1-kidney-one-clip; 1K1C) and without kidney-mass reduction (2-kidneysone-clip; 2K1C) was identified [8,9]. Aside from heart-rate changes, muscle sympathetic nerve activity [10] and functional data like cold-pressor test [11] were not affected by propranolol.
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