Effects of chronic sympatho‐inhibition on reflex control of renal blood flow and plasma renin activity in renovascular hypertension

Abstract

Background and purpose:We determined if chronic sympatho-inhibition with rilmenidine has functional significance for the kidney by altering responses of renal blood flow (RBF) and plasma renin activity (PRA) to stress and acute hypotension in rabbits with renovascular hypertension. Experimental approach: RBF to each kidney and renal sympathetic nerve activity (RSNA) to the left kidney were measured in rabbits in which a renal artery clip induced hypertension (2K1C) and in sham-operated rabbits. After 2 weeks, a subcutaneous minipump was implanted to deliver rilmenidine (2.5 mg·kg) to 2K1C rabbits for 3 weeks. Key results: After 5 weeks of renal artery stenosis, mean arterial pressure (MAP) was 23% higher and PRA 3-fold greater than in sham-operated rabbits. Blood flow and renal vascular conductance in the stenosed kidney were lower (-75% and -80%) compared with sham, and higher in the non-clipped kidney (68% and 39%). Responses of RBF and PRA to hypotension were similar in 2K1C and sham rabbits. Airjet stress evoked a greater increase in MAP in 2K1C rabbits than sham controls. Chronic rilmenidine normalized MAP, reduced RSNA and PRA, and did not reduce RBF in the stenosed kidney. Responses of RBF (clipped and non-clipped kidney), RSNA and PRA to hypotension and airjet were little affected by rilmenidine. Conclusions and implications:Our observations suggest that chronic sympatho-inhibition is an effective antihypertensive therapy in renovascular hypertension. It normalizes MAP and reduces basal PRA without compromising blood flow in the stenosed kidney or altering responses of MAP, haemodynamics and PRA to acute hypotension and stress.

Combined Aliskiren and L-arginine treatment reverses renovascular hypertension in an animal model

“…3,4,7,16 Blocking the RAAS by inhibiting renin with ALSK could therefore contribute to reducing renovascular hypertension in the rat model we studied. However, we found that ALSK monotherapy did not reduce SBP, while studies in humans have demonstrated a reduction of blood pressure.…”

“…10 Renal nerves are known to produce renal vasoconstriction, albeit at higher levels of RSNA than are required to release renin. 4 Importantly, in the two-kidney, one-clip (2K1C) model of renovascular hypertension, excitatory synaptic inputs to the rostral ventrolateral medulla and the cardiac sympathetic afferent reflex are enhanced, 10 factors that may partly contribute to sympathetic activation and hypertension. 11 In 2K1C renovascular hypertension, the renal artery stenosis caused by the clip reduces the perfusion of the clipped kidney, raising plasma renin activity and circulating angiotensin II (Ang II), and increasing systolic blood pressure (SBP).…”

“…8,9 In addition, the positive impact of a lower RSNA was associated with a trend toward greater blood flow and improved vascular conductance in the stenotic kidney. 4 However, the mechanism of sympathetic activation in hypertension is not well understood. 10 Renal nerves are known to produce renal vasoconstriction, albeit at higher levels of RSNA than are required to release renin.…”

“…Moreover, renal sympathetic denervation have recently been developed as treatments for resistant hypertension 12 as well as inhibition of the sympathetic nervous system is an appropriate and effective treatment for renovascular hypertension. 4 Aliskiren is an orally active, non-peptide, direct renin inhibitor, which acts by binding to the active site of renin. Aliskiren directly inhibits PRA, the initial and rate-limiting step in the RAAS, unlike the ACEIs and ARBs, which cause a reactive rise in PRA.…”

“…Overactivity of the sympathetic nervous system has been implicated in the development and maintenance of essential and renovascular hypertension in humans. [1][2][3][4] Studies in hypertensive animal models show an increase in basal renal sympathetic nerve activity (RSNA). 5,6 The excessive sympathetic nerve activity has a pathogenic role in triggering and sustaining both hypertension and a progression to organ damage.…”