Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

New Findings What is the central question of this study? We examined, in hypertensive rats, whether the angiotensin‐converting enzyme‐independent enzymes generating angiotensin II in the tissues modulate blood pressure, peripheral circulation and renal function. What is the main finding and its impo...

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Published in:Experimental physiology 2015-09, Vol.100 (9), p.1093-1105
Main Authors: Roszkowska‐Chojecka, Malwina Monika, Walkowska, Agnieszka, Gawryś, Olga, Baranowska, Iwona, Kalisz, Małgorzata, Litwiniuk, Anna, Martyńska, Lidia, Kompanowska‐Jezierska, Elżbieta
Format: Article
Language:English
Subjects:
Angiotensin II - metabolism
Animals
Blood Pressure - drug effects
Chymases - antagonists & inhibitors
Glomerular Filtration Rate - drug effects
Hemodynamics - drug effects
Hypertension, Renovascular - drug therapy
Hypertension, Renovascular - metabolism
Kidney - drug effects
Kidney - metabolism
Male
Oligopeptides - pharmacology
Peptidyl-Dipeptidase A - pharmacology
Rats
Rats, Sprague-Dawley
Renal Circulation - drug effects
Renal Elimination - drug effects
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Summary:New Findings What is the central question of this study? We examined, in hypertensive rats, whether the angiotensin‐converting enzyme‐independent enzymes generating angiotensin II in the tissues modulate blood pressure, peripheral circulation and renal function. What is the main finding and its importance? The results suggest that chymostatin‐sensitive enzymes diminish vascular tone in renal and extrarenal vascular beds. Chymase or similar chymostatin‐sensitive enzymes have a significant role in the synthesis of angiotensin II in different tissues but do not control blood pressure in the short term, similarly in salt‐dependent or Goldblatt‐type rat hypertension. In salt‐dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing the angiotensin II content in the kidney. Chymase is presumed to be a crucial enzyme of the non‐angiotensin‐converting enzyme pathway of angiotensin II (Ang II) generation in tissues, a process involved in vascular remodelling and development of hypertension. We examined the role of chymase in hypertension induced by exposure of uninephrectomized rats to high dietary salt intake (UNX HS) and in the Goldblatt renal artery stenosis (two‐kidney, one‐clip) model. In acute experiments with anaesthetized rats of either model, chymostatin at 2 mg kg−1 h−1 or 0.05% DMSO solvent was infused i.v. Mean arterial blood pressure, heart rate, iliac blood flow (a measure of hindlimb perfusion), total renal blood flow and intrarenal regional perfusion (laser‐Doppler technique) were measured continuously, along with the glomerular filtration rate and renal excretion. In both models, chymase blockade distinctly decreased plasma and tissue Ang II without lowering mean blood pressure or consistently altering the other functional parameters measured. Unexpectedly, in Goldblatt hypertensive rats the blockade increased the renal and hindlimb vascular resistances by 51 and 33%, respectively (P 
ISSN:0958-0670
1469-445X
DOI:10.1113/EP085325