Vasopeptidase inhibition normalizes blood pressure and restores endothelial function in renovascular hypertension.
OBJECTIVE
Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension.


METHODS
Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively.


RESULTS
Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups.


CONCLUSIONS
In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.
Quaschning
Thomas
T
Department of Nephrology, University Hospital of Freiburg, Freiburg, Germany. mail@thomas-quaschning.de
Hocher
Berthold
B
Ruhl
Sabine
S
Kraemer-Guth
Annette
A
Tilgner
Johannes
J
Wanner
Christoph
C
Galle
Jan
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D006339:Heart Rate; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects
C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D006575:Heterocyclic Compounds, 3-Ring; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D017257:Ramipril