Comparison of effect of endothelin antagonism and angiotensin-converting enzyme inhibition on blood pressure and vascular structure in spontaneously hypertensive rats treated with N omega-nitro-L-arginine methyl ester. Correlation with topography of vascular endothelin-1 gene expression.
Inhibition of nitric oxide synthase by L-arginine analogues such as N omega-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR) is associated with malignant hypertension and enhanced expression of the endothelin-1 gene in some blood vessels. In this study, SHR treated chronically with L-NAME (SHR-L-NAME) were given the angiotensin I-converting enzyme inhibitor cilazapril or the endothelin-A/endothelin-B receptor antagonist bosentan for 3 weeks. Systolic pressure was lowered slightly by cilazapril (213 +/- 2 versus 229 +/- 2 mm Hg in untreated SHR-L-NAME, P < .01) but was not significantly lowered by bosentan (223 +/- 2 mm Hg). Hypertrophy of aorta and small arteries (coronary, renal, mesenteric, and femoral) was decreased by cilazapril treatment and unaffected by bosentan. Expression of the endothelin-1 gene was evaluated in SHR-L-NAME by in situ hybridization histochemistry, which showed that endothelin-1 expression was enhanced in the endothelium of aorta but not in small mesenteric arteries in these rats. The absence of enhancement of endothelin-1 gene expression in small arteries may account for the absence of increased severity of hypertrophy of small vessels in SHR-L-NAME and may be a mechanism whereby L-NAME inhibits cardiovascular growth. These results suggest that in the absence of enhanced small-artery endothelin-1 expression, endothelin antagonism does not lower blood pressure. The blood pressure-lowering effect of angiotensin I-converting enzyme inhibition suggests a role for the renin-angiotensin system in the malignant form of hypertension that develops in SHR treated with L-NAME.
Li
J S
JS
Medical Research Council Multidisciplinary Research Group on Hypertension, University of Montréal, Quebec, Canada.
Deng
L Y
LY
Grove
K
K
Deschepper
C F
CF
Schiffrin
E L
EL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001794:Blood Pressure / Q000187:drug effects*; D000077300:Bosentan; D017315:Cilazapril / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D017403:In Situ Hybridization; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D017466:Receptors, Endothelin / Q000187:drug effects; D012083:Renin / Q000097:blood; D013449:Sulfonamides / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004791:Enzyme Inhibitors; D017466:Receptors, Endothelin; D013449:Sulfonamides; D017315:Cilazapril; D009569:Nitric Oxide; D001120:Arginine; D012083:Renin; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester