Regression of L-NAME-induced hypertension: the role of nitric oxide and endothelium-derived constricting factor.
N(G)-Nitro-L-arginine-methyl ester (L-NAME)-induced hypertension is a well established model of experimental hypertension. Although regression experiments are effective at approximating a clinical setting the reversal of already established L-NAME hypertension has not been intensively researched. We investigated whether spontaneous regression of L-NAME hypertension after discontinuing the drug administration was associated with recovery of endothelial dysfunction. Special attention was devoted to NO signaling and endothelium-derived constricting factor (EDCF) formation in various parts of the vascular tree. Male adult Wistar rats were divided into 4 groups: an L-NAME (5 weeks), a spontaneous recovery (5 weeks L-NAME + 3 weeks of recovery) and two age-matched control groups (a 5- and 8-week control group). The NO-mediated and EDCF-mediated components of acetylcholine-induced responses were evaluated in preconstricted small mesenteric and femoral arteries. The activity, mRNA and protein expression of NO synthase together with the mRNA expression of cyclooxygenase were determined in the aorta. L-NAME administration caused hypertension, impaired NO signaling (as indicated by the reduced NO component of acetylcholine-induced relaxation and decreased NO synthase activity) in all arteries investigated and reduced the inner diameter of the femoral artery. Moreover, we observed enhanced cyclooxygenase-dependent EDCF formation in the femoral arteries and enhanced cyclooxygenase-2 expression in the aortas of L-NAME-treated rats. During spontaneous recovery a functional restoration of NO signaling took place in all parts of the vascular tree. However, the increases in systolic blood pressure, EDCF formation, and cyclooxygenase expression and the reduction in femoral artery diameter were not completely restored. We conclude that impaired NO signaling was improved after the cessation of L-NAME administration. However, persisting arterial structural alterations and enhanced EDCF formation may decelerate blood pressure reduction even after the restoration of NO synthase activity.
Paulis
Ludovit
L
Institute of Pathophysiology, School of Natural Sciences, Comenius University, Bratislava, Slovak Republic. ludo@lfuk.sk
Zicha
Josef
J
Kunes
Jaroslav
J
Hojna
Silvie
S
Behuliak
Michal
M
Celec
Peter
P
Kojsova
Stanislava
S
Pechanova
Olga
O
Simko
Fedor
F
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D016232:Endothelins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016232:Endothelins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D019331:NG-Nitroarginine Methyl Ester