Increased vascular responsiveness to norepinephrine in rats with heart failure is endothelium dependent. Dissociation of basal and stimulated nitric oxide release.
BACKGROUND
Endothelial dysfunction and abnormal vascular responsiveness to vasoconstrictors may play an important role in chronic heart failure (CHF). The purpose of our study was to (1) evaluate whether the vascular response to norepinephrine is abnormal in a rat model of heart failure; (2) investigate the role of alpha 1- and alpha 2-adrenergic receptors; and (3) assess the contribution of the endothelium, and specifically endothelium-derived nitric oxide, to this response.


RESULTS
Concentration-response curves of rat thoracic aortic rings were studied in isolated organ baths at 1 week after coronary artery ligation. In CHF rats, norepinephrine-induced contractions were increased in intact rings compared with rings from sham rats, despite decreased contraction in denuded rings. Decreased alpha 1-receptor sensitivity was demonstrated by the increased EC50 of methoxamine in endothelium-denuded rings from CHF rats, although maximal responses to KCl contraction were also decreased in CHF. There was no difference in the vascular response to clonidine, and acetylcholine-mediated relaxations were preserved in CHF rats, suggesting normal stimulated nitric oxide release. However, nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester, as well as measurements of basal cGMP, demonstrated that basal nitric oxide release was decreased in CHF rats.


CONCLUSIONS
This study demonstrates that the increased vascular responsiveness to norepinephrine in intact vessels from rats with heart failure is the result of decreased basal nitric oxide release and suggests that the dissociation of basal and stimulated nitric oxide release may play a pathophysiology role at an early stage of heart failure.
Teerlink
J R
JR
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Gray
G A
GA
Clozel
M
M
Clozel
J P
JP
D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D011942:Receptors, Adrenergic, alpha; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D001120:Arginine; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine