© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs
Department of Physiology, Faculty of Medicine, Université de Montréal, and Institut de Cardiologie de Montréal, 5000 east Bélanger St., Montréal, Québec, Canada H1T 1C8
* Corresponding author. Tel.: +1-514-376-3330 extn. 3741; fax: +1-514-376-1355 lavallem{at}icm.umontreal.ca
Objective: To determine whether endothelin (ET)-dependent effects limit shear stress-induced dilation of large epicardial coronary arteries after blockade of nitric oxide (NO) formation. Methods: In conscious dogs instrumented for measuring coronary blood flow (CBF) and external diameter (CD) of the circumflex coronary artery, flow-dependent CD dilation was elicited by intracoronary (ic) adenosine (500 ng kg–1 min–1). Results: Ic adenosine increased CBF by 28±4 from 38±5 ml min–1 and CD by 0.25±0.03 from 3.53±0.07 mm without other hemodynamic effects. After N
-nitro-L-arginine methyl ester (L-NAME), baseline CD fell (P<0.01) to 3.35±0.08 mm but CBF was not significantly altered (36±5 ml min–1). CBF increases caused by adenosine were smaller (17±2 ml min–1, P<0.05) and CD responses were nearly abolished (0.02±0.01 mm, P<0.01). Ic Ro 61-1790, an ETA receptor blocker, given after L-NAME did not significantly influence baseline CBF (36±5 ml min–1) but increased (P<0.01) CD to 3.45±0.09 mm. CBF responses to adenosine were not significantly altered by Ro 61-1790 but CD responses (0.10±0.01 mm) were partially restored (P<0.01). In contrast, blockade of ETB receptors with Ro 46-8443 after L-NAME had no further effects on CD and CBF responses to adenosine. Conclusion: ETA receptor-mediated effects limit flow-dependent dilation of large epicardial coronary arteries in conscious dogs. Suppression of the L-arginine/NO-dependent pathway with L-NAME reveals significant ET-dependent effects.
KEYWORDS CBF: coronary blood flow; CD: external coronary artery diameter; ET: endothelin; HR: heart rate; Ic: intracoronary; Iv: intravenous; L-NAME: N-nitro-L-arginine methyl ester; LVP: left ventricular pressure; LV dP/dt: first derivative of LVP over time; MAP: mean arterial pressure; NO: nitric oxide; Ro 46-8443: (S)-4-tert.-butyl-N-[6-(2,3-dihydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(4-methoxyphenyl)pyrimidin-4-yl]benzenesulfonamide; Ro 61-1790: 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide disodium salt
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