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(Circulation. 2000;101:1303.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Profound Inhibition of Myogenic Tone in Rat Cardiac Allografts Is Due to eNOS- and iNOS-Based Nitric Oxide and an Intrinsic Defect in Vascular Smooth Muscle Contraction

Peter L. Skarsgard, MD; Xiaodong Wang, PhD; Paul McDonald, BSc; Amy H. Lui, BSc; Eugene K. Lam, BSc; Bruce M. McManus, MD, PhD; Cornelis van Breemen, DVM, PhD; Ismail Laher, PhD

From the Departments of Surgery (P.L.S.), Pharmacology and Therapeutics (P.L.S., X.W., A.H.L., E.K.L., C.v.B., I.L.), and Pathology and Laboratory Medicine (P.L.S., P.M., B.M.M.), and the Vancouver Vascular Biology Research Centre, University of British Columbia, Vancouver, Canada.

Correspondence to Peter L. Skarsgard, MD, Department of Pharmacology, Room 316, 2176 Health Science Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. E-mail pskar{at}interchange.ubc.ca

Background—The physiological consequences of inducible NO synthase (iNOS) expression were studied in allograft coronary arteries by pressure myography.

Methods and Results—Septal coronary arteries (diameter, 200.6±3.3 µm) were harvested from allograft and isograft hearts, and their myogenic properties were measured before and after iNOS and nonselective NOS inhibition with aminoguanidine (AG, 100 µmol/L) and N^G-nitro-L-arginine methyl ester (L-NAME) (200 µmol/L). Fura 2 fluorescence microscopy was used to measure [Ca²⁺]_i in isolated endothelial cells. Monoclonal anti-iNOS immunostains demonstrated iNOS protein in day 2, 7, 14, and 28 allograft vessels, but only in day 2 isograft vessels. Myogenic tone was profoundly inhibited in allograft vessels from day 4 onward. In day 4 allograft vessels, these differences were abolished by L-NAME but not AG, suggesting greater basal release of eNOS-based NO from allograft endothelium. Fluorescence measurements confirmed elevation of [Ca²⁺]_i in day 4 allograft endothelium, providing a mechanism for enhanced eNOS activity. For days 7 to 28, AG potentiated myogenic tone in allograft but not isograft vessels, indicating that vasoactive iNOS-based NO was present. In mature vessels, constriction via agonist- and depolarization-mediated mechanisms showed parallel inhibition, suggesting an intrinsic defect in vascular smooth muscle cell contraction.

Conclusions—Our data indicate that the profound inhibition of myogenic tone in allograft arteries involves direct vasodilation by eNOS- and iNOS-based NO, as well as an intrinsic defect in vascular smooth muscle contraction. The hemodynamic profile resulting from these changes in allograft resistance vessel function would favor movement of extracellular fluid from the intravascular space into the myocardial interstitium, resulting in edema, increased ventricular stiffness, and poor ventricular performance.

Key Words: nitric oxide • nitric oxide synthase • transplantation • hemodynamics

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