Vascular dysfunction and myocardial contractility in the JCR : LA-corpulent rat

Objective: The JCR:LA-corpulent rat is a unique animal model of human vascu lar disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular dysfunction. We tested the hypothesis that the defects affec t endothelial and smooth muscle function of the coronary microvasculature a s well as cardiac contractility. Coronary, myocardial and aortic function w ere assessed in obese (homozygous for the cp gene, cp/cp) and lean (heteroz ygous or homozygous normal, +/?) littermates aged 7 and 18 weeks. Methods: Coronary endothelial relaxation was examined in isolated perfused hearts by determining the effect of bradykinin (0.1-1000 nmol l(-1)) on coronary per fusion pressure (CPP), myocardial mechanical function was evaluated in term s of left-ventricular developed pressure (LVDevP), and aortic relaxation wi th the endothelium-dependent agonist, A 23187 (1-1000 nmol l(-1)). Results: In rats aged 7 weeks, bradykinin reduced CPP from 133+/-1 mmHg to 43+/-1 m mHg (-67%) in lean rats, but only to 64+/-3 mmHg (-52%) in corpulent rats ( n=6, P<0.05). Similar differences were found in rats aged 18 weeks (n=8). I nhibition of NO synthase with N-G-nitro-L-arginine (L-NNA; 0.2 mmol l(-1)) impaired, and tetrahydrobiopterin (0.1 mmol l(-1)), a NO synthase cofactor, restored relaxation in cp/cp rats. Spermine/NO equally reduced CPP in both groups (-58%). Mechanical function was similar in lean and corpulent rats, aortic endothelial relaxation was attenuated by similar to 30% and aortic smooth muscle function was normal (7 weeks) or improved (18 weeks) in the c p/cp genotype. Conclusion: These results suggest that (i) there is a specif ic impairment of NO-mediated relaxation of the coronary resistance vessels in the JCR:LA-corpulent rat that is not associated with impaired baseline m yocardial contractility, and (ii) exogenous tetrahydrobiopterin reversed th e relaxation defects that are part of the vascular complications typical fo r the insulin resistance syndrome. (C) 2000 Elsevier Science BN. All rights reserved.