© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat
aDepartment of Pharmacology and Toxicology, Karl-Franzens-University, Universitätsplatz 2, A-8010 Graz, Austria
bDepartment of Surgery, University of Alberta, Edmonton, Canada
cDiabetic Angiopathy Research Group, Department of Internal Medicine, Karl-Franzens-University, Graz, Austria
* Corresponding author. Tel.: +43-316-380-5559; fax: +43-316-380-9890 friedrich.brunner{at}kfunigraz.ac.at
Objective: The JCR:LA-corpulent rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular dysfunction. We tested the hypothesis that the defects affect endothelial and smooth muscle function of the coronary microvasculature as well as cardiac contractility. Coronary, myocardial and aortic function were assessed in obese (homozygous for the cp gene, cp/cp) and lean (heterozygous 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 nmoll–1) on coronary perfusion pressure (CPP), myocardial mechanical function was evaluated in terms of left-ventricular developed pressure (LVDevP), and aortic relaxation with the endothelium-dependent agonist, A 23187 (1–1000 nmoll–1). Results: In rats aged 7 weeks, bradykinin reduced CPP from 133±1 mmHg to 43±1 mmHg (–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). Inhibition of NO synthase with NG-nitro-L-arginine (L-NNA; 0.2 mmoll–1) impaired, and tetrahydrobiopterin (0.1 mmoll–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 
30% and aortic smooth muscle function was normal (7 weeks) or improved (18 weeks) in the cp/cp genotype. Conclusion: These results suggest that (i) there is a specific impairment of NO-mediated relaxation of the coronary resistance vessels in the JCR:LA-corpulent rat that is not associated with impaired baseline myocardial contractility, and (ii) exogenous tetrahydrobiopterin reversed the relaxation defects that are part of the vascular complications typical for the insulin resistance syndrome.
KEYWORDS Diabetes; Endothelial function; Microcirculation; Nitric oxide; Ventricular function
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