Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat.
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 nmol l(-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 nmol l(-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 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 approximately 30% and aortic smooth muscle function was normal (7 weeks) or improved (18 weeks) in the cp/cp genotype.


CONCLUSIONS
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.
Brunner
F
F
Department of Pharmacology and Toxicology, Karl-Franzens-University, Universitätsplatz 2, A-8010, Graz, Austria. friedrich.brunner@dfunigraz.ac.at
Wölkart
G
G
Pfeiffer
S
S
Russell
J C
JC
Wascher
T C
TC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007333:Insulin Resistance; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008833:Microcirculation; D009200:Myocardial Contraction; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D004791:Enzyme Inhibitors; D007476:Ionophores; D019335:Nitroarginine; D001708:Biopterins; D000001:Calcimycin; D019001:Nitric Oxide Synthase; C003402:sapropterin; D001920:Bradykinin