Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin‐resistant, obese JCR:LA‐cp rats

Abstract

1 The eects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were investigated. 2 Phenylephrine (PE; 0.1 nM ± 10 mM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium. 3 Acetylcholine (ACh; 0.1 nM ± 10 mM)-induced endothelium-dependent relaxation of rings was not signi®cantly dierent in the two genotypes. Both were inhibited to a similar extent by N G -nitro-Larginine methyl ester (L-NAME; 0.01 ± 1 mM) when administered in vitro. 4 The nitric oxide synthase (NOS) inhibitor (L-NAME; 0.3, 1 or 3 mg ml 71 , p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats. 5 L-NAME resulted in greater inhibition of ACh-induced relaxation in cp/cp rings compared with +/? rings. 6 L-NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats. 7 The NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM ± 10 mM)-induced relaxation of rings from +/? rats, an eect enhanced by the treatment with L-NAME in vivo. 8 Oral administration of L-NAME did not enhance the vasorelaxant eect of SNAP on rings of aorta from cp/cp animals. 9 Platelet aggregation and NOS activity were similar in both genotypes and were not modi®ed by oral administration of L-NAME. 10 These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exempli®ed by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.

Diet, obesity and endothelial dysfunction: of rats and men

“…Another interesting finding was the lack of increase in plasma non-esterified fatty acids (NEFAs) with the induction of obesity. This is significant owing to the emerging role of NEFAs in inducing both insulin resistance and endothelial dysfunction, at least in humans [8,9]. The lack of increase in NEFAs may be related to decreased fatty acid cycling in the rat model, and is consistent with previous reports [8].…”

Disturbances in nitric oxide/cyclic guanosine monophosphate system in SHR/NDmcr-cp rats, a model of metabolic syndrome

“…The JCR:LA-corpulent rats have the cp gene, as well as SHR-cp, and animals homozygous for the cp gene develop obesity, hyperlipidemia, and hyperinsulinemia, but are normotensive. In the aorta from the JCR:LA-corpulent rats, both endotheliumdependent and -independent relaxations are not dramatically different compared to those in the lean rats at 7 -24 weeks of age (Brunner et al, 2000;McKendrick et al, 1998;McNamee et al, 1994). Thus, alteration of vascular responsiveness may differ with animal species or age, and enhancement of endothelial NO production in SHR-cp can be enough to develop in parallel with the onset of the metabolic syndrome.…”

Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition

“…There is increasing evidence that insulin resistance has adverse effects on the reactivity of arteries and arterioles and promotes arterial hypertension and occlusive vascular diseases (Busija et al 2006). The sensitivity to contraction with PE was enhanced in insulin-resistant rats (McKendrick et al 1998). Also, thoracic aorta from fructose-fed rats showed exaggerated responses to PE and KCl (Iyer and Katovich 1996;Shinozaki et al 2004).…”