INHIBITION OF NITRIC-OXIDE GENERATION UNMASKS VASCULAR DYSFUNCTION ININSULIN-RESISTANT, OBESE JCR-LA-CP RATS

1 The effects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were inve stigated. 2 Phenylephrine (PE; 0.1 nM-10 mu M) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp r ats. The sensitivity to contraction with PE was enhanced in cp/cp comp ared with +/? rings. Rings from both genotypes showed an increased con traction upon removal of the endothelium. 3 Acetylcholine (ACh; 0.1 nM -10 mu M)-induced endothelium-dependent relaxation of rings was not si gnificantly different in the two genotypes. Both were inhibited to a s imilar extent by N-G-nitro-L-arginine methyl ester (L-NAME; 0.01-1 mM) when administered in vitro. 4 The nitric oxide synthase (NOS) inhibit or (L-NAME; 0.3, 1 or 3 mg ml(-1), p.o.) when administered in vivo inc reased blood pressure in cp/cp rats but not in +/? rats. 5 L-NAME resu lted in greater inhibition of ACh-induced relaxation in cp/cp rings co mpared with +/? rings. 6 L-NAME treatment in vivo caused a decrease in cyclic 6MP and NOS activity in rings from cp/cp but not +/? rats. 7 T he NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM-10 mu M )-induced relaxation of rings from +/? rats, an effect enhanced by the treatment with L-NAME in vivo. 8 Oral administration of L-NAME did no t enhance the vasorelaxant effect of SNAP on rings of aorta from cp/cp animals. 9 Platelet aggregation and NOS activity were similar in both genotypes and were not modified by oral administration of L-NAME. 10 These results show that unimpaired generation of NO is crucial for mai ntenance of vascular tone particularly under conditions of vascular in sult exemplified by insulin resistance, obesity and dyslipidemia detec ted in cp/cp rats.