Dietary copper deficiency increases inducible nitric oxide synthase-mediated vascular dilation in rat aorta†

Abstract

The attenuation of endothelium-dependent nitric oxide (NO)-mediated vasodilation is a consistent finding in both conduit and resistance vessels during copper deficiency. However, there is often no effect on systemic blood pressure in experimental animals, suggesting that peripheral vascular resistance is not altered. We hypothesized that baseline vascular smooth muscle relaxation may be maintained by a chronic increase in inducible NO synthase (iNOS) expression, as has been documented in hearts of copper-deficient rats. We used endothelium-denuded rat aortic rings to examine the role of iNOS in the regulation of vascular reactivity during dietary copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 5.6 mg Cu/kg diet) or copper-deficient diet (CuD, 0.33 mg Cu/kg diet) for 4 weeks. The induction of “functional” iNOS was indicated by a relaxation response to the NO precursor L-arginine or to Cu,Zn-superoxide dismutase (SOD), which preserves basal NO. Time to 50% relaxation in response to either compound was significantly shorter in the CuD than in the CuA aortas. The maximal relaxation response to L-arginine was blocked by the iNOS inhibitor L-NIL, and the relaxation response to Cu,Zn-SOD was blocked by the NO-sensitive guanylate cyclase inhibitor ODQ. Maximal activation of iNOS expression with lipopolysaccharide pretreatment did not cause a difference in vascular relaxation between dietary groups in response to L-arginine. Expression of the iNOS protein in the aortas was also not different between groups. These results suggest that although there is no apparent increase in protein expression, copper deficiency increases baseline iNOS activity in the vascular wall. J. Trace Elem. Exp. Med. 15:85–95, 2002. © 2002 Wiley-Liss, Inc.