Submitted to: Journal of Trace Elements in Experimental Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/15/2001
Publication Date: 4/29/2002
Citation: Gobejishvili, L., Saari, J.T., Adeagbo, A.S.O., Zhang, X., Schuschke, D.A. 2002. Dietary copper deficiency increases inducible nitric oxide synthase-vascular dilation in rat aorta. Journal of Trace Elements in Experimental Medicine. 15:85-95.
Interpretive Summary: Blood vessels from copper-deficient rats do not dilate as well as those from copper-adequate rats. Because blood vessel diameter is a major contributor to blood pressure, copper-deficient rats should have higher blood pressures, but this is not always observed. This indicates that a mechanism may exist to compensate for the altered dilation of blood vessels that prevents an increase in blood pressure in copper-deficient animals. Because the altered dilation of blood vessels in copper deficiency is caused by disruption of a chemical (nitric oxide) that is produced in cells (endothelium) lining the blood vessel wall, this study examined dilation of blood vessels in which this lining layer was removed, to determine whether the muscle cells of the vessels could produce enough nitric oxide to compensate for that no longer provided by the endothelium. This study showed that copper-deficient blood vessels with their endothelium removed dilated more rapidly than copper-adequate vessels in response to substances that caused release of nitric oxide in the smooth muscle. This indicates that impairment of dilation by endothelium-derived nitric oxide in copper-deficient blood vessels may be compensated for by a heightened production of nitric oxide in the underlying smooth muscle. Such information will help scientists and consumers understand the importance of adequate copper nutrition in the regulation of blood pressure.
Technical Abstract: The attenuation of endothelium-dependent nitric oxide (NO)-mediated vasodilation is a consistent finding 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 hypothesize 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 CuA aortas. The maximal relaxation response to L-arginine was blocked by the iNOS inhibitor L-NIL and the relaxation in response to Cu,Zn-SOD was blocked by the NO- sensitive guanylate cyclase inhibitor ODQ. Maximal activation of iNOS expression with LPS pretreatment did not cause a difference in vascular relaxation response to L-arginine between dietary groups. Expression of the iNOS protein in the aortas was also not different between groups. These results suggest that while there is no apparent increase in protein expression, copper deficiency increases baseline iNOS activity in the vascular wall.