HEME OXYGENASE-DERIVED ENDOGENOUS CARBON MONOXIDE IMPAIRS FLOW-INDUCED DILATION IN RESISTANCE VESSELS

Abstract

Vascular tissues normally express heat shock protein 32 (heme oxygenase [HO] 1), which degrades heme. A product of this reaction, carbon monoxide (CO), has been shown to promote relaxation of vascular smooth muscle, but it also inhibits NOS. Because flow-induced dilation is dependent upon the formation of endothelium-derived NO, we conducted the current study to determine if HO-mediated formation of CO impairs flow-induced dilation. In isolated pressurized first-order gracilis muscle arterioles, proximal and distal pressures were manipulated to generate intraluminal flows of 0 to 50 microL/min at a constant vascular midline pressure of 80 +/- 1 mmHg. Vehicle-treated vessels displayed flow-related vasodilation, which was abolished by a NOS inhibitor, Nomega-nitro-L-arginine methyl ester. Acute intraluminal pretreatment with an inhibitor of HO, chromium mesoporphyrin (CrMP), enhanced flow-induced responses in similarly prepared vessels. In contrast, a substrate for heme formation that drives CO generation, delta-aminolevulinic acid, abolished flow-induced dilation in a manner which could be fully prevented and reversed by CrMP. In addition, the HO product biliverdin had no effect on flow-induced dilation, whereas the responses were abolished by exogenous CO. Furthermore, spontaneous generation of CO was measured in isolated vascular segments to confirm that delta-aminolevulinic acid increased carbon formation by 29%, whereas CrMP reduced it by 43%. These data show flow-induced dilation can be impaired by a HO product, and that the impairment was not produced by biliverdin but is mimicked by CO. These results suggest that the HO-generated CO attenuates flow-induced dilation in the vasculature and, accordingly, may contribute to vascular dysfunction after injury.