Heme oxygenase-derived endogenous carbon monoxide impairs flow-induced dilation in resistance vessels.
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.
Johnson
Robert A
RA
Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. rjohnson@cvlabs.org
Johnson
Fruzsina K
FK
D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001664:Biliverdine / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D008652:Mesoporphyrins; C427471:chromium mesoporphyrin; D002248:Carbon Monoxide; D000622:Aminolevulinic Acid; D006419:Heme Oxygenase (Decyclizing); D001664:Biliverdine