Potentiation of carbon monoxide-induced relaxation of rat aorta by YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole].
The hypothesis that endogenous carbon monoxide (CO), produced during the oxidation of heme catalyzed by heme oxygenase (HO), plays a role similar to that of nitric oxide (NO) in the regulation of cardiovascular tone has been criticized because of the low potency of CO compared with NO in relaxing blood vessels and stimulating soluble guanylyl cyclase (sGC). This criticism has been muted by the demonstration that, in the presence of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole], CO has similar potency to NO in stimulating sGC activity. In this study, we determined that YC-1 potentiated CO-induced relaxation of rat aortic strips (RtAS) by approximately ten-fold. Furthermore, CO-induced relaxation of RtAS was shown to be mediated through stimulation of sGC because vasorelaxation was inhibited by ODQ (1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one), a selective sGC inhibitor, in the absence and presence of YC-1. A gas chromatographic-headspace method was used to measure CO concentration in Krebs' solution following the addition of CO-saturated saline solution to the tissue bath, in order to provide an accurate determination of RtAS exposure to CO. The tissue bath concentration of CO was shown to be approximately one-half of that calculated to be present. We conclude that should an endogenous compound exist with properties similar to that of YC-1, then the potency of CO as a vasorelaxant in the presence of this factor would be increased. As a consequence, CO could play a role in the regulation of cardiovascular tone, comparable to that of NO.
McLaughlin
B E
BE
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.
Chretien
M L
ML
Choi
C
C
Brien
J F
JF
Nakatsu
K
K
Marks
G S
GS
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology; D002248:Carbon Monoxide / Q000494:pharmacology*; D004357:Drug Synergism; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D002248:Carbon Monoxide; D006162:Guanylate Cyclase