A heme oxygenase product, presumably carbon monoxide, mediates a vasodepressor function in rats.
Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 mumol/kg IP) increased mean arterial pressure (19 +/- 2%, P < .05) and total peripheral resistance (47 +/- 4%, P < .05), decreased cardiac output (-16 +/- 2%, P < .05), but did not affect heart rate. Another heme oxygenase inhibitor, zinc protoporphyrin IX (45 mumol/kg IP), also increased arterial pressure (17 +/- 5%, P < .05), with no effect on heart rate. In contrast, neither the nonmetallic deuteroporphyrin 2,4-bis glycol (45 mumol/kg IP) nor bilverdin (45 mumol/kg IP) had any effect on blood pressure or heart rate. These findings suggest that ZnDPBG and zinc protoporphyrin IX increase arterial pressure by inhibiting heme oxygenase activity. After pretreatment with chlorisondamine (5 mg/kg IP) or prazosin (5 mg/kg IP) to inhibit autonomic ganglionic or alpha 1-adrenoceptor functions, respectively, ZnDPBG did not affect arterial pressure or heart rate. This suggests that ZnDPBG-induced increases in blood pressure rely on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system.
Department of Pharmacology, New York Medical College, Valhalla 10595.
R A
RA
Johnson
M
M
Lavesa
B
B
Askari
N G
NG
Abraham
A
A
Nasjletti
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism*; D002714:Chlorisondamine / Q000494:pharmacology; D003905:Deuteroporphyrins / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003905:Deuteroporphyrins; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D002714:Chlorisondamine; D011224:Prazosin