Mechanism of inhibition of VIP-induced LES relaxation by heme oxygenase inhibitor zinc protoporphyrin IX.
The putative heme oxygenase inhibitor zinc protoporphyrin IX (ZnPP IX) is known to exert diverse actions, including inhibitory action on smooth muscle relaxation by vasoactive intestinal polypeptide (VIP). The studies were performed in the opossum lower esophageal sphincter (LES) smooth muscle to determine the site of the inhibitory action of ZnPP IX in the smooth muscle relaxation by VIP. We also examined the effect of a direct Gs protein activator, cholera toxin (CTX), known to stimulate adenylate cyclase (AC). CTX caused relaxation of the LES smooth muscle by its action directly at the smooth muscle cells. The convergence of the common mechanisms of actions of VIP and CTX on AC was determined by the suppression of their effects by the AC inhibitor and CTX desensitization. ZnPP IX caused attenuation of the LES smooth muscle relaxation by VIP but not by CTX. ZnPP IX but not zinc deuteroporphyrin IX caused significant inhibition of VIP binding to the membrane receptor. We conclude that ZnPP IX attenuates VIP-induced LES smooth muscle relaxation by inhibition of VIP binding to G protein-coupled receptors linked to AC at a point proximal to G protein activation.
Rattan
S
S
Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Fan
Y P
YP
Chakder
S
S
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D003905:Deuteroporphyrins / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004943:Esophagogastric Junction / Q000187:drug effects*; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009893:Opossums; D011524:Protoporphyrins / Q000494:pharmacology*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D011524:Protoporphyrins; D018005:Receptors, Vasoactive Intestinal Peptide; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); C017803:zinc protoporphyrin; D014660:Vasoactive Intestinal Peptide; D002772:Cholera Toxin; D006419:Heme Oxygenase (Decyclizing)