Protection of endothelial damage and systemic shock by benidipine, a calcium antagonist, in rats subjected to splanchnic ischemia and reperfusion.
Splanchnic artery occlusion (SAO) with subsequent reperfusion elicits a severe form of circulatory shock. To study the possible involvement of Ca2+ overload in this shock state, we have examined the effects of benidipine, a novel long-acting calcium antagonist, in a rat model of SAO shock, focusing on endothelial damage. Pentobarbital-anesthetized rats were subjected to 90-min occlusion of both the celiac and superior mesenteric arteries, followed by reperfusion. Rats given only the vehicle for benidipine developed hypotension following reperfusion, and only 7 of 16 rats (44%) survived 2 hr of reperfusion. In isolated superior mesenteric rings from SAO-shock rats, the EDRF-dependent dilator response to acetylcholine (ACh) (100 mM) was severely depressed (9% vs. 97% in control artery rings, P less than 0.001), whereas the EDRF-independent dilator response to acidified NaNO2 (100 microM) was unchanged. By contrast, 90% (9 of 10, P less than 0.05) rats treated with benidipine 45 min postocclusion (3 micrograms/kg, i.v.) survived 2 hr, and the dilator response to ACh was markedly improved (49% of initial, P less than 0.001). SAO-shock rats treated with benidipine also exhibited significantly attenuated accumulation of free amino-nitrogenous compounds (5.5 vs. 7.9 U/ml, P less than 0.05) and myocardial depressant factor (34 vs. 62 U/ml, P less than 0.001). These results suggest that endothelial damage plays a role in the pathogenesis of shock following bowel ischemia and reperfusion and that Ca(2+)-entry blockade improves endothelial function, which is involved in the amelioration of the shock state.
Karasawa
A
A
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Rochester
J A
JA
Ma
X L
XL
Lefer
A M
AM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002445:Celiac Artery; D003250:Constriction; D004095:Dihydropyridines / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D007511:Ischemia / Q000150:complications*; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries; D009201:Myocardial Depressant Factor / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D012769:Shock / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009201:Myocardial Depressant Factor; C061004:benidipine; D000109:Acetylcholine