Effects of a hydroxylated metabolite of the β ‐adrenoreceptor antagonist, carvedilol, on post‐ischaemic splanchnic tissue injury

Reactive oxygen species have been demonstrated to play a critical role in post‐ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new β‐adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)‐induced shock and tissue injury. Administration of SB 211475 two min before R attenuated SI/R injury in a dose‐dependent manner. At doses of 0.5 mg kg −1 and 1.0 mg kg −1 , SB 211475 exerted significant anti‐shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium‐dependent vasorelaxation. Administration of 1 mg kg −1 carvedilol attenuated shock‐induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg −1 carvedilol had no protective effects on post‐ischaemic tissue injury. Previous studies have shown that SB 211475 has virtually no β‐blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post‐ischaemia tissue injury.British Journal of Pharmacology (1998) 123 , 292–298; doi: 10.1038/sj.bjp.0701598