G J Grover1, A J Baird, P G Sleph. 1. Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Abstract
OBJECTIVES: An interaction between adenosine A1 receptors and ATP-sensitive potassium channels (KATP) has been hypothesized to mediate preconditioning in several species. Unlike other species tested, KATP blockers and A1 antagonists do not abolish preconditioning in rat hearts. The purpose of this study was to determine if KATP and A1 receptors are pharmacologically linked in rat hearts as they are in other species. METHODS: Isolated rat hearts were given 0.03-1.00 microM R-PIA (adenosine A1 receptor agonist) with or without concomitant 0.3 microM glyburide starting 10 min pre-ischemia. After 25 min global ischemia, the hearts were reperfused for 30 min. Rat hearts were also treated with 1-30 microM cromakalim in the presence of 10 microM DPCPX (adenosine A1 antagonist). RESULTS: R-PIA produced a concentration-dependent bradycardia before ischemia which was blocked by DPCPX. R-PIA increased the time to onset of contracture in a concentration-dependent manner (EC25 = 0.13 microM) and this was unaffected by 0.3 microM glyburide (EC25 = 0.20 microM). This concentration of glyburide completely abolished the protective effects of 10 microM cromakalim. R-PIA also significantly enhanced post-ischemic recovery of function and reduced LDH release, and glyburide did not alter these responses. Cromakalim significantly increased the time to onset of contracture (EC25 = 4.5 microM) and 10 microM DPCPX had no effect on this (EC25 = 5.6 microM). Cromakalim also significantly enhanced post-ischemic recovery of function and reduced LDH release. DPCPX did not alter these cardioprotective effects while glyburide completely abolished the cardioprotective effects of cromakalim. CONCLUSIONS: While both cromakalim and R-PIA are cardioprotective in isolated rat hearts, they are not pharmacologically linked, possibly explaining why preconditioning may be different in this species.
OBJECTIVES: An interaction between adenosine A1 receptors and ATP-sensitive potassium channels (KATP) has been hypothesized to mediate preconditioning in several species. Unlike other species tested, KATP blockers and A1 antagonists do not abolish preconditioning in rat hearts. The purpose of this study was to determine if KATP and A1 receptors are pharmacologically linked in rat hearts as they are in other species. METHODS: Isolated rat hearts were given 0.03-1.00 microM R-PIA (adenosine A1 receptor agonist) with or without concomitant 0.3 microM glyburide starting 10 min pre-ischemia. After 25 min global ischemia, the hearts were reperfused for 30 min. Rat hearts were also treated with 1-30 microM cromakalim in the presence of 10 microM DPCPX (adenosine A1 antagonist). RESULTS:R-PIA produced a concentration-dependent bradycardia before ischemia which was blocked by DPCPX. R-PIA increased the time to onset of contracture in a concentration-dependent manner (EC25 = 0.13 microM) and this was unaffected by 0.3 microM glyburide (EC25 = 0.20 microM). This concentration of glyburide completely abolished the protective effects of 10 microM cromakalim. R-PIA also significantly enhanced post-ischemic recovery of function and reduced LDH release, and glyburide did not alter these responses. Cromakalim significantly increased the time to onset of contracture (EC25 = 4.5 microM) and 10 microM DPCPX had no effect on this (EC25 = 5.6 microM). Cromakalim also significantly enhanced post-ischemic recovery of function and reduced LDH release. DPCPX did not alter these cardioprotective effects while glyburide completely abolished the cardioprotective effects of cromakalim. CONCLUSIONS: While both cromakalim and R-PIA are cardioprotective in isolated rat hearts, they are not pharmacologically linked, possibly explaining why preconditioning may be different in this species.