Steroids protect the beta-adrenergic system during reperfusion after ischemia: effects of methylprednisolone on the beta-adrenergic response system.
Methylprednisolone sodium succinate (MPSS) administered during reperfusion may improve myocardial function. These effects have been related to adrenergic stimulation. The present study investigated (1) the effects of ischemia and reperfusion on the beta-adrenergic response system and (2) the ability of MPSS to modify the ischemic effects on the beta-adrenergic system. Isolated perfused rat hearts were used. The ischemic protocol consisted of aerobic perfusion (20 minutes) followed by total, global normothermic (37 degrees C) ischemia (30 minutes) and reperfusion (30 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). The non-ischemic protocol consisted of aerobic perfusion (20 minutes) followed by aerobic perfusion (20 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). At the end of the experiments all hearts were rapidly frozen in liquid nitrogen. Crude sarcolemmal membranes were prepared and stimulated at the beta-receptor, at the coupling (G.- or N-) protein, or directly at the adenylate cyclase enzyme (AC). Results were assessed by cyclic adenosine monophosphate (cAMP) production. Tissue specimens were analyzed for myocardial content of cAMP and methylprednisolone (MP). In the ischemic protocol, the responsiveness of the beta-adrenergic system was significantly reduced at the G.-protein level. The treatment with MPSS (100 or 500 mg/L) during reperfusion preserved the beta-adrenergic response. MPSS (1,000 mg/L) offered no protection. In the non-ischemic protocol, MPSS reduced the response of the beta-adrenergic system in a dose-dependent manner at the same level. The hearts in the ischemic protocol had significantly higher contents of MP than the hearts in the non-ischemic protocol at corresponding concentrations of MPSS. The present study suggests that postischemic cardiac failure may result in part from beta-adrenergic dysfunction. This loss of function, probably at the level of the protein connecting the receptor and AC, can successfully be prevented by an optimal dose of MPSS during reperfusion after ischemia.
Sellevold
O F
OF
Department of Anesthesiology and Pharmacology and Toxicology, Faculty of Medicine, University of Trondheim, Norway.
Holten
T
T
Gordeladze
J O
JO
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000032:analysis; D008297:Male; D008775:Methylprednisolone / Q000493:pharmacokinetics; D008776:Methylprednisolone Hemisuccinate / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D011943:Receptors, Adrenergic, beta; D008776:Methylprednisolone Hemisuccinate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008775:Methylprednisolone