Beta-adrenoceptor stimulation exacerbates detrimental effects of ischemia and reperfusion in isolated guinea pig ventricular myocytes.
We investigated whether beta-adrenoceptor stimulation exacerbates detrimental effects of ischemia and reperfusion on electrical and contractile function and on intracellular Ca(2+) homeostasis in isolated guinea pig ventricular myocytes. Myocytes were exposed to 20 min of simulated ischemia (37 degrees C) in the absence or presence of isoproterenol (10 nM, applied prior to and during ischemia) and reperfused with Tyrode's solution for 30 min. Unloaded cell shortening, Ca(2+) transients (fura-2), and cell viability were recorded at 5 min intervals in field-stimulated cells (2 Hz). In experiments using microelectrodes, membrane potentials, contractions, and transmembrane currents also were recorded at 5 min intervals. In the absence of ischemia, 10 nM isoproterenol had little effect on either contractile function or Ca(2+) homeostasis. In contrast, when cells were exposed to ischemia, isoproterenol increased the size of contractions and Ca(2+) transients and augmented the increase in diastolic Ca(2+) concentration during ischemia in field-stimulated myocytes. Exposure to isoproterenol also promoted contractile depression in reperfusion. In voltage clamp experiments, isoproterenol abolished the decrease in the magnitude of L-type Ca(2+) current caused by ischemia. Isoproterenol also increased the incidence of abnormal contractile activity and induced delayed afterdepolarizations and the arrhythmogenic transient inward current in ischemia. Additionally, the decline in cell viability in ischemia and reperfusion was exacerbated by isoproterenol. This study shows that beta-adrenoceptor stimulation strongly potentiates adverse effects of ischemia and reperfusion on electrical and contractile function. These adverse effects of isoproterenol are likely caused by an increase in intracellular Ca(2+) accumulation during ischemia.
Ross
Jenna L
JL
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Howlett
Susan E
SE
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D006706:Homeostasis / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D002118:Calcium