Propranolol regulates cardiac transient outward potassium channel in rat myocardium via cAMP/PKA after short-term but not after long-term ischemia.
It was recently suggested that the antiarrhythmic effect of propranolol, a ss-adrenoceptor antagonist, on ischemic myocardium includes restoration of I(K1) current and Cx43 conductance; however, little is known whether effects on the transient outward current I(to) contribute. A model of myocardial infarction (MI) by ligating the left anterior descending coronary artery was established. Propranolol was given 1 h or daily for 3 months, whole-cell patch-clamp techniques were used to measure I(to). Kv4.2 and PKA levels were analyzed by Western blot and cAMP level was determined by radioimmunoassay. The results showed that propranolol decreased the incidence of arrhythmias induced by acute ischemia and mortality in 3 month MI rats. Propranolol restored the diminished I(to) density and Kv4.2 protein in MI hearts. In addition, neonatal cardiomyocyte pretreatment with propranolol or administrated after hypoxia can resume I(to) density. cAMP/PKA was enhanced in acute MI, the reason of decreased Kv4.2 expression. Treatment with propranolol prevented the increased cAMP/PKA in 1 h MI, whereas propranolol had little effect on decreased cAMP/PKA in 3 months MI. This study demonstrated that both short- and long-term propranolol administrations protect cardiomyocytes against arrhythmias and mortality caused by cardiac ischemia; the involvement of cAMP/PKA signal pathway in the regulation of propranolol on I(to) acted differently along with the ischemic progression.
Zhang
Li
L
Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
Xu
Chao-Qian
CQ
Hong
Yuan
Y
Zhang
Jia-Lin
JL
Liu
Ying
Y
Zhao
Mei
M
Cao
Yan-Xiu
YX
Lu
Yan-Jie
YJ
Yang
Bao-Feng
BF
Shan
Hong-Li
HL
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051672:Shal Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D051672:Shal Potassium Channels; D011433:Propranolol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases