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Propranolol regulates cardiac transient outward potassium channel in rat myocardium via cAMP/PKA after short-term but not after long-term ischemia

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Abstract

It was recently suggested that the antiarrhythmic effect of propranolol, a ß-adrenoceptor antagonist, on ischemic myocardium includes restoration of IK1 current and Cx43 conductance; however, little is known whether effects on the transient outward current Ito 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 Ito. 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 Ito density and Kv4.2 protein in MI hearts. In addition, neonatal cardiomyocyte pretreatment with propranolol or administrated after hypoxia can resume Ito 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 Ito acted differently along with the ischemic progression.

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Abbreviations

cAMP:

cyclic adenosine monophosphate

PKA:

cAMP-dependent protein kinase A

MI:

myocardial infarction

Ito :

transient outward K+ current

APD:

action potential duration

LAD:

left anterior descending coronary arteries

EADs:

early after-depolarizations

GAPDH:

glyceraldehyde phosphate dehydrogenase

HEPES:

hydroxyethyl piperazine ethanesulfonic acid

EGTA:

egtazic acid

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Acknowledgements

This work was supported partially by National Basic Research Program of China (973 Program) 2007CB512000 (2007CB512006) to B.Y., the Science Foundation of Ministry of Education of China (207031), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars of Heilongjiang Province of China (LC07C10) to H.S.

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Authors and Affiliations

  1. Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China

    Li Zhang, Chao-Qian Xu, Yuan Hong, Jia-Lin Zhang, Ying Liu, Mei Zhao, Yan-Xiu Cao, Yan-Jie Lu, Bao-Feng Yang & Hong-Li Shan

  2. Cardiovascular Research Institute, Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China

    Yan-Jie Lu, Bao-Feng Yang & Hong-Li Shan

  3. Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China

    Hong-Li Shan

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  1. Li Zhang
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Corresponding author

Correspondence to Hong-Li Shan.

Additional information

The authors Li Zhang and Chao-Qian Xu made equal contributions to this study.

This work was partially supported by National Basic Research Program of China (973 Program) 2007CB512000 (2007CB512006) to B.Y., the Science Foundation of Ministry of Education of China (207031), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars of Heilongjiang Province of China (LC07C10) to H.S.

All authors have no conflicts of interest concerning the work.

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Zhang, L., Xu, CQ., Hong, Y. et al. Propranolol regulates cardiac transient outward potassium channel in rat myocardium via cAMP/PKA after short-term but not after long-term ischemia. Naunyn-Schmied Arch Pharmacol 382, 63–71 (2010). https://doi.org/10.1007/s00210-010-0520-y

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