Carvedilol inhibits activation of stress-activated protein kinase and reduces reperfusion injury in perfused rabbit heart.
Stress-activated protein kinase (SAPK/JNK) has been implicated in the signaling pathway that leads to cell death. Carvedilol, a new vasodilating beta-adrenoceptor antagonist with potent antioxidant activity, has been shown to convey a high degree of cardioprotection in a variety of experimental models of myocardial ischemia as well as in patients with congestive heart failure. The present study was designed to explore whether the cardioprotective effects of carvedilol involve inhibition of SAPK activation. Ex vivo ischemia (30 min)-reperfusion (60-120 min) of the rabbit heart resulted in 67% reduction of pressure-rate product, 45% necrosis of left ventricular tissue and 62% loss of myocardial creatine kinase (P < 0.01 vs. basal). SAPK levels in the perfused hearts increased markedly following reperfusion (5.6-fold increase, P < 0.01 vs. basal). Carvedilol, at 10 microM, administered at time of reperfusion, enhanced recovery of pressure-rate product by 61%, reduced necrotic size by 65% and decreased myocardial creatine kinase loss by 62% (P < 0.01 vs. vehicle). Carvedilol also inhibited reperfusion-induced activation of SAPK by 61% (P<0.01 vs. vehicle). Carvedilol, at 1 microM, displayed a trend of cardioprotection and inhibition of SAPK activation. Our results suggest that SAPK may play a role in ischemia/reperfusion-induced cardiac injury and inhibition of SAPK activation by carvedilol may contribute to its cardioprotective effects.
Yue
T L
TL
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA. tian-li_yue@sbphrd.com
Ma
X L
XL
Gu
J L
JL
Ruffolo
R R
RR
Feuerstein
G Z
GZ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011817:Rabbits
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D011412:Propanolamines; D016755:Proto-Oncogene Proteins c-jun; D000077261:Carvedilol; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases