Preischemic infusion of alpha-human atrial natriuretic peptide elicits myoprotective effects against ischemia reperfusion in isolated rat hearts.
Carperitide, a synthetic alpha-human atrial natriuretic peptide (ANP) is a newly developed drug for the treatment of heart failure. However, effects of carperitide on susceptibility to ischemia reperfusion injury are left to be determined. Isolated rat hearts were subjected to Langendorff perfusion. Six hearts received 0.1 microM of carperitide for 10 min, 6 hearts received 1 mM of a NO synthetase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min before the infusion of carperitide, 6 hearts received 0.02 microM of a PKC synthetase inhibitor chelerythrine chloride for 5 min before the infusion of carperitide, 6 hearts received 100 microM of a selective mitochondrial ATP-sensitive potassium (KATP) channel blocker 5-dehydroxydecanoate (5HD) before the infusion of carperitide, 6 hearts received 10 microM of a soluble guanylate cyclase inhibitor methylene blue for 5 min before the infusion of carperitide, and 6 hearts served as a control with no drug infusion. All hearts were then subjected to 20 min of global ischemia followed by 120 min of reperfusion. Left ventricular pressures and coronary flow were measured throughout the experiment and infarct size was detected at the end of experiment. Both plasma and tissue cGMP levels were also determined. The results showed: (1) Carperitide significantly reduced infarct size compared to control (26.1 +/- 2.8 vs. 42.7 +/- 2.3%, carperitide vs. control, p < 0.05). This effect was reversed by L-NAME, chelerythrine and 5HD, but not methylene blue. (2) Plasma cGMP levels were increased in carperitide-treated group. This effect was reversed by L-NAME (0.16 +/- 0.03 vs. 1.04 +/- 0.09* vs. 0.28 +/- 0.02 nmol/L, control vs. carperitide vs. L-NAME, *p < 0.01 vs. control). We conclude that preischemic infusion of carperitide exerts cardioprotective effects possibly through NO-PKC dependent pathway followed by mitochondrial KATP channel activation.
Okawa
Hirohisa
H
Department of Thoracic and Cardiovascular Surgery, Osaka Medical College, DAigakucho, Takatsuki, Japan.
Horimoto
Hitoshi
H
Mieno
Shigetoshi
S
Nomura
Yukiya
Y
Yoshida
Masataka
M
Shinjiro
Sasaki
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism* / Q000494:pharmacology; D053119:Benzophenanthridines; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007511:Ischemia; D019157:Ischemic Preconditioning, Myocardial; D008751:Methylene Blue / Q000494:pharmacology; D017202:Myocardial Ischemia; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015424:Reperfusion; D013997:Time Factors; D014018:Tissue Distribution
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; C472955:NPPA protein, human; D010617:Phenanthridines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D000255:Adenosine Triphosphate; C016299:chelerythrine; D011493:Protein Kinase C; D006152:Cyclic GMP; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester