Pretreatment with ramiprilat induces cardioprotection against free radical injury in guinea-pig isolated heart: involvement of bradykinin, protein kinase C and prostaglandins.
1. Pretreatment with ramiprilat, an angiotensin-converting enzyme (ACE) inhibitor, induced cardioprotection and its possible mechanism of action was investigated in guinea-pig Langendorff perfused heart. 2. Superoxide anion (*O2-), produced by hypoxanthine and xanthine oxidase, and the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical were used for triggering free radical injury in cardiac tissue. 3. 1,1-Diphenyl-2-picryl-hydrazyl and *O2- significantly reduced left ventricular developed pressure (LVDP), +/-dP/dt(max), heart rate and coronary flow. Left ventricular end-diastolic pressure (LVEDP) was elevated and lactate dehydrogenase (LDH) leakage and the formation of thiobarbituric acid-reactive substances (TBARS) formation were significantly increased. 4. Pretreatment with ramiprilat induced cardioprotection against DPPH and *O2- free radical injury. Cardiac functions (LVDP, LVEDP and +/-dP/dt(max)) were significantly improved. Both LDH and TBARS were reduced. 5. HOE 140 (a selective bradykinin B2 receptor antagonist), calphostin C (a protein kinase C (PKC) inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) all abolished the cardiac protective effect of ramiprilat. However, N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, had no effect. 6. In conclusion, ramiprilat pretreatment induces cardioprotection against either DPPH or *O2- free radical injury. The protective effect depends on activation of B2 receptors and PKC. Prostaglandin synthesis is also involved.
Jin
Z Q
ZQ
Department of Pharmacology, Hunan Medical University, Changsha, PR China. zqjin@public.cs.hn.cn
Chen
X
X
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015764:Bepridil / Q000031:analogs & derivatives / Q000494:pharmacology; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002317:Cardiovascular Agents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003971:Diastole; D005609:Free Radicals / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010851:Picrates; D011453:Prostaglandins / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D018002:Receptors, Bradykinin / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D002317:Cardiovascular Agents; D016861:Cyclooxygenase Inhibitors; D005609:Free Radicals; D009281:Naphthalenes; D010851:Picrates; D011453:Prostaglandins; D018002:Receptors, Bradykinin; D017392:Thiobarbituric Acid Reactive Substances; C052549:ramiprilat; D015764:Bepridil; C065679:icatibant; C004931:1,1-diphenyl-2-picrylhydrazyl; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; C058819:calphostin C; D017257:Ramipril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin