title: Effect of angiotensin converting enzyme inhibition with quinaprilat on the ischaemic and reperfused myocardium.
abstract: We assessed whether the local inhibition of myocardial converting enzyme by quinaprilat and captopril reduces the functional and metabolic damage caused by ischaemia and reperfusion. Quinaprilat and captopril were either subcutaneously injected (0.3 mg/kg once daily for 5-6 days) in the rabbit before isolation of the heart or delivered to the isolated hearts in the perfusate (10(-6) M) 60 min before ischaemia. Cardiac protection was evaluated in terms of left ventricular pressure recovery during reperfusion, creatine phosphokinase (CPK) release, mitochondrial function, ATP and CP tissue contents, calcium homeostasis and the occurrence of oxidative stress, established by measuring content and release of reduced and oxidized glutathione. Both drugs exerted cardioprotection. Optimal myocardial preservation is achieved when quinaprilat is prophylactically administered to the rabbit. Recovery of developed pressure on reperfusion improved from 11.3 +/- 2.7 (S.E.) to 25.4 +/- 5.4 mmHg, P < 0.01 and the release of CPK was reduced from 665.8 +/- 101.4 to 231.8 +/- 81.4 mU/min/g wet wt, P < 0.01. Peak of noradrenaline release was also attenuated, from 5.253 ng/min/g wet wt to 1.764 ng/min/g wet wt. The accumulation of tissue and mitochondrial calcium was reduced from 52.3 +/- 7.5 and 44.1 +/- 5.6 to 20.5 +/- 3.2 and 27.3 +/- 4.6 nmol/kg dry wt, respectively, P < 0.01. This resulted in significant (P < 0.01) improvement of left ventricular diastolic dysfunction during ischaemia and reperfusion and in a preservation of all indices of mitochondrial function, allowing a higher recovery of ATP and CP after reperfusion (from 4.1 +/- 0.5 and 5.2 +/- 0.5 to 11.1 +/- 1.1 and 24.8 +/- 1.0 mumol/g dry wt, respectively, P < 0.01). Reperfusion-induced myocardial accumulation and release of oxidized glutathione were reduced from 0.301 +/- 0.056 and 0.318 +/- 0.083 to 0.138 +/- 0.025 nmol/mg protein and 0.076 +/- 0.012 nmol/min/g wet wt, respectively, P < 0.01. Similar results were obtained when quinaprilat was administered to the isolated heart. These data suggest that the cardioprotective effect of quinaprilat is independent from haemodynamic changes or direct reduction of toxicity due to oxygen free-radicals but it is likely to be related to a reduction in the release of noradrenaline, maintenance of high energy phosphates and membrane integrity.
authors.affiliation: Fondazione Clinica del Lavoro, Centro di Fisiopatologia Cardiovascolare Salvatore Maugeri, Gussago, Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cargnoni
authors.forename: A
authors.initials: A
authors.lastname: Boraso
authors.forename: C
authors.initials: C
authors.lastname: Scotti
authors.forename: N
authors.initials: N
authors.lastname: Ghirardelli
authors.forename: M
authors.initials: M
authors.lastname: Benigno
authors.forename: P
authors.initials: P
authors.lastname: Bernocchi
authors.forename: P
authors.initials: P
authors.lastname: Pedersini
authors.forename: R
authors.initials: R
authors.lastname: Ferrari
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000627:therapeutic use; D003402:Creatine Kinase / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007546:Isoquinolines / Q000627:therapeutic use*; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010084:Oxidation-Reduction; D010725:Phosphocreatine / Q000378:metabolism; D011817:Rabbits; D044005:Tetrahydroisoquinolines
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D007773:Lactates; D044005:Tetrahydroisoquinolines; D010725:Phosphocreatine; D019344:Lactic Acid; C054501:quinaprilat; D000255:Adenosine Triphosphate; D002216:Captopril; D003402:Creatine Kinase; D002118:Calcium; D009638:Norepinephrine