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CARDIOVASCULAR

The Aminotetraline Derivative (±)-(R,S)-5,6-Dihydroxy-2-methylamino-1,2,3,4-tetrahydro-naphthalene Hydrochloride (CHF-1024) Displays Cardioprotection in Postischemic Ventricular Dysfunction of the Rat Heart

Department of Pharmacological Sciences, University of Milan, Milan, Italy (G.R.); Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy (G.R., B.M., F.B.); Department of Cardiology, Istituto di Ricovero e Cura a Carattere Scientifico, Centro Cardiologico "I. Monzino" Foundation, University of Milan, Milan, Italy (V.C., G.L.P.); and Department of Pharmacology, Chiesi Farmaceutici, Parma, Italy (R.R., S.B.)

To analyze the protective effects of the aminotetraline derivative (±)-(R,S)-5,6-dihydroxy-2-methylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride (CHF-1024), a compound endowed with DA₂-dopaminergic/₂-adrenergic receptor agonistic activity, in myocardial ischemia/reperfusion damage. A model of isolated and perfused (15 ml/min) electrically driven (300 beats/min) rat heart subjected to global ischemia (1 ml/min for 20 min) and reperfusion (15 ml/min for 30 min) was followed. Cardiac mechanics changes were evaluated together with biochemical markers of cardiac ischemia in perfusate and tissue tumor necrosis factor- (TNF-). CHF-1024, perfused through the heart for 15 min before ischemia at different molar concentrations (1-100 nM), significantly improved left ventricle developed pressure during reperfusion, and normalized left ventricular end-diastolic pressure and coronary perfusion pressure. This anti-ischemic effect of CHF-1024 was associated to a decrease in creatine kinase and lactate dehydrogenase, both released during heart reperfusion. These events were concomitant with maintenance of a higher production of 6-keto-prostaglandin F₁ The ability of CHF-1024 to improve postischemic ventricular dysfunction was correlated with a dose-dependent inhibition of the release of both norepinephrine (NE), from sympathetic nerve endings, and TNF- from cardiac tissue. The effect of CHF-1024 on NE release was almost completely antagonized by specific antagonists of presynaptic inhibitory receptors domperidone and rauwolscine. The finding that this new aminotetraline derivative possesses anti-ischemic properties and limits NE release from cardiac nerve endings may bear some therapeutic potential in cardiovascular diseases.

Address correspondence to: Dr. Giuseppe Rossoni, Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. E-mail: giuseppe.rossoni{at}unimi.it