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Combined phosphodiesterase inhibition and ß-blockade in the GI104313, decreases ischemia-induced arrhythmias in the rat

M.D. Carceles^*, F. Aleixandre^*, T. Fuente, J. López-Vidal^* and M.L. Laorden

From the Department of Physiology and Pharmacology,
^* Unit of Pharmacology, University School of Medicine, the Departments Of Anaesthesiology and
Nuclear Medicine, Csv Arrixaca Hospital, Murcia Spain.

Address correspondence to: Dr. M.L. Laorden, Departamento de Farmaocología, Facultad de Medicina, 30100 Murcia, España. Phone: 34-968-367155; Fax: 34-968-364150; E-mail: laorden{at}um.es

Purpose: The purpose of the present study was to evaluate the effects of GI104313, a chimeric molecule containing a phosphodiesterase inhibiting pyradazinone and a blocking phenoxpropanolamine, on ischemia-induced arrhythmias in anesthetized rats.

Method: The coronary artery was occluded 15 min after commencing drug administration and myocardial ischemia was maintained for 30 min during which the heart rate and mean blood pressure were recorded. Cyclic AMP and GMP were determined by radio-immunoassay.

Results: GI104313 (0.1 µmol•kg^-1 plus 0.01 µmol•kg^-1•min^–1 or 1 µmol•kg^-1 plus 0.1 µmol•kg^-1•min^–1) decreased the incidence of ventricular tachycardia (86% and 75%), ventricular fibrillation (28%, P <0.01 and 12%, P <0.001) and premature ventricular beats (164 ± 27.0 and 114 ± 28.5, P <0.05) following coronary artery ligation, resulting in a decrease in mortality (29% and 12%, P <0.05).

Changes in cyclic nucleotide concentrations have been implicated in the genesis of ischemia-induced arrhythmias. However, in the present study GI104313 did not change the concentrations of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) (1.0 ± 0.07 pmol•mg^–1, 1.0 ± 0.05 pmol•mg^–1) or guanosine 3' : 5'-cyclic monophosphate (cyclic GMP) (0.025 ± 0.008 pmol•mg^–1 protein, 0.017 ± 0.004 pmol•mg^–1 protein) in the left ventricle during ischemia-induced arrhythmias in anesthetized rats compared to saline (0.9 ± 0.1 pmol•mg^–1 and 0.013 ± 0.002 pmol•mg^–1, respectively).

Conclusion: Our results demonstrate that, in rats, GI104313 induced a decrease in both incidence of arrhythmias and mortality which was not associated with changes in ventricular cyclic nucleotide content.

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