Coronarotropic properties of cyclic GABA derivative TZ-146

Abstract

In the experiments on isolated contracting, fibrillating, and strophanthin K-arrested cat hearts, TZ-146, cyclic derivative of gamma aminobutyric acid enhanced the outflow of perfusate. When tested in vivo, this preparation increased the indices of phasic coronary blood flow in dogs, surpassing the effects of reactive hyperemia, which characterizes the dilatory capacity of coronary vessels. Pharmacological analysis and experiments with bilateral vagotomy in cats and dogs suggest that coronarotropic effects of TZ-146 can result from activation of adenylate cyclase and accumulation of cAMP.Key Words: GABA; coronary blood flow It has been shown that TZ-146 (cyclic GABA derivative, a structural analog of piracetam) prevents disturbances in both systemic and cardiac hemodynamics by enhancing coronary blood flow volume velocity (VVCF) in ischemized myocardium in vivo [2]. It is of interest, therefore, to study coronodilatory properties of TZ-146 in experiments on isolated hearts, its effect on phase coronary blood flow (CBF), the mechanisms of coronodilatory effects.These investigations were also prompted by the fact that GABA derivatives can interfere with sympathetic extracardiac regulation [4,15]. It is known that changes in the sympathetic tone can cause both direct (true neurogenic) and indirect (mediated via metabolic processes in the myocardium) coronary vasomotor reactions [3]. MATERIALS AND METHODSExperiments were carried out on 57 cats (body weight 2.6-3.5 kg), 20 dogs (15.5-21.5 kg), and 30 isolated cat hearts.The effects of TZ-146 on coronary vessels were studied on contracting, fibrillating, and strophanthin Department of Pharmacology, Kuban' State Medical Academy, Krasnodar K-arrested cat hearts (1:25,000) isolated according to Langendorff's technique [3].The effects of TZ-146 on the phase CBF were studied in dogs. The following indices were analyzed: end-diastolic CBF, diastolic stroke and minute CBF, CBF per beat and per minute, coronary perfusion pressure and end-diastolic resistance; the systolic stroke CBF; systolic perfusion pressure and CBF index of (diastolic to systolic stroke CBF ratio) [8]. Additionally, the following indices were recorded: systemic blood pressure (SBP), reactive 20-sec hyperemia after intravenous or intracoronary drug injection [13], left ventricular pressure, the rate of its changes (dp/dtm~ x and dp/dtmin), and heart rate (HR). Contractile heart function was assessed by shifts in the maximum rate of rise and fall in the left ventricle pressure, by relaxation and Veragut's indices, and the myocardiumdeveloped acceleration [7,14].The coronodilatory effects of TZ-146 were analyzed with pharmacological agents [3,5,6,9,10,12] administered intravenously, intraperitoneally (in cats), and intracoronary (in dogs). The following drugs were used: noncompetitive and competitive GABA A receptor antagonists picrotoxin and bicuculline, (1 mg/kg each. intravenously); muscarinic cholinergic receptor antagonist atropine sulfate (2.5 mg/kg intravenously); ~-adrenoblocker propranolol (Obsidan, ...