The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.

1 Purine compounds such as ATP and adenosine, respectively endothelium-dependent and -independent vasodilators, are largely involved in the control of vascular tone and vascular reactivity to contracting stimuli. We investigated the relaxing activity of ATP and adenosine in guinea-pig aorta rings exposed for 6 h to elevated glucose concentration (50 mM), in order to mimic hyperglycaemic conditions. Guinea-pigs were reserpine-treated (2 mg kg 71 , i.p., 48 and 24 h before death). 2 Rings of aortae incubated in 50 mM glucose, contracted submaximally by 1 mM noradrenaline, lost endothelium-dependent relaxation in response to acetylcholine (10 nM to 10 mM). Aortae incubated with 50 mM mannose, as a hyperosmotic control, relaxed to acetylcholine normally. Rings of aortae incubated in 50 mM glucose, contracted submaximally by 3 mM 4-aminopyridine, lost endothelium-dependent relaxation in response to ATP (30 mM) whereas endothelium-independent relaxation in response to adenosine (0.3 mM) was well preserved. 4 The relaxation induced by A23187 or sodium nitroprusside (10 nM to 0.1 mM) did not di er between rings exposed to control (5.5 mM) or elevated glucose (50 mM) and contracted submaximally by 3 mM 4-aminopyridine. 5 When incubated with aortic tissue in the presence of elevated glucose, the cyclo-oxygenase inhibitors, indomethacin (10 mM) and mefenamic acid (30 mM), or the scavenger of superoxide anions, superoxide dismutase (150 u ml 71 ), prevented the impairment of ATP-mediated relaxation. 6 The present results indicate that endothelium-dependent, receptor-induced relaxation in response to acetylcholine and ATP is impaired in guinea-pig aorta rings exposed to elevated glucose. The endothelial dysfunction caused by glucose might be located at a step between receptor activation and intracellular calcium increase, and might be related to an increased metabolism of arachidonic acid coupled to an increased production, or to a reduced inactivation of superoxide anions.

Two alkaloids 1 and 2 were isolated from the seeds of Erythrophleum lasianthum. Their structures were assigned by spectroscopic and chemical means as 3 beta-hydroxynorerythrosuamine (1) and its 3-O-beta-D-glucopyranoside (2). In spontaneously beating atria, both compounds 1 and 2 showed a marked and concentration-dependent positive inotropic activity and a weak negative chronotropic activity. The positive inotropic effect induced by 1 and 2 was not modified by propranolol, prazosin, carbachol, and ranitidine plus pyrilamine. Both 1 and 2 were very active in inhibiting the Na+/K(+)-ATPase isolated from bovine cardiac sarcolemmal vesicles.

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1. In spontaneously beating atria isolated from reserpine-treated guinea-pig adenosine, AMP, ADP, ATP (2 microM) and alpha, beta-methylene ATP (0.4 microM) induced a dual effect: a short lasting negative response, characterized by a reduction in contractile force and in frequency rate, followed by a positive phase of increased inotropism and chronotropism. N6-phenylisopropyladenosine (5 nM) induced only the depressant effects whereas inosine (2 microM) was completely inactive. 2. The early, negative influences were antagonized by 8-phenyltheophylline (0.5-10 microM), an alkylxanthine that competes with purines for P1 receptors. 3. The late, positive response was potentiated by 8-phenyltheophylline (0.5-10 microM) and suppressed by quinidine (5 microM), that blocks the effects of adenine compounds mediated by P2 receptors. 4. In spontaneously beating as well as in electrically driven atria, desensitization of P2 purinoceptors by long lasting exposure to alpha, beta-methylene ATP (8 microM) abolished the late positive response to ATP. In preparations treated with both alpha, beta-methylene ATP and 8-phenyltheophylline, ATP was ineffective. 5. These results suggest that, besides P1 receptors, P2 receptors are also present in guinea-pig atria, mediating stimulatory effects of adenine compounds.