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1 The pharmacological and biochemical effects of a novel cardiotonic agent, Org1O325 have been studied in isolated cardiac and vascular tissue preparations. 2 OrglO325 produced concentration-dependent (0.15-4.8mM) positive inotropic, positive chronotropic and vascular relaxant responses in rabbit isolated papillary, atrial and aortic preparations, respectively. The maximal chronotropic effect (45%) was significantly less than the isoprenaline maximum. The inotropic effects of OrglO325 were not modified by a-or,-adrenoceptor blockade or by pretreatment with reserpine. Org10325 was at least 23 times more potent at relaxing aortic strips pre-contracted with phenylephrine than with KCI. 3 Org1O325 (74pM) potentiated (10-14 fold) the positive inotropic effects of isoprenaline in rabbit isolated papillary muscles. Carbachol inhibited the positive inotropic effect of Org10325. Both the positive inotropic and vasorelaxant effects of OrglO325 were accompanied by increases in cyclic AMP but not cyclic GMP. 4 In rat perfused heart preparation OrglO325 increased phosphorylase a, cyclic AMP-dependent protein kinase activities and stimulated phosphorylation of contractile proteins (troponin-I and C-protein). 5 OrglO325 selectively inhibited the cyclic AMP hydrolytic activity of cyclic AMP high affinity cyclic nucleotide phosphodiesterase (PDE) isoenzymes, PDE III (IC50 65/Mm) and PDE IV (IC50 71 pM), from rabbit cardiac ventricle. Weak inhibition (IC50 > 250pUM) of PDE I and PDE II was observed.6 The results show that the cardiac and vascular effects of Org1O325 are mediated by an increase in cellular cyclic AMP due to inhibition of PDE III and PDE IV activities. However, in contrast to other PDE-inhibitors OrglO325 produced a marked increase in relaxation time of isolated papillary muscle suggesting the involvement of additional cyclic AMP-independent mechanisms of action.

The potential antiarrhythmic and electrophysiological actions of drugs known to inhibit calmodulin, i.e. trifluoperazine (TFP) and N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalene sulphonamide (W7) have been compared with bepridil, whose antiarrhythmic actions have previously been ascribed to blockade of the fast inward sodium current in cardiac tissue. Like bepridil, both TFP and W7 reduced the severity of arrhythmias evoked by 30 min of coronary artery occlusion in tha anaesthetized rat. TFP (2.5–10 mg kg−1, i.v.), W7 (2.5–10 mg kg−1, i.v.) and bepridil (1–5 mg kg−1, i.v.) also antagonized the development of ventricular fibrillation induced by 5 min of occlusion followed by reperfusion. All three drugs also reduced mortality. TFP and bepridil also reduced the incidence of reperfusion‐induced ventricular tachycardia whilst all 3 drugs reduced its duration. Although TFP was shown to possess α‐adrenoceptor blocking properties, the classical α‐blocker, phentolamine, failed to reduce significantly the incidence or severity of reperfusion arrhythmias. In contrast to bepridil (2–20 μM), which markedly reduced the maximum rate of depolarization (Vmax) of guinea‐pig isolated papillary muscle, W7 (5–50 μM) showed only weak effects on Vmax and was at least 10 times less potent than bepridil whilst TFP only reduced Vmax in high concentrations (40–100 μM) which lowered resting membrane potential. Unlike bepridil, neither TFP (4–40 μM) nor W7 prolonged the absolute refractory period. The results suggest that drugs which inhibit calmodulin confer protection against both ischaemia ‐ and reperfusion‐induced arrhythmias in the rat. Although the electrophysiological actions of bepridil would adequately account for its antiarrhythmic activity, the same cannot be said of W7 and especially TFP. In conclusion, calmodulin antagonism may constitute a mechanism of antiarrhythmic activity.

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