Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The positive inotropic effects of the bipyridine derivatives amrinone and milrinone and of the benzimidazole compounds sulmazole, pimobendane, and UD-CG 212 Cl are due at least in part to inhibition of cardiac phosphodiesterase activity and hence to an increase in myocardial cyclic AMP (cAMP) content. Compared with the other agents, the contribution of the cAMP system appears to be relatively small in the case of pimobendane and UD-CG 212 Cl. This reduced effect is probably advantageous because an increase in cAMP leads not only to positive inotropic but also to positive chronotropic effects and possibly to arrhythmogenesis. The latter in particular may limit the usefulness of new cardiotonic agents, although--at least theoretically--a cAMP-dependent arrhythmogenic action might be overcome by additional "antiarrhythmic" properties, e.g., prolongation of the action potential, depression of transient depolarizations, or depression of the fast Na+ inward current. Sulmazole and pimobendane have been shown to have an additional effect on the contractile properties in that they increase the sensitivity of the myofibrils to Ca++.
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PMID:Phosphodiesterase-inhibiting properties of newer inotropic agents. 241 48

The new cardiotonic agent 2-[(2-methoxy-4-methylsulfinyl)-phenyl]-1H-imidazo[4,5-b]pyridine (sulmazole, AR-L 115 BS) has marked positive inotropism but causes a depression in the plateau phase of the action potential of cardiac Purkinje fibres. This loss of plateau is known to occur with calcium antagonists which reduce contractility. In order to identify the mechanism underlying this possibly controversal effect the slow (calcium dependent) inward current (isi) was measured using the double microelectrode voltage clamp technique. In this current system, sulmazole was observed to have a slight effect on the inactivation parameter f infinity of isi by shifting it in hyperpolarizing direction. This increase in inactivation was considered when isi was determined. However, isi itself is reduced quite considerably and the linear instantaneous current voltage relationship is shifted to negative potentials. The kinetics of activation (d infinity) are not affected by sulmazole. From the more or less parallel shifts of isi we conclude that the reversal potential of isi is decreased which in turn strongly indicates an increase of intracellular calcium ion concentration. The reduction of isi by sulmazole is not the result of a specific membrane effect as in the case of some calcium antagonists. Sulmazole does not generate its positive inotropism by way of an increased slow inward current as do beta-adrenoceptor agonists but rather reduces the slow inward current by means of a negative shift of Eisi and a decrease in isi-driving force after it has affected intracellular calcium.
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PMID:Effects of the new cardiotonic agent sulmazole on the slow inward current of sheep cardiac Purkinje fibres. 609 28