Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.13.12.5 (aequorin)
 1,451 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In isolated canine ventricular trabeculae and papillary muscles driven electrically at 0.5 Hz at 37 degrees C, the positive inotropic effects of milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and forskolin were all associated with simultaneous elevations in tissue cyclic AMP levels. After the administration of sulmazole (AR-L 115 BS), the increase in force preceded that of cyclic AMP levels. Bay k 8644 increased the force of isometric contractions without producing any change in cyclic AMP levels. None of these agents affected the cyclic GMP level. Intracellular calcium transients were determined in similar preparations in which multiple superficial cells had been microinjected with the Ca++-sensitive bioluminescent protein aequorin. The aequorin signals increased in parallel with increases in force in response to cumulative administration of milrinone, amrinone, MDL 17,043, OPC-8212, forskolin, and low concentrations of sulmazole (less than or equal to 3 X 10(-4) M). Forskolin and sulmazole produced larger increases in the amplitude of the calcium transients than the other agents, and their inotropic effects were less variable in magnitude. High concentrations (greater than 3 X 10(-4)M) of sulmazole decreased the amplitude of the calcium transients while increasing further the force. The increases in cyclic AMP levels, calcium transients, and force produced by all of the inotropic agents except Bay k 8644 and high concentrations of sulmazole were effectively antagonized by carbachol. These results indicate that the accumulation of cyclic AMP resulting from the inhibition of cyclic AMP phosphodiesterase plays an important role in the action of new positive inotropic agents, milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and sulmazole (less than or equal to 3 X 10(-4)M), on dog ventricular muscle.
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PMID:Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. 241 45

We investigated the mechanisms of the effects of a newly synthesized cyclic AMP phosphodiesterase inhibitor (PDEI: 1,5-dihydro-7-(1-piperidinyl)imidazo[2,1-beta]quinazolin- 2(3H)-one dihydrochloride hydrate, DN-9693) on intracellular Ca2+ transients and tension in ferret papillary muscles. We used the aequorin method to measure Ca2+ transients in intact preparations. DN-9693 (1-100 microM) increased the peaks of both Ca2+ transients and tension. The potentiation of Ca2+ transients by DN-9693 was significant at lower concentrations (1-10 microM) but not at higher concentrations (50 and 100 microM). The peak of tension was significantly increased when the concentration of DN-9693 was increased (1-100 microM). In addition, the time to peak light was shortened at lower concentrations (1 and 5 microM). Other parameters of Ca2+ transients were not significantly altered. The time course of tension was not affected by DN-9693. In Triton X-100-treated skinned preparations, DN-9693 decreased the Ca2+ concentration required for half-maximal activation of the pCa-tension relation. These results suggest that the positive inotropic effect of DN-9693 is attributable to the alteration in Ca2+ handling of sarcoplasmic reticulum (SR) and Ca2+ sensitization of the myofilaments.
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PMID:Effects of a new inotropic drug (DN-9693) on Ca2+ transients and contraction in ferret ventricular muscles. 747 47

We studied the effects of a novel cardiotonic agent OPC-18790 [(+-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)- quinolinone] on isometric contractions, intracellular aequorin light transients, and cyclic AMP levels in isolated dog ventricular trabeculae. The positive inotropic effect (PIE) of OPC-18790 (1-30 microM) was consistently associated with an abbreviation of contractions and an increase in the amplitude of aequorin light transients. The maximum responses of Ca2+ transients and force to OPC-18790 were approximately 40% of the isoproterenol-induced maximum. Carbachol (3 microM) markedly attenuated the increases in force, light transients, and cyclic AMP accumulation induced by OPC-18790. These results indicate that OPC-18790 is a cardiotonic agent with moderate effectiveness, and that the PIE of OPC-18790 may be produced mainly by an increase in intracellular Ca2+ transients induced by cyclic AMP accumulation. For a given increase in amplitude of Ca2+ transients, OPC-18790 produced a more pronounced increase in force of contraction (FOC) than did isoproterenol, suggesting that OPC-18790 does not produce as great a decrease in Ca2+ sensitivity of contractile proteins as does isoproterenol. These observations indicate that among cardiotonic agents acting through cyclic AMP pathway, regulation of contractility produced by the selective cyclic AMP phosphodiesterase III (PDE-III) inhibitor OPC-18790 is qualitatively different from the regulation induced by isoproterenol that acts on cyclic AMP generation in intact myocardial cells.
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PMID:Effects of a novel cardiotonic agent (+-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolino ne (OPC-18790) on contractile force, cyclic AMP level, and aequorin light transients in dog ventricular myocardium. 752 54

Experiments were carried out to investigate the changes in intracellular Ca2+ transients associated with biphasic contractions that were elicited during interaction of theophylline with isoproterenol in the dog ventricular myocardium. For this purpose, effects of theophylline and isoproterenol on aequorin light transients and isometric contractions were assessed in the isolated canine ventricular trabeculae, superficial cells of which had been microinjected with the Ca2+ sensitive bioluminescent protein aequorin. The positive inotropic effect of theophylline (0.1-0.3 mM) was consistently associated with an increase in the amplitude of aequorin light transients. Theophylline at concentrations of 0.6 mM and higher decreased the amplitude of aequorin light transients, but the force of contraction increased further in association with a prominent prolongation of time to peak force. Theophylline (0.3 mM) enhanced the forskolin-induced increase in aequorin light transients and force. Theophylline (2 mM) inhibited the isoproterenol-induced increase in aequorin light transients associated with early phase of contraction in a reversible manner. A late phase of aequorin light transients was induced in association with late phase of contraction in the presence of both isoproterenol and theophylline. Thus, both the early and late phase of contraction were accompanied by corresponding phases of aequorin light transients. The relation between the amplitude of force and Ca2+ transients was markedly different and the late phase of contraction was associated with much lower aequorin light transients. The late phase of aequorin light transients induced by theophylline at a high concentration (10 mM) was enhanced by isoproterenol. These results indicate that theophylline (0.1-0.3 mM) increases the amplitude of Ca2+ transients through an accumulation of cyclic AMP by inhibition of the cyclic AMP phosphodiesterase activity. In concentrations of 0.6 mM and higher theophylline decreases the amplitude of the early phase aequorin light transients probably by inhibition of release of Ca2+ from the sarcoplasmic reticulum and induces simultaneously the late phase of contraction that may be associated with an increase in responsiveness to Ca2+ of myofibrils.
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PMID:The effects of theophylline on aequorin light transients and force in the isolated dog right ventricular myocardium. 819 72