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Biomedical subjects

Masao Endoh

Publications and source records attributed to Masao Endoh.

26 records · Page 2Linked to original sources
PubMed2003

The therapeutic potential of novel cardiotonic agents.

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as beta-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca(2+) mobilisation (upstream mechanism). These agents are associated with the risk of Ca(2+) overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca(2+) overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca(2+) ions (central and/or downstream mechanisms). Novel Ca(2+) sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca(2+) sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Inhibitory action of the phosphatase inhibitor cantharidin on the endothelin-1-induced and the carbachol-induced negative inotropic effect in the canine ventricular myocardium.

In the canine ventricular myocardium, endothelin-1 and the muscarinic agonist carbachol scarcely affect the basal force of contraction but do induce a pronounced negative inotropic effect in the presence of beta-adrenoceptor agonists. Experiments were performed to examine whether the protein phosphatase inhibitor cantharidin inhibits the negative inotropic effect induced by endothelin-1 and carbachol in isolated canine ventricular trabeculae. In the presence of 100 nM norepinephrine, endothelin-1 (10 nM) and carbachol (30 nM) decreased the norepinephrine-induced positive inotropic effect to about 40% of the norepinephrine-induced maximal response. Cantharidin at 10 microM affected neither the basal force of contraction nor the positive inotropic effect of 100 nM norepinephrine, but it did attenuate markedly the negative inotropic effect of endothelin-1. By contrast, the negative inotropic effect of carbachol was not affected by 10 microM cantharidin. At 30 microM, cantharidin induced a positive inotropic effect and enhanced the positive inotropic effect of norepinephrine by approximately 60%. Cantharidin (30 microM) markedly attenuated the negative inotropic effect of 30 nM carbachol and partially decreased the negative inotropic effect of 100 nM carbachol. The present results indicate that the activation of phosphatase that is susceptible to cantharidin is involved in both the endothelin-1-induced and the carbachol-induced negative inotropic effect. The observation that the negative inotropic effect of endothelin-1 is inhibited by cantharidin at 10 microM and that cantharidin does not affect the negative inotropic effect of carbachol supports the view that the extent of the contribution of phosphatase activation may be higher in the endothelin-1-induced negative inotropic effect than in the carbachol-induced negative inotropic effect.

Animals↗
PubMed2003

[Not Available].

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Journal Article↗
PubMed2002

Effects of OR-1896, a metabolite of levosimendan, on force of contraction and Ca2+ transients under acidotic condition in aequorin-loaded canine ventricular myocardium.

We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the influence of acidosis on the positive inotropic effect (PIE) of OR-1896 (R)- N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic in acidotic conditions (pH(o) 6.6) that was essentially the same as that in control conditions (pH(o) 7.4). The CRC for PIE of OR-1896 reached a plateau at 10(-6) M (first phase) and it became steeper again at 10(-3) M (second phase). Under acidotic conditions the efficacy of the first phase was 10% of the maximal response to isoproterenol (ISO(max)) and the PIE was associated with an increase in Ca(2+) transients of 2% of ISO(max) (P<0.05). The sensitivity of myofilaments to Ca(2+) ions was increased by OR-1896 in acidotic conditions, whereas the relationship of Ca(2+) transients and contractile force during an increase in elevation of the extracellular Ca(2+) concentration and during application of dihydroouabain was shifted prominently to the right in acidotic conditions. In conclusion, OR-1896 elicited a PIE due to an increase in the sensitivity of myofilaments to Ca(2+) ions even in acidotic conditions. The PIE of OR-1896 in acidotic conditions was much less than that in control conditions because the effect of the compound to induce an increase in intracellular Ca(2+) mobilization was markedly attenuated in acidotic conditions.

Acetamides↗
PubMed2002

Angiotensin II increases L-type Ca2+ current in gramicidin D-perforated adult rabbit ventricular myocytes: comparison with conventional patch-clamp method.

The effects of angiotensin II (Ang II) on L-type Ca2+ current (I(Ca,L)) remains controversial. We studied the effects of Ang II on I(Ca,L) in single adult rabbit ventricular myocytes using a perforated patch-clamp technique with gramicidin D. Ang II increased I(Ca,L) in a concentration-dependent manner (EC(50)=0.75 nM). In contrast, in conventional whole-cell patch-calmp, I(Ca,L)ran down gradually and the I(Ca,L) response to Ang II was variable, suggesting the potential loss of diffusible components crucial for the Ang II-induced signaling process. An AT(1) antagonist, CV11974 (0.1 microM), completely inhibited the increase in I(Ca,L) induced by Ang II (0.1 microM), whereas an AT(2) antagonist, PD123319 (10 microM), did not influence the I(Ca,L) increase. Neither pre- nor after-treatment with a Na+/H+ exchange (NHE) inhibitor HOE642 (1 microM) affected the Ang II-induced increase in I(Ca,L). The protein kinase C (PKC) inhibitor chelerythrine (1 microM) did not affect the Ang II-induced I(Ca,L) increase. The present findings indicate that Ang II increases I(Ca,L) via AT(1) receptors in adult rabbit ventricular myocytes. Neither the activation of NHE nor PKC may contribute to the Ang II-induced activation of I(Ca,L).

Action Potentials↗
PubMed2002

Mechanisms of action of novel cardiotonic agents.

Regulation of myocardial contractility by cardiotonic agents is achieved by an increase in intracellular Ca2+ mobilization (upstream mechanism), an increase in Ca2+ binding affinity to troponin C (central mechanism), or facilitation of the process subsequent to Ca2+ binding to troponin C (downstream mechanism). cAMP mediates the regulation induced by Ca2+ mobilizers such as beta-adrenoceptor agonists and selective phosphodiesterase III inhibitors acting through the upstream mechanism. These agents act likewise on the central mechanism to decrease Ca2+ sensitivity of troponin C in association with the cAMP-mediated phosphorylation of troponin I. In addition to such a well-known action of cAMP, recent experimental findings have revealed that Ca2+ sensitizers, such as levosimendan, OR-1896, and UD-CG 212 Cl, require the cAMP-mediated signaling for induction of Ca2+ sensitizing effect. These agents shift the [Ca2+] -force relationship to the left, but their positive inotropic effect (PIE) is inhibited by carbachol, which suppresses selectively the cAMP-mediated PIE. These findings imply that cAMP may play a crucial role in increasing the myofilament Ca2+ sensitivity by cross-talk with the action of individual cardiotonic agents. No clinically available cardiotonic agents act primarily via Ca2+ sensitization, but the PIE of pimobendan and levosimendan is partly mediated by an increase in myofilament Ca2+ sensitivity. Evidence is accumulating that cardiotonic agents with Ca2+ sensitizing action are more effective than agents that act purely via the upstream mechanism in clinical settings. Further clinical trials are required to establish the effectiveness of Ca2+ sensitizers in long-term therapy for congestive heart failure patients.

Animals↗
PubMed2002

The Na+-Ca2+ exchanger contributes to beta-adrenoceptor mediated positive inotropy in mouse heart.

The L-type Ca2+ current (I(Ca,L)) plays an important role in the regulation of cardiac contractility. However, there is little data with regard to the significance of the I(Ca,L)-independent mechanism of beta-adrenoceptor mediated positive inotropy. The effects of isoproterenol (ISO) on I(Ca,L) and contractility in the presence of Ca2+ channel blockers (nifedipine, verapamil) were examined in adult mouse ventricular myocytes. ISO increased contractility over the level before the administration of Ca2+ channel blocker, although it had a very limited effect on I(Ca,L). The positive inotropy of ISO disappeared after administration of Ni2+, an inhibitor of the Na+-Ca2+ exchanger. The addition of ISO after nifedipine pretreatment also increased the [Ca2+]i transient over the control level and the application of Ni2+ or KB-R7943, a selective Na+-Ca2+ exchange inhibitor (reverse mode), abolished the increase in [Ca2+]i transient. Therefore, an I(Ca,L)-independent mechanism plays a significant role in beta-adrenoceptor mediated positive inotropy. The Na+-Ca2+ exchanger is necessary for the development of this action.

Animals↗