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Masao Endoh

Publications and source records attributed to Masao Endoh.

At least 19 recordsLinked to original sources
PubMed2006

Signal transduction and Ca2+ signaling in intact myocardium.

The experimental procedures to simultaneously detect contractile activity and Ca(2+) transients by means of the Ca(2+) sensitive bioluminescent protein aequorin in multicellular preparations, and the fluorescent dye indo-1 in single myocytes, provide powerful tools to differentiate the regulatory mechanisms of intrinsic and external inotropic interventions in intact cardiac muscle. The regulatory process of cardiac excitation-contraction coupling is classified into three categories; upstream (Ca(2+) mobilization), central (Ca(2+) binding to troponin C), and/or downstream (thin filament regulation of troponin C property or crossbridge cycling and crossbridge cycling activity itself) mechanisms. While a marked increase in contractile activity by the Frank-Starling mechanism is associated with only a small alteration in Ca(2+) transients (downstream mechanism), the force-frequency relationship is primarily due to a frequency-dependent increase of Ca(2+) transients (upstream mechanism) in mammalian ventricular myocardium. The characteristics of regulation induced by beta- and alpha-adrenoceptor stimulation are very different between the two mechanisms: the former is associated with a pronounced facilitation of an upstream mechanism, whereas the latter is primarily due to modulation of central and/or downstream mechanisms. alpha-Adrenoceptor-mediated contractile regulation is mimicked by endothelin ET(A)- and angiotensin II AT(1)-receptor stimulation. Acidosis markedly suppresses the regulation induced by Ca(2+) mobilizers, but certain Ca(2+) sensitizers are able to induce the positive inotropic effect with central and/or downstream mechanisms even under pathophysiological conditions.

Acidosis↗
PubMed2006

Acute heart failure: inotropic agents and their clinical uses.

Inotropic agents are indispensable for the improvement of cardiac contractile dysfunction in acute or decompensated heart failure. Clinically available agents, including sympathomimetic amines (dopamine, dobutamine, noradrenaline) and selective phosphodiesterase-3 inhibitors (amrinone, milrinone, olprinone and enoximone) act via cAMP/protein kinase A (PKA)-mediated facilitation of intracellular Ca2+ mobilisation. Phosphodiesterase-3 inhibitors also have a vasodilatory action, which plays a role in improving haemodynamic parameters in certain patients, and are termed inodilators. The available inotropic agents suffer from risks of Ca2+ overload leading to arrhythmias, myocardial cell injury and ultimately, cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and cellular metabolism. Furthermore, they lose their effectiveness under pathophysiological conditions, such as acidosis, stunned myocardium and heart failure. Pimobendan and levosimendan (that act by a combination of an increase in Ca2+ sensitivity and phosphodiesterase-3 inhibition) appear to be more beneficial among existing agents. Novel Ca2+ sensitisers that are under basic research warrant clinical trials to replace available inotropic agents.

Acute Disease↗
PubMed2006

[Cav channels and Ca2+ antagonists: recent advances in molecular characteristics and pharmacology].

Voltage-dependent Ca(2+) channels (Ca(v) channels), a big family of Ca(2+) channels, gating of which is regulated in a voltage-dependent manner, play a crucial role as a molecular mechanism linking the extracellular neuronal and humoral signals to the intracellular Ca(2+) signals, with which various types of cells alter their function. Ca(v) channels, therefore, are important targets of drug development for therapeutic agents of cardiovascular and neuronal diseases. By further combined application of novel molecular biological techniques and electrophysiological (patch-clamp) procedures, specific tissue distribution of individual types of Ca(v) channels has been identified in more detail. It is evident now that Ca(v) channels play an important role in regulation of not only physiological and pathophysiological function of excitable cells, but also other non-excitable cells, responsible for immunological response, gene expression, apoptosis, and cell proliferation, providing further potential for development of novel agents for treatment of diverse cell disorders.

Calcium↗
PubMed2005

Cardiac-specific overexpression of diacylglycerol kinase zeta prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice.

BACKGROUND: Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy. METHODS AND RESULTS: To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels. CONCLUSIONS: These results demonstrated the first evidence that DGKzeta negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.

Angiotensin II↗
PubMed2005

Differential inhibition by the Rho kinase inhibitor Y-27632 of the increases in contractility and Ca2+ transients induced by endothelin-1 in rabbit ventricular myocytes.

The role of Rho kinase activation in the regulation of cardiac contractility and Ca(2+) signaling remains unclear, whereas its role in smooth muscle regulation has been well documented. To study the potential role of Rho kinase in the regulation of cardiac contractility and Ca(2+) transients induced by endothelin-1 (ET-1) and isoproterenol, we used the Rho kinase inhibitor Y-27632 in rabbit ventricular myocardium and myocytes loaded with indo-1/AM. Y-27632 (3-30 microM) inhibited significantly the baseline contractility and Ca(2+) transients. Furthermore, Y-27632 suppressed the increase in contractility and Ca(2+) transients induced by ET-1 in a concentration-dependent manner, when it was used in a concentration at which it did not affect the effects of isoproterenol via beta-adrenoceptors. In the presence of Y-27632, ET-1 increased cell shortening in the absence of an increase in Ca(2+) transients. This is an indication that the increase in myofilament Ca(2+) sensitivity induced by ET-1 is less susceptible to the inhibitory action of Y-27632. These findings imply that the Rho kinase activation may partially contribute to the ET-1-induced regulation of contractility, primarily due to an ET-1-induced increase in Ca(2+) transients in rabbit ventricular myocardium.

Adrenergic beta-Agonists↗
PubMed2005

Receptor subtypes mediating the inotropic effects and Ca(2+) signaling induced by endothelin-1 through crosstalk with norepinephrine in canine ventricular myocardium.

In canine ventricular myocardium, endothelin-1 (ET-1) alone induced only a weak transient negative inotropic effect (NIE). However, ET-1 induced a marked sustained positive inotropic effect (PIE) subsequent to a transient NIE in the presence of norepinephrine (NE) at low concentrations (0.1 - 1 nM) and elicited a pronounced sustained NIE in the presence of NE at high concentrations (around 100 nM). Thus, the extent of beta-adrenoceptor stimulation induced by NE played a crucial role in determining the characteristics of the inotropic effects of ET-1. The characteristics of ET receptor subtypes involved in contractile regulation and Ca(2+) signaling induced by ET-1 were determined. The ET-1-induced transient NIE and decrease in Ca(2+) transients were abolished by the selective ET(A)-receptor antagonist FR319317, but not by the selective ET(B)-receptor antagonist BQ-788. The sustained PIE and the increase in Ca(2+) transients induced by ET-1 were abolished by FR319317, but not inhibited by BQ-788. In contrast, the sustained NIE of ET-1 was abolished by the non-selective ET antagonist TAK-044, markedly attenuated by FR319317, and partially inhibited by BQ-788. ET-1 alone elicited a PIE in the presence of BQ-788, which indicates that the activation of ET(B)-receptors counteracts the development of the PIE of ET-1. The current findings indicate that both ET(A) and ET(B) receptors are involved in the regulation of Ca(2+) signaling and contractility in canine ventricular myocardium.

Animals↗
PubMed2005

Cross-talk between beta(1)-adrenoceptors and ET(A) receptors in modulation of the slow component of delayed rectifier K(+) currents.

Delayed rectifier K(+) currents (I(K)) play a critical role in determining cardiac action potential duration (APD). Modulation of I(K) affects cardiac excitability critically. There are three components of cardiac delayed rectifier, and the slowly activating component (I(Ks)) is influenced strongly by a variety of stimuli. Plasma levels of noradrenaline and endothelin are elevated in heart failure, and arrhythmias are promoted by such humoral abnormalities through modulation of ion channels. It has been reported that protein kinase A (PKA) and protein kinase C (PKC) modulate I(Ks) from human minK in a complex manner. In the present study, we coexpressed human minK with the human beta(1)-adrenoceptor (hbeta(1)AR) and the endothelin receptor subtype A (hET(A)R) in Xenopus oocytes and investigated the effects of receptor activation on the currents (I(Ks)) flowing through the oocytes. ET-1 modulated I(Ks) biphasically: a transient increase followed by a decrease. The PKC inhibitor chelerythrine completely inhibited the effects of ET-1. Intracellular EGTA abolished the transient increase by ET-1 and partially inhibited the subsequent decrease in the currents. When I(Ks) was increased by 10(-6) M isoproterenol (ISO), ET-1 did not increase but rather decreased the current to an even greater extent than under control conditions. In addition, the effects of ISO on I(Ks) were suppressed by ET(A)R stimulation. These data indicate that I(Ks) can be regulated by cross-talk between the ET(A)R and beta(1)AR systems in addition to direct regulation by each receptor system.

Adrenergic beta-Agonists↗
PubMed2005

Differential action of a protein tyrosine kinase inhibitor, genistein, on the positive inotropic effect of endothelin-1 and norepinephrine in canine ventricular myocardium.

Experiments were carried out in isolated canine ventricular trabeculae and acetoxymethylester of indo-1-loaded single myocytes to elucidate the role of protein tyrosine kinase (PTK) in the inotropic effect of endothelin-1 (ET-1) induced by crosstalk with norepinephrine (NE). The PTK inhibitor genistein was used as a pharmacological tool. Genistein but not daidzein inhibited the positive inotropic effect and the increase in Ca(2+) transients induced by ET-1 by crosstalk with NE at low concentrations. Genistein and daidzein antagonized the negative inotropic effect and the decrease in Ca(2+) transients induced by ET-1 by crosstalk with NE at high concentrations, but genistein did not affect the antiadrenergic effect of carbachol. Genistein but not daidzein enhanced the positive inotropic effect and the increase in Ca(2+) transients induced by NE via beta-adrenoceptors, while the enhancing effect of genistein was abolished by the protein tyrosine phosphatase inhibitor vanadate. These findings indicate that genistein (1) induces a positive inotropic effect in association with an increase in Ca(2+) transients, (2) inhibits the positive inotropic effect of ET-1 induced by crosstalk with NE, and (3) enhances the positive inotropic effect of NE induced via beta-adrenoceptors by inhibition of PTK. In addition, genistein inhibits the negative inotropic effect of ET-1 induced by crosstalk with NE through a PTK-unrelated mechanism. PTK may play a crucial role in the receptor-mediated regulation of cardiac contractile function in canine ventricular myocardium.

Animals↗
PubMed2005

Dual regulation of myofilament Ca2+ sensitivity by levosimendan in normal and acidotic conditions in aequorin-loaded canine ventricular myocardium.

Experiments were carried out in canine ventricular trabeculae loaded with aequorin to investigate the effects of levosimendan {(R)-([4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono)-propanedinitrile} on contractile force and Ca(2+) transients in normal and acidotic conditions. The concentration-response curve for the positive inotropic effect (PIE) of levosimendan was bell-shaped, that is, it declined markedly at 10(-4) M after achieving the maximum at 10(-5) M in normal (pH(o)=7.4) and acidotic conditions (pH(o)=6.6). The positive inotropic effect (PIE) of levosimendan up to 10(-5) M was associated with an increase in Ca(2+) transients and a shift of the relationship of Ca(2+) transients and force to the left of that of elevation of [Ca(2+)](o). Levosimendan at 10(-4) M elicited a negative inotropic effect (NIE) in association with a further increase in Ca(2+) transients, and during washout Ca(2+) transients increased further, while the force was abolished before both signals recovered to the control. In acidotic conditions, the relationship of Ca(2+) transients and force during the application of levosimendan in normal conditions was essentially unaltered, whereas the PIE was suppressed due to attenuation of the increase in Ca(2+) transients. In summary, in intact canine ventricular myocardium, levosimendan elicits a dual inotropic effect: at lower concentrations, it induces a PIE by a combination of increases in Ca(2+) transients and Ca(2+) sensitivity, while at higher concentrations it elicits an NIE due to a decrease in Ca(2+) sensitivity. Acidosis inhibits the PIE of levosimendan due to suppression of the increase in Ca(2+) transients in response to the compound.

Acidosis↗
PubMed2005

[Magnesium and cardiovasvular regulatory factor].

Magnesium ions (Mg(2+)) modulate cardiovascular cell function by suppressing Ca(2+) influx. Mg(2+) inhibit ion channels, including voltage-dependent Ca(2+) channels in cardiac myocytes, non-selective cation channels in smooth muscle cells and capacitative Ca(2+) channels in endothelial cells. Although the inhibitory action of Mg(2+) is not so efficacious as organic Ca antagonists, Mg(2+) exert cardioprotective action by antiarrhythmic action, decreasing cell injury, including cell death, induced by ischemia-reperfusion and suppression of myocardial stunning. On the other hand, depletion of intracellular Mg(2+) is an important factor to aggravate various types of cardiovascular disorder. Mg(2+) play a crucial role in pharmacological therapy in not only cardiovascular medicine, but also in cardiac and brain surgery and in the field of anesthesiology and obstetrics.

Animals↗
PubMed2004

Wortmannin inhibits the myofilament Ca2+ sensitization induced by endothelin-1.

Endothelin-1 induces a positive inotropic effect due to a combination of an increase in Ca2+ transients and myofilament Ca2+ sensitivity in rabbit ventricular myocardium. We carried out the experiments to examine the potential contribution of myosin light chain kinase to the Ca2+ sensitization induced by endothelin-1 by use of wortmannin that inhibits myosin light chain kinase at high concentrations (IC50=200 nM). Wortmannin at 3 microM suppressed the basal force of contraction, but did not affect the positive inotropic effect mediated by beta-adrenoceptors. Wortmannin at 1 and 3 microM markedly inhibited the positive inotropic effect of endothelin-1, but did not affect the increase in Ca2+ transients elicited by endothelin-1. The present findings imply that the increase in myofilament Ca2+ sensitivity induced by endothelin-1 may be in part due to activation of myosin light chain kinase in rabbit ventricular myocardium.

Actin Cytoskeleton↗
PubMed2004

Differential inotropic effects of endothelin-1, angiotensin II, and phenylephrine induced by crosstalk with cAMP-mediated signaling process in dog ventricular myocardium.

Endothelin-1 (ET-1), angiotensin II (Ang II), and phenylephrine, an alpha1-adrenoceptor agonist, share the common signaling process, resulting in activation of Gq protein-coupled receptor (GqPCR) to activate the hydrolysis of phosphoinositide (PI). They do not elicit any inotropic effect in isolated dog ventricular muscle. In the presence of forskolin or IBMX (3-isobutyl-1-methylxanthine), ET-1 produced a dual effect, that is, a positive inotropic effect (PIE) and/or a negative inotropic effect (NIE) depending on concentrations of forskolin or IBMX present simultaneously with ET-1. Phenylephrine produced a definite PIE and Ang II induced a small and transient PIE in the presence of forskolin or IBMX, but they did not elicit a NIE. Facilitation of Ca2+ influx via L-type Ca2+ channel may play a crucial role in the crosstalk because GqPCR agonists produced, likewise a PIE in the presence of Bay k 8644. GqPCR agonists failed to induce a PIE in the presence of dihydroouabain or elevated [Ca2+]o. These findings indicate that the accumulation of cAMP or activation of L-type Ca2+ channels markedly modulates the inotropic response to GqPCR agonists in a manner that leads to a PIE in dog ventricular myocardium. In addition, ET-1, but not Ang II or phenylephrine, activates the signal transduction process that results in a NIE.

Angiotensin II↗
PubMed2004

Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance.

The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. The FFR in most mammalian ventricular myocardium is positive; that is, an increase in contractile force in association with an increase in the amplitude of Ca(2+) transients is induced by elevation of the stimulation frequency, which reflects the cardiac contractile reserve. The relationship is different depending on the range of frequency and species of animal. In some species, including rat and mouse, a 'primary-phase' negative FFR is induced over the low-frequency range up to approximately 0.5-1 Hz (rat) and 1-2 Hz (mouse). Even in these species, the FFR over the frequency range close to the physiological heart rate is positive and qualitatively similar to that in larger mammalian species, although the positive FFR is less prominent. The integrated dynamic balance of the intracellular Ca(2+) concentration ([Ca(2+)](i)) is the primary cellular mechanism responsible for the FFR and is determined by sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) flux through the sarcolemma via L-type Ca(2+) channels and the Na(+)-Ca(2+) exchanger. Intracellular Na(+) concentration is also an important factor in [Ca(2+)](i) regulation. In isolated rabbit papillary muscle, over a lower frequency range (<0.5 Hz), an increase in duration rather than amplitude of Ca(2+) transients appears to be responsible for the increase in contractile force, while over an intermediate frequency range (0.5-2.0 Hz), the amplitude of Ca(2+) transients correlates well with the increase in contractile force. Over a higher frequency range (>2.5 Hz), the contractile force is dissociated from the amplitude of Ca(2+) transients probably due to complex cellular mechanisms, including oxygen limitation in the central fibers of isolated muscle preparations, while the amplitude of Ca(2+) transients increases further with increasing frequency ('secondary-phase' negative FFR). Calmodulin (CaM) may contribute to a positive FFR and the frequency-dependent acceleration of relaxation, although the role of calmodulin has not yet been established unequivocally. In failing ventricular myocardium, the positive FFR disappears or is inverted and becomes negative. The activation and overexpression of cardiac sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) is able to reverse these abnormalities. Frequency-dependent alterations of systolic and diastolic force in association with those of Ca(2+) transients and diastolic [Ca(2+)](i) levels are excellent indicators for analysis of cardiac excitation-contraction coupling, and for evaluating the severity of cardiac contractile dysfunction, cardiac reserve capacity and the effectiveness of therapeutic agents in congestive heart failure.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Differential inhibition by TAK-044 of the inotropic effects of endothelin-1 and endothelin-3.

The influence of a nonselective antagonist of endothelin receptors, TAK-044 (cyclo-[d-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-l-alanyl-l-alpha-aspartyl-d-2-(2-thienyl)glycyl-l-leucyl-d-tryptophyl] disodium), on the positive inotropic effect of endothelin-1 and endothelin-3 was investigated in isolated rabbit myocardium. While TAK-044 produced a concentration-dependent rightward shift of the concentration-response curve for endothelin-1 and endothelin-3, the effect of endothelin-3 was hundred times more sensitive to TAK-044 than that of endothelin-1. The combination of FR139317 ([2-(R)-[2(R)-[2(S)-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl] amino-3-(2-pyridyl)propionic acid]) and BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-l-gamma-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine) mimicked the inhibitory action of TAK-044 on the positive inotropic effect of endothelin-3 but enhanced the effect of endothelin-1. In a receptor-binding assay, TAK-044 was four times more potent in antagonizing the specific binding of endothelin-1 than that of endothelin-3. Endothelin-1 may activate receptor subtypes that trigger both positive and negative inotropic effects, the latter being more susceptible to the antagonistic action of TAK-044, which may explain in part the differential antagonistic action of TAK-044 on the inotropic effect of endothelin-1 and endothelin-3.

Animals↗
PubMed2003

Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium.

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca2+ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca2+ ions and a small increase in Ca2+ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKCepsilon from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na+-H+ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pHi did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca2+ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.

Animals↗
PubMed2003

Dissociation of E-4031 from the HERG channel caused by mutations of an amino acid results in greater block at high stimulation frequency.

OBJECTIVE: We have reported identification of the amino acid whose mutation reduces effects of quinidine on the HERG channel. Although the residue (isoleucine at 647) is not in the recently reported methanesulfonanilide binding site, a single concentration of E-4031 (10 microM) was less effective to I647 mutant channels than wild type HERG channel. We designed the present experiment to further investigate influence of mutations at 647 on the effects of methanesulfonanilides. METHODS AND RESULTS: HERG channels were expressed in Xenopus oocytes and their currents were measured by a two-microelectrode voltage clamp method. Of the two mutations initially studied (I647A and I647F), the I647F had a greater influence and differentially affected the effects of dofetilide and E-4031. The IC(50) for dofetilide of the two mutant channels (I647A and I647F) was increased only 2-fold, but the IC(50) for E-4031 was increased 6-fold (I647A) and 14-fold (I647F). Aromatic residues other than phenylalanine were then substituted for I647, and found to reduce the effects of E-4031. Whereas E-4031 dissociated from the mutant channels during rested state, dofetilide little dissociated. The mutant channels that showed recovery from E-4031 block were inhibited greater at 1 Hz than at 0.1 Hz. CONCLUSIONS: The present results indicate that dissociation of a drug from the HERG channel results in greater block at high frequency. Although the mechanism by which the mutations cause the dissociation of E-4031 is uncertain, it is noteworthy that one methanesulfonanilide dissociates from the channel more easily than another.

Animals↗