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1.
Background and purpose:Muscarinic stimulation increases myofilament Ca 2+ sensitivity with no apparent inotropic response in normal rat myocardium. Increased myofilament Ca 2+ sensitivity is a molecular mechanism promoting increased contractility in failing cardiac tissue. Thus, muscarinic receptor activation could elicit inotropic responses in ventricular myocardium from rats with heart failure, through increasing phosphorylation of myosin light chain (MLC). Experimental approach:Contractile force was measured in left ventricular papillary muscles from male Wistar rats, 6 weeks after left coronary artery ligation or sham surgery. Muscles were also frozen, and MLC-2 phosphorylation level was quantified. Key results:Carbachol (10 µmol·L −1) evoked a positive inotropic response only in muscles from rats with heart failure approximating 36% of that elicited by 1 µmol·L −1 isoproterenol (20 ± 1.5% and 56 ± 6.1% above basal respectively). Carbachol-evoked inotropic responses did not correlate with infarction size but did correlate with increased left ventricular end diastolic pressure, heart weight/body weight ratio and lung weight, primary indicators of the severity of heart failure. Only muscarinic receptor antagonists selective for M 2 receptors antagonized carbachol-mediated inotropic effects with the expected potency. Carbachol-evoked inotropic responses and increase in phosphorylated MLC-2 were attenuated by MLC kinase (ML-9) and Rho-kinase inhibition (Y-27632), and inotropic responses were abolished by Pertussis toxin pretreatment. Conclusion and implications:In failing ventricular muscle, muscarinic receptor activation, most likely via M 2 receptors, provides inotropic support by increasing MLC phosphorylation and consequently, myofilament Ca 2+ sensitivity. Enhancement of myofilament Ca 2+ sensitivity, representing a less energy-demanding mechanism of inotropic support may be particularly advantageous in failing hearts. 相似文献
2.
Ca 2+ sensitizers are cardiotonic agents that directly increase the Ca 2+ sensitivity of cardiac myofilament. To find a novel Ca 2+ sensitizer, we have screened a group of phenolic compounds by examining their effects on the Ca 2+-dependent force generation in cardiac muscle fibers. We found that propyl gallate, a strong antioxidant, increased the Ca 2+ sensitivity of cardiac myofilament in a dose-dependent and reversible manner. The present study indicates that propyl gallate is a novel type of Ca 2+ sensitizer with antioxidant activity, which might be more beneficial for the treatment of congestive heart failure associated with oxidative stress than existing Ca 2+ sensitizers. 相似文献
3.
Background and PurposeMucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown. Experimental ApproachTransepithelial short circuit currents (I SC) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca 2+] i were studied on freshly dissociated mouse tracheal epithelial cells. Key ResultsApical application of the nAChR agonist nicotine transiently increased I SC. The nicotine effect was abolished by the nAChR antagonist mecamylamine. α‐Bungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3β2, α4β2, α4β4 and α3β4) and A‐85380 (α4β2 and α3β4) increased I SC. The antagonists dihydro‐β‐erythroidine (α4β2, α3β2, α4β4 and α3β4), α‐conotoxin MII (α3β2) and α‐conotoxin PnIA (α3β2) reduced the nicotine effect. Nicotine‐ and epibatidine‐induced currents were unaltered in β2 −/−mice, but in β4 −/− mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca 2+‐ATPase inhibitor) or the ryanodine receptor antagonists JTV‐519 and dantrolene there was a reduction in the nicotine‐effect, indicating involvement of Ca 2+ release from intracellular stores. Additionally, the PKA inhibitor H‐89 and the TMEM16A (Ca 2+‐activated chloride channel) inhibitor T16Ainh‐A01 significantly reduced the nicotine‐effect. Conclusion and Implicationsα3β4 nAChRs are responsible for the nicotine‐induced current changes via Ca 2+ release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A. 相似文献
4.
3′,4′-Dihydroxyflavonol (DiOHF) exerts endothelium-independent relaxation in rat aortic rings. In this study, we hypothesized
that DiOHF reduces vascular contraction through Ca 2+ desensitization in permeabilized third-order branches of rat mesenteric arteries. The third-order branches of rat mesenteric
arteries were permeabilized with β-escin and subjected to tension measurement. Cumulative addition of phenylephrine (0.3–30 μM)
produced concentration-dependent vascular contraction of endothelium-intact and endothelium-denuded arterial rings, which
were inhibited by pretreatment with DiOHF (10, 30, or 100 μM). In addition, DiOHF dose-dependently decreased vascular contractions
induced by 3.0 μM phenylephrine. β-Escin-permeabilized third-order branches of mesenteric arteries were contracted with Ca 2+, NaF, or guanosine-5′-(γ-thio)triphosphate (GTPγS) 30 min after pretreatment with DiOHF or vehicle. Pretreatment with DiOHF
for 30 min inhibited vascular contraction induced by cumulative additions of Ca 2+ (pCa 9.0–6.0) or NaF (4.0–16.0 mM) in permeabilized arterial rings. Cumulative addition of DiOHF also reduced vascular contraction
induced by Ca 2+-controlled solution of pCa 6.0, 16.0 mM NaF, or 100 μM GTPγS in permeabilized arterial rings. DiOHF inhibited the increase
in vascular tension provoked by calyculin A, even though it did not affect vascular tension already produced by calyculin
A. DiOHF accelerated the relaxation induced by rapidly lowering Ca 2+. DiOHF reduced vascular contraction through Ca 2+ desensitization in permeabilized third-order branches of rat mesenteric arteries. These results suggest that DiOHF may have
a therapeutic potential in the treatment of cardiovascular diseases. 相似文献
5.
It was hypothesized that NaF induces calcium sensitization in Ca 2+-controlled solution in permeabilized rat mesenteric arteries. Rat mesenteric arteries were permeabilized with β-escin and subjected to tension measurement. NaF potentiated the concentration-response curves to Ca 2+ (decreased EC 50 and increased E max). Cumulative addition of NaF (4.0, 8.0 and 16 mM) also increased vascular tension in Ca 2+-controlled solution at pCa 7.0 or pCa 6.5, but not at pCa 8.0. NaF-induced vasocontraction and GTPγS-induced vasocontraction were not additive. NaF-induced vasocontraction at pCa 7.0 was inhibited by pretreatment with Rho kinase inhibitors H1152 or Y27632 but not with a MLCK inhibitor ML-7 or a PKC inhibitor Ro31-8220. NaF induces calcium sensitization in a Ca 2+-dependent manner in β-escin-permeabilized rat mesenteric arteries. These results suggest that NaF is an activator of the Rho kinase signaling pathway during vascular contraction. 相似文献
6.
The mechanisms of the smooth muscle contractile action of daunorubicin were investigated using guinea-pig aortae, and the involvement of the Ca 2+ entry mechanism was compared among different smooth-muscle preparations. In the aorta, daunorubicin showed a concentration-dependent contractile action at concentrations of 10–200 μm . The contractile response to daunorubicin was completely dependent on extracellular Ca 2+, but only slightly sensitive to verapamil or nifedipine. Trifluoperazine abolished the contraction by daunorubicin, but no significant effect was noted with amiloride, phentolamine, indomethacin or staurosporine. The order of potency (sensitivity) for daunorubicin-induced smooth muscle contraction was oesophagus = gall bladder = iliac artery > bronchus = aorta, while that of maximum reactivity was iliac artery = aorta > bronchus = oesophagus = gall bladder. In the portal vein, daunorubicin showed no contractile action. Although the smooth muscle contraction induced by daunorubicin was strongly dependent on extracellular Ca 2+ in the aorta, iliac artery, bronchus, oesophagus and gall bladder, its sensitivity to verapamil varied among the different smooth muscle preparations, with the sensitivity being iliac artery = gall bladder > bronchus = oesophagus > aorta. These results suggest that daunorubicin has contractile action on various kinds of smooth muscle, mainly via the transplasmalemmal Ca 2+ entry mechanism, but the degree of involvement of the voltage-dependent Ca 2+ channel differs among the different smooth muscle preparations. 相似文献
7.
Background and purpose:Uridine 5''-triphosphate (UTP) is a potent vasoconstrictor of cerebral arteries and induces Ca 2+ waves in vascular smooth muscle cells (VSMCs). This study aimed to determine the mechanisms underlying UTP-induced Ca 2+ waves in VSMCs of the rat basilar artery. Experimental approach:Isometric force and intracellular Ca 2+ ([Ca 2+] i) were measured in endothelium-denuded rat basilar artery using wire myography and confocal microscopy respectively. Key results:Uridine 5''-triphosphate (0.1–1000 µmol·L −1) concentration-dependently induced tonic contraction (pEC 50 = 4.34 ± 0.13), associated with sustained repetitive oscillations in [Ca 2+] i propagating along the length of the VSMCs as asynchronized Ca 2+ waves. Inhibition of Ca 2+ reuptake in sarcoplasmic reticulum (SR) by cyclopiazonic acid abolished the Ca 2+ waves and resulted in a dramatic drop in tonic contraction. Nifedipine reduced the frequency of Ca 2+ waves by 40% and tonic contraction by 52%, and the nifedipine-insensitive component was abolished by SKF-96365, an inhibitor of receptor- and store-operated channels, and KB-R7943, an inhibitor of reverse-mode Na +/Ca 2+ exchange. Ongoing Ca 2+ waves and tonic contraction were also abolished after blockade of inositol-1,4,5-triphosphate-sensitive receptors by 2-aminoethoxydiphenylborate, but not by high concentrations of ryanodine or tetracaine. However, depletion of ryanodine-sensitive SR Ca 2+ stores prior to UTP stimulation prevented Ca 2+ waves. Conclusions and implications:Uridine 5''-triphosphate-induced Ca 2+ waves may underlie tonic contraction and appear to be produced by repetitive cycles of regenerative Ca 2+ release from the SR through inositol-1,4,5-triphosphate-sensitive receptors. Maintenance of Ca 2+ waves requires SR Ca 2+ reuptake from Ca 2+ entry across the plasma membrane via L-type Ca 2+ channels, receptor- and store-operated channels, and reverse-mode Na +/Ca 2+ exchange. 相似文献
8.
Summary Procaine (8.5×10 –5 M) inhibited the action of acetylcholine but not that of bradykinin on the guinea pig ileum. Attempts were made to identify the difference in stimulus-response coupling which would explain this difference in sensitivity. The responses to both agonists were dependent upon the presence of Ca 2+ in the extracellular fluid, were inhibited to approximately the same extent by the addition of 0.25 mM Mn 2+ to the bathing fluid and were equally sensitive to reduction in Na + concentration of the extracellular fluid. Neither acetylcholine nor bradykinin could provoke ileal contraction when Sr 2+ was substituted for Ca 2+. Thus there was no indication of the difference in the stimulus-response pathways for the two agonists which must exist to explain the differential sensitivity to procaine. 相似文献
9.
The functional role of the sodium–calcium exchanger in mouse ventricular myocardium was evaluated with a newly developed specific inhibitor, SEA0400. Contractile force and action potential configuration were measured in isolated ventricular tissue preparations, and cell shortening and Ca 2+ transients were measured in indo-1-loaded isolated ventricular cardiomyocytes. SEA0400 increased the contractile force, cell shortening and Ca 2+ transient amplitude, and shortened the late plateau phase of the action potential. -adrenergic stimulation by phenylephrine produced a sustained decrease in contractile force, cell shortening and Ca 2+ transient amplitude, which were all inhibited by SEA0400. Increasing the contraction frequency resulted in a decrease in contractile force in the absence of drugs (negative staircase phenomenon). This frequency-dependent decrease was attenuated by SEA0400 and enhanced by phenylephrine. Phenylephrine increased the Ca 2+ sensitivity of contractile proteins in isolated ventricular cardiomyocytes, while SEA0400 had no effect. These results provide the first pharmacological evidence in the mouse ventricular myocardium that inward current generated by Ca 2+ extrusion through the sodium–calcium exchanger during the Ca 2+ transient contributes to the action potential late plateau, that -adrenoceptor-mediated negative inotropy is produced by enhanced Ca 2+ extrusion through the sodium–calcium exchanger, and that the negative staircase phenomenon can be explained by increased Ca 2+ extrusion through the sodium–calcium exchanger at higher contraction frequencies. 相似文献
10.
Mavacamten is a small molecule modulator of cardiac myosin designed as an orally administered drug for the treatment of patients with hypertrophic cardiomyopathy. The current study objectives were to assess the preclinical pharmacokinetics of mavacamten for the prediction of human dosing and to establish the potential need for clinical pharmacokinetic studies characterizing drug–drug interaction potential. Mavacamten does not inhibit CYP enzymes, but at high concentrations relative to anticipated therapeutic concentrations induces CYP2B6 and CYP3A4 enzymes in vitro. Mavacamten showed high permeability and low efflux transport across Caco-2 cell membranes. In human hepatocytes, mavacamten was not a substrate for drug transporters OATP, OCT and NTCP. Mavacamten was determined to have minimal drug–drug interaction risk. In vitro mavacamten metabolite profiles included phase I- and phase II-mediated metabolism cross-species. Major pathways included aromatic hydroxylation (M1), aliphatic hydroxylation (M2); N-dealkylation (M6), and glucuronidation of the M1-metabolite (M4). Reaction phenotyping revealed CYPs 2C19 and 3A4/3A5 predominating. Mavacamten demonstrated low clearance, high volume of distribution, long terminal elimination half-life and excellent oral bioavailability cross-species. Simple four-species allometric scaling led to predicted plasma clearance, volume of distribution and half-life of 0.51?mL/min/kg, 9.5?L/kg and 9?days, respectively, in human. 相似文献
11.
To determine whether Kil769, a novel K +-channel opener, acts intracellularly in vasorelaxation, we compared the effects of Kil 769 on force of contraction, intracellular Ca 2+ concentration ([Ca 2+] i) and inositol phosphate (IP 1) formation with those of Ca 2+-channel blockers in isolated porcine coronary artery. Kil 769 (10 μm) and verapamil (1 μm), which produced submaximal relaxation, reduced the increase in [Ca 2+] i and force of contraction induced by 25 mM KC1. Verapamil reduced [Ca 2+] i and the force of contraction to a similar extent but Kil 769 reduced force of contraction more strongly than it did [Ca 2+] i. Kil 769 also inhibited U46619 (9,11-dideoxy-9α, 11α-methano-epoxy-PGF 2a)-induced IP 1 formation and glibenclamide blocked its inhibitory effect. These results suggest that the opening of K + channels induced by Kil 769 reduces the Ca 2+ sensitivity of contractile elements and inositol phospholipid hydrolysis which is related to the Ca 2+ release from intracellular storage. 相似文献
12.
Recently, a family of guanine nucleotide exchange factors have been identified in many cell types as important effectors of cyclic adenosine 3′,5′‐monophospahte (cAMP) signalling that is independent of protein kinase A (PKA). In the heart, investigation of exchange protein directly activated by cAMP (Epac) has yielded conflicting results. Since cAMP is an important regulator of cardiac contractility, this study aimed to examine whether Epac activation modulates excitation–contraction coupling in ventricular preparations from rat hearts. The study used 8‐(4‐chlorophenylthio)‐2′‐O‐methyladenosine‐3′, 5′‐cyclic monophosphate (cpTOME), an analogue of cAMP that activates Epac, but not PKA. In isolated myocytes, cpTOME increased Ca 2+ spark frequency from about 7 to 32/100 μm 3/s ( n = 10), P = 0.05 with a reduction in the peak amplitude of the sparks. Simultaneous measurements of intracellular Ca 2+ and isometric force in multicellular trabeculae ( n = 7, 1.5 mmol/L [Ca 2+] o) revealed no effect of Epac activation on either the amplitude of Ca 2+ transients (Control 0.7 ± 0.1 vs cpTOME 0.7 ± 0.1; 340/380 fura‐2 ratio, P = 0.35) or on peak stress (Control 24 ± 5 mN/mm 2 vs cpTOME 23 ± 5 mN/mm 2, P = 0.20). However, an effect of Epac in trabeculae was unmasked by lowering extracellular [Ca 2+] o. In these depotentiated trabeculae, activation of the Epac pathway increased myofilament Ca 2+ sensitivity, an effect that was blocked by addition of KN‐93, a Ca 2+/calmodulin‐dependent protein kinase II (CaMK‐II) inhibitor. This study suggests that Epac activation may be a useful therapeutic target to increase the strength of contraction during low inotropic states. 相似文献
13.
Background and PurposeOmecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. Experimental ApproachesCa 2+-dependent active force production ( Factive), its Ca 2+ sensitivity (pCa 50), the kinetic characteristics of Ca 2+-regulated activation and relaxation, and Ca 2+-independent passive force ( Fpassive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM). Key ResultsIn permeabilized cardiomyocytes, OM increased the Ca 2+ sensitivity of force production (ΔpCa 50: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration–response relationship of the Ca 2+ sensitization was bell-shaped, with maximal effects at 0.3–1 μM OM (EC 50: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC 50 value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. Conclusions and ImplicationsOM acted as a Ca 2+-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation–relaxation kinetics and at higher OM concentrations increased Fpassive production. 相似文献
14.
Background and purpose:Diabetes mellitus (DM) causes multiple dysfunctions including circulatory disorders such as cardiomyopathy, angiopathy, atherosclerosis and arterial hypertension. Rho kinase (ROCK) and protein kinase C (PKC) regulate vascular smooth muscle (VSM) Ca 2+ sensitivity, thus enhancing VSM contraction, and up-regulation of both enzymes in DM is well known. We postulated that in DM, Ca 2+ sensitization occurs in diabetic arteries due to increased ROCK and/or PKC activity. Experimental approach:Rats were rendered hyperglycaemic by i.p. injection of streptozotocin. Age-matched control tissues were used for comparison. Contractile responses to phenylephrine (Phe) and different Ca 2+ concentrations were recorded, respectively, from intact and chemically permeabilized vascular rings from aorta, tail and mesenteric arteries. Key results:Diabetic tail and mesenteric arteries demonstrated markedly enhanced sensitivity to Phe while these changes were not observed in aorta. The ROCK inhibitor HA1077, but not the PKC inhibitor chelerythrine, caused significant reduction in sensitivity to agonist in diabetic vessels. Similar changes were observed for myofilament Ca 2+ sensitivity, which was again enhanced in DM in tail and mesenteric arteries, but not in aorta, and could be reduced by both the ROCK and PKC blockers. Conclusions and implications:We conclude that in DM enhanced myofilament Ca 2+ sensitivity is mainly manifested in muscular-type blood vessels and thus likely to contribute to the development of hypertension. Both PKC and, in particular, ROCK are involved in this phenomenon. This highlights their potential usefulness as drug targets in the pharmacological management of DM-associated vascular dysfunction. 相似文献
15.
Background and PurposeMetabolites of the endocannabinoid, 2‐arachidonoylglycerol (2‐AG) have been postulated to act as endogenous activators of TRPV4, a Ca 2+‐permeable cation channel that plays a critical role in endothelium‐dependent relaxation. However, it is unclear if TRPV4 contributes to the vascular actions of 2‐AG. Experimental ApproachIsometric tension recording of rat small mesenteric arteries and aortae were used to assess the effect of 2‐AG and the synthetic TRPV4 activator, GSK1016790A (GSK) on vascular reactivity. Changes in intracellular Ca 2+ concentration and single‐channel currents were measured in TRPV4‐expressing human coronary endothelial cells. Key ResultsIn mesenteric arteries, endothelium‐dependent relaxation to both 2‐AG and GSK was attenuated by structurally distinct TRPV4 antagonists, HC067047, RN1734 and ruthenium red. The responses were inhibited by K Ca inhibitors (apamin + charybdotoxin) and a gap junction inhibitor (18α‐glycyrrhetinic acid). In contrast to GSK, 2‐AG elicited considerable relaxation independently of the endothelium or TRPV4. Inhibition of 2‐AG metabolism via monoacylglycerol lipase and COX (by MAFP and indomethacin) caused potentiation, while cytochrome P450 and lipoxygenase inhibitors had no effect on 2‐AG relaxation. In coronary endothelial cells, 2‐AG (with and without MAFP) induced HC067047‐sensitive increases in intracellular Ca 2+ concentration. 2‐AG also increased TRPV4 channel opening in inside‐out patches. However, in aortae, GSK induced a relaxation sensitive to HC067047 and ruthenium red, whereas 2‐AG induced contractions. Conclusions and ImplicationsThese data suggest that 2‐AG can directly activate endothelial TRPV4, which partly contributes to the relaxant response to 2‐AG. However, the functional role of TRPV4 is highly dependent on the vascular region. Abbreviations- 4α‐PDD
- 4α‐phorbol‐12,13‐didecanoate
- GSK
- GSK1016790A
- JTE907
-
N‐(1,3‐benzodioxol‐5‐ylmethyl)‐1,2‐dihydro‐7‐methoxy‐2‐oxo‐8‐(pentyloxy)‐3‐quinolinecarboxamide
- SKF525A
- α‐phenyl‐α‐propylbenzeneacetic acid 2‐(diethylamino)ethyl ester N,N‐diethylaminoethyl 2,2‐diphenylvalerate
相似文献
16.
Background and Purpose7‐[2‐[4‐(2‐Chlorophenyl)piperazinyl]ethyl]‐1,3‐dimethylxanthine (KMUP‐1) is a xanthine‐based derivative. It has soluble GC activation and K +‐channel opening activity. Effects of this compound on ion currents in pituitary GH 3 cells were investigated in this study. Experimental ApproachThe aim of this study was to evaluate effects of KMUP‐1 on the amplitude and gating of voltage‐gated Na + current ( I
Na) in pituitary GH 3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca 2+‐activated K + current and the activity of large‐conductance Ca 2+‐activated K + (BK Ca) channels were also studied. Key ResultsKMUP‐1 depressed the transient and late components of I
Na with different potencies. The IC 50 values required for its inhibitory effect on transient and late I
Na were 22.5 and 1.8 μM respectively. KMUP‐1 (3 μM) shifted the steady‐state inactivation of I
Na to a hyperpolarized potential by −10 mV, despite inability to alter the recovery of I
Na from inactivation. In cell‐attached configuration, KMUP‐1 applied to bath increased BK Ca‐channel activity; however, in inside‐out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP‐1 decreased the peak I
Na with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. Conclusions and ImplicationsApart from activating BK Ca channels, KMUP‐1 preferentially suppresses late I
Na. The effects of KUMP‐1 on ion currents presented here constitute an underlying ionic mechanism of its actions. Abbreviations- AC
- action current
- AP
- action potential
- BKCa
- channel large‐conductance Ca2+‐activated K+ channel
- IK(Ca)
- Ca2+‐activated K+ current
- INa
- voltage‐gated Na+ current
- I–V
- current versus voltage
- KATP
- channel ATP‐sensitive K+ channel
- ODQ
- 1H‐[1,2,4]oxadiazolo‐[4,3‐a] quinoxalin‐1‐one
- TEA
- tetraethylammonium chloride
- τinact(S)
- slow component of inactivation time constant for I
Na
- YC‐1
- 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole
相似文献
17.
Summary The modes by which Endothelin-1 (ET) induces Ca 2+-influx and the relative functional importance of the different sources of Ca 2+ for ET-induced contraction were studied using fura 2-loaded and unloaded rat aortic strips. ET caused an increase in the cytosolic free Ca 2+ level ([Ca 2+] i) followed by a tonic contraction in Ca 2+-containing solution, and produced a transient elevation of [Ca 2+] i followed by a small sustained contraction in Ca 2+-free medium. ET also stimulated 45Ca influx into La 2+-inaccessible fraction significantly. With the same change of [Ca 2+] i, ET caused a larger tension than that induced by high K. ET-induced contraction and [Ca 2+] i elevation were not significantly inhibited by 0.1–0.3 M nicardipine which nearly abolished the contraction and [Ca +] i elevation produced by high K. During treatment of the strips with high K, addition of ET induced further increases in [Ca 2+] i and muscle tension, and vice versa. In Ca 2+-free medium, ET-induced contraction was influenced neither by ryanodine-treatment nor by high K-treatment, although the former attenuated and the latter potentiated the [Ca 2+] i transient induced by ET. Further, the ET-induced sustained contraction under Ca 2+-free conditions began to develop after the [Ca 2+] i level returned to the baseline. Thus, it seems that the Ca 2+ released from the ryanodine-sensitive and -insensitive Ca 2+ stores by ET may provide only a minor or indirect contribution, if any, to the tension development. ET might cause a contraction mainly by stimulating Ca 2+-influx through Ca 2+ channel(s) other than voltage-dependent Ca 2+ channels in character, and by increasing the sensitivity of the contractile filaments to Ca 2+ or activating them Ca 2+-independently.Visiting from Zun Yi Medical College, China
Send offprint requests to I. Takayanagi at the above address 相似文献
18.
The contractile properties of vastus lateralis muscle fibres were examined in prostate cancer (PrCa) patients undergoing androgen deprivation therapy (ADT) and in age‐ and activity‐matched healthy male subjects (Control). Mechanically‐skinned muscle fibres were exposed to a sequence of heavily Ca 2+‐buffered solutions at progressively higher free [Ca 2+] to determine their force‐Ca 2+ relationship. Ca 2+‐sensitivity was decreased in both type I and type II muscle fibres of ADT subjects relative to Controls (by ?0.05 and ?0.04 pCa units, respectively, P < .02), and specific force was around 13% lower in type I fibres of ADT subjects than in Controls ( P = .02), whereas there was no significant difference in type II fibres. Treatment with the reducing agent dithiothreitol slightly increased specific force in type I and type II fibres of ADT subjects (by ~2%‐3%, P < .05) but not in Controls. Pure type IIx fibres were found frequently in muscle from ADT subjects but not in Controls, and the overall percentage of myosin heavy chain IIx in muscle samples was 2.5 times higher in ADT subjects ( P < .01). The findings suggest that testosterone suppression can negatively impact the contractile properties by (i) reducing Ca 2+‐sensitivity in both type I and type II fibres and (ii) reducing maximum specific force in type I fibres. 相似文献
19.
Wan Wan Lin, C. Y. Lee and J. W. Burnett. Effect of sea nettle ( Chrysaora quinquecirrha) venom on isolated rat aorta. Toxicon26, 1209–1212, 1988.—The venom from sea nettle ( Chrysaora quinquecirrha) (1–10μg/ml) produced an irreversible contraction of the isolated rat aortic ring that was slow in onset, increased with time, and reached maximum in about 10–20 min. The contraction was not inhibited by pretreatment with phenoxybenzamine, atropine, indomethacin, tetrodotoxin, ouabain, low Na + or Na +-free medium, however, it was markedly decreased by the Ca 2+ channel blockers, nifedipine and verapamil. In Ca 2+-free medium, no increase in tension was produced by the venom. It is concluded that sea nettle venom causes a contraction of the rat aortic ring by increasing Ca 2+ influx through the voltage-dependent Ca 2+ channels. 相似文献
20.
The effects of okadaic acid (OA), a monocarboxylic acid produced by marine dinoflagellates belonging to the genera Dinophysis and Prorocentrum, and their interactions with theophylline and caffeine were studied on the rat-isolated uterus in a calcium-containing medium and a calcium-free medium in the presence of 10 –3 M EGTA.Okadaic acid (5 × 10 –6 to 5 × 10 –5 M) induced a concentration-dependent contraction of the rat-isolated uterus corresponding, with 5 × 10 –5M, to 142.3±6.1% ( n = 7) of the contraction induced by oxytocin 10 –6 M. The time to peak tension was inversely proportional to the maximum effect produced. The contraction was not sustained and was followed by a concentration-dependent decrease in tone. In a Ca 2+-free medium containing 10 –3 M EGTA the contractile effects of OA were significantly inhibited or reduced. A 30 min pretreatment with theophylline (3 × 10 –3 M) or caffeine (2 × 10 –2 M) significantly reduced, in a Ca 2+-containing medium, the maximum contractile effect of OA 10 –5 and/or 2 × 10 –5 M and shortened the relative time to peak tension. In a Ca 2+-free medium containing 10 –3 M EGTA, only the second effect was observed. With a 1 min pretreatment and in a Ca 2+-containing medium, theophylline 3 × 10 –3 M and caffeine 10 –2 M did not modify the maximum effect of OA 10 –5 M but shortened the time to peak tension. The same concentrations of the xanthines potentiated the E max of OA 5 × 10 –6 M in the Ca 2+-containing medium or in a Ca 2+-free medium containing 10 –3 M EGTA. Okadaic acid 10 –6 M used as 30 min pretreatment versus OA 10 –5 M and 2 × 10 –5 M behaved like caffeine or theophylline.These results suggest that the OA-induced contraction of the rat uterine smooth muscle is partly effected by transmembrane calcium movements which can be inhibited in an O-Ca 2+–10 –3 M EGTA solution or by theophylline or caffeine. This contraction also involves mobilization of Ca 2+ from an intracellular pool which is also xanthine-sensitive. The latter effect seems to be important in inducing the contractile effect. This study does not exclude the possibility of other mechanisms being involved in the contraction induced by OA.
Correspondence to: M. L. Candenas at the above address in Burjassot-València 相似文献
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