Excitation-Contraction Coupling Mechanisms in Visceral Smooth Muscle Cells

Itoh, Takeo; Kuriyama, Hiroshi

doi:10.1007/978-3-642-78920-5_3

Cited by 2 publications

(1 citation statement)

References 405 publications

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“…In a given organ, the affinity constant is influenced by the physicochemical properties of the blocker and drug equilibrium in the receptor biophase, the cellular distribution of receptors in the organ, the type of the contraction coupling processes, intracellular calcium homeostasis, pH and temperature. (Furchgott 1964(Furchgott , 1972Salazar et al 1976;Waud et al 1978;Jarv et al 1980;Barlow & Chan 1982;Motulsky & Mahan 1984;El Tayar et al 1988;Itoh & Kuriyama 1994;Barlow 1995). In a given system, if equilibrium of the agonist:antagonist interaction is instantaneously reflected with the equilibrium of the mechanical response, then the IC50/K B ratio will be close to 1.…”

Section: Introductionmentioning

confidence: 99%

Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Patil

2004

Journal of Pharmacy and Pharmacology

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There are two distinct kinetic functional pharmacological procedures by which the equilibrium affinity constant, KB, of a competitive reversible blocker is obtained. The classical method on an organ system requires the study of the parallel displacement of the agonist concentration-response curve in the presence of the blocker. In the second method, the agonist-evoked functional mechanical response is reduced to half by the blocker IC50 (the concentration required for 50% inhibition). In relation to these parameters the role of the ionization constant pKa and liposolubility log Pc or log D of blockers was examined. On the ciliary muscle from human eye, IC50/KB ratios for (+/-)-atropine, its quaternary analogue (+/-)-methylatropine, (-)-scopolamine, (+/-)-cyclopentolate, (-)-tropicamide, (+/-)-oxybutynin and pirenzepine were 15, 23, 4.4, 2.6, 1.66, 1.46 and 1.71, respectively. The ratios on the iris sphincter were comparable with those of ciliary muscle. When compared with large proportions of ionized molecules with water soluble properties of (+/-)-atropine and (+/-)-methylatropine, relatively high amounts of un-ionized and/or with greater partitioning of all other blockers in the lipoid barrier correlated well to low IC50/KB ratios, as predicted by the classical theory of competitive drug antagonism. It was hypothesized that due to receptor biophase access, the reduction of the mechanical response of the agonist by the highly ionized water-soluble antagonist at IC50 represented time-distorted "pseudoequilibrium" estimation, where a higher concentration of the blocker was needed. On the other cholinergic effectors, like that of rat anococcygeus muscle or frog rectus abdominus muscle, IC50/KB ratios of respective blockers atropine or (+)-tubocurarine and hexamethonium were close to 1. Thus physicochemical properties, which affect the distribution coefficient log D and the tissue morphology (where asymmetric distribution of receptors may occur), appeared to be a critical factor in the analysis of the affinity parameters of the competitive reversible blocker. On the intraocular muscles, two functional pharmacological procedures for obtaining KB and IC50 values were not kinetically equivalent.

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Section: Introductionmentioning

confidence: 99%

Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Patil

2004

Journal of Pharmacy and Pharmacology

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Changes in intracellular Ca²⁺concentration induced by L-type Ca²⁺ channel current in guinea pig gastric myocytes

Kim

Ahn

Kim

et al. 1997

American Journal of Physiology-Cell Physiology

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We investigated the relationship between voltage-operated Ca2+ channel current and the corresponding intracellular Ca2+concentration ([Ca2+]i) change (Ca2+ transient) in guinea pig gastric myocytes. Fluorescence microspectroscopy was combined with conventional whole cell patch-clamp technique, and fura 2 (80 μM) was added to CsCl-rich pipette solution. Step depolarization to 0 mV induced inward Ca2+ current ( I Ca) and concomitantly raised [Ca2+]i. Both responses were suppressed by nicardipine, an L-type Ca2+ channel blocker, and the voltage dependence of Ca2+transient was similar to the current-voltage relation of I Ca. When pulse duration was increased by up to 900 ms, peak Ca2+ transient increased and reached a steady state when stimulation was for longer. The calculated fast Ca2+ buffering capacity ( B value), determined as the ratio of the time integral of I Ca divided by the amplitude of Ca2+ transient, was not significantly increased after depletion of Ca2+ stores by the cyclic application of caffeine (10 mM) in the presence of ryanodine (4 μM). The addition of cyclopiazonic acid (CPA, 10 μM), a sarco(endo)plasmic reticulum Ca2+-ATPase inhibitor, decreased B value by ∼20% in a reversible manner. When KCl pipette solution was used, Ca2+-activated K+ current [ I K(Ca)] was also recorded during step depolarization. CPA sensitively suppressed the initial peak and oscillations of I K(Ca) with irregular effects on Ca2+transients. The above results suggest that, in guinea pig gastric myocyte, Ca2+ transient is tightly coupled to I Caduring depolarization, and global [Ca2+]iis not significantly affected by Ca2+-induced Ca2+ release from sarcoplasmic reticulum during depolarization.

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Excitation-Contraction Coupling Mechanisms in Visceral Smooth Muscle Cells

Cited by 2 publications

References 405 publications

Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Changes in intracellular Ca²⁺concentration induced by L-type Ca²⁺ channel current in guinea pig gastric myocytes

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Excitation-Contraction Coupling Mechanisms in Visceral Smooth Muscle Cells

Cited by 2 publications

References 405 publications

Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles

Changes in intracellular Ca2+concentration induced by L-type Ca2+ channel current in guinea pig gastric myocytes

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Changes in intracellular Ca²⁺concentration induced by L-type Ca²⁺ channel current in guinea pig gastric myocytes