The Mode of Action of Pinacidil and Its Analogs P1060 and P1368

Weston, A.H.; Southerton, J. S.; Bray, Katharine; Newgreen, Donald; Taylor, Simon

doi:10.1097/00005344-198812002-00004

Cited by 34 publications

(17 citation statements)

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“…The (Hamilton et al, 1986;Quast, 1987;Cook et al, 1988b;Quast & Baumlin, 1988 (Hamilton et al, 1986;Bray et al, 1987;Weston et al, 1988;Hamilton & Weston, 1989 (Kaergaard Nielsen & Arrigoni-Martelli, 1981;Cook et. al., 1988a), rat aorta (Mikkelsen & Lederballe Pedersen, 1982), rat mesenteric and femoral arteries (Videbaek et al, 1988b), rat tail artery (Hermsmeyer, 1988) and human crural vein (Mikkelsen & Lederballe Pedersen, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, this action of pinacidil will have a great influence on the Ca2 +-activated K+ channels as has been demonstrated for other Ca2 + influx inhibitors (Casteels & Droogmans, 1985;Aaronson & Jones, 1985). In contrast with these observations, it was demonstrated that high concentrations (30 and 100 yM) of pinacidil had little or no effect on 80mM K+-induced contractions in rat aorta (Bray et al, 1987; C) Macmillan Press Ltd, 1990 Weston et al, 1988). The purpose of the present study was to determine whether pinacidil interacts with both ATP-sensitive and Ca2+-activated K+ channels in strips of canine mesenteric artery.…”

Section: Introductionmentioning

confidence: 93%

“…The mechanism of action has not yet been fully established, but it has recently been suggested that vascular relaxant responses to pinacidil are associated with the opening of smooth muscle K+ channels (Bray et al, 1987;Cook et al, 1988a;Weston et al, 1988;Videbaek et al, 1988a). This mechanism of action was first proposed for the vasodilator effects of cromakalim on the basis that cromakalim enhanced 86Rb (or 42K) efflux from preloaded vascular smooth muscle preparations and hyperpolarized the cell membrane (Hamilton et al, 1986;Quast, 1987;Cook et al, 1988b;Quast & Baumlin, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

Masuzawa

Matsuda

Asano

1990

British J Pharmacology

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I The effects of cromakalim and pinacidil on contraction and 86Rb effilux were investigated in strips of canine mesenteric artery.2 Cromakalim and pinacidil relaxed arterial strips precontracted with 20.9 mm K+ with pD2 values of 6.56 and 5.88, respectively. 3 High (above 1OpM) concentrations of pinacidil, but not cromakalim, relaxed arterial strips bathed by a medium containing 65.9 mm K+, and inhibited Ca2+-induced contractions in strips bathed by a medium containing 80 mm K+. These findings suggested that pinacidil may act as an inhibitor of Ca2+ influx. 4 In arterial strips preloaded with 86Rb, cromakalim and pinacidil increased the basal 86Rb efflux. 5 When the effects of cromakalim and pinacidil on 86Rb efflux were determined in arterial strips contracted with 65.9 mm K , both drugs increased 86Rb efflux. The increase in 86Rb efflux induced by pinacidil was much smaller than that induced by cromakalim. Under the same conditions, nifedipine decreased 86Rb effiux.6 After the addition of nifedipine to arterial strips contracted with 65.9 mm K+, pinacidil produced a greater increase in 86Rb efflux than in the absence of nifedipine, whereas the effects of cromakalim were the same for the two conditions. Therefore, the effects of pinacidil on 86Rb efflux may be the resultant of two opposing effects: an increased 86Rb efflux due to the opening of ATP-sensitive K+ channels, and a decreased efflux due to the closing of Ca2 + -activated K + channels. 7 In causing relaxation, cromakalim was competitively antagonized by glibenclamide with a pA2 value of 7.16. However, glibenclamide antagonism of pinacidil was not of the simple competitive type, suggesting that inhibition of Ca2 + influx may contribute to the relaxant action of pinacidil. 8 It may be concluded that although the ability of pinacidil to increase 86Rb efflux via ATP-sensitive K + channel opening was similar to that of cromakalim, the inhibition of Ca2 + influx by pinacidil may reduce the opening of Ca2 +-activated K+ channels in K+-contracted arterial strips.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

Masuzawa

Matsuda

Asano

1990

British J Pharmacology

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“…Charybdotoxin blocks the large-conductance Ca 2-activated K+ channel in cultured rat skeletal muscle (Miller, Moczydlowski, Latorre & Phillips, 1985), while the small-conductance Ca2+-activated K+ channel in the same preparation is blocked by apamin (Blatz & Magleby, 1986). K+ channels sensitive to these toxins have been identified in smooth muscle cells (Banks, Brown, Burgess, Burnstock, Claret, Cooks & Jenkinson, 1979;Beech & Bolton, 1989b (Hamilton, Weir & Weston, 1986;Weston, Southerton, Bray, Newgreen & Taylor, 1988). These substances have recently been suggested to act on ATP-regulatedK+ channels in smooth muscle cells (Standen, Quayle, Davies, Brayden, Huang & Nelson, 1989).…”

Section: Introductionmentioning

confidence: 99%

Role of K+ channels in spontaneous electrical and mechanical activity of smooth muscle in the guinea‐pig mesotubarium.

Lydrup

1991

The Journal of Physiology

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SUMMARY1. The spontaneous electrical and mechanical activity and the efflux rate of 86Rb+ in the guinea-pig mesotubarium were studied in the presence of agents interacting with K+ channels.2. Tetraethylammonium (TEA, 10 mM) increased the amplitude of the action potentials while having no consistent effect on the frequency or amplitude of spontaneous contractions.3. 4-Aminopyridine (4-AP, 1-5 mM) caused a graded increase in the duration of the contractions and of the electrical slow waves, and a decrease in the duration of the relaxed period between contractions. At 4 mM-4-AP or more the cell was unable to repolarize from the slow wave and the membrane depolarized to -26 mV from the normal resting potential of -63 mV. The rate of 86Rb+ efflux in the presence of 5 mm-4-AP was higher than that at 60 mM-K+, where the membrane potential is -24 mV.4. 4-AP (5 mM) evoked a contracture in Ca2`-free solution, containing 1 mM-EGTA, both at the normal [K+]o of 5.9 mm and at 60 mM-K+, suggesting release of intracellular Ca2+. 5. Apamin (0-1-1 ,SM) and charybdotoxin (1-10 nM), blockers of Ca2+-dependent K+ channels, were without effects on the spontaneous electrical and mechanical activity.6. The K+ channel opener pinacidil (10 ,lM) inhibited the spontaneous contractions and hyperpolarized the membrane by about 7 mV. The permeability to 86Rb+ was increased by a factor of 1-4.7. It is concluded that different K+ channels are involved in the generation of spikes and slow waves: one sensitive to TEA and responsible for repolarization of the individual action potential, and another sensitive to 4-AP and responsible for repolarization of the slow wave. The duration of the relaxed period can be influenced by activation of K+ channels sensitive to pinacidil.

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“…In isolated vascular smooth mus cle, both compounds act directly on the smooth muscle cells and inhibit the contrac tions evoked by various agonists [2,[4][5][6]. Although the cellular mechanism of action of diazoxide is not fully understood [3], recent findings suggest that pinacidil could activate membrane K+ channels, thereby holding the membrane potential of the smooth muscle cells at or close to the potassium equilibrium potential [4,5,7], Because it was recently reported that pi nacidil could have relaxant effects on nonvascular smooth muscles [5,8], we decided to compare the effects of pinacidil and diaz oxide on the mouse isolated distal colon. This preparation exhibits spontaneous activ ity and has been shown to represent a sensi tive tool to study the mechanisms by which various agonists and antagonists modulate intestinal tone [9,10].…”

Section: Introductionmentioning

confidence: 99%

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

Lebrun¹,

Fontaine²

1990

Pharmacology

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Pinacidil and diazoxide induced concentration-related relaxations of the longitudinal muscle of the mouse distal colon. The relaxing effects of pinacidil and diazoxide were unaffected by tetraethylammonium, but were antagonized by tolbutamide and glibenclamide. Relaxations provoked by nifedipine were not counteracted by the two hypoglycaemic sulfonylureas. It is tempting to suggest that the relaxation response to pinacidil and diazoxide could reflect the ability of both compounds to interfere with membrane K⁺ channels sharing common pharmacological properties with the K⁺_ATP channels recently described in other tissues.

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The Mode of Action of Pinacidil and Its Analogs P1060 and P1368

Cited by 34 publications

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Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

Role of K+ channels in spontaneous electrical and mechanical activity of smooth muscle in the guinea‐pig mesotubarium.

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

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The Mode of Action of Pinacidil and Its Analogs P1060 and P1368

Cited by 34 publications

References 0 publications

Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca2+‐activated K+ channels in K+ ‐contracted canine mesenteric artery

Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca2+‐activated K+ channels in K+ ‐contracted canine mesenteric artery

Role of K+ channels in spontaneous electrical and mechanical activity of smooth muscle in the guinea‐pig mesotubarium.

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

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Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery

Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca²⁺‐activated K+ channels in K⁺ ‐contracted canine mesenteric artery