1. Taenia preparations from the guinea-pig caecum yielded reproducible concentration-response curves to Ca2+ (EC50 134 +/- 8 mumol/1) when maintained in depolarizing Tyrode solution containing K+ (40 mmol/1). Drugs which are claimed to be "Ca2+ -antagonists" displaced the curves to the right without depression of the maximum response. In this test nifedipine, verapamil, diltiazem, pimozide, cinnarizine, flunarizine and fendiline appeared qualitatively similar but had different potencies. 2. The antagonist effects of nifedipine, verapamil and diltiazem were readily reversed by washout of the drugs from the bathing fluid, but the effects of the other drugs were not. 3. Cinnarizine, flunarizine, pimozide and fendiline were only weakly active as relaxants of Ca2+ (100 mumol/1)-induced contractions, when compared with their antagonist activity when applied initially in Ca2+ -free media. As the presence of Ca2+ (100 mumol/1) in the K+ -Tyrode reduced the antagonist effects of cinnarizine and pimozide, but not that of verapamil and diltiazem, the weak activity of some of the antagonists as relaxants of Ca2+ -induced contractions can be attributed to a protective effect of Ca2+ during the incubation period with the antagonist. 4. The problems associated with the assessment of the potency of drugs as "Ca2+ -antagonists" are discussed and it is proposed that three subgroups of drugs may exist within the overall classification.

Assessment of "Ca2+ -antagonist" effects of drugs in K+ -depolarized smooth muscle. Differentiation of antagonist subgroups.

The effects of papaverine and of the organic calcium-antagonistic agents D 600 and nifedipine on the contraction induced by noradrenaline and calcium were studied on the isolated aorta and mesenteric artery. The affinities of both agonists, given as pD2-values, were significantly higher on the aorta than on the mesenteric artery. Under our experimental conditions D 600, nifedipine and papaverine were found to act as antagonists against calcium and noradrenaline in a non-competitive fashion. In either vessel, the calcium-antagonistic activity of D 600 and nifedipine was about 1000-fold greater than that of papaverine, whereas their antagonistic activity against noradrenaline was about 1000-times weaker, i.e. D 600 as well as nifedipine were about equipotent with papaverine. The comparison between the calcium-and the noradrenaline-antagonistic activity offers the possibility to evaluate the specificity of calcium antagonistic agents.

Influence of papaverine, D 600, and nifedipine on the effects of noradrenaline and calcium on the isolated aorta and mesenteric artery of the rabbit

1 In helically cut strips of canine cerebral arteries exposed to Ca2+-free media and depolarized by K+, the addition of Ca2+ caused biphasic (transient and sustained) contractions, while in coronary and mesenteric arteries, the additon of Ca2+ produced a sustained contraction sometimes preceded by a slight transient contraction. 2. These Ca2+-induced contractions were attenuated by Cd2+ (50 to 100 micron) in a dose-dependent manner, the attenuation being greater in cerebral than in coronary and mesenteric arteries. The inhibitory effect of Cd2+ was prevented and partially reversed by 1 mM cysteine. 3. Verapamil and papaverine were also effective in attenuating the Ca2+-induced contrations in cerebral and peripheral arteries: susceptibility to verapamil was in the order, cerebral greater than coronary greater than mesenteric, while that to papaverine was in the order, cerebral=coronary greater than mesenteric. 4. It may be concluded that the agents that interfere with trans-membrane influxes of Ca2+ cause a greater relaxation in cerebral than in peripheral arteries, as is seen with papaverine, a non-specific vasodilator.

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Inhibition by Cd2+ verapamil and papaverine of Ca2+-induced contractions in isolated cerebral and peripheral arteries of the dog.

High K-induced contractions in the smooth muscle of rabbit aorta and guinea pig taenia coli may be described as follows: High K depolarizes the smooth muscle cell membrane and opens voltage dependent Ca channels, resulting in an influx of extracellular Ca and an activation of contractile machinery. A part of the cellular Ca is taken up by mitochondria. Oxygen consumption of the muscle increases to compensate for the ATP consumed by contraction. Hyperosmotic high K solution induces osmotic shrinkage of the cell which uncouples membrane excitation from contraction. Isosmotic high K, Na deficient solution induces swelling of the cell and also inhibits the synport of Na and glucose resulting in an ATP deficiency; both of the changes could inhibit muscle contractile tension. Na deficiency may also stimulate Ca influx coupled to Na efflux in some smooth muscle preparations although such mechanism does not seem to play an important role in rabbit aorta and guinea pig taenia coli.

https://www.jstage.jst.go.jp/article/jsmr1965/20/6/20_6_427/_pdf

Potassium-induced contraction in smooth muscle.

1. Effects of papaverine (5 × 10-6-5 × 10-5M) were studied on the spontaneous and evoked electrical and mechanical activity of the guinea-pig taenia coli. In normal Locke solution, papaverine slowed and finally stopped the spontaneous spike discharge, usually with a small hyperpolarization of a few mV.

2. Papaverine did not change the membrane resistance in normal Locke solution. It abolished the repetitive firing of spikes during the depolarization in response to a current pulse, but a single spike of normal amplitude could always be evoked.

3. The mechanical response elicited by a single spike was reduced by papaverine in normal Locke solution. During the maintained depolarization produced by a long current pulse the tonic component of the contraction was more reduced than the phasic component related to the initial spike activity.

4. The effects of papaverine were essentially the same as in normal Locke solution when NaCl was replaced with LiCl, or in excess K (24 mM), except that the membrane resistance was increased by papaverine in the presence of excess K.

5. Excess Ca (6 mM) antagonized the effect of papaverine on the mechanical response, but not on the electrical response. When the muscle was depolarized in Ca-free solution, papaverine caused repolarization of the membrane and electrical activity reappeared. This effect was similar to that of Mg (4 mM).

6. The mechanism by which papaverine suppresses the spontaneous spike activity is discussed and is compared with that of isoprenaline, from which it appears to differ. The observations indicate that papaverine, like Mg, may bind with a site at the membrane with which Ca normally binds, thereby modifying the electrical and mechanical activity controlled by Ca.

/pdf/the-effects-of-papaverine-on-the-electrical-and-mechanical-3a4dlbwyv7.pdf

M Ferrari

Papers

On the mechanism of action of some myolytic agents on depolarized guinea pig taenia coli.