1 An assessment was made of the potencies of nifedipine, gallopamil, diltiazem, cinnarizine and salbutamol as inhibitors of tension development by the uterus and cardiovascular tissues from the term pregnant rat.2 The rank order of potency was nifedipine > gallopamil > diltiazem for those preparations on which these compounds were potent, viz. spontaneous and oxytocin-induced tension development of the uterus, spontaneous tension development of hepatic portal vein, potassium chloride (KCI)-induced pressure rises of perfused mesenteric bed and electrically-stimulated (0.5 Hz) ventricular muscle. 3 The rank order of potency of nifedipine, gallopamil and diltiazem was different for those preparations on which they exhibited low potency, viz. noradrenaline-induced pressure rises of perfused mesenteric bed and tension development of aorta. 4 Gallopamil and diltiazem, but not nifedipine, were more potent against tension development by ventricular muscle stimulated at 2.5 Hz than at 0.5 Hz, suggesting that nifedipine interacts at a different site from the other compounds. 5 Cinnarizine was less potent than the other calcium antagonists on the uterus and portal vein, was the second most potent compound against KCI-induced pressure rises of the mesenteric bed and was equipotent against responses to noradrenaline and KCI of the mesenteric bed (unlike the other compounds). This suggests that the site of action of cinnarizine differs from that of the other calcium antagonists. 6 Nifedipine, gallopamil and diltiazem, like salbutamol, exhibited selectivity for inhibition of tension development by the uterus relative to the cardiovascular tissues.
1Spontaneous and potassium chloride (KCI)-induced tension development of strips of whole uterus from the day-22 pregnant rat was reduced when the tissues were incubated in a calcium ion (Ca2')-free medium. 2 Strips of whole uterus, in an initially Ca2 -free medium, responded to the cumulative addition of Ca2" with graded phasic tension development and associated rapid electrical discharges. The spasms were inhibited by gallopamil (100 nM) and diltiazem (I JM). 3 Strips of whole uterus in a depolarizing (40mM K+) medium, which was initially Ca2+-free, responded to the cumulative addition of Ca2+ with graded tonic tension development without associated electrical discharges. These spasms were inhibited by calcium entry blockers with a rank order of potency of nifedipine = gallopamil > diltiazem > cinnarizine. 4 KCl-induced tension development in endometrium-free uterine strips was antagonized by calcium entry blockers with a rank order of potency of nifedipine > gallopamil> diltiazem> cinnarizine. 5 Ca2+ influx into endometrium-free uterine strips was assessed by means of the 'lanthanum method'. KCl induced a concentration-dependent increase in 45Ca2+ influx which was suppressed or abolished by nifedipine (2.5 nM), gallopamil (100 nM), diltiazem (500 nM) or cinnarizine (5 JAM). 6 It is concluded that spontaneous and KCI-induced tension development of rat uterus involves Ca2+ influx from the extracellular medium into the myometrial cell. These results support the hypothesis that nifedipine, gallopamil, diltiazem and cinnarizine inhibit Ca2+-and KCI-induced tension development of rat uterus by reduction of Ca2" influx.
1 A low concentration (0.2 nM) of oxytocin induced phasic tension development in the isolated uterus of the day-22 pregnant rat. Tonic spasm was also induced by higher concentrations of oxytocin (2 and 20 nM). Spasmogenic responses to bradykinin and potassium chloride (KCI) also contained phasic and tonic components while acetylcholine induced tonic spasm only. 2 The phasic component of the responses to oxytocin and to bradykinin and both components of the response to KCI were inhibited by (+ )-cis diltiazem (0.1 and I JsM). The tonic component of the responses to oxytocin and to bradykinin and the responses to acetylcholine were only reduced by (+ )-cis diltiazem at concentrations >10O M. 3 (-)-cis Diltiazem was less potent than (+ )-cis diltiazem as an inhibitor of calcium (Ca2+)-induced spasm in a depolarizing medium and of the phasic spasms induced by oxytocin. The two isomers were of similar potency as inhibitors of oxytocin-induced tonic spasm. 4 Spasmogenic responses to oxytocin, bradykinin, acetylcholine and KCI were decreased when uteri were bathed in media which were Ca2+-free or of low Na+ content. However, there was no correlation between the rank order of sensitivity of the four spasmogens to the changed media and to their inhibition by (+ )-cis diltiazem. 5 Oxytocin (0.2 nM) increased the frequency, duration and amplitude of spike activity, measured by extracellular electrical recording, in parallel with enhancement of phasic tension development. With higher concentrations of oxytocin (2 and 20 nM) spike firing was initially continuous but often subsequently ceased despite the associated tonic contracture. After incubation in (+)-cis diltiazem (1OILM), oxytocin (0.2, 2 and 20 nM) produced graded tonic spasm without spike activity. 6 Oxytocin (0.2 nM) produced a small increase in 45Ca2+ influx into myometrium as assessed by the 'lanthanum method'. Higher concentrations of oxytocin (2 and 20 nM) did not increase 45Ca2" influx.7 It is concluded that the phasic component of the response of the uterus to oxytocin and bradykinin is associated with Ca2" influx via voltage-dependent Ca2+ channels. The tonic component is due to another mechanism(s) which does not appear to involve Ca2+ influx. All of the spasmogenic response to KCl can be explained by Ca2+ influx through voltage-dependent Ca2+ channels. These channels do not appear to be involved in the spasmogenic response to acetylcholine.
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