Calcium antagonists and contractile responses in rat vas deferens and guinea pig ileal smooth muscle

Abstract

The effect of depletion of extracellular Ca2+ (Ca2+ext) on the loss of responsiveness of the guinea pig ileal longitudinal muscle (g.p.i.l.m.) and the rat vas deferens (r.v.d.) to K+ and cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide (CD), and K+ and noradrenaline (NA), has been examined and compared with the effects of a variety of local anesthetics and calcium antagonists. The results indicate that qualitative similarities are apparent with respect to the dependence of agonist-induced activity on Ca2+ext in both the g.p.i.l.m. and r.v.d. Distinct differences, however, in the Ca2+ translocation processes in these two tissues, in response to the different agonists, can be shown by the use of a variety of 'calcium antagonists' thus indicating that such translocation processes are both tissue and agonist selective. It is thus noted that, contrary to the Ca2+ depletion studies, D 600 and the usually more potent BAY-1040 showed no discrimination of action or potency in their ability to inhibit components of the NA response in the r.v.d. In contrast, D 600 and the more potent BAY-1040 selectively inhibited the tonic component of the K+ response. Treatment with SKF 525A and parethoxycaine (PC) in the g.p.i.l.m. and SKF 525A in the r.v.d. resulted in a nonselective inhibition of responses of the tissues to all stimulants. However, in the r.v.d. PC potentiated NA action, and its methobromide (MeBr) derivative potentiated both NA and K+ action and also, like PC, partially shifted to the left the dose-response curve to Ca2+ in NA-depolarizing Ca-free Tyrode's. The quaternary MeBr and the tertiary 2-chloroethyl (2Cl) derivatives of SKF 525A and PC were selectively more effective against CD- than K+ supported contractile activity in the g.p.i.l.m. and the 2Cl derivatives were more effective against NA than K+ responses in the r.v.d. The 2Cl derivative of PC also was more effective in antagonizing the Ca2+ dose-response curve in high-CD or high-NA than in high-K+ Ca2+-free Tyrode's.

EFFECTS OF SOME ORGANIC CALCIUM ANTAGONISTS AND OTHER PROCEDURES AFFECTING Ca2+ TRANSLOCATION ON KCl‐INDUCED CONTRACTIONS IN THE RAT VAS DEFERENS

“…Components ofthe KCI response resistant to Ca2" deprivation In agreement with Swamy et al (1976), Triggle et al (1979) and Shimodan & Sunano (1981), we have found that lanthanum, verapamil and methoxyverapamil completely block KCI contractions. Since it is well established that these drugs inhibit the movement of Ca2" into smooth muscle, this is strong evidence that both phases of the KCI contraction in the rat vas deferens use extracellular Ca2+.…”

“…Finally, the rise in tension is maintained at a lower level (tonic response) intracellular cation concentration produced by any of (Shimodan & Sunano, 1981). These responses are these processes may secondarily mobilize intracelluantagonized by calcium-free conditions, by lanthlar calcium stores (Bolton, 1979 nifedipine, verapamil and methoxyverapamil (Swamy, Triggle & Triggle 1976;Triggle, Swamy & Triggle, 1979;Shimodan & Sunano, 1981). These results show that in the vas deferens, K+ primarily utilizes extracellular calcium for contraction.…”

The effects of calcium channel inhibitors and other procedures affecting calcium translocation on drug‐induced rhythmic contractions in the rat vas deferens

“…Furthermore, a-adrenoceptor agonists induce rhythmic activity in human vasa deferentia (Ratnasooriya, Wadsworth & Gilmore, 1979), present in both longitudinal and circular muscle layers (Anton & McGrath, 1977). Although analysis of the biphasic response to high concentrations of noradrenaline in the rat vas deferens has been performed, involving Ca2l-deprivation studies and the use of La3" and calcium channel inhibitors (Swamy, Triggle & Triggle, 1976;Triggle, Swamy & Triggle, 1979;Stone, 1981;Hay & Wadsworth, 1983b), there have been no investigations into the involvement of Ca2+ in the rhythmic contractions produced by a-adrenoceptor stimulation. Thus, the purpose of this study was to examine excitationcontraction coupling mechanisms involved in rhythmic activity in the rat vas deferens, using calcium channel inhibitors and analysis of the Ca2+-dependence of the responses.…”

Different Pathways for Ca2+ Influx and Intracellular Release of Ca2+ Mediated by Muscarinic Receptors in Ileal Longitudinal Smooth Muscle.

“…Receptor-mediated Ca 2+ influx has been demonstrated in many tissues and cells, but in some tissues, agonist-induced Ca 2+ influx is sensitive to voltage-dependent Ca2+ channel blockers (8,9,13), whereas in others, it is not (14,15). These findings suggest that these channels are tissue-specific (16).…”

“…However, the dose-response curve for IP3 formation does not coincide with that for muscle contraction, the latter being in a lower concentration range of CCh (7). Moreover, contraction of ileal longitudinal muscle is known mainly to depend on the extracellular Ca 2+ concentration (8). These facts indicate that not only release from intracellular stores, but also influx of extracellular Ca 2+ through the receptor-operated Ca 2+ channels may con tribute to the increase in [Ca 2+]; in longitudi nal ileal smooth muscle.…”