Pharmacological characteristics of cimetropium bromide (cimetropium), a muscarinic receptor antagonist, were studied in longitudinal muscle preparations with myenteric plexus of guinea-pig ileum. Cimetropium was shown to have more potent antimuscarinic effect than butylscopolamine in inhibition of contraction of the preparations. Interestingly, when the inhibitory effects of cimetropium were compared in respect of relative potency to atropine between its effects on electrical field stimulation- or nicotine-, and exogenous AChinduced contraction, it has a more potent effect on the former contraction than that on the latter one. In the superfusion experiments of the preparation which had been preloaded with labelled choline, cimetropium decreased the labelled ACh release induced by electrical field stimulation under the muscarinic autoinhibition blocked-condition. From these findings, two pharmacologically characteristic effects of cimetropium in addition to postsynaptic muscarinic receptor antagonism were suggested: one is a weak effect on muscarinic autoreceptors in comparison to atropine and the other is an inhibitory effect on the ACh release.

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We performed experiments to investigate the actions of protein kinase C (PKC) on mechanical contraction during agonist stimulation in guinea-pig stomach. We used carbachol and high K condition to enhance mechanical contraction by mobilizing intracellular Ca²⁺ and increasing Ca²⁺ influx through voltage-dependent Ca²⁺ channel, respectively. Phorbol 12, 13-dibutyrate (PDBu) increased spontaneous contractions sensitive to verapamil (438±82.2%, n=7) and potentiated high K-induced contraction (189±22.5%, n=5). However, carbachol (CCh)-induced contractions in PDBu-treated condition depended on extracellular Ca²⁺. In the presence of extracellualr Ca²⁺, CCh-induced contraction was potentiated, while it was suppressed in the absence of extracellular Ca²⁺ in Ca²⁺-preloaded muscle strips. To prove the hypothesis that such phenomena might be related with changes of myoplasmic Ca²⁺ concentration, we investigated the effect of PDBu on voltage-dependent Ca²⁺ current (I_Ca) and CCh-induced Ca²⁺-activated K current (I_{K (Ca)} ) transient using whole-cell voltage clamp technique. For recording voltage-dependent Ca²⁺ current (I_Ca), 10mM Ba²⁺, instead of Ca²⁺, was used to enhance the current size. Voltage-dependent Ba²⁺ current (I_{K Ba}) was increased by PDBu (212±32.2% of steady state currents, n=5), while CCh-induced increase of I_{K (Ca)} transient was inhibited by PDBu (n=5), the changes of which were similar to those of muscle contractions. To analyze the steps involved in the inhibition of CCh-induced I_{K (Ca)} transient by PDBu, we investigated the effect of PDBu on I_{K (Ca)} in the cells perfused with Ins (1, 4, 5) P3. However, Ins (1, 4, 5) P3-induced I_{K (Ca)} was not inhibited by the treatment with phorbol ester. From these results, it is concluded that inhibition of phosphatidylinositol-phospholipase C (PI-PLC) system and potentiation of I_Ca by PKC are important regulatory mechanisms in agonist-induced muscle contraction.

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Effects of chronic treatment of stroke-prone spontaneously hypertensive rats (SHRSP) with carvedilol, an agent which has both α- and β-adrenoceptor blocking actions, on spontaneous muscle tone and on structural and functional abnormalities of endothelium were studied. The treatment of SHRSP with the drug of the dose of 30 to 200mg/kg/day lowered the blood pressure significantly. Spontaneous muscle tone in endothelium-removed preparation disappeared by the treatment. Noradrenaline-induced contraction was depressed by the treatment in endothelium-intact preparation but not in endothelium-removed preparation. The treatment prevented the structural and functional abnormalities of endothelium. Similar results were obtained by the treatment with propranolol.
These results indicate that carvedilol prevented abnormal contraction of SHRSP aorta through protective effects on smooth muscle and endothelium. These effects may play roles in blood pressure lowering effect of carvedilol.

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