The effects of chloroquine on the smooth muscle of isolated rat aortic segments were investigated in preparations contracted with either noradrenaline or high-potassium. At rest, chloroquine (up to 10^-4 M) produced no mechanical response, while noradrenaline (10^-6 M) produced a sustained contraction. In the presence of 10^-4 M chloroquine, however, the amplitude of contractions produced by noradrenaline was attenuated by about 70%, with no alteration of the resting tension. In preparations contracted either with noradrenaline or with high-K solutions, chloroquine produced a concentration-dependent relaxation. The tension decreased below resting level as a result of the co-application of these stimulants. The relaxing actions of chloroquine were not altered by methylene blue (an inhibitor of guanylate cyclase), suggesting that the cyclic GMP-related mechanism was not involved. The ratio of the amplitude of chloroquine-induced relaxation was similar in contractions produced by different concentrations of potassium ions, suggesting that chloroquine did not cause relaxation as a result of membrane hyperpolarization. These results suggest that the inhibition of aortic smooth muscle contraction caused by chloroquine is different to that produced by endothelium-derived vasodilating factors. It is possible that the inhibition of aortic smooth muscle contraction by chloroquine involves modulation of the contractile systems and of their regulatory proteins.

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The mechanisms of the β-adrenoceptor-mediated relaxation induced by dopamine in guinea pig taenia caecum were examined. The relaxant response to dopamine was unaffected by propranolol (10^-8 - 10^-5 M) or phentolamine (10^-8 - 10^-5 M). Atenolol (3 × 10^-7 - 3 × 10^-4 M), butoxamine (10^-7 - 10^-4 M), prazosin (10^-8 - 10^-5 M), yohimbine (10^-8 - 10^-5 M), SCH 23390 (10^-8 - 10^-5 M) and haloperidol (10^-8 - 10^-5 M) had no effect on the potency of dopamine. The response to dopamine was antagonized in a concentration-dependent manner by bupranolol (3 × 10^-6 - 3 × 10^-5 M), and Schild plot of the data revealed the pA₂ value of 5.55 and the slope of the regression line was 1.13. These results suggest that the relaxant response to dopamine in the guinea pig taenia caecum is mainly mediated by the β₃-adrenoceptors.

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The effects of the type V phosphodiesterase (PDE V) inhibitors, MBCQ, zaprinast and dipyridamole, on the relationship between relaxation and cyclic nucleotide content were investigated in rat ileal smooth muscle. Each of MBCQ (0.01-10 μM), zaprinast (0.1-100 μM) and dipyridamole (0.1-100 μM) inhibited carbachol (CCh; 10 μM)-induced contractions in a concentration-dependent manner. When compared with the concentrations of these agents producing 50% relaxation (IC₅₀) of CCh-induced contraction, MBCQ was 14-20 fold more potent than the other agents. The inhibitory potency of these agents against high K⁺ (65 mM KCl)-induced contractions were similar to that for CCh. MBCQ (1, 10 μM) did not significantly increase the cGMP content above control levels in the presence of CCh (10 μM). Both Zaprinast (1-100 μM) and dipyridamole (1-100 μM) increased the cGMP content of smooth muscle preparations in a concentration-dependent manner. There was a positive correlation between the inhibition of the CCh-induced contraction and the increase in cGMP content elicited by zaprinast and dipyridamole (zaprinast; r=0.72, P<0.05, dipyridamole; r=0.92, P<0.05). However, MBCQ at a concentration which induced a medium-sized relaxation did not significantly increase the cGMP content. Neither MBCQ, zaprinast nor dipyridamole significantly increased the cAMP content of the preparations above control. In summary, it is suggested that the inhibition of CCh-induced contractions by zaprinast and dipyridamole involves increases in cGMP content via inhibition of PDE V. However the inhibition of CCh-induced contraction by MBCQ may not involve cyclic nucleotides in rat ileal smooth muscle.

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The effects of nifedipine and nickel ions (Ni²⁺), known inhibitors of L- and T-type voltage-gated Ca-channels respectively, were investigated on plateau potentials recorded from submucosal interstitial cells distributed in the mouse proximal colon. Plateau potentials were generated at a frequency of about 15 times min^-1 and were formed of two components. The primary component had an initial fast rate of rise with a transient potential (rate of rise, 130 mV/s; peak amplitude, 35 mV) and was followed by a secondary plateau component with a sustained potential (amplitude, 25 mV; duration, 2.6 s). Each cell from which recordings were made was injected with neurobiotin. Subsequent morphological examination with a confocal microscope indicated successful visualization of injected cells only in the presence of 18β-glycylrhetinic acid (an inhibitor of gap junctional connections), suggesting that these cells were dye-coupled with surrounding cells. The cells injected with neurobiotin exhibited an oval-shaped cell body with bipolar processes and were distributed in the submucosal layer, suggesting that they were submucosal interstitial cells of Cajal (ICC-SM). The plateau potentials were not altered by 0.01 μM nifedipine, but were reduced in duration by 0.1 μM nifedipine, and abolished by 1 μM nifedipine. The rate of rise of plateau potentials, but not their amplitude, was reduced by Ni²⁺ (> 10 μM), with no significant alteration of the membrane potential. In the presence of 100 μM Ni²⁺, the plateau potentials were changed to a triangular form. Thus, the plateau potentials were formed by two types of voltage-gated channel current: the initial component was produced by a Ni²⁺-sensitive channel current and the plateau component by a nifedipine-sensitive current. The possible involvement of two different types of voltage-gated Ca²⁺-channels in the generation of submucosal pacemaker potentials was discussed.

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