We investigated the effects of inhibitors of the sarcoplasmic reticulum (SR) functions on the tonic contractions induced by norepinephrine (NE) in the Ca²⁺-depleted Mn²⁺-loaded was deferens of the guinea pig in the absence of both Ca²⁺ and Mn²⁺ (Mn²⁺-dependent NE-contraction). In control preparations without Ca²⁺ depletion and Mn²⁺ loading, either cyclopiazonic acid (CPA, 10μM) or ryanodine (RYA, 3μM) inhibited the initial phasic and tonic components but not the large phasic component of NE-induced contraction in normal medium containing 2.2mM Ca²⁺. In contrast, CPA did not affect the Mn²⁺-dependent NE-contractions. The inhibitory effect of RYA slowly developed with each repetition of the Mn²⁺-dependent NE-contraction and the magnitude of the inhibition was slight. A23187 (10μM) inhibited the NE-induced contractions of the control preparations in the same manner as CPA and RYA. Although A23187 did not induce contractions in the Mn²⁺-loaded preparations, A23187 augmented the Mn²⁺-dependent NE-contractions. The augmented tonic contractions returned to the resting level by washing NE and A23187. The augmentation remained for 3 successive contractions in the absence of A23187. However, the 2nd application of A23187 did not augment the contraction. These results suggest that neither Mn²⁺-release from SR nor Mn²⁺-influx from the extracellular space contributes to the Mn²⁺-dependent NE-contractions. We concluded that NE induces Mn²⁺-dependent contractions by increasing Mn²⁺ sensitivity ofcontractile processes but not by increasing intracellular Mn²⁺ concentration.

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The influences of blood pressure and age of spontaneously hypertensive rats on endothelium-dependent tension oscillation of aortic preparation were studied. Rats with different blood pressures, normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and malignant type of SHRSP (M-SHRSP), were used. The effects of antihypertensive treatment of SHRSP on the tension oscillation were also studied. High doses of noradrenaline induced tension oscillations in endothelium-intact preparations of all strains of young rats. The rate of the occurrence of the tension oscillation decreased age-dependently. The decrease was faster when the blood pressure of the rats was higher. Application of acetylcholine in the presence of noradrenaline induced a relaxation and tension oscillations, both of which were negatively dependent on age and blood pressure. Antihypertensive treatment of hypertensive rats with hydralazine or captopril prevented a decrease in incidence of the tension oscillation. These influences of age and blood pressure as well as antihypertensve treatments on the tension oscillation resembled those on the endothelium-dependent relaxation and are thought to be brought about by functional changes of the endothelium.

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The effects of optical isomers of ephedrine (EPH) and methylephedrine (MEP) on the twitch response to electrical stimulation (1msec, 1Hz) in the isolated ratwas deferens were investigated to clarify the action on α₂-adrenoceptors. l-EPH (10^-7-3×10^-5M) and d-EPH (10^-6-10^-4M) markedly inhibited the twitch response in the presence of prazosin (10^-6M). l-MEP also inhibited the twitch response at high concentrations (3×10^-5-10^-3M). The rank order of inhibitory potency was l-EPH>d-EPHH>H>l-MEP. Yohimbine (3×10^-7M), a selective α₂-adrenoceptor antagonist, attenuated the twitch-inhibitory effects of EPH isomers and l-MEP. Furthermore, the twitch-inhibitory effects of EPH isomers and l-MEP were attenuated by reserpine treatment (8mg/kg, s.c.). On the other hand, d-MEP showed the potentiation of twitch response, and competitively antagonized the twitch-inhibitory effect of clonidine (10^-9-10^-6M) with the pA₂ value of 4.3 in the presence of prazosin. These results suggest that EPH isomers and l-MEP have stimulating activity for presynaptic α₂-adrenoceptors. In addition, the twitch-inhibitory effect of EPH isomers and l-MEP may be at least partly mediated through the release of noradrenaline. It is also suggested that d-MEP has competitive α₂-adrenoceptor antagonist activity.

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Contractile responses to serotonin (5-HT) of fundic smooth muscle strips isolated from both control and streptozotocin (STZ)-induced diabetic rats were investigated. Contrary to carbachol (CCh) which causes contractile hyperreactivity in DM, 5-HT response tended to decrease in DM compared to that of the control. Pindolol (10^-5M) increased the value of EC₅₀ of the concentration-response to 5-HT about 2.5 times in both the control and DM. After treatment with pindolol, the maximal tension to 5-HT in DM significantly decreased compared to that of the control. Pindolol showed no effect on the contractile response to CCh. Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control. Mianserin (10^-5M) increased the EC₅₀ of the response to 5-HT about 2-2.5 times in both groups, but did not cause a significant difference between the control and DM. The Ca²⁺-induced contraction caused hyperreactivity in DM in the presence of 10^-6M CCh, but that in DM was not significantly different from the control in the presence of 10^-6M 5-HT. Pretreatment of phorbol 12-myristate 13-acetate (PMA, 10^-5M) significantly attenuated the response to 5-HT in the control, but not in DM. Results suggest that the contractile response to 5-HT in DM is related to the altered Ca²⁺ signal transduction system via disturbed protein kinase C (PKC) activity, and that there are alterations of receptor characteristics and of the density in 5-HT receptor subtypes, especially 5-HT_1A, during DM development.

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