Effects of calcium channel blockers from structurally different classes and hydralazine on epinephrine-induced stimulation of glucose output from primary cultured rat hepatocytes were examined in vitro. Diltiazem, verapamil, and nifedipine dose-dependently inhibited the epinephrine-induced stimulation of glucose output from the primary cultured rat hepatocytes. In contrast to these agents, nicardipine caused decreases in the basal and epinephrine-stimulated glucose output from rat hepatocytes in primary culture. Hydralazine treatment was found to reduce the response in a dose-dependent manner. These results indicate that the calcium channel blockers and hydralazine did not potentiate but reduce the epinephrine-induced stimulation of glucose output from primary cultures of rat hepatocytes in vitro.

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In order to study the elimination rate of perfluorochemical (PFC) emulsion from the blood and the PFC contents in the main organs of the tumor-bearing animals, Wistar strain rats were intramuscularly implanted with Walker 256 carcinosarcoma and 9L glioma cells were innoculated into the femoral muscle of Fischer rats. After 7 d the Wistar rats received an injection of 4 g PEC/kg of a PFC emulsion. The Fischer rats received a similar injection after 11 d. The rats injected with the PFC emulsion were periodically sacrificed for a week. There was no significant difference in PFC contents in the blood and main organs between normal rats and the tumor-bearing rats with either Walker 256 carcinosarcoma or 9L glioma. The PFC contents in Walker tumor were about 10 times as much as those of 9L tumor. The innoculated tumors did not substantially affect the PFC retention in the blood and the accumulation of PFC in main organs after intravenously injected with the PFC emulsion.

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Effects of mazindol on the contraction induced by nerve stimulation and agonist drugs were investigated to examine the inhibition of catecholamine uptake by mazindol in the vas deferens. Mazindol at 10^-9-10^-7M potentiated a single electrical pulse-elicited neurogenic contraction which consisted of a twitch and phasic contraction. This potentiation was almost completely antagonized by prazosin. Mazindol leftwardly shifted the dose-response curve to norepinephrine in a dose-dependent manner ; the dose-ratio was 6.2-fold and 83.2-fold at 10^-9M and 10^-7M mazindol, respectively. The dose-response curves to dopamine and methacholine were also slightly shifted by mazindol. In the dibenamine-treated vas deferens, mazindol did not affect the dose-response curve to methacholine. These results suggest that mazindol potently inhibits the norepinephrine uptake without acting on the smooth muscle cells in the rat vas deferens.

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The effects of acetylcholine on pulse rate were examined in the conscious state of diabetic KK-CA^y male mice. By subcutaneously-administered acetylcholine at 3 and 10 mg/kg the pulse rate was increased in the prediabetic state, whereas it was decreased in the diabetic state. The acetylcholine induced responses in pulse rate were significantly and multiply correlated with both the blood glucose level and the dose of acetylcholine in KK-CA^y mice (r=0.47, p<0.01). The diabetic state and adrenalectomy produced an acetylcholine-hypersensitive syndrome, respectively. The hypersensitivity to acetylcholine in a whole body of diabetic mice was attenuated by repeated cold stress producing acetylcholine-subsensitivity, and was enhanced by adrenalectomy. The diabetic KK-CA^y mice are an acetylcholine-hypersensitive animal model.

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The effects of quinidine on pharmacokinetics and pharmacodynamics of propranolol were investigated in a double-blind, placebo-controlled design. Healthy subjects of group A (n=5) and group B (n=11) were given oral propranolol (dose : group A 10 mg, group B 20 mg) with placebo or propranolol with quinidine (dose : group A 100 mg, group B 200 mg) on separate occasions. Quinidine induced a significant rise in the plasma concentrations of propranolol, and the area under the propranolol concentration-time curves (AUC) was also increased about 3-fold in both groups, indicative of an alteration of propranolol pharmacokinetics. In order to estimate the pharmacodynamic action of the pharmacokinetic interaction, the change in the heart rate during treadmill exercise testing was studied in group A. A significant inhibition of exercise-induced tachycardia was observed after administration of propranolol alone, but in combination with quinidine an even greater suppression was evident. These results indicate that the coadministration of propranolol and quinidine provides not only the potentiation of quinidine action by propranolol, which has been reported, but also the enhancement of propranolol action by quinidine, due to an increased plasma concentration of propranolol.

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Bioavailability of a newly-synthesized and chemically-stable 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) as a vitamin C supplement was investigated in rats and guinea pigs. Oral administration of AA-2G to the animals resulted in an increase of serum ascorbic acid (AA) levels. However, in these sera the intact form was not detectable by the high performance liquid chromatography (HPLC) method, indicating its hydrolysis through the process of absorption. After an intravenous injection of AA-2G, the intact form diminished rapidly from the serum, followed by prolonged and marked elevation of serum AA levels. Various tissue homogenates from rats and guinea pigs were examined for their releasing activity of AA from AA-2G. High activity was observed in kidney, small intestine and serum of rats and in small intestine and kidney of guinea pigs. These hydrolytic activities were completely inhibited by castanospermine, a specific α-glucosidase inhibitor, suggesting the participation of α-glucosidase in the in vivo hydrolysis of AA-2G. AA-2G was found to exhibit obvious therapeutic effect in scorbutic guinea pigs by its repeated oral administrations. These results indicate that AA-2G is a readily available source of vitamin C activity in vivo.

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The effects of dilevalol on vascular adrenoceptors were investigated using helical strips of cat arteries. In coronary arteries partially pre-contracted with prostaglandin F_2α (PGF_2α), the concentration-relaxant response curves for isoproterenol were shifted to the right by dilevalol with a potency similar to that of propranolol, although dilevalol itself did not relax the arteries. Contractions induced by norepinephrine of mesenteric arteries were attenuated by low concentrations of prazosin but were not influenced by yohimbine of up to 10^-8M. In contrast, the norepinephrine-induced contractions of middle cerebral arteries were attenuated by yohimbine but only slightly attenuated by prazosin. With mesenteric arteries, treatment with dilevalol (10^-7 to 10^-5M) attenuated the contractions induced by norepinephrine and phenylephrine in a concentration-dependent manner. On the other hand, contractions induced by norepinephrine and clonidine in middle cerebral arteries were not attenuated by treatment with dilevalol of up to 10^-6M. Treatment with low concentrations of dilevalol (10^-8 to 10^-7M) potentiated the contractile response to the electrical stimulation of adrenergic nerves in mesenteric arteries while high concentrations (3×10⁷ to 10⁵M) attenuated it. The potentiation was reversed to attenuation by pretreatment with propranolol. Treatment with isoproterenol (10^-10 to 10^-9M) also potentiated the contractile response to the electrical stimulation in the arteries. Isoproterenol did not cause any relaxation of mesenteric arteries precontracted with PGF_2α. Attenuations by clonidine of the response to the electrical stimulation in the arteries did not significantly differ in control arteries and those treated with a high concentration (10^-6M) of dilevalol. These results suggest that dilevalol has a potent β-receptor blocking activity, weak α₁-blocking activity and β-agonistic activity but has no effect on the α₂-adrenoceptor. The potentiating effect of dilevalol on the contractile response to adrenergic nerve stimulation seems to occur only in arteries which do not relax with β-agonist.

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The cytotoxicity of γ-linolenic acid (C18 : 3n-6) against rat hepatoma AH-109A cells and the effect of bovine serum albumin (BSA) on its toxicity were examined in culture. The proliferation of AH-109A cells, evaluated by the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide assay, was significantly suppressed by γ-linolenic acid above 5 μg/ml concentration in a serum-free culture medium. However, its toxicity was reduced by supplement of BSA. Similar observation of reduced toxicity by BSA was shown by the method of trypan blue dye exclusion and a colony formation assay. The cytotoxicity of γ-linolenic acid was correlated closely with the concentration of unbound (free) γ-linolenic acid. Production of thiobarbituric acid reactive material, one of the indicators of lipid peroxidation, was stimulated by γ-linolenic acid and inhibited by BSA. These results suggested that the presence of albumin suppressed the cytotoxicity of the free fatty acid.

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Species difference in codeine uridine diphosphate-glucuronyltransferase (UDPGT) activity was studied in liver microsones of mice, rats, guinea pigs and rabbits. Codeine UDPGT activity was the highest in guinea pigs, followed by that in rabbits, and the lowest in mice and rats among these four animal species. The specific activities of codeine UDPGT in liver microsomes were not correlated well with those toward morphine, 4-nitrophenol, and 4-hydroxybiphenyl in liver microsomes of each of the species. Inducibility of liver microsomal codeine UDPGT activity in rats was examined by pretreatment with phenobarbital and 3-methylcholanthrene and compared with those of other UDPGT activities. The activity was inducible by phenobarbital pretreatment as the activity toward morphine and 4-hydroxybiphenyl. The inducibility of codeine UDPGT activity by phenobarbital pretreatment was not as high as that of morphine UDPGT activity.

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