It is generally accepted that full and partial agonists interact with the same receptors according to the classical receptor mechanisms. We have modified the drug receptor mechanisms of M₃-, α₁- and β-receptors. Among the muscarinic receptors, there are two subtypes of M₃-cholinoceptors, propylbenzilylcholine mustard (PrBCM)-sensitive receptors and (PrBCM)-resistant ones. Full agonists contract the guinea pig ileum through both types of cholinoceptors, while the partial agonists produce contractions through only the PrBCM-sensitive receptors. Two subtypes of α₁-adrenoceptors, α_1A and α_1B, were demonstrated in some arteries. Full agonists contracted the rabbit aorta through both the α_1A- and α_1B-adrenoceptors, while the partial agonists mediated contraction through only the α_1A-adrenoceptors. β-Chloroethylamines (PrBCM and chloroethylclonidine) can discriminate the subtype of M₃ or α₁-receptors in the presence of GTP. β-Adrenoceptors have two different types of binding sites, high and low affinity sites. The competitive antagonistic effect of the partial agonist is due to their ability to compete with the full agonists for the high affinity site, while the partial agonists interact with the low affinity site to induce the β-adrenergic effect. A regional difference in α₁-adrenoceptor mechanisms was discussed. The potency of norepinephrine in veins is related to α₁-adrenoceptor densities. In contrast, the potency of norepinephrine is linearly related to the agonist dissociation constant. This discrepancy suggests a qualitative difference between α₁-adrenoceptor mechanisms in the veins and arteries.

View full abstract

The effects of orally administered ambroxol HCl (ambroxol) on guinea pig tracheal mucous secretion and rat pulmonary surfactant secretion were investigated histologically and biochemically. Ambroxol significantly increased the number of active goblet cells in guinea pig tracheal epithelium and total mucopolysaccharide level. Moreover, ambroxol significantly increased the neutral mucopolysaccharide level and PAS-positive substance in the guinea pig tracheal submucosal glands. Ambroxol did not show a significant effect on the content of the total phosphatidylcholine in rat lung lavage fluid, while ambroxol significantly increased the ratio of disaturated phosphatidylcholine to total phosphatidylcholine. From these results, it is suggested that ambroxol increases both the tracheal mucous secretion, especially the neutral mucopolysaccharide, and pulmonary surfactant secretion and these effects reflect part of the expectorant mechanism of the drug.

View full abstract

The effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, were studied in mice. The combination of enoxacin at 30 or 100 mg/kg, p.o. and fenbufen at 100 mg/kg, p.o. induced convulsions; and the mice died as a result of the convulsions. Pretreatment with either phenobarbital, phenytoin, valproic acid intraperitoneally, or morphine intravenously did not influence the convulsions. A high dose of diazepam or clonazepam prolonged the survival time, but could not prevent the mice from dying. After the occurrence of convulsions induced by enoxacin with fenbufen, administration of the excitatory amino acid antagonist MK-801 at 1 mg/kg, i.v. extended the survival time, even though all the mice died as a result of the convulsions. Simultaneous intravenous injections of MK-801 and diazepam suppressed the convulsions. This suppression was stronger than that produced by MK-801 or diazepam, injected separately. However, no mouse survived at the end. From these results, participation of both GABA-ergic and exitatory amino acidergic systems in the convulsions induced by enoxacin and fenbufen was discussed.

View full abstract

“Tsumura-shuuji-bushi-matsu” (TJ-3021) is a herbal medicine produced from Aconiti tuber through autoclaving to decrease its toxicity. In this study, the analgesic effects of TJ-3021 and mesaconitine (MA) was examined in rats and mice. TJ-3021 (300 mg/kg, p.o.) or MA (0.5 mg/kg, p.o.) depressed the acetic acid-induced writhing significantly. In Randall-Selitto's method, TJ-3021 (1000 mg/kg) increased the pain threshold ratio in the inflamed foot significantly but not in the normal foot. In the hot plate method or on adjuvant-induced arthritic pain, TJ-3021 (1000 mg/kg) significantly increased the pain threshold, and its effect was less than that of “nama-bushi-matsu” (TNB), which was produced from the same Aconiti tuber without autoclaving. Repeated cold stress (RCS) for 65.5 hr decreased the pain threshold ratio on the paw pressure in rats by 60%. TJ-3021 (300 mg/kg) significantly increased the pain threshold ratio in RCS rats, and its activity was almost the same degree as that of TNB. MA (0.5 mg/kg) significantly increased the pain threshold ratio in RCS rats or on the adjuvant-induced arthritic pain; and in RCS rats, it was more potent than morphine (1 mg/kg, p.o.).

View full abstract

The spasmolytic mechanisms of nicorandil, a novel antianginal drug, were investigated using 3, 4-diaminopyridine (3, 4-DAP)-induced phasic contractions of isolated canine coronary arteries in comparison with those-of cromakalim and pinacidil. Nicorandil (10^-4 M), cromakalim (10^-6 M) and pinacidil (10^-5 M) suppressed the phasic contractions. Pretreatment with glibenclamide (10^-6 M), a specific blocking agent of ATP-sensitive K⁺ channel, eliminated the suppression of phasic contractions by these drugs; glibenclamide completely eliminated the suppression by cromakalim, while the eliminations against nicorandil and pinacidil were incomplete. The recoveries of peak tensions were only 56.8 % and 76.1 % for nicorandil and pinacidil, respectively. Nicorandil and pinacidil may suppress the phasic contractions via K⁺ channel opening and additional mechanisms. Methylene blue (10^-7 ?? 10^-5 M) alone, a guanylate cyclase inhibitor, had no effect on the suppression of phasic contractions by nicorandil. In the presence of glibenclamide (10^-6 M), however, the pretreatment with methylene blue significantly augmented the recovery of peak tension for nicorandil. These results indicate that K⁺ channel openers may suppress the phasic contractions induced by 3, 4-DAP via ATP-sensitive K⁺ channels, and that additionally, nicorandil may suppress the phasic contractility through guanylate cyclase stimulation, as a nitrate.

View full abstract

The effects of tiropramide on the isolated detrusor and intravesical pressure of the bladder in situ in rats were compared with those of flavoxate, oxybutynin and terodiline. The IC50 values (×10^-5 M) of tiropramide for carbachol (CCh)-, K⁺ (60 mM)-, Ba²⁺ (10 mM)-, and electrical stimulation-induced contractions were 3.6, 4.2, 5.8, and 2.9, respectively. The four antispasmodics used (2 and 4 mg/kg, i.v., each) abolished the rhythmic bladder contractions in situ in anesthetized rats. Of the four compounds, oxybutynin was most potent and no significant differences were observed between the inhibitory effects of tiropramide, flavoxate and terodiline. The administration of flavoxate (30 and 60 mg/kg) into the duodenum little influenced the rhythmic bladder contractions. Tiropramide, flavoxate, oxybutynin and terodiline (8 and 12 mg/kg, i.v., each) dose-dependently prolonged the time to the volume-evoked micturition reflex, and the activity of tiropramide was not statistically different from those of the other three antispasmodics. Under unilateral pelvic and bilateral hypogastric nerve transection, both of the contractions induced by electrical stimulation of the peripheral and central cut ends of the pelvic nerve were dose-dependently inhibited to the same extent by tiropramide and terodiline. These results suggest that the effects of tiropramide on the function of urinary bladder in rats may be mainly due to direct actions on the smooth muscle, and that tiropramide is more potent than flavoxate and less potent than oxybutynin and terodiline.

View full abstract

The naturally occurring Tinospora crispa (T.c.) at Chiang Mai in Thailand has been found to inhibit carrageenin-induced foot pad edema. Compared with the control group, oral administration of the 50% methanol extract (10 mg/kg) from its stems inhibited the edema by 38% in volume, which was induced 4 hr after stimulation by carrageenin in rats. This inhibitory effect on edema formation has been most significant in the n-butanol soluble fraction compared with the ethyl ether- or water-soluble ones, and the action of the n-butanol fraction has been observed in a dose-dependent manner in the range of 1 to 30 mg/kg, p.o. Administration of this fraction by the s.c., or i.p. route also inhibited the carrageenin-induced edema formation to the same degree as that by the oral route. The 3 mg/kg, s.c. dosage of the fraction corresponds roughly to 250 mg/kg sulpyrine and 10 mg/kg diphenhydramine, s.c. Moreover, the fraction administered i.v. also reduced LPS-induced fever in rabbits, and had an antagonistic effect equivalent to 100 mg/kg sulpyrine and 1 mg/kg morphine hydrochloride (in i.p.-administration). The comprehensive anti-inflammatory substance(s) contained in T.c. stems are moderately nonpolar compounds soluble in n-butanol and absorbable from both walls of the gut and vessels. The usefulness of a modified dosage of this plant extract for clinical treatment of various types of inflammation is highly suggested.

View full abstract

Gomishi and Shosaiko-to were administered to the rats at a dose of 10 ?? 100 mg/kg daily for 2 weeks, and their effects on lipid peroxidation of rat brain were compared with that of α-tocopherol. Administration of Gomishi and Shosaiko-to showed almost the same suppressive action on the lipid peroxidation. Gomishi and Shosaiko-to exhibited a radical-trapping action on a stable free radical, 1, 1-diphenyl-2-picrylhydrazyl (DPPH), which was estimated photometrically. The effects of Gomishi or Shosaiko-to at concentrations of 10^-3 to 10^-5g/ml on lipid peroxidation of rat brain homogenates were investigated. The lipid peroxidation was inhibited by the addition of these drugs, and the suppressive effect was also dependent on the concentration. These suppressive effects with Shosaiko-to were stronger than those of Gomishi. These results suggest that the radical trapping action of Gomishi or Shosaiko-to is the likely mechanism suppressing brain lipid peroxidation; Particularly, the suppressive effect on the brain's lipid peroxidation by Shosaiko-to is at least in part due to its radical trapping action and inhibition of O₂^- production.

View full abstract

To clarify the therapeutic effects of several traditional Chinese medicines to improve disorders of carbohydrate, lipid and mineral metabolism, spontaneously diabetic rats (WBN/Kob) were treated with Vit. D₂, 1×10⁵ I.U./kg b.w./day, for 4 days, and then fed a hyperlipidemic diet containing traditional Chinese medicines for 6 weeks. The following results were obtained: 1) In the diabetic rats, the 3 traditional Chinese medicines further decreased the blood glucose level at 120 min after glucose loading in the glucose tolerance test. 2) The drugs increased the inorganic phosphate in the liver and normalized mineral metabolic disorder. 3) Hachimi-zio-gan decreased the cholesterol content in the kidney, and Sho-saiko-to decreased the cholesterol content in the elastin fraction (elastin-cholesterol) of the kidney. Such experimental results suggest that traditional Chinese medicines may be effective against the pathological conditions of diabetes millitus that involve disorders of lipid and mineral metabolism.

View full abstract

Antinociceptive effects of sodium hyaluronate (Na-HA) were studied on the basis of improvement in the graded abnormal gait elicited by arthritis induced by intra-articular administration of monosodium urate crystal (MSU) to rats. One hour before MSU injection, intra-articular administration of a 1.0% solution of Na-HA with different molecular weights, ranging from 4.70×10⁵ to 2.02×10⁶ (HA-200), improved the score of abnormal gait in a molecular weight-dependent manner in the experimental arthritis model. Similarly, administrations of HA-200 at concentrations ranging from 0.1 to 1.0 % prior to MSU treatment resulted in improvement of the score in abnormal gait in a dose-dependent manner. To elucidate the antinociceptive mechanisms of Na-HA, effects of pretreatment with Na-HA (1.0%) of different molecular weights on prostaglandin E₂ (PGE₂) and bradykinin (BK) releases in synovial fluid 3 hr after MSU injection were studied. Increases in PGE₂ and BK concentration in the synovial fluid were depressed in a molecular weight-dependent manner by Na-HA (1.0 %) pretreatment. These results indicate that Na-HA attenuates the nociceptive responses inflicted by the MSU-induced arthritis. Such an antinociceptive effect may be due to the inhibition of PGE₂ and BK synthesis in the synovial joint of rats.

View full abstract