Using two-stage coronary ligation-, digitalis- and epinephrine-induced canine ventricular arrhythmia models, we examined whether a new positive inotropic agent, NKH477, 6-(3-dimethylaminopropionyl)forskolin hydrochloride, a water-soluble derivative of forskolin, had deleterious effects on arrhythmias. NKH477 increased heart rate (HR) and decreased blood pressure (BP) in dogs with all the arrhythmia models. Unexpectedly, NKH477 suppressed digitalis- and epinephrine-induced arrhythmias, but did not suppress two-stage coronary ligation arrhythmia or aggravate it. These results indicate that NKH477, unlike other new positive inotropic agents such as amrinone, milrinone, sulmazole and vesnarinone, did not worsen these arrhythmias; thus, NKH477 may be a useful positive inotropic agent with little arrhythmogenic effect.
The pharmacological properties of a new type of anti-cancer agent, 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and uracil (U), in a molar ratio of 1:4, were investigated and compared with those of FT, 5-fluorouracil (5-FU) and uracil. UFT at doses larger than 874.8 (FT: 270.0) mg/kg p.o. produced slight central nervous depression in mice and rats, as demonstrated by prolongation of the thiopental anesthesia, analgesic activity in the acetic acid stretching test, an anticonvulsant effect on maximal electroshock convulsions and decrease in body temperature. In rabbits UFT at a dose of 291.6 (FT: 90.0) mg/kg p.o. produced an increase in the drowsy EEG pattern. UFT at high dose produced clonic convulsions in mice and rats and cardiac fibrillation in rabbits. UFT had slight cardiorespiratory effects in anesthetized rabbits and dogs and at a dose of 291.6 (FT: 90.0) mg/kg i.v. it increased the voltage of the T-wave in ECG in anesthetized dogs. At high doses UFT inhibited gastrointestinal transit in mice and it caused emesis in dogs. At doses larger than 291.6 (FT: 90.0) mg/kg p.o. it had a diuretic effect and at higher doses it slightly increased the blood glucose level in rats. FT at equal doses to UFT had the same effects as UFT and the effect of 5-FU was similar to that of UFT. The pharmacological activity of uracil was much less potent. It was concluded that the pharmacological effect of UFT was almost entirely due to FT, however, UFT had much less effect than FT in inducing clonic convulsions, increasing the voltage of the T-waves in ECG and inducing emesis, its depressant effect is probably due to its constituent uracil.
The effects of propiverine hydrochloride (P-4, CAS 60569-19-9), a new drug to treat pollakiuria, was investigated on the spontaneous contractions of isolated guinea-pig urinary bladder strip and rhythmic urinary bladder contractions of anesthetized dog. At 10(-6)-10(-5) mol/l P-4 raised the base line of an isolated guinea-pig urinary bladder strip and accelerated its spontaneous contraction. At 10(-4) mol/l P-4 raised, and then lowered the baseline, and accelerated then suppressed its spontaneous contractions. Papaverine at 10(-6)-10(-4) mol/l also showed a similar action as P-4 in the isolated guinea-pig urinary bladder strip. Flavoxate at 10(-6)-10(-4) mol/l raised its base line and accelerated its spontaneous contractions. Those of P-4 at 10(-5) mol/l were not inhibited by tetrodotoxin 10(-6) mol/l). At doses of 50 mg/kg or more, intraduodenal administration of P-4 suppressed the frequency of rhythmic urinary bladder contractions of anesthetized dog in a dose-dependent manner. These results indicate that P-4 shows mainly an accelerating action on the endogenous spontaneous contractions of urinary bladder, but on exogenous contractions induced by the Balloon's method it shows an suppressing action and regulates the functions of the urinary bladder, so P-4 might become a useful drug for the clinical treatment of micturitional dysfunction, for example, pollakiuria.
To investigate the pharmacological properties of Ascaris muscle, comparative studies were undertaken on the actions of various drugs on Ascaris muscle, guinea pig isolated ileum and frog isolated rectus preparations. In Ascaris muscle and frog isolated rectus preparations, the contractile activities with acetylcholine (ACh, 10(-5) g/ml in Ascaris and 10(-6) g/ml in frog rectus) and 1, 1-dimethyl-4-phenylpiperazinium (DMPP, 10(-6) g/ml) were inhibited significantly and reversely by d-tubocurarine (d-Tc, 10(-5) g/ml) and mecamylamine (Meca, 10(-5) g/ml), and slightly by atropine (Atr, 10(-4) g/ml) and hexamethonium (C6, 10(-4) g/ml). In guinea pig isolated ileum preparation, the contractile activity with ACh (10(-6) g/ml) was inhibited markedly and reversely but Atr (10(-6) g/ml), while the activity with DMPP (10(-6) g/ml) was similarly inhibited by Meca (10(-6) g/ml), C6 (10(-6) g/ml) and Atr (10(-6) g/ml). Although frog isolated rectus preparation was contracted with 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium (McN-A-343, 10(-5) g/ml) but not with pilocarpine (10(-4) g/ml), Ascaris muscle preparation was not affected by these agonists. Frog isolated rectus preparation was contracted with 5-hydroxytryptamine (5 HT, 10(-4) g/ml) but was not affected by histamine (His, 10(-3) g/ml) and gamma-aminobutyric acid (GABA, 10(-4) g/ml), whereas Ascaris muscle was contracted with His (10(-3) g/ml) and relaxed with 5-HT (10(-4) g/ml) and GABA (10(-5) g/ml). These results suggest that Ascaris muscle as well as skeletal muscle have nicotinic receptors and that the Ascaris muscle has properties which differ specifically from skeletal muscle.
Summary— The pharmacological properties of TH‐142177 (N‐n‐butyl‐N‐[2′‐(1‐H‐tetrazole‐5‐yl)biphenyl‐4‐yl]‐methyl‐(N‐carboxymethyl‐benzylamino)‐acetamide), a novel antagonist of the angiotensin II (AII) AT 1 receptor, were studied in vitro and in vivo, and compared to those of losartan. In the rat isolated aorta, TH‐142177 produced parallel shifts to the right of the concentration‐response curves for AII‐induced contractions without affecting the maximal response (pA 2 = 9.07). The inhibitory potency of TH‐142177 in the aorta was about three times greater than that of losartan. TH‐142177 completely inhibited the specific binding of [ 125 I]AII to AT 1 receptor in rat aortic membranes (K i = 1.6 × 10 −8 M), whereas specific [ 125 I]AH binding to AT 2 receptor in bovine cerebellum and human myocardium was not affected by concentrations of TH‐142177 up to 10 −5 M. Losartan also inhibited the [ 125 I] AII binding to rat aortic membranes ( K i = 2.2 × 10 −8 M). Following the intravenous administration to anesthetized normotensive rats, TH‐142177 dose‐dependently inhibited the increase in systolic blood pressure induced by an intravenous bolus injection of AII that was 1.5 times less potent than losartan. Furthermore, the oral administration of TH‐142177 to conscious renal hypertensive rats exerted a dose‐dependent reduction of systolic blood pressure without significantly effecting the heart rate. TH‐142177 was at least three times more potent than losartan. These results demonstrate that TH‐142177 is a potent and selective antagonist of AT 1 receptors and by oral administration has a long‐lasting antihypertensive activity.
