Trimebutine maleate is known to have beneficial effect in the treatment of gastrointestinal disorders. In conscious dogs with implanted force transducers, effects of trimebutine maleate on the gastrointestinal motility were investigated by intravenous injection, and the results were compared to those with metoclopramide and hyoscine-N-butylbromide. When trimebutine maleate was administered during the motor quiescence in the interdigestive state, contractions were evoked or the quiescent time was shortened in the gastrointestinal tract. In the digestive state, the gastric antral contractile activity was reduced, and duodenal activity was somehow suppressed by trimebutine maleate; but in the jejunum, ileum or colon, the activity was augmented. Injection of metoclopramide evoked a continuous contraction in the gastric antrum and duodenum during the period of motor quiescence in the interdigestive state. In the digestive state, metoclopramide caused a slight enhancement in the contractile activity of the gastric antrum. On the other hand, hyoscine-N-butylbromide produced no effect during the period of motor quiescence in the interdigestive state and suppressed the activity of the gastrointestinal tract during the digestive state. Thus, the pattern of action of trimebutine maleate was different from metoclopramide and hyoscine-N-butylbromide. It was concluded that trimebutine maleate produces dual actions, suppression and acceleration, on the gastrointestinal motility in conscious dogs.

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Transdermal application of isosorbide dinitrate (ISDN) in the form of a tape (ISDN-Tape) to conscious dogs, in a dose of 40 mg/dog, caused a slow decrease in pulse pressure. The maximum effect was obtained 12 hour after application. The pulse pressure was still under the initial level even after 48 hours of application. In contrast, a sustained-release tablet of ISDN (ISDN-SR-Tablet), given in a dose of 40 mg/dog, significantly decreased the pulse pressure of conscious dogs by reducing systolic pressure and slightly elevating diastolic pressure. The plasma concentrations of ISDN and its two metabolites, isosorbide 2-mononitrate (2-ISMN) and isosorbide 5-mononitrate (5-ISMN), were measured by gas chromatography after application of ISDN-Tape or ISDN-SR-Tablets. The time course pattern of the plasma concentration of ISDN after application of the both preparations ran quite parallel with their decreasing effect on the pulse pressure. After application of the ISDN-Tape, the plasma concentration of ISDN was maintained at a higher level than after the application of the ISDN-SR-Tablet. The maximum plasma concentrations of the two metabolites, however, were considerably lower in the case of the ISDN-Tape than in the case of the ISDN-SR-Tablet. These results were ascribed to the fact that ISDN given through the transdermal route, in contrast to that given by the peroral route, does not undergo the first-pass effect in the liver. It was concluded that the transdermal dosage form of ISDN, which possesses a more prolonged pharmacologic effect than the oral dosage form, may be useful in the prevention and cure of angina pectoris.

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The diuretic effect of azosemide in HgCl₂-induced acute renal failure of rats was investigated in comparison with that of furosemide. Acute renal failure was induced by the single s.c. injection of 1, 2, or 4 mg/kg HgCl₂; and the test drug was administered 48 hr after treatment with HgCl₂. Treatment with HgCl₂ resulted in a dose related elevation of plasma urea nitrogen and creatinine levels (mg/dl). In rats with 1 mg/kg HgCl₂ induced acute renal failure, azosemide at doses ranging from 10 to 40 mg/kg p.o. dose-dependently increased urinary volume (ml/5 hr) and urinary Na⁺, K⁺, and Cl^- excretions (mEq/5 hr). In this case, azosemide at 40 mg/kg caused a 3.5-fold increase in urinary volume and 4.5-, 2.1, and 4.1-fold increases in urinary Na⁺, K⁺, and Cl^- excretions, respectively. Although plasma electrolyte levels were little affected by azosemide, plasma urea nitrogen and creatinine levels were significantly elevated by doses of more than 20 mg/kg of this drug. The diuretic effect of azosemide was more markedly reduced in rats with 2 mg/kg HgCl₂-induced acute renal failure than in rats with 1 mg/kg HgCl₂-induced acute renal failure. In the case of treatment with HgCl₂ of 2 mg/kg, the diuretic effect of azosemide at doses ranging from 40-320 mg/kg p.o. was dose-dependent. However, azosemide had no effect on plasma electrolyte, urea nitrogen, and creatinine levels. The diuretic effect of azosemide in rats given 4 mg/kg HgCl₂ was more pronouncedly reduced as compared with that in the case of 2 mg/kg HgCl₂. In this case, azosemide at 320 mg/kg brought about a 2.6-fold increase in urinary volume and 4.8-, 4.6-, and 3.9-fold increases in urinary Na⁺, K⁺, and Cl^- excretions, respectively. This drug had no effect on any plasma parameters. The diuretic effect of azosemide was slightly more potent than those of furosemide in the case of acute renal failure induced by 2 and 4 mg/kg HgCl₂.

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Effects of CV-2619 (10 and 30 mg/kg/day, p.o.) or ubiquinone-10 (Q-10, 10 mg/kg/day, p.o.) treatment for 5 weeks on systolic blood pressure (SBP) and myocardial energy metabolism were studied in spontaneously hypertensive rats of 20 weeks of age. The systolic blood pressure was about 205 mmHg at the start of the experiment, and a slight increase was noted thereafter in the control (vehicle) group. CV-2619, but not Q-10, inhibited the increase in the blood pressure. At 25 weeks of age, cardiac hypertrophy was noted to the same extent in either treated group. Myocardial contents of glycolytic intermediates (glycogen, glucose, pyruvate and lactate) and creatine phosphate (Cr-P), ATP, ADP, and AMP were not significantly influenced by CV-2619 or Q-10 treatment. CV-2619, however, significantly increased the energy charge, an index of myocardial energy state, with higher dose and lowered the lactate/pyruvate ratio with either dose. These results suggest that CV-2619 has a mild antihypertensive effect and improves the myocardial energy state in the hypertrophied heart during the sustained phase of hypertension in SHR rats.

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Antidote actions of CV-2619 and ubiquinone-10 (Q-10) against adriamycin (ADM) cardiotoxicity were studied in spontaneously hypertensive rats. ADM (1 mg/kg/day, i.p.) elicited widening of the QRS complex in the ECG. The widening of the QRS complex was couteracted by a 10-day treatment with CV-2619 (10 and 30 mg/kg/day, p.o.) or Q-10 (10 mg/kg/day, p.o.), which was started on the 15th day of the ADM treatment. CV-2619 or Q-10, however, did not influence ADM-induced decrease in body and heart ventricular weights. Systemic hypotension caused by adriamycin was accelerated by CV-2619 or Q-10. The ADM treatment significantly decreased myocardial glycogen and glucose contents, while it did not affect the lactate content. Furthermore, ADM did not affect the myocardial content of adenine nucleotides, but significantly increased that of creatine phosphate. CV-2619 or Q-10 medication did not counteract changes in these contents by ADM. On the contrary, both agents decreased the lactate content and increased the phosphorylation potential, an index of myocardial energy state. In conclusion, CV-2619 might be as effective as Q-10 to protect the heart against ADM cardiotoxicity, and both test agents improved the myocardial energy state.

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Effect of a novel compound, 14-ethoxycarbonyl-(3α, 16α-ethyl)-14, 15-eburnamenine (vinpocetine, TCV-3B), on the cyclic nucleotide metabolism and in vitro response of a vascular strip was investigated. The concentration of vinpocetine producing relaxation of the canine basilar arterial strip induced by 30 μM arachidonate peroxide was 3 μM. Cyclic GMP content in the vascular strip increased dose-dependently by addition of vinpocetine, and 2.5-fold elevation of cyclic GMP content in the vascular strip was observed by 10 μM vinpocetine. Administration of vinpocetine concentrations ranging from 1 to 100 μM did not produce a significant increase in cyclic AMP of the vascular strip. Vinpocetine did not stimulate guanylate cyclase, but selectively inhibited Ca²⁺-calmodulin dependent phosphodiesterase (Ca²⁺-PDE). Increase in cyclic GMP by vinpocetine is due to inhibition of Ca²⁺-PDE because Ca²⁺-PDE is known to hydrolyze cyclic GMP preferentially. Our results suggest that vinpocetine, a selective Ca²⁺-PDE inhibitor, produces relaxation of the vascular strip by the increase in cyclic GMP.

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