The hypotensive and antimyocardial-stunning effects of a new 1,5-benzothiazepine antihypertensive agent, S-2150, were investigated in dogs. S-2150 (30 mg/kg, p.o.) decreased the blood pressure in conscious renal hypertensive dogs. Although the maximal hypotensive effect of S-2150 was observed at 5-9 h after administration, the effect of diltiazem was seen at 2.0 h. Arrhythmia was not observed as a hypotensive effects of S-2150 but was markedly induced by diltiazem. In anesthetized open-chest dogs, S-2150 (20 micrograms/kg/min, i.v.) caused by hypotensive effect similar to that of diltiazem but decreased myocardial work (double product) by much less than did diltiazem. S-2150 more promptly improved the local myocardial stunning caused by occlusion of the left anterior descending coronary artery and its reperfusion. This effect did not accompany the energy-sparing action in ischemic/reperfused myocardium, which was different from the case of diltiazem. In isolated dog mesenteric arteries, S-2150 relaxed KCl and phenylephrine contracture. These results suggest that S-2150 is a favorable hypotensive agent for hypertensive patients with ischemic heart disease. Blockage of both Ca2+ channels and alpha 1-adrenoceptors by S-2150 seems to lead to cardiovascular effects different from those of diltiazem.
Various 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-azoles were synthesized and investigated for beta-adrenoceptor-blocking and antiarrhythmic activities. Although no compounds showed more potent beta-blocking effects than propranolol in the isolated guinea pig right atria, many compounds exhibited significant antiarrhythmic effects against aconitine or ischemic arrhythmia in mice or dogs. 1-[2,5-Dichloro-6-[1-(1H-imidazol-1-yl)-ethenyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol hydrochloride (48) (711389-S) was selected as a candidate for clinical evaluation in man, since its antiarrhythmic effects were superior to those of quinidine, disopyramide, or propranolol. Asymmetric synthesis of (R)-(+)- and (S)-(-)-48 is described, and it is proven that there is no stereospecificity in the antiarrhythmic effect of 48.
Following the isolation of galanthamine by Proskurina (1) and Uyeo (2), Mashkovskiy (3, 4) reported that cholinesterase activity was depressed and sensitivity of striated muscles to acetylcholine was increased by the administration of galanthamine. Sedova (5) also recognized that galanthamine administration caused myosis, salivation, and the activation of smooth muscle movement in experimental animals. Hence the application of galanthamine for the therapy of myopathy, myasthenia gravis, radiculitis, and polyneuritis was suggested. Anticholinesterase activities of galanthamine were further examined by Irwin et at. (6, 7). After examining both the anticholinesterase activity and twitch potentiation of several galanthamine derivatives, they concluded that galanthamine methiodide was the most active.It seems, however, that something still re_naines to be clarified in the correlation between the twitch potentiation and anticholinesterase activity of galanthamine derivatives.The present experiments were chiefly carried out to clarify this point. Subsequently, comparisons of galanthamine were made with other anticholinesterases i.e. neostigmine, physostigmine, and DFP, in regards to muscle twitch potentiation, anticholinesterase activity, and in the activation of the motor nerve terminals.* The contents of this paper were successively published at the 20th Kinki meeting (Takarazuka, Hyogo) and at the 34th general meeting (Sapporo, Hokaido) of the Japanese Pharmacological Society.
METHODSFor the comparison of the twitch potentiation of anticholinesterases the sciatic gastrocne mius preparation and the phrenic nerve diaphragm preparation of Bulbring (8,9) were used. Contractions of M. gastrocnemius and isolated diaphragm were obtained either by direct or indirect electric sti nulation (0.2 c/s, 1 msec). Also the M. gastrocnemius paralyzed with 0.25--0.30 m/kg of d-tubocurarine was employed for comparison of the anticurare activity. This activity was determined 3 minutes after the administration of anticholinesterases. In addition, after 15 minutes of incubation with anticholinesterases, the contraction of M. rectus abdominis of frogs by acetylcholine was compared in order to evaluate the potency of anticholinesterases. The effects of anticholineesterases on the movements of rabbit intestine in vitro and in viva were observed using the Magnus and Trenderenburg method respectively. Anticholinesterase activity was also tested bioche
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