Triazolo- and tetrazolopyridazine derivatives and their hypotension and heart rate activity.

6-Chloro-, 6-morpholino- and 6-N-methylpiperazino-1,2,4-triazolo[4,3-b]- or 1,2,3,4-tetrazolo[1,5-b]pyridazines [II-VII] were synthesized from 3-chloro-6-hydrazinopyridazine [I]. Positive effect of a series of tetra- and triazolopyridazines for lowering blood-pressure without affecting the heart rate was found in tests on rats. Their lipophilicity and other properties are discussed.

Cerebrovascular effects of angiotensin converting enzyme inhibition involve large artery dilatation in rats.

BACKGROUND AND PURPOSE: The aim of the study was to selectively examine the effects of converting enzyme inhibition on the large brain arteries by using concomitant inhibition of carbonic anhydrase to cause severe dilatation of mainly parenchymal resistance vessels. METHODS: Cerebral blood flow was measured using the xenon-133 injection technique in three groups of Wistar rats either during carbonic anhydrase inhibition with acetazolamide (treatment A, n = 8), during carbonic anhydrase inhibition followed by converting enzyme inhibition with captopril 40 minutes later (treatment B, n = 10), or during carbonic anhydrase inhibition preceded by converting enzyme inhibition 20 minutes earlier (treatment C, n = 7). RESULTS: After treatment A, cerebral blood flow rose rapidly and stabilized within 20 minutes at an average of 220 ml/100 g.min; flow remained stable until at least 60 minutes. After treatment B, cerebral blood flow increased by a further 17.4%, from an average of 219 ml/100 g.min to an average of 257 ml/100 g.min (p less than 0.01). After treatment C, cerebral blood flow stabilized at an average of 238 ml/100 g.min, with flow from 20 to 60 minutes always being higher (from 5% to 17%) than during carbonic anhydrase inhibition alone (p less than 0.02). Thus the additional inhibition of converting enzyme resulted in higher cerebral blood flow than during inhibition of carbonic anhydrase alone. CONCLUSIONS: These results suggest that converting enzyme inhibition reduced resistance of large brain arteries and support the hypothesis that there is some angiotensin II-induced tone in large cerebral arteries.

Dose-related effects of dopamine on microcirculatory blood flow in resting and active state.

We compared the effects of low and high doses of dopamine and dobutamine (a synthetic catecholamine) on blood flow in relaxed or exercising muscles. Experiments were performed on rabbits. Blood flow in the muscles (calf) was estimated with the clearance method of radionuclide 133Xe. Dopamine and dobutamine were infused (iv) in doses of 20 or 40 micrograms/kg/min. Dopamine reduced muscle blood flow in resting state; this effect was more pronounced after higher doses. Dobutamine increased the flow; low doses were less effective. Dopamine may be an important determinant of the distribution of cardiac output to various vascular regions.

Effect of thymoanaleptic agents on the course of experimental arterial hypertension and catecholamine content in tissues and urine.

Experimental hypertension was induced in rats by two methods. In the course of hypertension development the rats of experimental groups were treated with following tricyclic antidepressive agents: Imipramine, Opipramol, Amitriptylline and Nortriptylline injected in doses of 5.0 or 0.5 mg per 1 kg of body weight. Higher doses of the above drugs inhibited the development of hypertension, whereas the lower doses had no effect on arterial blood pressure.

Sesquiterpene lactones. XIX. Preliminary studies on the mode of action. Inhibition of synthesis of tumor cell protein and RNA.

The isotopic examinations of the mode of action of cytostatic active acid 8a-isobuetyric-14,15-dihydroxy-germacran-1 (10),4,11(13)-trienolide 12(6) (alatolide) have demonstrated that the compound at concentration 5-6 X 10(-5) M induces defective changes in HeLa cells resulting in the inhibition of protein synthesis in 93-8% and RNA in 91-9% and, in consequence, cell death. At lower concentrations 2-8 X 10(-6) M, the compound inhibits protein synthesis in 73% and RNA in 5-7%. The direct influence of alatolide on DNA synthesis is doubtful.

The role of cyclic adenosine 3',5'-monophosphate (cAMP) in the mechanism of action of tricyclic antiderpressants.

In the course of investigations on experimental arterial hypertension in rats, it has been stated, that imipramine prevents the development of hypertension and that is simultaneously causes an accumulation of cAMP in the vessel walls. The relationship between the two phenomena has been discussed.

The influence of premedication with 6-OH-dopamine and long-term administration of thymoanaleptics on development of experimental arterial hypertension.

Administration of 6-OH-DA into the lateral cerebral ventricle did not prevent development of hypertension or influence the effects of administration of tricyclic antidepressant drugs (TA). Injection os 6-OH-DA intraperitoneally prevented development of hypertension, and TA apparently protected against the consequences of administration of 6-OH-DA.

Sesquiterpene lactones. Part XIII. Cytotoxic activity of eupatolide and eupatoriopicrin on human and animal malignant cells in tissue culture in vitro.

The activity was determined in tissue culture of KB, HeLa human tumor cells. RK normal animal and EAC-E4 Ehrlich ascites carcinoma cells. Eupatolide (EUP) and eupatoriopicrin (EUPP) show similar cytotoxic activity (ED50 from 0-5 to 1-3 mug/ml), dependent on the cell strain used. In plate test EUP and EUPP give inhibition zones of 18--19 mm. EUPP exerts progressively destructive influence on EAC-E4 cells in the conditions of Miyamura test. The decrease in EUPP activity was noted in aqueous (pH = 9) and acetone solutions.

Influence of tricyclic antidepressant drugs on experimental arterial hypertension.

The tricyclic antidepressant drugs: imipramine, opipramol, amitryptiline and nortryptiline inhibit development of experimental arterial hypertension in rats.

Sesquiterpene lactones. XVI. In vitro studies on cytotoxic properties of sesquiterpene lactones in tissue cultures of human and animal malignant cells.

Cytoxicity of 18 new sesquiterpene lactones and related compounds was studied by tissue culture method using human malignant KB and HeLa cells, normal RK 13 animal cells, and by the modified plate test of Miyamura. On the basis of criteria of CCNSC HIH, USA, seven compounds with ED50 activities between 0-41 and 3-5 mug/ml were qualified for further investigation in vivo. Cytotoxic activity of sesquiterpene lactones was dependent on presence of an unsaturated lactone ring, (see article). As a rule activity of germacranolids was higher than that of guaianolides.

[Postsynaptic attack of tricyclic antidepressive agents in the circulatory system]. / Untersuchungen über den postsynaptischen Angriffspunkt trizyklischer Antidepressiva im Kreislaufsystem

Tricyclic antidepressives (TA) exert differential effects on the circulatory system, though all of them have one principle in common: inhibition of back resorption of noradrenaline in the adrenergic synapses. Of more importance, however, seems to be the dose rather than the type of substance used. Smaller doses were found to potentiate the pressoric effects of noradrenaline, while higher doses frequently had an inhibitory action. In rats pretreated with 6-OH-dopamine, only an inhibitory action has been established. It is concluded that the TA must have a postsynaptic influence that becomes effective either through the membrane receptors and/or other factors within the cell.