Amiloride is one of the major molecular probes in basic and applied investigations on the physiology of cation transport in animal cells. In these cells the drug also exerts growth inhibitory activity. Recently, we discovered that amiloride causes growth inhibition also on bacterial cells. In this paper we report that medium pH influences amiloride activity on Streptococcus faecalis. The lowering of external pH causes a drop in the susceptibility of this bacterium to amiloride up to an almost complete resistance. This finding, constitutes a novel aspect of the in vitro experimental pharmacology of this diuretic potentially useful also in clinical pharmacology and in animal cell investigations.
The effect of ST91, a clonidine derivative crossing poorly the blood-brain barrier, was compared to that of clonidine on exocrine pancreatic secretion in rats. The experiments were performed in anaesthetized rats after stimulation by a maximal dose of 2-deoxy-D-glucose, and in conscious rats under basal interdigestive conditions.
1) Responsiveness of guinea-pig ileal longitudinal smooth muscle-myenteric plexus preparations to drugs activating GABA-B receptors was studied in morphine-tolerant animals. For this purpose morphine pellets (75 mg each) were implanted subcutaneously in guinea-pigs and experiments were performed three days later in electrically-stimulated ileal strips. 2) Activation of GABA-B receptors with GABA (10(-6) -10(-3) M) or (-)-baclofen (10(-6)-10(-3) M) caused a dose-related inhibition of twitch response that was about 80% lower in preparations from morphine-tolerant animals than in controls. This was found both in preparations maintained in the presence of morphine (10(-6) M) and in morphine-free Krebs. The effect was evident also in ileal preparations from morphine-tolerant animals in which a withdrawal syndrome was induced by the administration of naloxone before sacrifice. 3) The phenomenon was specific since the dose-response curve of the adenosine-inhibitory effect was comparable in preparations from tolerant animals and controls. 4) The hyporesponsiveness to GABA-B receptor activation began 12 h after pellet implantation and was maximal on the third day. 5) It is concluded that during tolerance to and withdrawal from morphine there is a hyporesponsiveness of GABA-B receptors in "in vitro" guinea-pig ileal longitudinal muscle-myenteric plexus preparations.
Alterations in vascular alpha-adrenoceptor responsiveness following sinoaortic denervation was studied in conscious rats. The arterial hypertension observed in baroreceptor denervated rats decreased progressively during the 30 days of observation. A pressor hyperresponsiveness to methoxamine (10–80 μg/kg, iv), was observed 3 to 7 days after baroreceptor denervation followed by a gradual normalization of the vascular reactivity. The results indicate a possible participation of an enhanced alpha1-adrenoceptor-mediated vasoconstrictor component in the early phase of neurogenic hypertension.
This chapter discusses approach to the chemotopography of the digitalis recognition matrix in Na+/K+ transporting ATPase as a step in the rational design of new inotropic steroids. The need for new inotropic drugs follows from the prevalence and mortality of congestive heart failure in the developed countries, and from the fact that the cardiac drugs currently available are clearly inadequate to restore health or even to minimize discomfort and disability. The most suitable method for the quantitative evaluation of the positive inotropic effect of a cardioactive steroid is at present the assessment of its influence on the isometric contraction curve, measured in isolated papillary muscles. To obtain reliable data for the comparison of the inotropic potency of the various cardioactive steroids, it is important to perform the experiments under identical conditions. All inhibitors of the Na+/K+ pump irrespective of their 'microscopic' inhibitory mechanism produce positive inotropic effects if they do not additionally affect other biochemical systems which preclude the manifestation of the inotropic action.
Much of the therapy of peptic ulcer disease deals with the aggressive agents and particularly acid. Antisecretory drugs, such as the H2-antagonists and, more recently, the H+/K+-ATPase inhibitors, are the principal agents in use. Recent studies have focused on the degree and duration of acid suppression required for optimal therapy of acid related diseases. A single dose of an H2-antagonist at night has been found to have approximately equal efficacy in duodenal ulcer (DU) as qid dosing, emphasizing the importance of the control of nocturnal secretion. However, the situation is less clear for gastric ulcer (GU) and gastro-esophageal reflux disease (GERD): the higher efficacy of omeprazole, which suppresses acid secretion over a 24 hour period, suggests that in these diseases (as well as in DU) higher acid inhibition equates with improved efficacy. This conclusion is supported by a meta-analysis relating acid inhibition to the rapidity of healing. The optimal acid inhibition profile for each disease has yet to be established; the importance of this is highlighted by potential toxicity problems associated with omeprazole. In rat carcinogenicity studies, omeprazole produced gastric carcinoid tumors that are believed to be caused by the sustained hypergastrinemia associated with prolonged anacidity. However, a debate over a direct genotoxic effect for omeprazole has recently opened. Although no comparable toxicity has been demonstrated in human till date, gastrin can act as a tumor growth factor. Safety concerns are reflected in the fact that the use of omeprazole in peptic ulcer disease is usually restricted to short term therapy in patients failing to respond to the H2-antagonist therapy. Despite their efficacy in the short term healing of peptic ulcer disease, antisecretory agents are not permanent cures; relapse occurs in 80%-90% of the cases in the first or second year after cessation of the therapy.
A reinvestigation of the roots of Guettarda platypoda afforded in addition to morronoside and sweroside isolated previously further two iridoids, loganic acid and loganin and a rare secoiridoid, secoxyloganin. The structures were elucidated by NMR techniques. This is the first report of the isolation of such compounds from G. platypoda. Some chemotaxonomic conclusion can be drawn.
