Taurine antagonizes the alpha-adrenergic-positive inotropic effect of phenylephrine.
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Animals↗
Biomedical subjects
S Manzini
Publications and source records attributed to S Manzini.
Octylonium bromide: a smooth muscle relaxant which interferes with calcium ions mobilization.
A series of "in vitro" experiments have been carried out to determine the mechanisms(s) responsible for the smooth muscle relaxant properties exhibited by octylonium bromide. Unlike N-butyl-scopolammonium bromide, octylonium bromide possesses both competitive and non competitive antimuscarinic and antihistaminic properties. Pretreatment of ileal segments with dibenamie, which destroyed muscarinic spare receptors, revealed the non competitive nature of octylonium bromide antagonism. The competitive antagonism toward BaCl2-induced contraction of rat ileum and aorta suggested that octylonium bromide interferes with Ca++ mobilization. As compared with verapamil a known Ca++ entry blocker and unlike it, octylonium bromide is more effective in antagonizing Ca++-induced contraction in K+ depolarized rat colon than aorta. Both octylonium bromide and verapamil reduced in a concentration-dependent manner the tonic contraction produced by exposure to high K+ of rat duodenum and rabbit ear artery. Both octylonium bromide and verapamil antagonized carbachol-induced phasic plus sustained tonic contraction of rat colon in high K+ Ca++-free medium. Unlike octylonium bromide, verapamil antagonized the phasic contraction only and inhibition of the overall contraction did not exceed 60%. Unlike verapamil, octylonium bromide antagonized norepinephrine-induced contraction of rabbit ear artery in high K+ C++-free medium. Interference with mobilization of cellular and extracellular Ca++ pools produced by different neurohormones is likely to be the mechanism responsible for octylonium bromide smooth muscle relaxant properties in both animals and humans.
Animals↗
A simple procedure for assessing norepinephrine-induced cellular and extracellular Ca++ mobilization in rabbit ear artery.
Although the response of vascular smooth muscle to norepinephrine (NE) is biphasic in nature, there is no simple procedure for the separate quantitative analysis of intracellular and extracellular Ca++ dependent NE-induced contractions. Intraluminal NE in high-K+Ca++-free medium produces a dose-dependent contraction which is selectively antagonized by procaine (1 X 10(-3) M--5 X 10(-3) M). Subsequent reperfusion with normal Krebs of NE-pretreated arterial segments results in a dose-dependent contraction which is strictly related to extracellular Ca++ concentration and is selectively inhibited by verapamil (5 X 10(-6) M--5 X 10(-5) M). These results can be interpreted as an indication that this procedure is suitable for the separate analysis of the capability of vasoactive drugs to differentially mobilize cellular and extracellular Ca++ pools in perfused rabbit ear artery preparations.
Animals↗
The effect of taurine on high potassium-and noradrenaline-induced contraction in rabbit ear artery.
1 Intraluminal administration of taurine (40 mM) did not affect the contractile tone of rabbit isolated ear artery 2 Taurine (10-80 mM) exerted a powerful concentration-dependent, vasodilator action in arteries contracted with high potassium medium. 3 In the same experimental conditions, the taurine analogues beta-alanine and homotaurine, had no effect. 4 Taurine (40-80 mM) did not affect in a significant manner the tonic component of the noradrenaline (5x10(-6 M)-induced contraction. 5 When noradrenaline (5x10(-6M) was followed by the administration of high potassium medium a further increase in intraluminal pressure was observed. Under these conditions taurine (40 mM) reversed specifically the component due to the high potassium medium.
Alanine↗
Aminophylline-induced contractions of rabbit ear artery in high-K+ Ca2+-free medium.
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Aminophylline↗
Observations on the action of taurine at arterial and cardiac levels.
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Animals↗
The influence of some cardiodepressant drugs on the histamine-induced restoration of contractility in potassium-depolarized heart preparations.
The ability of some drugs to affect calcium movements in cardiac fibers was tested using a simple method. Guinea-pig ventricular strips were depolarized by 22 mM K+ and their mechanical activity was restored by histamine (10(-5) M); in in these conditions, the effects on contractility of the classic calcium antagonistic drugs nifedipine, verapamil and D600, of the antiarrhythmic drugs lidocaine, quinidine and propafenon, and of a barbiturate, thiopental, were assessed. These drugs were chosen because all of them have been reported as affecting cardiac contractility. It was observed that the ED50 values obtained for the calcium antagonists were in good agreement with those calculated by other authors using different techniques. Moreover, it was found that at high concentrations either the antiarrhythmic drugs or thiopental showed a cardiodepressant activity; the likely explanation of their effects is discussed.
Animals↗
The effect of thiorphan and epithelium removal on contractions and tachykinin release produced by activation of capsaicin-sensitive afferents in the guinea-pig isolated bronchus.
(1) We have studied the effect of epithelium removal (rubbing) and the endopeptidase 24.11 inhibitor, thiorphan, on the contractile response of the guinea-pig isolated bronchi (atropine and indomethacin in the bath) produced by electrical field stimulation, capsaicin or exogenously administered tachykinins (substance P and neurokinin A). (2) The response to field stimulation, thought to involve release of endogenous tachykinins, was potentiated by thiorphan in both epithelium-free and intact bronchi. However, at low frequencies (1-5 Hz), the effect of thiorphan was more evident in intact preparations. (3) The response to capsaicin was enhanced by both epithelium removal and thiorphan administration. (4) The response to exogenous substance P or neurokinin A was potentiated by thiorphan both in epithelium-free and intact bronchi. (5) Capsaicin (1 microM) evoked a consistent release of substance P-like immunoreactivity (determined by radioimmunoassay) and tachykinin-like immunoreactivity (determined by a novel immunoenzyme assay), which was enhanced by thiorphan in both epithelium-free and intact bronchi. (6) These findings suggest that a thiorphan-sensitive mechanism, presumably 'enkephalinase' (endopeptidase 24.11), plays a major role in inactivating endogenous tachykinins released from sensory nerves and that this enzymatic activity is still present after removal of the bronchial epithelium.
Animals↗
New developments in antitumor anthracyclines.
Doxorubicin is a major anticancer agent introduced to extended clinical use in the early 1970s. The fulfillment of a wide program of analogue synthesis led to the development of the better tolerated epirubicin and of a highly potent antileukemic drug, idarubicin. In recent years, on the basis of the available information on the molecular requirements for action, a new synthetic program, coupled with target-oriented pharmacological experiments, was carried out. Various interesting derivatives, namely, the 8- and 10-fluoro compounds and the disaccharides, were obtained. The latter compounds exhibited a strong dependence of biological activity on the orientation (axial vs. equatorial) of the second sugar moiety, daunosamine. A member of this group, namely, 7-O-(4'-O-alpha-L-daunosaminyl-2'-deoxy-alpha-L-fucosyl)-4-demetho xy-adriamycinone, is presently undergoing clinical trials as a third generation antitumor anthracycline.
Animals↗
Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK(1) receptor antagonist.
We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK(1) receptors. MEN 11467 potently inhibits the binding of [(3)H] substance P (SP) to tachykinin NK(1) receptors in the IM9 limphoblastoid cell line (pK(i) = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK(1) receptors, since it has negligible effects (pK(i) <6) on the binding of specific ligands to tachykinin NK(2) or NK(3) receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK(1) receptors is insurmountable in saturation binding experiments, both K(D) and B(max) of SP were significantly reduced by MEN 11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produced a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pK(B) = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2-3h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK(1) receptor agonist, [Sar(9), Met(O(2))(11)]SP in anaesthetized guinea-pigs (ID(50)s' = 29+/-5, 31+/-12 and 670+/-270 microg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met(O(2))(11)] (ID(50) = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized animals (ID(50) = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED(50) = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK(1) receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK(1) receptors with a long duration of action.
Administration, Oral↗
Induction by histamine of oscillatory activity in sheep Purkinje fibers and suppression by verapamil or lidocaine.
Histamine (1--2 x 10(-5) M) induced or enhanced oscillatory activity in four of five sheep Purkinje fibers depolarized by a low-potassium medium. These effects of histamine were readily antagonized by 2 x 10(-5) M burimamide but were unaffected by 10(-5) M practolol. Oscillatory activity was consistently induced or enhanced by 5 x 10(-6) M adrenaline in five preparations. Oscillatory activity, whether induced by histamine or adrenaline, was always abolished by verapamil (0.22--2.2 x 10(-6 M) but in only one of five experiments by lidocaine (4.2 x 10(-5) M). We conclude that induction of oscillatory responses may be added to the other arrhythmogenic mechanisms produced by histamine through the stimulation of H2 receptors. We confirmed that oscillatory activity is very effectively suppressed by verapamil.
Action Potentials↗
Electrophysiological and antiarrhythmic properties of propafenon in isolated cardiac preparations.
Propafenon, a new antiarrhythmic drug, caused a 30% decrease in maximal driving frequency and a 65 ms net increase in functional refractory period of isolated guinea pig atria at a concentration as low as 0.5 microgram/ml. The spontaneous rate of isolated atria and the contractility of electrically driven ventricular strips were reduced after treatment with propafenon 1 microgram/ml. Propafenon 0.5 microgram/ml also altered action potentials of sheep Purkinje fiber. It reduced the action potential and overshoot amplitudes, decreased the maximum rate of depolarization of the action potential upstroke in a frequency-dependent fashion, shortened the action potential and effective refractory period, and depressed the membrane responsiveness. Moreover, propafenon antagonized the chronotropic and inotropic effects of isoprenaline in isolated guinea pig heart preparations; the pA2 value was about 6.4. Finally, propafenon possessed very weak calcium antagonist properties, being about 100 times less potent than verapamil in this respect. We conclude that propafenon is an antiarrhythmic drug with beta-adrenoceptor blocking and "membrane stabilizing" activities in the same range of concentrations and that it has a calcium antagonistic activity only at much higher concentrations.
Action Potentials↗
Antioxidant and cardioprotective properties of the sulphydryl angiotensin-converting enzyme inhibitor zofenopril.
Zofenopril, a new potent sulphydryl angiotensin-converting enzyme (ACE) inhibitor, is characterized by high lipophilicity, selective cardiac ACE inhibition, and antioxidant and tissue protective activities. In vitro and in vivo experiments suggest that zofenopril exerts antioxidant properties at clinically achievable tissue concentrations. In endothelial cells, zofenopril enhances nitric oxide production, attenuates atherosclerotic lesion development and inhibits adhesion molecule expression by reducing reactive oxygen species. These peculiar characteristics are reflected in the drug's cardioprotective activity, which has been shown to be greater than that of non-sulphydryl ACE inhibitors. Cardiac hypertrophy was also reduced by chronic zofenopril administration, independently of its blood pressure-reducing effect. ACE inhibitors with a sulphydryl group could have an advantage in improving vascular function and reducing cardiac impairment compared with non-sulphydryl-containing ACE inhibitors. This could explain zofenopril's remarkable clinical efficacy post-infarction, and potentially beneficial use in prevention and therapy of cardiovascular diseases, such as atherosclerosis, thrombosis and heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Capsaicin desensitization selectively inhibits lipoxin A4-induced contraction in guinea pig bronchus.
The pharmacological ablation of capsaicin-sensitive afferents by means of capsaicin desensitization is usually utilized as a first functional criterion to identify substances whose biological effects might involve activation of this type of nerves. We have studied, in guinea pig epithelium-denuded bronchial rings (in the presence of the neutral endopeptidase inhibitor thiorphan), the effect of in vitro capsaicin desensitization (10 microM for 15 min) on bronchomotor responses elicited by leukotriene D4 (10-100 nM), 15-HETE (3-6 microM) and lipoxin A4 (3-6 microM). While all these three lipid mediators contract bronchial preparations, only lipoxin A4 effects were markedly depressed by previous capsaicin challenge. As expected, capsaicin desensitization abolished subsequent motor responses to capsaicin itself or stimulation of non-adrenergic non-cholinergic nerves, while it left unaffected cholinergic responses. It is proposed that endogenously-generated lipoxin A4 acts, at least partially, through the activation of capsaicin-sensitive sensory nerve fibers.
Animals↗
IP66 (1[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) enhances beta-adrenoceptor-induced vasodilatation in rat mesenteric vascular bed.
The effect of the antihypertensive drug IP66 on dopamine-induced vasodilatation has been investigated in isolated perfused rat mesenteric bed. Experiments were carried out in phenoxybenzamine-pretreated preparations to avoid the involvement of alpha-adrenoceptors. Dopamine (1-100 microM) elicited a concentration-dependent relaxation of high-K(+)-induced vasoconstriction, which was resistant to propranolol (3 microM), but antagonized by the DA1-receptor antagonist SCH 23390 (0.1 microM). However, the dopamine-vasodilating component resistant to SCH 23390 (0.1 microM) could be abolished by simultaneous administration of propranolol. Thus, dopamine-induced vasodilatation is mainly ascribable to stimulation of DA1-receptors, although an action on beta 2-adrenoceptors might contribute as well. In presence of IP66 (10 nM), dopamine-induced vasodilatation was significantly enhanced. This amplifying activity was not observed with prazosin and it was blocked by propranolol (3 microM) but unaffected by SCH 23390 (0.1 microM) or by chemical sympathectomy. Furthermore, IP66 (10 nM) also increased, in a significant manner, the amplitude of vasodilatation elicited by the beta 2-adrenoceptor agonist terbutaline, both in rat mesenteric bed and in rat aortic strips. In rat aortic membranes, IP66 (10 nM) enhanced the stimulatory effect of terbutaline (1 microM) on adenylate cyclase activity. In conclusion, IP66 is able to enhance the vasodilatation of rat mesenteric vasculature induced by dopamine or terbutaline. It is proposed that this action might be consequent to an increase in efficiency of the coupling between beta 2-adrenoceptors and membrane adenylate cyclase.
Adenylyl Cyclases↗
Metabolism of isbufylline in humans. Isolation, identification, and synthesis of plasma and urine metabolites.
Isbufylline metabolism after oral administration to humans was studied. The main metabolites detected by the HPLC method, in plasma, were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-hydroxy-2-methyl-propyl) xanthine (II), and 1-methyl-7-(2-methyl-propyl) xanthine (III). The main metabolites detected in urine were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-carboxy-propyl) xanthine (IV), and 1,3-dimethyl-7-(2-hydroxymethyl-propyl) xanthine glucuronic acid (V)-Gluc. They were isolated by HPLC, identified by GC/MS, HPLC/MS, or HPLC/MS/MS, and finally synthesized. Recovery of these metabolites, along with the absence of unmetabolized isbufylline in the urine, indicated biotransformation and renal excretion as the main routes of isbufylline elimination in humans. HPLC quantitation of the characterized urine metabolites revealed that 49% of the drug was eliminated as (I), 9% as (V)-Gluc, and 5% as (IV).
1-Methyl-3-isobutylxanthine↗