Relaxant actions of khellin on vascular smooth muscle

To clarify the mechanism of the vasodilatory action of khellin on calcium, we have investigated its relaxant action on base line and on K+ and noradrenaline-induced contractile tensions in rat aorta smooth muscle and on spontaneous contractile activity of rat portal vein. Khellin relaxed both of these preparations with a similar potency, which suggests a non-specific inhibition of calcium flux, without any difference related to the specific calcium channels. We have also studied the capacity of khellin to interfere with the loading and release mechanisms of caffeine and noradrenaline-sensitive calcium stores in Ca-free medium. Khellin's Ca2+ loading reduction may be related with its capacity to inhibit calcium influx. Khellin applied during Ca2+ release also caused relaxation. We propose that this drug may enhance calcium extrusion or sequestration rather than the calcium release mechanism. These actions on calcium influx and intracellular mobilization can contribute to its vasorelaxant action.     

Relaxant effects of lithium on guinea-pig tracheal smooth muscle in vitro.

The effect of lithium was studied on resting tension of guinea-pig spiral tracheal strips and their responses to carbachol and histamine in vitro. Lithium reversibly relaxed tracheal smooth muscle in a dose-dependent manner. In addition, lithium increased the ED50 for carbachol 10 fold and that for histamine by over 100 fold; maximum responses for each agonist were also reduced. Lithium-induced relaxation of tracheal smooth muscle was unaffected by changes in extracellular calcium concentration over the range 0-11 mM, verapamil, ouabain, procaine, propranolol or reduction in extracellular sodium concentration. The ability of lithium to reduce carbachol- and histamine-induced contraction of tracheal smooth muscle was also not altered by propranolol, procaine, ouabain, verapamil or lowered extracellular sodium. We conclude that lithium acts directly on tracheal smooth muscle to relax it by an as yet unknown mechanism. This may or may not be related to the ability of this agent to alter agonist-induced contraction of tracheal smooth muscle.     

Relaxant effects of forskolin in smooth muscle

Forskolin was found to cause concentration dependent, reversible relaxations of isolated smooth muscle preparations including rat aorta, bovine coronary artery, canine coronary artery, guinea pig taenia caeci and rabbit small intestine. The relaxant effects of forskolin in guinea pig taenia caeci and rabbit small intestine were potentiated by cyclic nucleotide phosphodiesterase inhibitors Ro 20-1724 and MIX. In rabbit small intestine, Ro 20-1724 also potentiated the relaxant effects of isoproterenol but not those of verapamil or 2-chloroadenosine. However, in bovine coronary arteries the phosphodiesterase inhibitors had to be used at concentrations of 100 nM or below because of relaxant effects and did not alter forskolin-induced relaxations. Forskolin caused a concentration dependent activation of adenylate cyclase in broken cell preparations from guinea pig taenia caeci and rabbit small intestine, exceeding the stimulatory effect of 10 mM NaF. These results indicate that relaxations of smooth muscle by forskolin are mediated by cyclic AMP and, in turn, that cyclic AMP may well serve as an intracellular mediator of physiological relaxant stimuli.     

The quinolone,flumequine, has no effect on theophylline pharmacokinetics

The kinetics of a single i. v. dose of theophylline given either alone or with flumequine was studied in eight healthy volunteers. No statistically significant differences were observed in the pharmacokinetic parameters of theophylline (volume of distribution, elimination half-life, AUC, plasma clearance) following the two treatments.Pretreatment for 5 days with oral flumequine (400 mg, three times daily) had no significant effect on the disposition of a single i. v. dose of theophylline in healthy volunteers.     

Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers

Summary The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier t_max and a higher C_max and AUC were observed in the subjects who received piperine and propranolol. It produced a higher C_max, longer elimination half-life and a higher AUC with theophylline.In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.     

葛根素对猫离体血管平滑肌的作用

本文研究葛根素对离体血管的作用。异丙肾上腺素使猫的股静脉及肾动脉对甲氧明引发的收缩产生的舒张作用呈剂量依赖式。葛根素能阻滞此种舒张反应,并呈剂量依赖式。普萘洛尔也能阻滞异丙肾上腺素引起的这种舒张。葛根素不能阻滞硝酸甘油引起的舒张反应。这些结果表明葛根素对猫的离体静脉及动脉具有β—受体阻断作用。     

Theophylline steady state pharmacokinetics is not altered by omeprazole

Summary The effect of omeprazole treatment on theophylline pharmacokinetics was studied in eight, non-smoking healthy male volunteers during repeated administration of a slow release formulation of theophylline. In a randomized double-blind cross-over study, the subjects received theophylline 5 mg·kg^–1 per day with omeprazole 20 mg per day or identical placebo during two periods, each of 7 days, separated by a washout period of 7 days.The oral clearance of theophylline remained unchanged whether it was administered alone or with omeprazole (54.2 ml·min^–1). The average urinary excretion of theophylline and its metabolites, 1,3 dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) amounted to 9%, 32%, 12% and 22% of the administered dose, respectively, and no significant change occured during concomitant treatment with omeprazole.Thus, the formation and clearance of the metabolites was not altered by omeprazole. Consequently, omeprazole in the recommended dose of 20 mg daily can safely be administered to patients on theophylline therapy.     

Effect of ampicillin on mefloquine pharmacokinetics in thai males

Summary The kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers.There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml^–1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg^–1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 g·ml^–1 day).These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.     

Effect of tetracycline on mefloquine pharmacokinetics in Thai males

Summary The kinetics of a single oral dose of mefloquine given either alone or with tetracycline has been studied in 20 healthy Thai male volunteers.There was a significantly higher maximum whole blood mefloquine concentration after coadministration with tetracycline (1600 vs 1160 ng · ml^–1), as well as a significantly reduced terminal half-life (14.4 vs 19.3 days), mean residence time (11.9 vs 16.0 days) and volume of distribution at steady state (13.3 vs 19.91 · kg^–1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 7 days was significantly increased by tetracycline (6.18 vs 4.76 g · ml^–1 · day).The changes in mefloquine disposition after tetracycline treatment are probably due to a reduction in enterohepatic recycling. The initial increase in mefloquine AUC without an apparent increase in side-effects suggests that this combination may have a place in the treatment of multi-drug resistant falciparum malaria.     

Cyclic nucleotide phosphodiesterase inhibition and vascular smooth muscle relaxation

The inhibitory effects of theophylline, papaverine and isoquinoleine derivatives and the activating action of imidazole were compared on purified 3′,5′-cylcic nucleotide phosphodiesterase and on isolated rat aorta. A quantitative correlation was found between inhibition of the enzyme activity (K_i) and prevention of isolated rat aorta contractions elicited by barium.     

The effects of theophylline and cyclic AMP on intestinal smooth muscle contractions

The effects of 10^?4-10^?3 M theopphylline, cyclic 3'5'-adenosine monophosphate (cyclic AMP), dibutyryl cyclic AMP (DBC) and theophylline plus DBC were observed on the spontaneous and potassium (K)-induced contractions of the guinea-pig taenia coli. All of the compounds inhibited spontaneous contractions as well as the phasic and tonic components of the K-contracture. The effects of cyclic AMP, a compound which will not readily penetrate the cell membrane, were similar to those of the other compounds in inhibiting the spontaneous and phasic contractions, but it was a less effective inhibitor of the tonic contracture. Inhibition of spontaneous and phasic activity may occur at the cell membrane while the inhibitory actions on the tonic contracture may depend on cellular penetration by the inhibitor. There was no evidence that theophylline and DBC have different sites of action.     

Relaxant effects of estradiol through non-genomic pathways in male and female pig bladder smooth muscle

The precise effect of low estrogen levels on urinary bladder contractility remains controversial. The present study was designed to analyze the effect of 17beta-estradiol in bladder smooth muscle contractility and the involvement of specific estrogen receptor stimulation in this effect. Castrated male and female pig detrusor strips were mounted for tension recording in an organ bath, superfused with Krebs solution at 37 degrees C and stimulated electrically and pharmacologically. In order to verify the acute effect of 17beta-estradiol on muscle contractility, the strips were incubated with different concentrations of the hormone. Muscle contractions were induced by potassium chloride, acetylcholine chloride and electrical field stimulation. The involvement of the estrogen receptor in the effects of 17beta-estradiol was assessed by incubation of some strips with the selective estrogen receptor antagonist ICI 182.780 before estradiol was applied. Estradiol at a dose of 30 micromol/l elicited a lower amplitude of contractions induced by EFS, Ach and KCl in female as well as in castrated male pig bladder smooth muscle strips. The effects of 17beta-estradiol were stronger in contractions induced by potassium chloride than those induced by other forms of stimulation. Pre-treatment with the pure estrogen receptor antagonist had no effect on 17beta-estradiol-induced inhibition of muscle contractility. These observations suggest that 17beta-estradiol induces lower amplitude of contraction of female as well as castrated male pig detrusor which is not mediated by the classic estrogen receptor. Furthermore, we can conclude that estradiol has a stronger inhibitory effect on the depolarization of muscle cell membrane compared to a muscarinic receptor-induced contraction.     

Relaxant effects of mercury and mercury uptake in the smooth muscle of guinea-pig taenia coli

Hg2+ (0.005-0.5 mM) induced a concentration-dependent reduction on high-K+-induced contraction of taenia coli. The K+-induced increase in 45Ca uptake was significantly reduced in the presence of Hg2+ (0.05-0.5 mM). The contractions of the glycerinated taenia coli were inhibited by an increase in Hg2+ concentration. Mercury uptake increased along the duration of Hg2+ incubation. When muscles were rinsed with a medium containing 5 mM EDTA after 0.5 mM Hg2+ treatment for 90 min about 30% of the original level of tissue mercury was retained. Possible mechanism for the tension inhibitory action of Hg2+ include: (1) that Hg2+ bound to cell membrane initially interferes with the permeability of Ca2+ and that (2) the cellular mercury fraction that is not eliminated by EDTA subsequently correlates with the tension inhibitory action.     

Kinetic interaction between theophylline and a newly developed anti-allergic drug,pemirolast potassium

The effect of a newly developed anti-allergic drug, pemirolast potassium (TBX), on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in seven healthy male volunteers. A sustained-release theophylline formulation (100 mg twice daily at 12 h intervals) was given as monotherapy and coadministered with TBX (10 mg twice daily at 12 h). Plasma concentration-time curves and the urinary excretion of theophylline and its major metabolites after administration of theophylline alone and after coadministration with TBX were compared.No significant adverse effects from this study were observed. There were no significant differences in the total body clearance, renal clearance and maximum concentration of theophylline between the two treatments, although coadministration of TBX significantly delayed the time to reach maximum concentration of theophylline. In the case of urinary excretion, no significant changes in the fraction of urinary excretion of theophylline and its metabolites were observed. These results indicate that TBX has little or no effect on the pharmacokinetics and metabolism of theophylline and suggest that TBX is safe for asthma patients receiving theophylline therapy for treatment of chronic obstructive airway diseases.     

Voltage-dependent effects of barnidipine in rat vascular smooth muscle

The effects of the dihydropyridine nifedipine and its more lipophilic congener, barnidipine, were investigated in smooth muscle preparations from the rat in resting and depolarizing conditions. Both drugs relaxed precontracted aortic rings more potently in depolarizing conditions, barnidipine being more potent than nifedipine. Currents through Ca2+ channels in rat vascular smooth muscle cells (A7r5) and in isolated rat cardiomyocytes were reduced more potently by both drugs at a holding potential of -40 mV than at -80 mV. However, barnidipine and nifedipine were more effective in reducing the current in A7r5 cells than in cardiomyocytes. The IC(50) obtained in aortic rings and in A7r5 cells were similar for barnidipine but an order of magnitude different for nifedipine. The results show that, in depolarizing conditions, barnidipine was more effective than nifedipine. It is suggested that the higher potency of barnidipine acting in vascular smooth muscle is related to both a higher affinity to the inactivated state of vascular Ca2+ channels and to a more lipophilic property as compared with nifedipine.     

Relaxant actions of isoprenaline on guinea-pig isolated tracheal smooth muscle.

1. The effects of isoprenaline on membrane potential and intracellular Ca2+ concentration ([Ca2+]i) in guinea-pig isolated tracheal muscle were studied by use of intracellular micro-electrodes and fura-2 signals respectively. Measurements of membrane potential were carried out in the presence of spontaneously-generated muscle tone, whereas fura-2 signals were measured during contraction produced by exogenous prostaglandin E2 (100 nM). The potency of isoprenaline in causing relaxation was the same in these two different situations. 2. Isoprenaline (0.01 microM) produced relaxation accompanied by 5 mV hyperpolarization. A combination of tetraethylammonium (TEA, 10 mM) and verapamil (3 microM) did not alter the effects of isoprenaline. Removal of external K+ did not increase the degree of hyperpolarization produced by isoprenaline. 3. In the presence of TEA (10 mM) and verapamil (3 microM), isoprenaline (0.03-1 microM) reduced [Ca2+]i concentration-dependently. A similar degree of inhibition was observed when isoprenaline was applied during the maintained contraction induced by prostaglandin E2 and against the contraction evoked by the addition of Ca2+ to tissues bathed in a Ca(2+)-free medium and pretreated with both isoprenaline and prostaglandin E2. 4. It is concluded that activation of TEA-sensitive Ca(2+)-dependent K+ channels does not play a significant role in isoprenaline-induced relaxation. We propose that, in the guinea-pig tracheal muscle, isoprenaline may produce relaxation mainly by inhibiting a receptor-operated pathway for Ca2+ influx across the plasma membrane which is normally activated by prostaglandins.