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PubMed1985

Some effects of nifedipine in guinea-pig isolated trachealis.

In trachealis depolarized by a K+-rich medium, nifedipine (0.001-1 mumol 1(-1) caused concentration-dependent antagonism of CaCl2-induced increase in tension, moving the CaCl2 log concentration-effect curve to the right and depressing the maximal response. In trachealis in normal Krebs solution, similar concentrations of nifedipine had marked antispasmogenic activity against the responses to potassium chloride (KCl) and tetraethylammonium (TEA). However, nifedipine had little, if any, antispasmogenic activity against the responses to acetylcholine or histamine. Nifedipine 1 mumol 1(-1) was tested for spasmolytic activity in tissues generating tension in response to the EC50 of acetylcholine, KCl or CaCl2. In producing spasmolysis nifedipine was most effective against CaCl2 and least effective against acetylcholine. Nifedipine (0.01-1 mumol-1) had little or no effect on the tone of trachealis in normal Krebs solution. Intracellular electrophysiological recording showed that nifedipine 1 mumol 1(-1) could abolish spontaneous slow wave activity. This was associated with very minor depolarization and little or no loss of mechanical tone. In tissues treated with TEA (8 mmol 1(-1) nifedipine abolished spike and slow wave discharge and reduced mechanical activity to the pre-TEA level. It is concluded that nifedipine prevents KCl- or TEA-induced spasm by inhibition of Ca2+ influx. Spasm evoked by acetylcholine or histamine and the maintenance of spontaneous tone depend largely on mechanisms for increasing the cytoplasmic concentration of free Ca2+ which are resistant to nifedipine.

Animals↗

PubMed1988

Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat.

1. The protective effects of ten slow channel inhibitor drugs against severe progressive hypoxia were investigated in rats breathing spontaneously during light anaesthesia. Respiration, heart rate, electrocorticogram (ECoG) and/or electroencephalogram (EEG) were recorded. 2. Tolerance times were monitored from hypoxia onset until cessation of respiration, ECoG, EEG synchronization, and 'background-EEG'. Drugs were administered i.v. 5 min before the onset of hypoxia. 3. Verapamil, gallopamil, and nimodipine resulted in a significant increase of tolerance times; fendiline and bepridil showed a small increase (not significant); bencyclan and prenylamine were ineffective; cinnarizine and diltiazem slightly reduced tolerance times as did flunarizine at low doses. 4. At protective doses, verapamil, gallopamil, and nimodipine significantly raised the respiration rate but had little or no cardiac depressor effects. Bencyclan showed ventilatory drive but cardiocirculatory depression. A clear-cut ventilatory drive did not occur with the other ineffective slow channel inhibitors. 5. It is suggested that the protective actions observed were not due to slow channel inhibition per se, nor to spasmolytic potency or increased cerebral blood flow. Ventilatory drive associated with other cardiopulmonary actions which secondarily raise the brain oxygen supply are likely to be responsible for this effect.

Animals↗

PubMed1989

Co-axial bioassay of a smooth muscle relaxant factor released from guinea-pig tracheal epithelium.

1. The ability of guinea-pig trachea to release an epithelium-derived relaxant factor (EpDRF) was assessed in a co-axial bioassay system. 2. Histamine (100 microM) and methacholine (25 microM) caused endothelium-dependent relaxation of rat isolated aorta, presumably via the release of endothelium-derived relaxant factor (EDRF). In contrast, endothelium-denuded rat aorta did not relax in response to these agents. 3. EDRF release was detected in response to methacholine in a co-axial bioassay system, consisting of intact rabbit aorta tube (EDRF donor) and endothelium-denuded rat aorta strip (assay preparation). These results indicated the transfer of EDRF from a donor to an assay preparation, thereby validating the co-axial bioassay method. 4. Substitution of endothelium-intact rabbit aorta tube by epithelium-intact guinea-pig tracheal tube tissue in co-axial assemblies, still allowed the assay preparation to relax in response to histamine or methacholine. Removal of the intact tracheal tube from the system, or removal of the epithelium from the donor tracheal tube in co-axial preparations, abolished such relaxant responses. These observations are consistent with histamine- or methacholine-induced release of an epithelium-derived relaxant factor (EpDRF) from the trachea. 5. In the co-axial assembly comprising intact guinea-pig trachea and endothelium-denuded rat aorta, histamine and methacholine produced concentration-dependent, EpDRF-induced aortic relaxation. Mean concentrations of histamine and methacholine producing 50% of the maximum relaxation (EC50) were 39.8 microM and 2.7 microM respectively. Histamine-induced relaxation was inhibited in the presence of mepyramine (2 microM) and responses to methacholine were inhibited by atropine (0.1 microM). 6. Methylene blue (50 microM) had no effect on such relaxant responses, indicating that EpDRF does not activate guanylate cyclase. Furthermore, the cyclo-oxygenase inhibitor indomethacin (5 microM), the cyclo-oxygenase/lipoxygenase inhibitor BW 755C (150 microM) and the leukotriene receptor antagonist FPL 55712 (10 microM) each failed significantly to alter EpDRF-mediated relaxation of vascular smooth muscle suggesting that EpDRF is not a prostanoid. Platelet activating factor (Pat) failed to cause relaxation of endothelium-denuded rat aorta, indicating that this mediator was also not EpDRF. 7. EpDRF was also released from human bronchial segments. 8. This study provides direct evidence for the release of an EpDRF from non-diseased airway tissue and further suggests that healthy airway reactivity to spasmogens is modulated by the release of an endogenous protective, spasmolytic substance. The bronchial hyperreactivity of asthma may be partly caused by attenuated production of such an inhibitory signal.

Animals↗

PubMed1990

A salivary vasodilator in the blood-sucking bug, Rhodnius prolixus.

1. Salivary gland homogenates of the blood-sucking bug, Rhodnius prolixus induced transient, dose-dependent relaxation of rabbit aortic preparations pre-constricted with 200 ng ml-1 noradrenaline, 1 microgram ml-1 histamine or 20 ng ml-1 angiotensin II. Such relaxations were less marked when the aorta was constricted by 60 mM KC1. These effects were observed with as little as 0.2 microgram ml-1 of crude salivary gland protein. 2. The vasodilator effect was endothelium-independent, abolished by 50 microM hydroquinone or 50 microM methylene blue, and potentiated by 30 mu ml-1 superoxide dismutase. 3. Salivary homogenates generated a coloured compound when reacted with sulfanilic acid in the presence of N-(1-naphthyl)-ethylediamine, indicating the presence of reactive nitrogen groups, equivalent to 35 +/- 3 ng of sodium nitrite per pair of glands. 4. Molecular sieving high performance liquid chromatography of salivary gland homogenates generated a single peak of vasorelaxant activity which coincided with the presence of platelet antiaggregating and spasmolytic (guinea-pig ileum contracted with histamine) activities, as well as with reactive nitrogen groups. 5. It is concluded that a protein of molecular weight 16.500 daltons in the salivary glands of R. prolixus contains reactive nitrogen groups which assist the bug during a blood meal. It is suggested that saliva of blood sucking anthropods is a natural resource of novel pharmacological activities.

Animals↗

PubMed1991

Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF2 alpha or endothelin.

1. The spasmolytic effects of smooth muscle relaxant drugs with different mechanisms of action have been examined on isolated preparations of guinea-pig trachea and rat pulmonary artery. The preparations were contracted with concentrations of prostaglandin F2 alpha (PGF2 alpha) or endothelin selected to give approximately 80% of the agonist maximum response on each tissue. These concentrations also caused similar levels of tone (% of tissue maximum contraction) on each tissue. 2. With endothelin as the spasmogen, the potassium channel opening drug, pinacidil, was more potent on trachea (-log IC50 5.49) than on pulmonary artery (4.39), i.e. was airway-vascular selective, whereas with PGF2 alpha as the spasmogen it was more potent on pulmonary artery (6.01) than on trachea (5.27), i.e. was vascular-airway selective. 3. With endothelin as the spasmogen, fenoterol was also airway-vascular selective (8.35 on trachea; little effect on pulmonary artery), nitroprusside was vascular-airway selective (7.50 on pulmonary artery; 5.99 on trachea) and forskolin was non-selective (6.69 on trachea; 6.70 on pulmonary artery). Thus, the airway-vascular selectivity of the relaxant drugs varied with the drug. 4. On pulmonary artery, pinacidil, nitroprusside and forskolin were all more potent against PGF2 alpha than against endothelin, i.e. 42, 4 and 7 fold respectively. On trachea, these drugs were equipotent against PGF2 alpha and endothelin. 5. The results suggest that, in pulmonary artery, but not in trachea, the relative contribution of protein kinase C activation and calcium influx to the maintenance of tonic contractions to endothelin and PGF2 alpha may be different. If protein kinase C activation should be the predominant mechanism for endothelin in pulmonary artery, then it may be more difficult to reverse this with relaxant drugs that lower intracellular calcium. 6. The study indicates that the airway-vascular selectivity of relaxant drugs can be spasmogen-dependent as well as dependent on the mechanism of action of the relaxant drug. Thus, relaxant drugs, whether of interest for their airway or vascular effects, should be tested against a full range of spasmogens of likely pathophysiological importance.

Animals↗

PubMed1995

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide-resistant, ATP-sensitive potassium current.

1. The effects of the benzopyran K-channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly-isolated single cells derived from these tissues. 2. BRL55834 (3 nM-1 microM) produced a concentration-dependent relaxation of bovine trachealis precontracted with 100 microM histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1-10 microM) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis. 3. BRL55834 (10 nM-10 microM) did not relax segments of bovine trachealis precontracted with 80 mM KCl. 4. In some freshly-isolated single cells from bovine trachealis held at -10 mV, BRL55834 (3 microM) induced a time-independent outward K-current which was partially resistant to inhibition by glibenclamide (10 microM). In other cells, a very noisy, outwardly-rectifying and charybdotoxin-sensitive current developed in the presence of BRL55834 (3 microM) and in time-matched control cells. 5. In freshly-isolated single cells from rat portal vein held at -10 mV, BRL55834 (3 microM) induced a time- and calcium-independent outward K-current which was partially resistant (approximately 25% inhibition at +40 mV) to subsequent inhibition by glibenclamide (10 microM). In contrast, levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 microM. 6. With the non-hydrolysable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at +40 mV) whereas the effects of 10 microM levcromakalim were totally inhibited. 7. The glibenclamide-resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 microM), a concentration that had no effect on the peak current (IBK(Ca)) induced by NS1619 (33 microM). 8. Stationary fluctuation analysis of the noise associated with the glibenclamide-insensitive K-current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKCa. 9. It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K-channels. These are probably identical to the ATP-sensitive K-channel opened by levcromakalim, although the involvement of an additional K-channel cannot be excluded. The reduced sensitivity of the BRL55834-induced changes to glibenclamide and toAMP-PCP may result from avid binding of BRL55834 to its site of action.

Adenosine Triphosphate↗

PubMed1996

Inhibition of bronchospasm and ozone-induced airway hyperresponsiveness in the guinea-pig by CDP840, a novel phosphodiesterase type 4 inhibitor.

1. The activity of CDP840, a novel, potent and selective cyclic nucleotide phosphodiesterase type 4 (PDE 4) inhibitor, was evaluated in guinea-pig models (in vitro and in vivo) of bronchospasm, ozone-induced airway hyperresponsiveness (AHR) and non-cholinergic bronchoconstriction. Comparisons were made with (i) other PDE 4 inhibitors: CT1731 (S-enantiomer of CDP840), rolipram, RP73401 and (ii) the clinically used agents salbutamol and theophylline. 2. CDP840 relaxed isolated trachea, under basal tone (EC50 4.5 +/- 1.1 microM) being 17 fold less potent than rolipram (EC50 0.26 +/- 0.13 microM) but attaining the same Emax (83 +/- 6% of the response to 300 microM papaverine). 3. CDP840 relaxed tracheae pre-contracted with carbachol (IC25 39 +/- 9 microM) and histamine (IC25 4 +/- 1 microM) producing monophasic curves. Stereoselectivity was not observed with CT1731 against either carbachol (IC25 33 +/- 11 microM) or histamine (IC25 17 +/- 10 microM). Aminophylline was 1.6 fold (carbachol) and 11 fold (histamine) less potent than CDP840. Rolipram and RP73401 produced tri-phasic relaxation curves but were of similar potency (at the IC25 level) to CDP840 against carbachol (rolipram 18 +/- 5 microM, RP73401 39 +/- 1 microM) whereas against histamine they were approximately 20 fold more potent (rolipram 0.2 +/- 0.1 microM, RP73401 0.2 +/- 0.1 microM). In producing > 30% (carbachol) and > 60% (histamine) relaxation these inhibitors had similar potency and were poor compared to salbutamol. 4. Pre-incubation with CDP840 (10 microM) did not antagonize histamine-induced contraction of isolated trachea; however, it did cause a slight potentiation of the subsequent relaxation to salbutamol (IC50 23 +/- 1 to 15 +/- 2 nM). 5. Pretreatment (1 h) with either CDP840 (1 mg kg-1, i.p. or 3 mg kg-1, i.v.) or rolipram (1 mg kg-1, i.p.) did not bronchodilate or antagonize bronchospasm due to inhaled histamine in anaesthetized, ventilated guinea-pigs. Salbutamol (1 mg kg-1, i.p.) did not bronchodilate but caused a parallel 7 fold rightward shift in the histamine dose-response curve. 6. Stimulation of the vagus nerve in the presence of atropine resulted in a frequency-related bronchoconstriction. CDP840 and rolipram (i.v.) inhibited the response being approximately equipotent (EC50 approximately 10 micrograms kg-1). Neither drug inhibited bronchospasm to inhaled substance P. 7. CDP840 (1-10 micrograms kg-1 i.p.) dose relatedly inhibited ozone-induced bronchoconstriction. CT1731 (1 mg kg-1), rolipram (1 mg kg-1), RP73401 (10 micrograms kg-1) and aminophylline (10 mg kg-1) had no effect. Ozone-induced AHR to inhaled histamine was inhibited by CDP840 in a dose-related manner, 10 micrograms kg-1 abolishing the AHR. This effect was stereoselective as CT1731 was approximately 30 fold less potent than CDP840. Rolipram was approximately 100 fold less potent and RP73401 and aminophylline had no effect. CDP840 was orally active being approximately 10 fold less potent compared to i.p. administration. 8. CDP840 is a poor spasmolytic and anti-spasmogenic agent in response to exogenous mediators; however, it potently inhibits vagally mediated non-cholinergic bronchoconstriction and ozone-induced AHR to histamine. It is possible that regulation of cyclic AMP by PDE 4 contributes to neuronal sensitivity in the airways. Furthermore, CDP840 may suppress AHR without being an overt bronchodilator. Such a profile of activity may have therapeutic benefit in airways diseases such as asthma.

Analysis of Variance↗

PubMed1996

Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein.

1. The effects of the cytochrome P450 inhibitors, proadifen, clotrimazole and 17-octadecynoic acid (17-ODYA) on K-currents in freshly-isolated single cells derived from rat portal vein and on mechanical activity in whole veins were studied. 2. When cells were stepped from -90 mV to a series of test potentials (from -80 to +50 mV), a delayed rectifier current (IK(V)) and an A-type current (IK(A)) could be identified. Proadifen (10 microM), clotrimazole (30 microM) and 17-ODYA (5 microM) each inhibited IK(V) but had little effect on IK(A). 3. When cells were held at -10 mV to inactivate the time-dependent K-currents, IK(V) and IK(A), levcromakalim (3 microM) induced a time-independent outward K-current (IK(ATP)) which was totally inhibited by clotrimazole (30 microM) and almost fully inhibited by proadifen (10 microM). 17-ODYA (5 microM) had no effect on IK(ATP) and exerted only a minor inhibitory action on this current at 20 microM. 4. 17-ODYA (5 microM) potentiated current flow through the large conductance, Ca-sensitive K-channel (BKCa). In contrast, proadifen (10 microM) had no effect on IBK(Ca) whereas clotrimazole (30 microM) exerted a small but significant inhibitory action. 5. Proadifen (10 microM) and clotrimazole (30 microM) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole portal veins. 17-ODYA (5 microM) had no effect on spontaneous contractions but these were inhibited when the concentration of 17-ODYA was increased to 50 microM. 6. The spasmolytic effect of levcromakalim on spontaneous contractions was antagonized by proadifen (10-30 microM) in a concentration-dependent manner but 17-ODYA (up to 50 microM) was without effect. 7. These results in portal vein show that cytochrome P450 inhibitors exert profound effects on a variety of K-channel subtypes. This suggests that enzymes dependent on this cofactor may be important regulators of K-channel activity in smooth muscle. The relevance of these findings for the identification of the pathway involved in the synthesis of the endothelium-derived hyperpolarizing factor is discussed.

Animals↗

PubMed1995

Occult caffeine as a source of sleep problems in an older population.

OBJECTIVE: To evaluate the impact of caffeine in medication on sleep complaints in a community population of persons aged 67 or older. DESIGN: Cross-sectional analysis. SETTING: Iowa 65+ Rural Health Study. PARTICIPANTS: Those who completed their own interview, including a section on the use of medications, during the third annual in-person follow-up in 1984-1985. MEASUREMENTS MAIN OUTCOMES: trouble falling asleep or other sleep complaints. Covariates: use of caffeine-containing medication, spasmolytic, or sympathomimetic drug; number of drugs used; depressive symptoms; self-perceived health; comorbidity, hip fracture, arthritis, ulcer of stomach or intestines; and consumption of caffeinated beverages. RESULTS: The prevalence of caffeinated medication use by participants was 5.4%. Those reporting the use of any caffeine-containing medication were at an increased risk of having trouble falling asleep (Odds Ratio [OR] = 1.79, 95% confidence interval [CI] = 1.19-2.68). There was no significant risk of other reported nighttime or daytime sleep problems associated with use of caffeine-containing drugs. Even after adjusting for other factors that could interfere with initiation of sleep, such as painful disease, depressive symptoms, polypharmacy, use of specific medications known to interfere with sleep, and coffee consumption, the use of caffeine-containing medication still presented a significantly increased risk of having trouble falling asleep (OR = 1.60, CI = 1.04-2.46). Although those participants using over-the-counter analgesic medication containing caffeine had an increased risk of trouble falling asleep (OR = 1.88, CI = 1.22-2.90), there was no significant risk of trouble falling asleep for those who took similar noncaffeinated OTC analgesic drugs (OR = 1.26, CI = 0.87-1.83). CONCLUSIONS: The use of caffeine-containing medication is associated with sleep problems. Healthcare providers should be aware of potential problems associated with over-the-counter medications containing caffeine and should counsel patients about the potential of sleep problems. Older patients should be encouraged to read the label on medications and to select drugs that are caffeine-free when that is possible.

Aged↗

PubMed1978

Depression of spasticity by alpha-adrenergic blockade.

In spastic patients the alpha-adrenergic blocking drug thymoxamine (Opilon Forte) was found capable of depressing most propioceptive reflex parameters within 1 min after intravenous administration. The action seems to be of CNS origin, probably exerted as a depression of spindle stretch sensitivity through descending alpha-adrenergic bulbospinal pathways, but an additional action on the mechanism of presynaptic inhibition is likely. With oral administration, the drug is also capable of depressing distressing clonus, and it is concluded that it deserves further testing as a spasmolytic.

Administration, Oral↗

PubMed1985

The effect of indomethacin on the motility of isolated sheep ureters.

The possible spasmolytic effect of indomethacin was studied on isolated sheep ureteral preparations. Ureteral ring preparations suspended in an organ bath exhibited long lasting rhythmic contractions quite similar to the in vivo situation. This spontaneous motility was unaffected by hyoscine, phenoxybenzamine, propranolol, mepyramine and methysergide. Addition of indomethacin resulted in a dose dependent reduction in amplitude and frequency of the contractions, the threshold value being 10(-8) M. Washing reestablished motility and both PGE2 and PGF2 alpha were powerful stimulators of rhythmic contractions. Our conclusion is that in vitro rhythmic activity of the ureter is dependent on endogenous PG-synthesis and the cyclooxygenase inhibitor indomethacin dose-dependently blocks this.

Animals↗

PubMed1985

The use of two different pharmacological principles to inhibit a cholinergic bronchospasm in guinea pig.

The ability of inhaled atropine and clonidine to inhibit a bronchospasm produced by injected acetylcholine or by vagal stimulation, was studied in anaesthetized guinea pigs. Vagally mediated airway constriction was restrained in a concentration-related fashion by inhaled clonidine and reached nearly 100% inhibition (EC50 = 2 X 10(-5) mol/l in the nebulizer). Atropine expressed initially about the same level of spasmolytic effect but only a final prevention of 60% was possible to reach with this drug. On the contrary, inhaled atropine was able to produce a complete inhibition (EC50 = 2 X 10(-6) mol/l) when the bronchoconstriction was elicited by exogenous acetylcholine. This type of spasm was also to some degree inhibited by clonidine.

Aerosols↗

PubMed1998

Ketobemidone plus (RS)-3-dimethylamino-1,1-diphenylbut-1-ene (A29) is more potent at NMDA receptors than ketobemidone alone: evidence for A29 as a non-competitive NMDA receptor antagonist.

The opioid, ketobemidone, has previously been shown to be a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ketobemidone is available in a formulation which contains ketobemidone and a spasmolytic compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride (A29), in a one to five ratio. Using in vitro receptor binding techniques and an in vitro electrophysiological preparation consisting of rat cerebral cortex, we have characterized the interaction between A29 and the different glutamate receptor subtypes. A29 selectively inhibited binding of the non-competitive NMDA receptor antagonist 3H-MK-801 with a Ki value 16 +/- 4.5 microM, but was inactive in assays measuring affinities for other glutamate receptors. In agreement with the binding studies, A29 was found to selectively inhibit responses to NMDA in the rat cortical wedge preparation, whereas responses to kainate and AMPA were unaffected. Analysis of dose response curves showed A29 to be a NMDA receptor antagonist with an IC50 value of 100 microM versus responses to 10 microM NMDA. The inhibitory effects of ketobemidone and A29 on responses to 10 microM NMDA were additive. These data show that the combination of A29 and ketobemidone exert more potent antagonism at the NMDA receptor than does ketobemidone alone.

Allylamine↗

PubMed1987

Actions of some vasodilators on isolated human hand veins.

Vasospasm is a well recognized complication during microvascular surgery of the hand. In the search for new spasmolytic drug therapies, the effects of papaverine, nitroprusside, nimodipine and lidocaine on isolated human hand veins contracted by several postulated mediators of vasospasm were examined. Mechanical activity was recorded isometrically in ring segments of the vessels. Potassium ions, noradrenaline (NA), 5-hydroxytryptamine (5-HT) and prostaglandin F2 alpha (PGF2 alpha) all produced strong contractions that were highly dependent on the presence of extracellular Ca2+. Papaverine acted as a nonselective vasodilator, as it produced an almost identical inhibition of contractile responses to all examined stimulants. Nitroprusside inhibited contractions induced by agonists more than those evoked by K+, whereas the opposite was found for nimodipine. Nitroprusside also seemed to display a certain degree of selectivity among the agonist-induced responses (NA greater than PGF2 alpha greater than 5-HT). Lidocaine increased the contractile response to K+ and at high concentrations (greater than 10(-5) M) produced a contraction per se. The clinical efficacy of lidocaine as a vasodilator after topical application therefore seems to reflect an inhibitory action on vasoconstrictor nerves. Papaverine, nitroprusside, nimodipine and lidocaine differ considerably in their profiles of action and therefore deserve to be further evaluated in the treatment of vasospasm during microvascular surgery.

Adolescent↗

PubMed1987

Differentiation of calcium antagonists with respect to their effects in normal and skinned taenia caeci preparations.

In taenia preparations, depolarized by a K+-rich medium, Ca2+ caused contraction and cinnarizine (0.4-100 microM), trifluoperazine (2-100 microM) and verapamil (0.02-10 microM) caused concentration-dependent antagonism of Ca2+, displacing the Ca2+ log concentration-effect curve to the right and depressing the maximal response. Equieffective (IC75) antispasmogenic concentrations were selected. The antispasmogenic effects of verapamil were readily offset by removing the drug from the bathing fluid but those of the other drugs were not. The calcium antagonists (antispasmogenic IC75) were then tested for spasmolytic activity in tissues generating tension in response to the EC80 of Ca2+. Verapamil was more effective in producing spasmolysis than cinnarazine or trifluoperazine. In skinned taenia preparations, verapamil (100 microM) did not inhibit Ca2+-induced contractions. High concentrations of cinnarizine (100 microM) and trifluoperazine (100 microM) inhibited Ca2+-induced activation of the contractile proteins. However, antispasmogenic IC75s from intact taenia were not able to produce this effect on skinned preparations. It is concluded that there are differences between calcium antagonists. The action of verapamil on intact taenia is mainly exerted on the plasma membrane. Cinnarizine and trifluoperazine act both on the plasma membrane and upon the intracellular contractile machinery.

Animals↗

PubMed1987

Depressant action of oxybutynin on the contractility of intestinal and urinary tract smooth muscle.

Experiments were carried out in-vitro using segments of guinea-pig ileum, taenia caeci, ureter and detrusor. In the ileum, oxybutynin (30, 100 nM) competitively antagonized acetylcholine-induced contractions but did not alter those induced by histamine. Higher concentrations of oxybutynin (up to 10 microM) induced a non-competitive depression of responses to both agonists and caused a parallel shift to the right of the Ca2+-induced contractions in taenia caeci strips bathed in a Ca2+-free, high-K+ medium. In the ureter, oxybutynin (1-10 microM) impaired rhythmic muscular contractions in normal medium and after CaCl2 addition in Ca2+-free medium. Similarly to verapamil (10, 30 microM), oxybutynin (10, 30 microM) depressed both the cholinergic and non-adrenergic, non-cholinergic components of the electrically-induced contractions of detrusor strips. It is concluded that oxybutynin has anticholinergic properties and, at higher concentrations, exerts a direct spasmolytic activity possibly mediated by blockade of the transmembrane Ca2+ fluxes responsible for smooth muscle contraction.

Acetylcholine↗

PubMed1990

Effects of cularine and other isoquinoline alkaloids on guinea-pig trachea and human bronchus.

The relaxant effects of the isoquinoline alkaloids, cularine, antioquine, obaberine and 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline, with structures related to that of papaverine, have been studied on the guinea-pig isolated trachea and human bronchus against contractions induced by acetylcholine (ACh), histamine, neurokinin A (NKA) and KCl. These effects were compared with those of papaverine and theophylline. Among the alkaloids tested, the most potent was cularine, the relaxant activity of which, in terms of pD2, was between those of papaverine and theophylline. The results showed that for the guinea-pig isolated trachea and the human bronchus, the cularine concentrations required to inhibit K(+)-induced contractions were close to those necessary to counteract ACh-, histamine- and NKA-induced contractions. The relaxant activity of cularine was not modified when it was tested on tracheal preparations under resting tone or after epithelium removal. In addition, cularine was able to inhibit Ca2(+)-induced contractions in a Ca2(+)-free, K(+)-enriched solution at the same concentrations as those which inhibited the action of the different contractile agents in normal Krebs solution. All these data show that cularine displays non-specific antispasmogenic activity on guinea-pig and human airways. The lower relaxant activity (pD2) of cularine compared with papaverine suggests the importance of free rotation of the isoquinoline-benzyl ring linkage as well as of the degree of hydrogenation of the heterocyclic ring in the spasmolytic effects of isoquinoline compounds.

Adenosine↗

PubMed1997

In-vitro binding of propiverine hydrochloride and some of its metabolites to serum albumin in man.

The distribution and pharmacological action of propiverine, a bladder spasmolytic agent, are affected by the extent of plasma-protein binding. Because attempts to assess the albumin-binding of propiverine have produced conflicting results, the binding parameters of the drug and some of its metabolites to serum albumin in man have been re-evaluated. In man propiverine is bound to serum albumin at a single site with high affinity (KA1 = 1.45 x 10(4) L mol-1) and at least two sites with low affinity (KA2 = 2.5 x 10(2) L mol-1). The metabolites of propiverine, namely M2 (dealkylated propiverine), M5 (the N-oxide of propiverine) and M6 (the N-oxide of M2), are less firmly bound to serum albumin; this is considered to be non-specific binding. Binding experiments with human serum revealed that there are additional binding proteins. At therapeutic plasma levels the extent of binding was calculated to be 90, 15, 60, and 20% for propiverine and the metabolites M2, M5, and M6, respectively. The strong binding of propiverine to serum proteins controls its availability to the liver. Because the metabolites are not tightly bound to serum proteins, after metabolism of propiverine its metabolites are easily eliminated.

Benzilates↗