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M Spedding

Publications and source records attributed to M Spedding.

At least 109 records · Page 6Linked to original sources
PubMed1982

Assessment of "Ca2+ -antagonist" effects of drugs in K+ -depolarized smooth muscle. Differentiation of antagonist subgroups.

1. Taenia preparations from the guinea-pig caecum yielded reproducible concentration-response curves to Ca2+ (EC50 134 +/- 8 mumol/1) when maintained in depolarizing Tyrode solution containing K+ (40 mmol/1). Drugs which are claimed to be "Ca2+ -antagonists" displaced the curves to the right without depression of the maximum response. In this test nifedipine, verapamil, diltiazem, pimozide, cinnarizine, flunarizine and fendiline appeared qualitatively similar but had different potencies. 2. The antagonist effects of nifedipine, verapamil and diltiazem were readily reversed by washout of the drugs from the bathing fluid, but the effects of the other drugs were not. 3. Cinnarizine, flunarizine, pimozide and fendiline were only weakly active as relaxants of Ca2+ (100 mumol/1)-induced contractions, when compared with their antagonist activity when applied initially in Ca2+ -free media. As the presence of Ca2+ (100 mumol/1) in the K+ -Tyrode reduced the antagonist effects of cinnarizine and pimozide, but not that of verapamil and diltiazem, the weak activity of some of the antagonists as relaxants of Ca2+ -induced contractions can be attributed to a protective effect of Ca2+ during the incubation period with the antagonist. 4. The problems associated with the assessment of the potency of drugs as "Ca2+ -antagonists" are discussed and it is proposed that three subgroups of drugs may exist within the overall classification.

Animals↗
PubMed1980

Depression of sympathetic nervous function by DL-alpha-monofluoromethyldopa, an enzyme-activated, irreversible inhibitor of L-aromatic amino acid decarboxylase.

We investigated the effects on peripheral sympathetic nervous function of monofluoromethyldopa (MFMD, RMI 71963), a selective, enzyme-activated, irreversible inhibitor of L-aromatic amino acid decarboxylase. Three daily injections of 2.5, 25, or 100 mg/kg MFMD to rats reduced the dopamine and norepinephrine concentrations in the heart and increased those of L-dopa. Sedation was seen with the two highest doses of MFMD. Cardiovascular responses in the pithed rat to stimulation of the whole spinal sympathetic outflow and to injections of tyramine were reduced by treatment with MFMD. Both the reduced sympathetic function and the depleted transmitter store were restored by infusions of dopamine. Norepinephrine depletion and functional inhibition were obtained with smaller doses of MFMD (3, 6, and 10 mg/kg daily) given for longer periods (10 days). Blood pressure in spontaneously hypertensive rats was reduced by treatment with MFMD, 25 mg/kg, daily for 3 days. In vitro responses to nerve stimulation of portal veins declined during incubation with MFMD or alpha-methyl-p-tyrosine; responses of atria were unaffected. Changes in norepinephrine concentrations of portal veins and atria closely paralleled the changes in function. MFMD is the first compound which depletes peripheral norepinephrine concentrations by inhibiting transmitter biosynthesis at the decarboxylase step. Such depletion results in inhibition of sympathetic function in vivo and introduces a novel approach to pharmacological manipulation of the activity of the peripheral sympathetic nervous system.

Animals↗
PubMed1980

Effects of metoclopramide and isoprenaline in the rat vas deferens; interactions with alpha-adrenoceptors.

1 Metoclopramide (2.8 to 280 microM) augmented contractions of rat vas deferens preparations induced by field stimulation (6 Hz for 1 s). This effect was antagonized by phentolamine (0.1 microM). Metoclopramide (2.8 to 280 microM) did not affect phenylephrine-induced contractions. 2 Metoclopramide (2.8 to 280 microM) antagonized the inhibitory effects of clonidine on the contractions induced by field stimulation, but not the inhibitory effects of purine nucleosides. 3 From these results it is concluded that metoclopramide (2.8 to 280 microM) is a presynaptic alpha-adrenoceptor antagonist in the rat vas deferens. 4 Following beta-adrenoceptor blockade with (+/-)-propranolol (3.3 microM), (-)-isoprenaline (0.47 to 14 microM) inhibited responses to field stimulation but not to phenylephrine. These propranolol-resistant effects of isoprenaline were antagonized by metoclopramide (2.8 to 280 microM) and by phentolamine (0.1 to 10 microM), indicating that isoprenaline may stimulate presynaptic alpha-adrenoceptors in this preparation.

Animals↗
PubMed1978

Anatagonism of the inhibitory effects of adenosine 5'-triphosphate on the isolated taenia of the guinea-pig caecum: structure-activity relationships within a series of isatogen derivatives.

1 A series of eight isatogen derivatives was studied on isolated tissues taken from guinea-pigs. The ability of the compounds to relax the taenia, to inhibit adenosine 5'-diphosphate (ADP)-stimulated respiration in mitochondria and to antagonize the inhibitory effects of adenosine 5'-triphosphate (ATP) on smooth muscle was measured. 2 All the derivatives inhibited ADP-stimulated respiration in mitochondria and relaxed the smooth muscle. These two effects were found to be significantly correlated. 3 Only half the compounds blocked the inhibitory effects of ATP, and all of these had a chemically reactive group (nitro, methoxy or pyridyl) in the 2'2-position. 2-2'-Pyridylisatogen was the most effective blocking agent. 4 The blockade of the inhibitory effects of ATP is not related to the other actions of the derivatives.

Adenosine Diphosphate↗
PubMed1978

The mechanism of the relaxant effect of 2-2'-pyridylisatogen on the isolated taenia of the guinea-pig caecum.

1 2-2'-Pyridylisatogen tosylate (PIT) slowly relaxed taenia caeci preparationg of the guinea-pig in a concentration-dependent manner (threshold 2.5 muM). The relaxant effect did not show tachyphylaxis.2 The relaxation was not affected by tetrodotoxin (0.3 muM), guanethidine (17 muM) nor by a combination of phentolamine (36 muM) and propranolol (4 muM)3 In taenia caeci preparations suspended in K(+)-depolarizing, Ca(2+)-free Ringer, addition of Ca(2+) (0.1 to 30 mM) resulted in a slow contraction. PIT (50 muM) and papaverine (15 muM) antagonized these contractions, whereas indomethacin (28 muM) was ineffective.4 Although PIT (50 muM for 30 min) caused a relaxation of the taenia, and, when the tone of the preparations was restored with carbachol, antagonized adenosine 5'-triphosphate (ATP)-induced relaxations, relaxation of the taenia with papaverine (30 muM for 5 min) did not antagonize ATP-induced relaxations. It is concluded that the relaxant and ATP-receptor blocking actions of PIT are independent properties of the compound.

Adenosine Triphosphate↗
PubMed1976

Identification of separate receptors for adenosine and adenosine 5'-triphosphate in causing relaxations of the isolated taenia of the guinea-pig caecum.

1 The mechanisms by which adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and adenosine relax the taenia caecum preparation of the guineapig have been studied. ATP and ADP produced similar effects which were qualitatively different from those of AMP and adenosine. 2 2-2'Pyridylisatogen tosylate (PIT: 50 muM for 30 min) blocked the effects of ATP and ADP, but exhibited weak activity against AMP and failed to antagonize the effects of adenosine. The action of PIT was unaffected by the inclusion of dipyridamole (2muM) in the bathing fluid. 3 There was a significant correlation between the sensitivity of individual preparations to ATP or ADP and the blocking potency of PIT. 4 The presence of adenosine in the bathing fluid (2 mM for greater than 30 min) desensitized the taenia to subsequent applications of adenosine. The effects of ATP were increased by this procedure. 5 The results indicate that ATP and adenosine relax the taenia by different mechanisms.

Adenosine↗
PubMed1975

Antagonism of adenosine 5'-triphosphate-induced relaxation by 2-2'-pyridylisatogen in the taenia of guinea-pig caecum.

1. 2-2' Pyridylisatogen tosylate (PIT) (greater than 2.5 muM) relaxed the guinea-pig isolated taenia caeci by an unknown mechanism. 2. With higher concentrations of PIT (greater than 12.5 muM) subsequent applications of adenosine 5'-triphosphate (ATP) (2-600 muM) revealed a blockade of the ATP receptors. The antagonism was characterized by a delayed onset of action (greater than 10 min incubation with 50 muM PIT) and eventually became irreversible (greater than 50 muM PIT for greater than 30 minutes). The antagonism was specific for ATP, was not competitive, and was not dependent upon the relaxant effect. 3. The presence of either acetylcholine (0.05-1.0 muM) or carbachol (0.05-1.0 muM) increased the antagonistic effect of PIT (50 muM) approximately five-fold. 4. Following prolonged exposure, PIT (50 muM for 90 min) did not block the inhibitory effects of fiedl stimulation (2 Hz, 10 s) of the taenia caeci in the presence of hyoscine (0.33 muM). These results do not support the purinergic nerve hypothesis.

Adenosine Triphosphate↗
PubMed1972

The presence of -adrenoceptors in the guinea-pig seminal vesicle.

1. The preparation of longitudinal smooth muscle strips from guinea-pig seminal vesicles is described.2. Isoprenaline and salbutamol inhibited contractions produced by parasympathomimetic agents.3. The inhibitory action of isoprenaline was blocked by low concentrations of propranolol and butoxamine. It was concluded that beta(2)-adrenoceptors were present in the tissue.4. The inhibitory action of isoprenaline was not apparent when adrenaline, noradrenaline, hypogastric nerve or transmural stimulation were used to contract the tissue.

Acetylcholine↗
PubMedDate not supplied

A functional correlate for the dihydropyridine binding site in rat brain.

Calcium channels, controlling the influx of extracellular Ca2+ and hence neurotransmitter release, exist in the brain. However, drugs classed as calcium antagonists and which inhibit Ca2+ entry through voltage-activated Ca2+ channels in heart and smooth muscle, seem not to affect any aspect of neuronal function in the brain at pharmacologically relevant concentrations. Yet the dihydropyridine calcium antagonists (for example, nitrendipine) bind stereospecifically with high affinity to a recognition site on brain-cell membranes thought to represent the Ca2+ channel and consequently, the physiological relevance of these sites has been questioned. However, activation of voltage-dependent Ca2+ channels can increase cytoplasmic Ca2+ and neurotransmitter release in neuronal tissue. We show here that Bay K8644, a dihydropyridine Ca2+-channel activator, can augment K+-stimulated release of serotonin from rat frontal cortex slices and that these effects can be antagonized by low concentrations of calcium antagonists. As 3H-dihydropyridine binding to cortical membrane preparations resembles the binding in heart and smooth muscle where there are good functional correlates we conclude that the dihydropyridine binding sites in the brain represent functional Ca2+ channels that can be unmasked under certain circumstances.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMedDate not supplied

Differences between the effects of calcium antagonists in the pithed rat preparation.

The drugs classed as calcium antagonists display marked differences in vitro and it has been proposed that different subclasses of antagonists exist (Spedding M. Naunyn Schmiedebergs Arch Pharmacol 1982; 318:234-40). The effects of these drugs have now been compared in vivo using the pithed rat preparation. Whereas the hypotensive effects of verapamil (0.1-3 mumol/kg i.v.) and diltiazem (0.1-10 mumol/kg i.v.) were accompanied by prolongation of PR intervals and second-degree atrioventricular block with little bradycardia, fendiline (0.1-30 mumol/kg i.v.), cinnarizine (0.1-10 mumol/kg i.v.), and pimozide (0.1-10 mumol/kg i.v.) reduced heart rate at hypotensive doses but had less marked effects on AV conduction, thus implying different selectivities among calcium antagonists for the sinus or AV nodes. These differences were not secondary to effects on the autonomic nervous system. In contrast, nifedipine (0.01-1 mumol/kg i.v.) had no effect on the ECG in doses which markedly reduced blood pressure elevated by an infusion of angiotensin II and thus showed specificity for vascular smooth muscle. The marked differences between the effects of the calcium antagonists in vivo confirm the disparate nature of this group of drugs. The reasons for these differences are discussed.

Animals↗
PubMedDate not supplied

Vasodilation by medroxalol mediated by beta 2-adrenergic receptor stimulation.

A contribution by active vasodilation to the hypotensive effect of medroxalol was investigated in anesthetized dogs and reserpinized pithed rats. In anesthetized dogs, intravenous doses of medroxalol, which decreased blood pressure and heart rate, also produced a dose-related vasodilation in the isolated perfused gracilis muscle in situ. This vasodilator effect of medroxalol was completely blocked by propranolol; the hypotensive effect of medroxalol was inhibited 50% by propranolol but not at all by practolol. In reserpinized pithed rats with angiotensin-supported blood pressure, intravenous doses of medroxalol also produced propranolol-sensitive decreases in diastolic blood pressure and did not alter heart rate. Labetalol produced similar effects but was significantly less potent. Comparatively, equivalent amounts of isoproterenol and pindolol decreased diastolic blood pressure but increased heart rate. In the isolated guinea pig trachea, medroxalol produced a propranolol-sensitive relaxation at concentrations that antagonized the relaxant effects of salbutamol. Identical concentrations of medroxalol did not increase rate of isolated guinea pig atria. It is concluded that a substantial portion of the hypotensive effect of medroxalol is due to a beta 2-adrenergic-receptor-mediated vasodilation.

Adrenalectomy↗