摘要:

Pinacidil (N’’-cyano-N-4-pyridyl-N’-l,2,2-trimethylpropylguanidine monohydrate; P1134) is a new vasodilator drug with a direct relaxant effect on vascular smooth muscle. Its hemodynamic properties, in comparison with those of hydralazine, were studied in conscious normotensive and spontaneously hypertensive rats; anesthetized normotensive rats; pithed normotensive rats; pithed normotensive rats subjected to electrical stimulation of the spinal cord. Radioligand binding studies on rat cerebral membranes were carried out to study a possible affinity for pinacidil towards α1 and α2-adrenoceptors, respectively. The observations made in conscious and anesthetized rats suggest that both pinacidil and hydralazine are predominantly arterial vasodilators. In conscious animals reflex tachycardia was elicited by both drugs. Neither pinacidil nor hydralazine possessed substantial affinity for α1 or α2adrenoceptors, as concluded from radioligand binding studies. Pinacidil interferes with the pressor response to postsynaptic α2-adrenoceptor stimulation in pithed rats, possibly reflecting weak calcium antagonistic activity of the drug. Pinacidil did not interfere with the electrically induced release of noradrenaline from presynaptic sites. All results suggest that pinacidil is a direct-acting arteriolar dilator, which on a molar base is somewhat more potent than h

ISSN:0031-7012    

DOI:10.1159/000137878

出版商:S. Karger AG    

年代:1983

数据来源: Karger

摘要:

Pirlimycin adenylate (U-63,440) is a clindamycin analog possessing antiarrhythmic activity. In the anesthetized dog, the sustained ventricular tachycardia produced by ouabain intoxication is converted to a normal sinus rhythm with an average dose of 26.0 ± 5.1 mg/kg of pirlimycin adenylate (range 13.4–40.7 mg/kg i.v.). The drug failed, however, to decrease arrhythmia frequency in a modified 2-day Harris dog preparation even with doses of up to 100 mg/kg. The efficacy of pirlimycin adenylate against ouabain-induced arrhythmias cannot be ascribed to a local anesthetic action, since concentrations of up to 5 × 10–3M produced only a small (26 ± 5%) reduction in the spike amplitude of desheathed isolated frog sciatic nerves. In contrast, lidocaine (5 × 10–3M) produced a 91 % reduction in single spike amplitude. Neither did pirlimycin adenylate (up to 10–3M) produce any negative inotropic effect in isolated cat papillary muscles, while both lidocaine and quinidine were cardiodepressant at 10–3M. It is concluded that pirlimycin adenylate may be an interesting prototype antiarrhythmic agent and further chemical modification of the drug molecule might increase the spectrum of antiarrhythmic activity without altering the dr

ISSN:0031-7012    

DOI:10.1159/000137879

出版商:S. Karger AG    

年代:1983

数据来源: Karger

摘要:

A variety of prostaglandin synthetase inhibitors are cooxygenated during arachidonic acid peroxidation catalyzed by rat renal medulla prostaglandin synthetase or soybean lipoxygenase. Phenylbutazone, aminopyrine, 1,3-diphenylisobenzofuran, paracetamol, p-aminophenol, p-phenetidine and other o- and m-substituted aminophenol derivatives were cooxygenated, whereby prostaglandin synthetase inhibition was significantly weakened due to the formation of less inhibitory metabolites. In contrast, the inhibitory potency of diclofenac, indomethacin and phenacetin and its analogues remained unchanged during prostaglandin synthesis inhibition, because these compounds were no suitable cooxygenation substrates. Evidence is given that quinone imines may not be involved in the cooxidative metabolism of paracetamol and other aminophenols. As to the mechanisms of cooxygenation of suitable substrates dependent on their chemical structures either the arachidonic acid oxygenase or the subsequent hydroperoxidase reaction may trigger the oxygenation. 1,3-Diphenylisobenzofuran is metabolized during the formation of arachidonic acid hydroperoxides in contrast to paracetamol, which requires an additional peroxidase reaction to yield reactive metabolites.

ISSN:0031-7012    

DOI:10.1159/000137880

出版商:S. Karger AG    

年代:1983

数据来源: Karger

摘要:

A dose-response curve for the hypoprothrombinemic effect of brodifacoum 3-[-3(4’-bromobiphenyl-4-yl) 1,2,3,4-tetrahydronaphth-1-yl]-4-hydroxycoumarin, was constructed using doses ranging from 0.1 to 0.33 mg/kg. Brodifacoum exhibited a remarkably steep dose-response curve. Brodifacoum failed to exhibit a dose-dependent effect on the degradation rate constant (kdeg) for prothrombin complex activity (PCA) after a PCA-synthesis-blocking dose of warfarin. Both phenobarbital pretreatment and SKF525A treatment altered to anticoagulant response to brodifacoum. Phenobarbital decreased the anticoagulant effect, whereas SKF525A increased it, suggesting that a substantial portion of brodifacoum-induced hypoprothrombinemia is mediated by brodifacoum itself rather than by metabolites. Finally, rats dosed orally with brodifacoum (0.2 mg/kg p.o.) were sacrificed in groups of 3–5 at various times up to 120 h after the dose. Brodifacoum was assayed in serum, small intestine, and liver by an HPLC method. Brodifacoum disappeared slowly from serum with a half-life of 156 h. Disappearance from small intestine was rapid, for 24 h, but intestinal levels began increasing from 24 to 72 h after the dose. Concentrations in liver were rapidly established, and exceeded serum concentrations by 20-fold. Brodifacoum levels in liver remained relatively constant for 96 h. Sustained liver concentrations after a single dose may partially account for brodifacoum’s apparent potency relative to war

ISSN:0031-7012    

DOI:10.1159/000137881

出版商:S. Karger AG    

年代:1983

数据来源: Karger

摘要:

Previous work indicates that one consequence of the accumulation of several xenobiotics in the lung is compromised pulmonary disposition of 5-hydroxytryptamine (5-HT). In the present studies, we examined whether pulmonary accumulation of chlorpromazine (CPZ), propranolol (P), imipramine (IMP), and clomipramine (Cl-IMP) affected 5-HT disposition in rabbit lungs. Pulmonary ecxtraction and metabolism of [14C]-5-HT during single pulmonary passage were examined using the reference indicator radioisotope dilution technique in male New Zealand albino rabbits. After control experiment, animals received CPZ or P (2.5, 5, or 10 mg/kg), IMP or Cl-IMP (0.25, 0.5 or 1.0 mg/kg) via the jugular vein. Pulmonary clearance was 83% of administered 5-HT. A significant proportion (28%) of total radioactivity in the bloodstream after single passage was recovered as 5-HIAA in control experiments. These values were reduced significantly to 70 and 20%, respectively upon prior administration of IMP (0.25 mg/kg). Cl-IMP was more effective in reducing these values further. CPZ and P were marginally effective at the highest dose. While prior administration of IMP and Cl-IMP resulted in pulmonary accumulation of both drugs, the latter accumulated to a significantly greater extent. These results suggest that Cl-IMP has higher affinity to the rabbit lung than IMP and may inhibit pulmonary uptake of 5-HT by competition for uptake and binding sites more than IMP.

ISSN:0031-7012    

DOI:10.1159/000137882

出版商:S. Karger AG    

年代:1983

数据来源: Karger

摘要:

Membrane fragments of isolated cells from guinea pig gastric mucosa, enriched to 65% parietal cells, bind with high affinity the opioid peptide 3H-D-Ala2-D-Leu5-enkephalin (3H-DADLE). Binding was saturable and reversible. Scatchard analysis revealed a second binding site with low affinity but high capacity. Acid secretion by isolated, enriched parietal cells was determined by means of 14C-aminopyrine uptake. Basal acid secretion was not influenced by DADLE but that stimulated by histamine was further augmented by the enkephalin analog. This potentiating effect was prevented by the opioid antagonist naloxone. The present data provide for the first time evidence that gastric acid secretion is modulated by an opioid mechanism probably located on the parietal cell.

ISSN:0031-7012    

DOI:10.1159/000137883

出版商:S. Karger AG    

年代:1983

数据来源: Karger