Inhibitory muscarinic cholinoceptors on postganglionic sympathetic nerves in the guinea pig isolated atrium are of the M3 subtype.

Pre- and postjunctional effects of four muscarinic (m)-cholinoceptor antagonists were investigated against carbachol in isolated spontaneously beating guinea pig atria which were also exposed to brief periods of electrical field stimulation. The cholinoceptor agonist carbachol concentration-dependently inhibited the contraction rate of the atria with an EC50 value of 92.3 +/- 20.

Effects of m-cholinoceptor antagonists on the neuromuscular junction.

The effects of four m-cholinoceptor antagonists and d-tubocurarine on carbachol- or nicotine-induced contractions of frog rectus abdominus muscle were investigated. The n-cholinoceptor-mediated contractile responses of frog rectus abdominis muscles were inhibited competitively by d-tubocurarine whereas m-cholinoceptor antagonists inhibited them noncompetitively. Antagonistic potencies for m-cholinoceptor antagonists, assessed by pD'2 values, indicated a rank order of potency which was 4-DAMP > AF-DX 116 > atropine > pirenzepine.

Direct vascular smooth muscle contractile effect of cyclosporin A and its vehicle in rabbit isolated arteries.

cyclosporin A is a widely used immunosuppressant agent which has direct vascular effects such as contraction of the arterial smooth muscle and potentiation of other vasoconstrictor agents. In rabbit isolated arterial segments, the contractile effects of a cyclosporin A preparation (Sandimmun; 10(-6) M) and its solvent (Cremophor-EL) were investigated. Both caused an increase in the basal tension of arterial segments after an incubation period of 1 hour.

Superoxide dismutase and allopurinol prevent the pressor effects of angiotensin II and histamine in the guinea-pig isolated perfused lung exposed to hypoxia.

1. In the guinea-pig isolated perfused lung exposed to hypoxia by infusing N2-gassed Krebs solution, angiotensin II and histamine produced a reduced vasoconstrictor response when compared with the responses obtained in nonhypoxic lung. 2.

Epithelial modulation of antigen-induced tracheal smooth muscle contractions in actively sensitized guinea-pigs.

Coaxial bioassay system (guinea-pig trachea and rat anococcygeus muscle as donor and bioassay organs, respectively) and tracheal open ring preparations from ovalbumin-sensitized guinea-pigs were used to investigate the role of the epithelium in response to the antigen challenge. Ovalbumin induced concentration-dependent relaxations in the phenylephrine precontracted rat anococcygeus muscle suspended in the lumen of sensitized guinea-pig tracheal tube preparations in the presence of either indomethacin or mepacrine. Removal of the epithelium abolished ovalbumin-induced relaxation responses.

Evaluation of the alpha-adrenoceptor antagonistic action of berberine in isolated organs.

The selectivity and specificity of berberine (CAS 2086-83-1) for alpha-adrenoceptor subtypes have been studied. alpha 1-Adrenoceptors were investigated in rat and rabbit aorta and alpha 2-adrenoceptors in guinea-pig ileum preparations. Subtype selectivity was then assessed by calculating the selectivity ratios from Ke (equilibrium constant) values.

Actions of cyclosporin A preparation and Cremophor-EL in rabbit mesenteric artery and thoracic aorta in vitro.

1. We studied the in vitro and direct effects of intravenous cyclosporin A preparation (Sandimmun) and its solvent (Cremophor-EL) on acetylcholine-induced endothelium-dependent relaxation, phenylephrine-induced contraction and drug-induced contraction of rabbit thoracic aorta and superior mesenteric artery segments. 2.

Evaluation of alpha-adrenoceptor agonistic activity of RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane) in rabbit and rat aortae.

The alpha-adrenergic activity of a dopamine receptor agonist, 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127), has been studied on isolated rabbit and rat aortic strips. In both tissues, RDS-127 produced concentration-dependent contractions and its potency was not significantly different from that of phenylephrine. RDS-127-induced contractions were antagonized competitively by both prazosin and phentolamine in rabbit aortic strips, but the antagonists were noncompetitive in rat aortic strips.

Antagonism of acetylcholine action in guinea-pig tracheal smooth muscle and epithelium by pirenzepine, 4-DAMP and atropine.

Acetylcholine-induced guinea-pig tracheal smooth muscle contraction and epithelium-derived relaxant factor release were evaluated using guinea-pig open tracheal rings and rat anococcygeus muscle bioassay to get insight into the participation of muscarinic receptor subtypes in these responses. There was a significant difference between the two pA2 values obtained in contraction and relaxation experiments for pirenzepine, but no difference was found either for atropine or for 4-DAMP. This difference seems to be due to the participation of M1-receptors in smooth muscle contraction.

Dopamine receptor agonists, N,N-dipropyl-2-aminotetralin (TL-68) and 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) antagonize oxotremorine-induced tremors by antimuscarinic action in mice.

Central antimuscarinic actions of dopamine receptor agonists: N,N-dipropylaminotetrain (TL-68) and 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127), were evaluated against oxotremorine-induced tremors in mice. Both TL-68 and RDS-127 inhibited the tremor intensity but were less potent than atropine.

Epithelium-dependent relaxation of guinea-pig tracheal smooth muscle by histamine: evidence for non-H1- and non-H2-histamine receptors.

Epithelium-dependent modulation of the effect of histamine on airway smooth muscle of guinea-pig was studied by using the coaxial bioassay system. Histamine-induced contraction was followed by epithelium-dependent relaxation in the presence of indomethacin, propranolol, atropine and cimetidine. Mepyramine failed to prevent histamine-induced epithelium-dependent relaxation of carbachol-precontracted tracheal smooth muscle in the presence of cimetidine.

The antimuscarinic activity of a dopamine receptor agonist (RDS-127) differentiates M2-muscarinic receptors of heart, ileum and trachea in guinea-pig.

The antimuscarinic action of a dopamine receptor agonist, 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) was evaluated using guinea-pig isolated electrically paced left atria, spontaneously beating atria, ileal longitudinal muscle and tracheal strip. RDS-127 competitively antagonized the responses to carbachol in all these tissues. RDS-127 exhibits higher selectivity for tracheal M2-muscarinic receptors than for cardiac and ileal receptors.

Epithelium-dependent relaxation of guinea-pig tracheal smooth muscle by carbachol.

Modulation of the effect of carbachol by epithelium on tracheal smooth muscle of guinea-pig was studied by using coaxial bioassay system. The contractile response of the bioassay organ (epithelium-free tracheal smooth muscle of guinea-pig) to carbachol was well maintained along the observation period of 30 min. When the same bioassay organ was taken into epithelium-intact tracheal tube of guinea-pig, a significant relaxation followed the carbachol-induced initial contraction within 30 min which was abolished by the removal of epithelial cell layer.

The rat anococcygeus muscle is a convenient bioassay organ for the airway epithelium-derived relaxant factor.

The response to epithelium-derived relaxant factor (EpDRF) released from guinea-pig trachea by acetylcholine was studied in the precontracted rat anococcygeus muscle in a coaxial bioassay system. Acetylcholine caused no relaxation of rat anococcygeus muscle which was precontracted with phenylephrine. When the same muscle was placed into a guinea-pig trachea with intact epithelium, acetylcholine produced a slowly developing relaxation which was potentiated by neostigmine and antagonized by atropine but was not altered by indomethacin, propranolol, hydroquinone nor methylene blue.

An evidence for presynaptic excitatory alpha 2-adrenergic receptors in frog myocardium.

This study was undertaken to determine the effects of clonidine on sympathetic neurotransmission in frog myocardium. In the electrically driven ventricular strips of frog heart, clonidine was found to be ineffective on contractility. However, clonidine increased the positive inotropic responses to transient additional stimulations.

Effect of ouabain on norepinephrine-induced contractions of isolated rabbit aorta.

The acute potentiating effect of ouabain on norepinephrine (NE) induced contractions of isolated rabbit aorta was investigated. Ouabain, at concentrations of 3 X 10(-7) to 10(-5) mol/l potentiated the vasoconstrictor effect of NE as demonstrated by a shift to the left of the NE concentration-response curve in a parallel manner and a concentration-dependent increase in the EC50 ratio. A significant increase in maximal contractility was observed by ouabain at 3 X 10(-6) and 10(-5) mol/l.

Cardioselective antimuscarinic action of a dopamine receptor agonist, N,N-dipropyl-2-aminotetralin (TL-68).

The antimuscarinic action of N,N-dipropyl-2-amino-tetralin (TL-68) was evaluated using guinea-pig isolated electrically paced left atria, spontaneously beating atria and ileal longitudinal muscle. TL-68 competitively antagonized the responses to carbachol but was less potent than atropine in these preparations. TL-68 exhibits higher affinity towards cardiac muscarinic receptors than ileal receptors and, therefore, possesses cardioselective antimuscarinic properties.

Effect of naloxone on physostigmine-induced pressor response in adrenalectomized rats.

Physostigmine-induced pressor response was studied in adrenalectomized rats. The increase in mean arterial blood pressure elicited by intravenous administration of physostigmine was not altered by adrenalectomy or sham-operation. The pressor response to intracerebroventricular administration of physostigmine was found to be partially inhibited in both acutely adrenalectomized and sham-operated rats, but not in those adrenalectomized 24 h earlier.

Anticholinergic activity of the dopamine receptor agonist, TL-68 (N,N-dipropyl-2-aminotetralin).

The anticholinergic properties of a dopamine receptor agonist, a non-hydroxylated derivative of N,N-dipropylaminotetralin (TL-68), were evaluated using the guinea-pig isolated tracheal strip and rat phrenic nerve-diaphragm preparations. TL-68 competitively antagonized carbachol-induced contractions in guinea-pig trachea with a pA2 value of 5.88 +/- 0.

Tracheal epithelium releases a vascular smooth muscle relaxant factor: demonstration by bioassay.

Acetylcholine caused no relaxation of a rubbed strip from rabbit aorta (RASR) which was precontracted with phenylephrine. When the same strip was taken into epithelium-intact guinea-pig trachea, acetylcholine produced a slow-developing relaxation which was antagonized by atropine but not by propranolol, indomethacin, theophylline or hydroquinone. RASR was not relaxed by acetylcholine when it was taken from epithelium-rubbed trachea.

Surgical stress inhibits physostigmine-induced pressor effect.

Physostigmine-induced pressor response was studied in adrenalectomized rats. The pressor response to intracerebroventricular administration of physostigmine was found to be inhibited in both acutely adrenalectomized and sham-operated rats, but not in animals adrenalectomized 24 h earlier. Laparatomy performed just before the experiment also inhibited the pressor effect of physostigmine.

Evaluation of dopaminergic and alpha adrenergic activities of TL-99 in peripheral tissues in vitro.

The dopaminergic and alpha adrenergic activities of TL-99 were investigated using in vitro preparations including cat right atria, guinea-pig atria, rat vas deferens and rabbit aortic strip. TL-99 was found to be as potent as clonidine as a stimulant of presynaptic alpha-2 adrenoceptors of noradrenaline nerve endings in guinea-pig atria and rat vas deferens. In the cat right atria, TL-99 preferently stimulates presynaptic dopamine receptors.

Cis- and trans-4-n-Propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinolines.

Cis- and trans-4-n-Propyloctahydrobenzo(f)quinolines 4a,b were prepared for further assessment of dopaminergic effects of non-oxygenated dopamine congeners. The trans isomer 4b exhibited marked dopamine-like effects in the cat cardioaccelerator nerve assay and in a rat rotation model. Compound 4b produced dose-related lowering of blood pressure in the cat.

Clonidine-induced desensitization differentiates presynaptic alpha-2 adrenoceptors of the guinea-pig ileum and rat vas deferens.

Clonidine-induced inhibitions of twitch responses of coaxially stimulated guinea-pig ileum and transmurally stimulated rat vas deferens were antagonized by yohimbine in a competitive manner. In contrast to rat vas deferens, clonidine caused desensitization of presynaptic alpha 2-adrenoceptors on cholinergic neurons of guinea-pig ileum. Cross desensitization was observed between clonidine and oxymetazoline.

Dopamine receptor agonistic activities of R- and S-enantiomers of 4-hydroxy-2-di-n-propylaminoindan in cat hearts.

In-vitro and in-vivo studies were used to evaluate the presynaptic dopamine receptor stimulating activities of R- and S-enantiomers of 4-hydroxy-2-di-n-propylaminoindan in cat hearts. Bioassay results show that the R-enantiomer is 100 times more potent than the S-enantiomer in both in-vitro and in-vivo preparations.