Nicotinic action of anatoxin-a on guinea pig ileum antagonized by thymopentin

(+)-Anatoxin-a (ANTX) stimulated guinea pig ileum contraction with a potency similar to that of acetylcholine (ACh); the stimulation was blocked by tubocurarine, hexamethonium, or atropine. Although the contraction stimulated by ANTX was blocked by atropine, no specific inhibition of the binding of [3H]N-methylscopolamine to ileum membranes was observed in the presence of ANTX. Furthermore, ANTX failed to stimulate the secretion of alpha-amylase from pancreatic acinar cells, a process that is activated by cholinergic agonists at the muscarinic receptors. When the ileum itself was stimulated by ACh, the contraction was not blocked by either hexamethonium or tubocurarine. Preincubation of the ileum with hemicholinium caused a 50% reduction in the ability of ANTX to stimulate contraction. Based upon these data, it was inferred that ANTX binds to postganglionic synaptic nicotinic receptors in the ileum, thus releasing endogenous ACh, which in turn causes ileum contraction by interacting with the postsynaptic muscarinic receptors. It was also observed that thymopentin (TP-5), a pentapeptide corresponding to positions 32-36 of thymopoietin, blocked the stimulation of ileum contraction by ANTX.     

Alpha-1-acetylmethadol and its N-demethylated metabolites have potent opiate action in the guinea pig isolated ileum

α-1-Acetylmethadol (LAM) and its N-demethylated metabolites α-1-noracetylmethadol (NAM) and α-1- dinoracetylmethadol (NNAM) exhibited opiate-like actions $\text{in}$$\text{vitro}$ by depressing the electrically induced twitch of the longitudinal muscle of the guinea pig ileum. These effects were reversed by the opiate antagonist naloxone. The effect of both NAM and NNAM was approximately 15 times greater than LAM. The 50 percent inhibitory concentrations of the metabolites were well below those levels in plasma reported for man. The long duration of action of LAM as an opiate substitute is most likely due to the conversion to its metabolites.     

PAF antagonists: different effects on platelets, neutrophils, guinea pig ileum and PAF-induced vasodilation in isolated rat lung

The effects of structurally different PAF receptor blockers were investigated in platelets, neutrophils, guinea pig ileum, rat isolated lung and rat isolated pulmonary artery. PAF caused serotonin release from platelets and a characteristic shape change and adhesion of neutrophils. The antagonists (CV 3988, alprazolam, 48740 RP and Merck-Sharp and Dohme L-652, 731) inhibited platelet serotonin release but not neutrophil shape change adhesion or lysosomal enzyme release. The antagonists in high concentrations (10(-5)-10(-4)M) inhibited nonspecifically the PAF-induced (10(-8)M) guinea pig ileum contraction, but were ineffective at concentrations which inhibited platelet responses. In the rat lung the compounds, in high concentrations, partially inhibited the low dose PAF-induced pulmonary vasodilation and the high dose PAF induced pulmonary vasoconstriction and edema. Our data indicate that some platelet PAF antagonists may be ineffective in blocking the action of PAF on neutrophils and smooth muscle preparations and suggest either PAF-receptor independent actions of PAF or different classes of PAF receptors.     

PAF antagonists: different effects on platelets, neutrophils, guinea pig ileum and PAF-induced vasolidation in isolated rat lung

The effects of structurally different PAF receptor blockers were investigated in platelets, neutrophils, guinea pig ileum, rat isolated lung and rat isolated pulmonary artery. PAF caused serotonin release from platelets and a characteristic shape change and adhesion of neutrophils. The antagonists (CV 3988, alprazolam, 48740 RP and Merck-Sharp and Dohme L-652, 731) inhibited platelet serotonin release but not neutrophil shape change adhesion or lysosomal enzyme release. The antagonists in high concentrations (10⁻⁵ −10⁻⁴M) inhibited nonspecifically the PAF-induced (10⁻⁸M) guinea pig ileum contraction, but were ineffective at concentrations which inhibited platelet responses. In the rat lung the compounds, in high concentrations, partially inhibited the low dose PAF-induced pulmonary vasodilation and the high dose PAF induced pulmonary vasoconstriction and edema. Our data indicate that some platelet PAF antagonists may be ineffective in blocking the action of PAF on neutrophils and smooth muscle preparations and suggest either PAF-receptor independent actions of PAF or different classes of PAF receptors.     

Potentiation of the effects of bradykinin on its receptor in the isolated guinea pig ileum

Angiotensin I-converting enzyme (ACE/kininase II) inhibitors potentiated guinea pig ileum's isotonic contractions to bradykinin (BK) and its analogues, shifting the BK dose-response curve to the left. ACE inhibitors added at the peak of the contraction immediately enhanced it further (343 +/- 40%), although the ileum inactivated BK slowly (t(1/2) = 12-16 min). Chymotrypsin and cathepsin G also augmented the activity of BK up to three- or four-fold, but in a manner slower than that of ACE inhibitors. The BK B(2) receptor blocker HOE 140 inhibited all effects. Histamine and angiotensin II were not potentiated. ACE inhibitors potentiate BK independent of blocking its inactivation by inducing crosstalk between ACE and the BK B(2) receptor; proteases activate the receptor by different mechanism.