ABSTRACT
CP-96,345, a non-peptide, selective tachykinin NK1 receptor blocker and its inactive enantiomer, CP-96,344, inhibit ligand binding of phenylalkylamine but not dihydropyridine Ca2+ channel antagonists. Whether these Ca2+ channel antagonist properties of CP-96,345 and CP-96,344 can be expressed as cardiovascular effects in vitro and in vivo is unknown. The cardiovascular effects of CP-96,345 and CP-96,344 in isolated vascular smooth muscle and in anesthetized dogs were compared to those of verapamil and nifedipine, phenylalkylamine and dihydropyridine Ca2+ channel antagonists, respectively. CP-96,345, CP-96,344, verapamil and nifedipine inhibited Ca(2+)-induced contractions in rat isolated portal vein with pD2' values of 5.9, 5.8, 6.8 and 8.1, respectively. In closed chest, anesthetized, spinal-pithed dogs, CP-96,345 caused dose-related hypotension and depressed heart rate. In open chest, anesthetized beagles at equihypotensive doses, CP-96,345, 1 mg/kg, CP-96,344, 1 mg/kg and verapamil, 0.5 mg/kg caused significant negative chronotropic, dromotropic and inotropic effects that were not observed with nifedipine, 0.01 mg/kg or nitroglycerin, 0.02 mg/kg. We conclude that the cardiovascular effects of CP-96,345 and its isomer are due to 'verapamil-like' Ca2+ channel antagonism and are not related to blockade of NK1 receptors.
Subject(s)
Biphenyl Compounds/pharmacology , Calcium Channel Blockers/pharmacology , Hemodynamics/drug effects , Muscle, Smooth, Vascular/drug effects , Neurokinin-1 Receptor Antagonists , Vasoconstriction/drug effects , Animals , Blood Pressure/drug effects , Calcium/pharmacology , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Female , Heart Rate/drug effects , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/cytology , Portal Vein/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
Amphotericin B (AmB) increased unidirectional Na transport and net transcellular sodium movements across the skin of the frog, Rana pipiens, when added to the solution bathing the corium side, but not from the outer epidermal surface. The AmB response was prevented with pretreatment with amiloride, ouabain and mucosal sodium substitution. Alteration in pH markedly reduced the permeability changes induced by AmB. AmB did not interfere with the increase in sodium transport induced by antidiuretic hormone. The present study demonstrates that AmB interacts with the skin of the frog, Rana pipiens, from the corium side specifically increasing transepithelial sodium transport. The increase in transport apparently occurs through the existing sodium pathway.
Subject(s)
Amphotericin B/pharmacology , Cell Membrane Permeability/drug effects , Potassium/metabolism , Skin/metabolism , Sodium/metabolism , Animals , Electrophysiology , Hydrogen-Ion Concentration , In Vitro Techniques , Potassium Radioisotopes , Rana pipiens , Skin/drug effects , Sodium RadioisotopesABSTRACT
The synthesis of fully deuterated amphetamine (phenyl-2-aminopropane-d11) in which 11 deuterium atoms are bonded to carbons and two other highly deuterated analogues is described. Their toxicities and in vivo spontaneous locomotor activities in mice were examined and compared with that of the parent protioamphetamine. A significant reduction in toxicities and a decrease in spontaneous locomotor activity were observed for these highly enriched deuterated analogues, as compared to protioamphetamine.
