Neuronal muscarinic receptors attenuate vagally-induced contraction of feline bronchial smooth muscle.

In anaesthetized cats, stimulation of the vagus nerves produced bradycardia and a bronchoconstriction which was measured as an increase in lung resistance (RL) and a fall in dynamic lung compliance (Cdyn); these effects were abolished by atropine. Gallamine potentiated vagally-mediated changes in RL and Cdyn at doses that blocked muscarinic receptors in the heart and inhibited neuromuscular transmission. (+)-Tubocurarine and suxamethonium did not affect the response of the lung or the heart to vagal stimulation.

The response of cat airways to histamine in vivo and in vitro.

The effects of histamine have been examined in anaesthetized cats and on cat cat isolated lung parenchyma strip. Histamine infused intravenously for 2 min produced a small and inconsistent effect on central airways and a small but consistent constriction of peripheral airways. Histamine bronchoconstriction of the central airways was unmasked by non-selective and beta 2-adrenoceptor blockade but not by beta 1-adrenoceptor blockade.

Beta 1-selective adrenoceptor antagonists. 3. 4-Azolyl-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines has been prepared and examined for beta-adrenoceptor activity. The 4-substituents, di- and triazole ring systems connected to the phenoxy ring by different length chains, were chosen as a means of introducing cardioselectivity. This has been achieved, especially in the 1-[4-[(4-chloropyrazol-1-yl)methoxy] phenoxy]-3-(isopropylamino)-2-propanol (11), the 4-[(2H-1,2,3-triazol-2-yl)methoxy] analogue (21), and the 4-[2-(2H-1,2,3-triazol-2-yl)ethoxy] analogue (22), which show potent beta 1-blockade with selectivity ratios in excess of 100:1.

The effects of bufuralol, a beta-adrenoceptor antagonist with predominant beta 2-adrenoceptor agonistic activity, in the cat and the dog.

The effects of bufuralol and its carbinol metabolite have been compared with those of propranolol in the anaesthetised and conscious cat and dog. Bufuralol and its carbinol metabolite are nonselective beta-adrenoceptor antagonists; the former has equivalent potency to propranolol, whereas the latter is six times more potent. In anaesthetised animals both bufuralol and its metabolite exhibited partial agonistic activity, resulting in tachycardia and vasodilation.

beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity.

beta 1-selective adrenoceptor antagonists. 1. Synthesis and beta-adrenergic blocking activity of a series of binary (aryloxy)propanolamines.

A series of binary (aryloxy)propanolamines has been prepared and examined in vitro and in vivo for beta-adrenoreceptor blocking activity. These symmetrical compounds consist of two (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths. Examples of such binary compounds linked through the 2,2', 3,3', and 4,4' positions in the aromatic rings of the pharmacophores have been prepared.

Tiapamil, a new calcium antagonist. 1. Demonstration of calcium antagonistic activity and related studies.

N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride (tiapamil, Ro 11-1781), a new homoveratrylamine derivative, was studied under various experimental conditions which allow the recognition of calcium antagonistic activity, and compared with the reference calcium antagonist verapamil. Similar to verapamil, tiapamil inhibited in a concentration-dependent manner calcium-induced contractions in isolated, potassium-depolarized preparations of rat renal artery, dog coronary artery and rabbit main pulmonary artery. The inhibitory effects of tiapamil and verapamil were overcome by raising the calcium concentration of the bath fluid and a competitive antagonism between calcium ions and both compounds was found.

The prejunctional actions of some non-depolarizing blocking drugs.

1. Trains of end-plate potentials (e.p.

The mechanism of the facilitatory action of edrophonium in cat skeletal muscle.

1. The effects of edrophonium have been observed in the transversely cut tenuissimus muscle of the cat.2.

Studies on the repetitive discharges evoked in motor nerve and skeletal muscle after injection of anticholinesterase drugs.

Repetitive discharges recorded from the ventral root and from the gastrocnemius muscle in response to single motor nerve shocks applied close to the muscle after injection of edrophonium, neostigmine or ambenonium were studied in cats anaesthetized with chloralose. Two closely spaced volleys with an interval of 1 to 5 msec between them produced more repetitive firing than did a single shock. With longer intervals, the repetitive firing was not potentiated by the second volley.

Facilitation of neuromuscular transmission by anticholinesterase drugs.

A close correlation has been shown to exist between the in vitro anticholinesterase potencies of ambenonium, neostigmine, methoxyambenonium and edrophonium chloride and their abilities to increase muscle contractions produced by close-arterial injections of acetylcholine. No correlation was found between the anticholinesterase potencies of the drugs and their potentiations of the maximal twitch in response to electrical stimulation, or their antagonisms of tubocurarine. It is concluded that some action, in addition to inhibition of cholinesterase, contributed to their facilitation at the neuromuscular junction, and it is suggested that this action may be at the prejunctional site.