J. P. Long

Dopaminergic nature of apomorphine-induced pecking in pigeons.

Abstract Apomorphine induces a pecking response in pigeons and the effects of various drugs on this pecking response were studied. The pecking induced by apomorphine (1.64 μmole/kg) has a rapid onset, and lasts for approximately 1 hr. Pecking induced by apomorphine can be blocked by dopaminergic receptor-blocking agents such as chlorpromazine, haloperidol, bulbocapnine and morphine, but not by α- or β-adrenergic receptor-blocking agents. Cholinergic agents have an inhibitory effect on pecking. The inhibitory effect of oxotremorine can be reversed by the prior administration of atropine. Apomorphine can induce both pecking and emesis while apomorphine methiodide causes only emesis. This ivestigation indicates that the pecking induced by apomorphine is caused by the stimulation of central dopaminergic receptors and that central cholinergic systems have a modulating effect on pecking. Serotonergic systems might also inhibit the pecking induced by apomorphine.

The Interaction of Diazepam with Myoneural Blocking Agents

The interaction of diazepam with neuromuscular blocking agents was studied in patients and in several animal nerve-muscle preparations. This drug did not alter the recovery slope of blockade produced by d-tubocurarine, decamethonium, or gallamine. In higher doses diazepam produced a decrease in muscle contractions and blocked the actions of exogenously applied nicotine and acetylcholine in the superfused chick biventer cervicis nerve—muscle preparation. In low doses the commercially available drug given intra-arterially reversed the myoneural blockades produced by both depolarizing and nondepolarizing blockers. However, this property was due to the solvent system of the drug.

Acetylcholine-Releasing Effects of Some Nicotinic Agents on Chick Biventer Cervicis Nerve Muscle Preparation

Summary The mechanism of action of some nicotinic agents has been studied on the baby chick biventer cervicis nerve muscle preparation. The effects of various nicotinic agents on this preparation were blocked by 1.2 × 10—2 M triethylcholine (TEC) or by neuromuscular blockade achieved by TEC treatment with interrupted tetanic nerve stimulation, whereas the dose-responsive curve of acetylcholine (ACh) was not altered. These results suggest that the nicotinic agents tested are presumably acting primarily at the nerve terminals rather than at the receptor sites on the postjunctional membrane. After the effects of the nicotinic agents were completely blocked by TEC alone, the muscle was still responsive to nerve stimulation. This suggests that the TEC blockade of the nicotinic effects of the drugs tested may be at the membrane site of the nerve terminal since ACh is still available in the storage site for release after TEC blockade. In the same preparation, the responses to most of the nicotinic agents were markedly enhanced and prolonged by the presence of 7.7 × 10—7 M physostigmine. Since the nicotinic agents tested are not susceptible to the enzymatic hydrolysis of cholinesterases, the potentiation of their nicotinic effects is probably due to the ACh released by these nicotinic agents from the nerve terminals.

Neuromuscular Blocking Properties of Various Polypeptide Antibiotics.

Summary Colistin sulfate, neomycin sulfate, polymyxin A sulfate, polymyxin B sulfate, and viomycin sulfate produced neuromuscular blockade when tested on sciatic nerve-gastrocnemius muscle preparations of the rabbit. Data obtained from the neuromuscular preparations were statistically analyzed and the relative potencies of the antibiotics in relation to colistin sulfate were determined. Polymyxin B sulfate was the most active antibiotic, approximately 1.5 times as active as colistin sulfate. Neostigmine methylsulfate antagonized the neuromuscular blockade produced by neomycin sulfate and viomycin sulfate, but was not an effective antagonist of the blockade produced by colistin sulfate, polymyxin A sulfate, and polymyxin B sulfate. Colistin sulfate, polymyxin A sulfate and polymyxin B sulfate do not produce contracture when administered to the chicken. The amino acids and other constituents comprising the various peptide antibiotics failed to show neuromuscular blocking activity.

Central noradrenergic activity is responsible for nitroglycerin-induced cardiovascular effects in the nucleus tractus solitarii

The studies show that unilateral microinjection of nitroglycerin (NTG) into nucleus tractus solitarii (NTS) produce dose-dependent decreases in mean arterial pressure (MAP) and heart rate, but injection of sodium nitroprusside (SNP) into the area induced slight effects. Hypotensive responses to NTG injected into the NTS showed that the compound was 20 times more potent than after i.v. administration. Responses to NTG injected into the NTS were abolished in an additive fashion by either rauwolscine, an alpha 2-adrenoceptor antagonist, or guanethidine which inhibits release of norepinephrine (NE). Injection of prazosin, an alpha 1-adrenoceptor antagonist, into the NTS reduced the hypotensive responses of NTG, but did not alter the bradycardia induced by the drug. Tachycardic responses following i.v. administration of either NTG or SNP were attenuated by bilateral injection of rauwolscine into the NTS, whereas only hypotensive responses to i.v. NTG were reduced by the pretreatment. NTG produced a dose-dependent increase in concentrations of 3,4-dihydroxyphenylalanine in media bathing medulla-pons, which were quantified using high-performance liquid chromatography with electrochemical detection. NE and 3,4-dihydroxyphenylglycol concentrations in media of incubated medulla-pons slices were simultaneously increased following higher concentrations of NTG. The results suggest that NTG in the NTS induces hypotensive and bradycardiac responses, and an increase in turnover of NE may stimulate alpha 2-adrenoceptors and be responsible for the effects of the drug. The NTS may contribute a component of action to the cardiovascular effects of intravenous NTG. The cardiovascular responses of intravenous SNP appear to involve peripheral action.

Congeners of the .beta. conformer of dopamine derived from cis- and trans-octahydrobenzo[f]quinoline and trans-octahydrobenzo[g]quinoline

The so-called beta conformer of dopamine has been proposed to be involved in agonist--receptor interactions at several sites in the dopaminergic nervous system. Further to evaluate this proposal, rigid congeners of the beta conformer derived from linearly and angularly annelated octahydrobenzoquinolines have been synthesized. Certain N-alkylated trans-angularly annelated systems exhibited unusually potent and highly selective dopamine-like effects in an assay on a cardioaccelerator nerve preparation in the cat, but these compounds were inactive in a variety of assays for CNS effects. These compounds present a clear separation of CNS effects from some potent peripheral effects.

The depressant effect of fatty acids on the isolated rabbit heart.

Summary The toxic effects of stearic and oleic acids on the rabbit myocardium were investigated in a plasma-free system using a modified Langendorf isolated heart preparation. A 0.1% stearic acid or 0.1% oleic acid solution was added to the solution which perfused the coronary vessels. The coronary flow, and the rate and amplitude of contractions progressively deteriorated until there was death of the heart. Equimolar albumin incubated with the fatty acid solutions prevented this toxic effect. The time of incubation was important to the blocking of toxicity for stearic acid but not for oleic acid. No incubation period was required to prevent the toxicity of the oleic acid when combined with albumin. This suggested a difference in the rate of albumin-fatty acid binding for different fatty acids. Unbound fatty acids, saturated or unsaturated, were extremely toxic to the heart.

Noradrenergic mechanisms and the cardiovascular actions of nitroglycerin

In this article we review noradrenergic activities of nitroglycerin in the central and peripheral nervous systems. Nitroglycerin may cause paradoxical bradycardia and occasional life threatening hypotension in patients. Intracisternal injections and microinjections of nitroglycerin into nucleus tractus solitarii produce hypotension and bradycardia, effects which mimic the baroreflex and may involve central noradrenergic mechanisms. The drug also triggers an alpha 2-adrenoceptor-mediated sympatho-inhibition reflex through vagal afferents. Nitroglycerin mimics biological responses associated with sympathetic neuronal activity, e.g., increase in outflow of norepinephrine and its metabolites from perfused guinea pig atria, medulla-pons tissue and cerebrospinal fluid. The sympathomimetic effects of nitroglycerin are antagonized by pre-treatment with yohimbine or rauwolscine. Clinical studies and animal experiments show that hemodynamics of nitroglycerin and sodium nitroprusside are different. Nitroglycerin is lipophilic and the compounds readily enters cells to form nitric oxide, but sodium nitroprusside is very hydrophilic and the compound has difficulty crossing membranes. Thus, intravenous nitroglycerin-induced increases in central noradrenergic activation and inhibitory reflexes may account for at least some of the therapeutic actions and side effects of the drug. In contrast, minimal central responses are produced by intravenous administration of sodium nitroprusside.

Dopaminergic effects of non-hydroxylated rigid analogs of apomorphine☆

A series of rigid analogs of apomorphine lacking aromatic hydroxyl substitutents were evaluated for dopaminergic properties. Three compounds, N-methyl-N-propyl-2-aminotetralin (Me-Pr-2-AT), N-N-dipropyl-2-aminotetralin (Di-pr-2-AT) and N,N-dipropyl-2-aminoindane (Di-Pr-2-AI) induced emesis in dogs, contralateral circling in unilaterally lesioned rats, and inhibited prolactin secretion. The induced circling responses, however, were attenuated by prior treatment with alpha-methyl-p-tyrosine methyl ester (AMPTME) and the compounds were weak inhibitors of 3-H-dopamine binding in calf caudate homogenates. The possibility that these agents may be metabolically activated in vivo is discussed.

Effect of various antibiotics on neuromuscular transmission

Abstract The effects of streptomycin, neomycin, kanamycin, polymixin and gentamycin on release of acetylcholine from nerve terminal and on muscle twitch were studied using the frog sciatic nerve-gastrocnemius muscle preparation. The first 4 agents were found to be devoid of any inhibitory action on prejunctional acetylcholine release while producing myoneural blockade. Gentamycin reduced acetylcholine output concomitant with myoneural blockade. It is concluded that the first 4 antibiotics act postsynaptically while gentamycin has a presynaptic component of action.