Hypothalamic site of action for N-methyl-D-aspartate (NMDA) on LH secretion

Excitatory amino acids have been shown to increase luteinizing hormone (LH) secretion following ventricular or systemic administration. In the present study we attempted to determine possible hypothalamic sites of action for the potent excitatory amino acid agonist, N-methyl-D-aspartate (NMDA). The ability of NMDA to enhance LH release was tested in male rats following infusion into the medial preoptic nucleus (MPO), anterior hypothalamic nucleus (AHY), ventromedial hypothalamic nucleus (VMH), and arcuate nucleus (ARC). In the MPO, infusion of 50 or 500 pmole NMDA increased pituitary LH secretion, resulting in a 2-7 fold increase in plasma LH. The 50 pmole dose was selected to test more caudal hypothalamic sites. Plasma LH levels were not affected following microinfusion of NMDA (50 pmole) into the AHY, VMH, and ARC. The present results indicate a regional specificity for NMDA in the enhancement of LH secretion. This regional specificity may reflect either a greater density of LHRH perikarya in the MPO or the presence of specific amino acid receptors on neuronal elements in the MPO, but not on neuronal elements in the other areas tested.     

Electrochemical determination of N-oxidized procainamide metabolites and functional assessment of effects on murine cells in vitro

Because of the implication of N-oxidized metabolites of procainamide in the induction of drug-related lupus, we have studied the electrochemical behavior of these metabolites and developed an electrochemical synthesis of nitrosoprocainamide. This synthesis was developed using procainamide hydroxylamine as the starting material which was oxidized to the nitroso species at an applied potential of 700 mV vs Ag/AgCl using a carbon packed bed bulk electrolysis flow cell. Conversion efficiencies of greater than 95% were achieved with this method. Subsequent studies with a chemically diverse series of biocompounds were used to investigate possible reactions between the procainamide hydroxylamine and nitroso species and these selected molecules. Only antioxidants such as cysteine, glutathione and ascorbic acid were found to react with the nitroso compound as determined by electrochemical methods, and this reaction was characterized as primarily a simple redox reaction at physiological pH. Animal studies conducted with murine spleen cells incubated with mitogens and various procainamide compounds demonstrated that the N-oxidized metabolites are the active immunopharmacologic agents.     

NG-nitro-L-arginine inhibits non-adrenergic, non-cholinergic relaxation in rabbit urethral smooth muscle.

Electrical field stimulation induced a relaxation response in female rabbit urethral smooth muscle strips precontracted with phenylephrine. The relaxation response was inhibited by tetrodotoxin, but not by atropine, propranolol, or hexamethonium. The relaxation response thus results from stimulation of inhibitory non-adrenergic, non-cholinergic nerves. The electrically induced relaxation response was inhibited by an inhibitor of nitric oxide biosynthesis, NG-nitro-L-arginine. This inhibition was overcome by addition of a precursor of nitric oxide, L-arginine. An inhibitor of soluble guanylate cyclase, methylene blue, reduced the relaxation response, and a selective cyclic GMP phosphodiesterase inhibitor, M & B 22948, potentiated the relaxation response. These data indicate that agents which affect the biosynthesis of nitric oxide are associated with the urethral relaxation response evoked by electrical field stimulation, and that cyclic GMP may mediate the relaxation response.     

Subcutaneous terbutaline and control of brittle asthma or appreciable morning dipping.

In a pilot study two patients with brittle asthma and two with morning dipping received terbutaline or a placebo administered subcutaneously either by continuous infusion or in injections every six hours. In two patients brittle asthma was completely suppressed by terbutaline 1 mg/day given by either method. In the two others early morning dipping responded only to continuous subcutaneous infusions of terbutaline 12 mg/day. Terbutaline administered subcutaneously may be an effective treatment in asthmatic patients who show important diurnal variations in air flow.