Biomedical subjects
Publications and source records attributed to M Zacour.
AR-C68397AA is a dual dopamine D(2)-receptor and beta(2)-adrenoceptor agonist and bronchodilator under development by AstraZeneca (formerly Astra) and undergoing phase I trials for asthma and phase II trials for chronic obstructive pulmonary disease (COPD). AstraZeneca expects to file for drug registration in 2004. Marketing of AR-C68397AA in the US will be assigned to the AstraZeneca/Merck joint marketing venture.
Nitric oxide (NO) is known to be synthesized from L-arginine in a reaction catalyzed by NO synthase. Liver cytochrome P-450 enzymes also catalyze the oxidative cleavage of C==N bonds of compounds containing a -C(NH2)==NOH function, producing NO in vitro. The present study was designed to investigate whether there was evidence of a similar pathway for the production of NO in tracheal smooth muscle cells. Formamidoxime (10(-2) to 10(-4) M), a compound containing -C(NH2)==NOH, relaxed carbachol-contracted tracheal rings and increased intracellular cGMP in cultured tracheal smooth muscle cells, whereas L-arginine had no such effect. NO was detectable in the medium containing cultured tracheal smooth muscle cells when incubated with formamidoxime. Ethoxyresorufin (10(-7) to 10(-4) M), an alternate cytochrome P-450 substrate, inhibited formamidoxime-induced cGMP accumulation as well as tracheal ring relaxation in cultured tracheal smooth muscle cells. The NO synthase inhibitors Nomega-nitro-L-arginine (10(-3) M) and NG-monomethyl-L-arginine (10(-3) M) had no effect on formamidoxime-induced cGMP accumulation. These results suggest that NO can be synthesized from formamidoxime in tracheal smooth muscle cells, presumably by a reaction catalyzed by cytochrome P-450.
To explore the possibility that VIP modulates cholinergic neurotransmission in the airways, we studied the effects of exogenous VIP on contractile responses of an isolated innervated guinea pig tracheal preparation to vagal nerve stimulation (NS), electrical field stimulation (EFS) and exogenous acetylcholine (ACh). VIP (2.5 x 10(-8), 2.5 x 10(-7) M) caused concentration-dependent reductions in responses to NS and EFS. Low frequency stimulations (1 Hz) were significantly more inhibited than higher frequencies (5 and 20 Hz). VIP inhibited NS significantly more than EFS at 1 and 5 but not 20 Hz. In contrast, VIP (2.5 x 10(-7) M) did not significantly reduce responses to ACh (3 x 10(-7), 10(-6), and 3 x 10(-6) M). The neutral endopeptidase inhibitor phosphoramidon (5 x 10(-6) M) enhanced responses of NS to VIP but did not affect responses to NS in the absence of VIP. We conclude that in the isolated guinea pig tracheal preparation, VIP can modulate cholinergic neurotransmission by actions that are predominantly on post-ganglionic nerves but it has also a small additional effect on ganglionic transmission.