Functional characterization of muscarinic autoreceptors in rat and human neocortex.

Electrically evoked overflow of [(3)H]acetylcholine in slices of rat neocortex and of human neocortex (freshly obtained during neurosurgical treatment of epilepsy or deep-seated tumors) was used to functionally characterize the muscarinic receptor subtype, which mediates autoinhibition of acetylcholine release in these tissues. In the rat neocortex, the following pK(B) values [CI(95)] were calculated from the shifts to the right of the concentration-response curves of the full agonist oxotremorine in presence of subtype preferring muscarinic receptor antagonists: tripitramine: 9.1 [8.

Celecoxib dilates guinea-pig coronaries and rat aortic rings and amplifies NO/cGMP signaling by PDE5 inhibition.

Objective: Celecoxib carries a smaller cardiovascular risk for myocardial infarction and hypertension than other cyclooxygenase-2 (COX-2)-selective non-steroidal anti-inflammatory drugs NSAIDs ("coxibs") and may ameliorate endothelial dysfunction. We aimed to determine which mechanism possibly accounts for the beneficial effect by investigating its vascular action in different in vitro preparations in comparison with other coxibs and reference phosphodiesterase-5 (PDE5) inhibitors.

Methods: To uncover potential effects on coronary flow, the effects of celecoxib in comparison with other NSAIDs and the PDE5 inhibitors, sildenafil and zaprinast, were investigated in guinea-pig Langendorff heart.

Montelukast exerts no acute direct effect on NO synthases.

The cysteinyl leukotrienes (CysLTs) LTC(4), LTD(4) and LTE(4) are potent proinflammatory lipid mediators that play a central role in inflammation, contraction and remodelling of airways observed in asthmatics. Montelukast, a competitive inhibitor of the cysteinyl leukotriene-1 (CysLT(1)) receptor attenuates asthmatic airway inflammation, contraction and remodelling. As a number of studies have shown that montelukast reduced exhaled nitric oxide (NO) levels, a marker of inflammation that correlates with the severity of asthma, we investigated whether or not a direct inhibition of NO synthase (NOS) by montelukast takes place.

In vivo characterization of the novel imidazopyridine BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a potent and highly selective inhibitor of inducible nitric-oxide synthase.

Excessive release of nitric oxide from inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible isoform. In the present study, we tested the in vivo potency of BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo-[4,5-b]pyridine], a selected member of this inhibitor class, in three different rat models of lipopolysaccharide-induced systemic inflammation.

The novel imidazopyridine 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) is a highly selective inhibitor of the inducible nitric-oxide synthase.

We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NO synthases at 86 nM, 17 microM, and 162 microM, respectively. Inhibition of inducible NO synthase was competitive with l-arginine, pointing to an interaction of BYK191023 with the catalytic center of the enzyme.