cp-154526 and sauvagine

The goal of this study was to test whether central corticotropin-releasing factor (CRF) was involved in angiotensin II (Ang II) and Ang II type 1 (AT1) receptor-mediated facilitation of micturition reflex and to investigate whether peripherally administered telmisartan, AT1 receptor antagonist, suppresses the central Ang II-induced facilitation of micturition reflex in rats.. Urethane anesthetized male Wistar rats were placed under continuous cystometry before and after intracerebroventricular administration of each drug. Rats were intracerebroventricularly administered telmisartan (AT1 receptor antagonist), CP154526 (CRF1 receptor antagonist), or K41498 (CRF2 receptor antagonist) 30 minutes before intracerebroventricular administration of Ang II. Some male Wistar rats were perorally pretreated with either vehicle, AT1 receptor antagonist telmisartan or valsartan, once daily for 8 days, then measured blood pressure. Thereafter, Ang II was intracerebroventricularly administered for continuous cystometry.. Intracerebroventricularly administered telmisartan or CP154526 dose-dependently suppressed the central Ang II-induced intercontraction interval (ICI) reduction. In contrast, intracerebroventricularly administered K41498 did not affect the central Ang II-induced response compared to vehicle pretreatment. Peripherally administered telmisartan but not valsartan suppressed the central Ang II-induced ICI reduction in rats compared to vehicle administration without altering blood pressure.. Central Ang II induced facilitation of the micturition reflex through AT1 and CRF1 receptors. Peripherally administered telmisartan suppressed central Ang II-induced facilitation of micturition reflex.

Topics: Amphibian Proteins; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Male; Peptide Hormones; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Telmisartan; Urination

Corticotropin-releasing factor (CRF) receptors are members of the superfamily of G-protein coupled receptors that utilise adenylate cyclase and subsequent production of cAMP for signal transduction in many tissues. Activation of cAMP-dependent pathways, through elevation of intracellular cAMP levels is known to promote survival of a large variety of central and peripheral neuronal populations. Utilising cultured primary rat central nervous system neurons, we show that stimulation of endogenous cAMP signalling pathways by forskolin confers neuroprotection, whilst inhibition of this pathway triggers neuronal death. CRF and the related CRF family peptides urotensin I, urocortin, and sauvagine, which also induced cAMP production, prevented the apoptotic death of cerebellar granule neurons triggered by inhibition of phosphatidylinositol kinase-3 pathway activity with LY294002. These effects were negated by the highly selective CRF-R1 antagonist CP154,526. CRF even conferred neuroprotection when its application was delayed by up to 8 h following LY294002 addition. The CRF peptides also protected cortical and hippocampal neurons against death induced by beta-amyloid peptide (1-42), in a CRF-R1 dependent manner. In separate experiments, LY294002 reduced neuronal protein kinase B activity while increasing glycogen synthase kinase-3, whilst CRF (and related peptides) promoted phosphorylation of glycogen synthase kinase-3 without protein kinase B activation. Taken together, these results suggest that the neuroprotective activity of CRF may involve cAMP-dependent phosphorylation of glycogen synthase kinase-3.

Topics: 1-Methyl-3-isobutylxanthine; Amphibian Proteins; Amyloid beta-Peptides; Animals; Animals, Newborn; Apoptosis; Blotting, Western; Cell Survival; Cells, Cultured; Cerebellum; Cerebral Cortex; Chromatin; Chromones; Colforsin; Corticotropin-Releasing Hormone; Cyclic AMP; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Glycogen Synthase Kinase 3; Hippocampus; In Situ Nick-End Labeling; Inhibitory Concentration 50; L-Lactate Dehydrogenase; Mitogen-Activated Protein Kinase Kinases; Morpholines; Neurons; Neuroprotective Agents; Peptide Fragments; Peptide Hormones; Peptides; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Thionucleotides; Time Factors; Urocortins; Urotensins; Vasodilator Agents