Central Transient Receptor Potential Vanilloid 4 Contributes to Systemic Water Homeostasis through Urinary Excretion.

Intracerebroventricular (icv) injection of transient receptor potential vanilloid 4 (TRPV4) agonists 4α-phorbol-12, 13-didecanoate (4α-PDD) and GSK101690A increased urinary excretion under the physiological condition. TRPV4 antagonists ruthenium red and HC-067047 significantly blocked increased urinary volume after intragastric administration of water and 4α-PDD-induced diuresis. Administration of the TRPV4 agonists did not significantly change the plasma concentration of vasopressin or atrial natriuretic factor. Pretreatment with indomethacin inhibited the diuresis induced by 4α-PDD. Moreover, icv injection of prostaglandin (PG) F2α produced diuretic effects. These findings indicate that central TRPV4 regulates urine excretion, which contributes to systemic water homeostasis in vivo. The underlying mechanisms are suggested to involve PG synthesis, but not release of vasopressin or atrial natriuretic factor.

Reduction of NO-mediated Relaxing Effects in the Thoracic Aorta in an Experimental Chronic Kidney Disease Mouse Model.

AIM: Chronic kidney disease (CKD) is known to frequently cause cardiovascular events. However, it is unclear how renal dysfunction affects the vascular response. We herein studied the effects of renal dysfunction on the aortic behavior in adenine-fed mice, investigating mechanisms underlying the occurrence of cardiovascular events in CKD patients. METHODS: Biochemical analyses of the plasma creatinine, blood urea nitrogen (BUN) and glucose levels and measurements of the blood pressure were performed using C57BL/6 mice fed with and without an adenine-containing diet. The relaxing effects of acetylcholine (ACh) or sodium nitropurusside (SNP) and effects of NO synthase (NOS) inhibitors on the contractions induced by phenylephrine (PE) were measured in endothelium-intact aortas obtained from both mice. RESULTS: The mice fed 0.25% adenine for four weeks showed greater plasma creatinine and BUN concentrations than the control mice, suggesting that adenine-fed mice are a useful CKD model. Furthermore, ACh relaxed the PE-stimulated, endothelium-intact aortas, the effect of which was less potent in the adenine-fed mice than in the control mice. In contrast, the degree of SNP-induced relaxation of the aortas was the same in the adenine-fed mice and control mice. The α1-adrenergic agonist, PE, induced more potent absolute tension of the endothelium-intact aortas in the CKD model mice than in the control mice, while the NOS inhibitors, N-nitro-L-arginine (LNA) and asymmetric dimethylarginine (ADMA) enhanced the contraction effects of PE in both mice. CONCLUSIONS: The findings of this study indicate that spontaneous and stimulated NO release from the endothelium is decreased in the CKD model mouse aorta. The NO-mediated correlation between renal and elastic arterial endothelial dysfunction is suggested to be a cause of cardiovascular events in patients with CKD.

Role of Rho/Rho-kinase and NO/cGMP signaling pathways in vascular function prior to atherosclerosis.

AIM: Atherosclerosis is a cardiovascular disease; however, there is little information on signal transduction for vascular function in the early stage of atherosclerosis. In this work, we investigated the role of Rho/Rho-kinase and nitrogen oxide (NO)/cyclic GMP (cGMP) signaling pathways in the aorta prior to atherosclerosis. METHODS: Tension, the expression of RhoA protein, Rho-kinase activity and the cGMP level were measured using endothelium-intact or -denuded aorta prepared from apolipoprotein E-deficient (apoE-KO) and C57BL/6 wild-type (WT) mice at 2 months of age. RESULTS: Phenylephrine (PE) induced less maximal contraction in the endothelium-denuded aorta from apoE-KO than from WT mice. A Rho-kinase inhibitor (Y-27632) reduced more effectively the contraction of apoE-KO than WT mice, but their RhoA proteins and Rho-kinase activities were not so different. Acetylcholine caused larger relaxation of the PE-stimulated, endothelium-intact aorta in apoE-KO due to endothelial NO release than WT mice. The basal cGMP level in the endothelium-intact aorta of apoE-KO mice was higher than that of WT. CONCLUSIONS: Smooth muscle contraction via alpha(1)-adrenergic receptor shows higher dependency on Rho-kinase activity, suggesting down-regulation of the mechanism different from Rho/Rho kinase signaling in the aorta prior to atherosclerosis. Endothelium-dependent relaxation is also intensified through the NO/cGMP pathway.