ns-309 and Obesity

Obesity usually induces overactive bladder (OAB) associated with detrusor overactivity, which is related to increased contractility of the detrusor smooth muscle (DSM). Small-conductance Ca. Female Sprague-Dawley rats were fed a normal diet (ND) or a high-fat diet (HFD) and weighed after 12 weeks. Urodynamic studies, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and isometric tension recording were performed.. Increased average body weights and urodynamically demonstrated OAB were observed in HFD rats. qRT-PCR experiments revealed a decrease in the mRNA expression level of SK channel in DSM tissue of the HFD rats. Isometric tension recordings indicated an attenuated relaxation effect of NS309 on the spontaneous phasic and electrical field stimulation-induced contractions that occurred via SK channel activation in HFD DSM strips.. Reduced expression and activity of SK channels in the DSM contribute to obesity-related OAB, indicating that SK channels are a potential therapeutic target for OAB.

Topics: Anal Canal; Animals; Apamin; Diet, High-Fat; Disease Models, Animal; Female; Indoles; Muscle Contraction; Muscle, Smooth; Neuromuscular Agents; Obesity; Oximes; Rats; Rats, Sprague-Dawley; Small-Conductance Calcium-Activated Potassium Channels; Urinary Bladder, Overactive; Urodynamics

NO and a non-NO/prostacyclin EDH mechanism are major contributors of vascular tone and cerebral blood flow. However, the effect of metabolic syndrome on EDH-mediated responses in cerebral vessels remains unknown and may offer another avenue for therapeutic targeting. The purpose of this study was to investigate EDH-dependent responses in cerebral arteries during metabolic syndrome.. EDH-dependent dilations were assessed in MCAs isolated from nondiabetic obese and lean Zucker rats in the presence and absence of NS309, an activator of SKCa and IKCa channels. IKCa channel expression and activity were assessed by western blotting and pressure myography, respectively.. EDH-mediated dilations were significantly attenuated in the obese compared to the lean Zucker rat MCA. Luminal delivery of 1 μM NS309 enhanced EDH-mediated responses in lean and obese Zucker cerebral vessels. Both dose-dependent dilations to luminal NS309 and IKCa protein expression in pooled cerebral arteries were comparable between the two groups.. Our results suggest that pharmacological targeting of IKCa channels can rescue EDH-mediated dilations in obese Zucker rat MCAs. Compromised EDH-mediated dilations in obesity are not due to impaired IKCa channel expression or activity.

Topics: Animals; Endothelium, Vascular; Gene Expression Regulation; Indoles; Intermediate-Conductance Calcium-Activated Potassium Channels; Male; Obesity; Oximes; Rats; Rats, Zucker; Small-Conductance Calcium-Activated Potassium Channels; Vasodilation

Endothelial small- and intermediate-conductance KCa channels, SK3 and IK1, are key mediators in the endothelium-derived hyperpolarization and relaxation of vascular smooth muscle and also in the modulation of endothelial Ca2+ signaling and nitric oxide (NO) release. Obesity is associated with endothelial dysfunction and impaired relaxation, although how obesity influences endothelial SK3/IK1 function is unclear. Therefore we assessed whether the role of these channels in the coronary circulation is altered in obese animals.. In coronary arteries mounted in microvascular myographs, selective blockade of SK3/IK1 channels unmasked an increased contribution of these channels to the ACh- and to the exogenous NO- induced relaxations in arteries of Obese Zucker Rats (OZR) compared to Lean Zucker Rats (LZR). Relaxant responses induced by the SK3/IK1 channel activator NS309 were enhanced in OZR and NO- endothelium-dependent in LZR, whereas an additional endothelium-independent relaxant component was found in OZR. Fura2-AM fluorescence revealed a larger ACh-induced intracellular Ca2+ mobilization in the endothelium of coronary arteries from OZR, which was inhibited by blockade of SK3/IK1 channels in both LZR and OZR. Western blot analysis showed an increased expression of SK3/IK1 channels in coronary arteries of OZR and immunohistochemistry suggested that it takes place predominantly in the endothelial layer.. Obesity may induce activation of adaptive vascular mechanisms to preserve the dilator function in coronary arteries. Increased function and expression of SK3/IK1 channels by influencing endothelial Ca2+ dynamics might contribute to the unaltered endothelium-dependent coronary relaxation in the early stages of obesity.

Topics: Animals; Calcium Signaling; Coronary Vessels; Endothelium, Vascular; Indoles; Intermediate-Conductance Calcium-Activated Potassium Channels; Male; Myography; Obesity; Oximes; Rats; Rats, Zucker; Small-Conductance Calcium-Activated Potassium Channels; Up-Regulation; Vasodilation