Abstract
Background and AimsEndothelial 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.Methods and ResultsIn 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.ConclusionsObesity 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.
Highlights
Endothelial calcium-activated K (KCa) channels, including small conductance (SK3 or KCa2.3) and intermediate conductance (IK1 or KCa3.1) isoforms, are important effectors modulating arterial tone, since their opening is a starting point in the so-called nonchemical endothelial-derived hyperpolarization (EDH)
General parameters At 17–18 weeks of age, Obese Zucker Rats (OZR) displayed a significant increase in body weight compared with Lean Zucker Rats (LZR) and exhibited mild hyperglycemia and hyperinsulinemia along with elevated total cholesterol and triglyceride levels (Table S1)
NOS inhibition with L-NOARG increased basal tone in both LZR and OZR arteries, and ACh-induced relaxations were abolished in LZR and reduced by about 80% in OZR (Fig. 1, Table 1), suggesting that nitric oxide (NO) mediates these relaxations in both healthy and obese animals
Summary
Endothelial calcium-activated K (KCa) channels, including small conductance (SK3 or KCa2.3) and intermediate conductance (IK1 or KCa3.1) isoforms, are important effectors modulating arterial tone, since their opening is a starting point in the so-called nonchemical endothelial-derived hyperpolarization (EDH). This response causes vascular smooth muscle (VSM) relaxations resistant to nitric oxide (NO) synthases (NOS) and cyclooxygenases inhibitors [1,2] and implies electrotonical coupling between endothelial and VSM cells which leads to VSM hyperpolarization and relaxation [1,3]. We assessed whether the role of these channels in the coronary circulation is altered in obese animals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
