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Changes in Kca Subtype Activity May Underlie Altered Endothelium-Derived Hyperpolarization in Diet-Induced Obese Rat Mesenteric Artery
Abstract   Peer reviewed

Changes in Kca Subtype Activity May Underlie Altered Endothelium-Derived Hyperpolarization in Diet-Induced Obese Rat Mesenteric Artery

R E Haddock, L Howitt, M J Morris and Shaun L Sandow
Journal of Vascular Research, Vol.45(Supplement 1), p.63
International Symposium on Resistance Arteries (ISRA), 9th (Hamilton Island, Australia, 17-Feb-2008–21-Feb-2008)
2008
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Abstract

Medical and Health Sciences hyperpolarization myoendothelial gap junctions
Introduction: In rat small mesenteric artery ACh evokes smooth muscle cell (SMC) hyperpolarization and relaxation due to transfer of endothelium-derivedhyperpolarization (EDH) via myoendothelial gap junctions; a response differentially sensitive to block of small and intermediate conductance KCa. The aims of this study are to determine whether this differential functional SKCa and IKCa activity may be related to SKCa and IKCa distribution, and whether such activity and distribution is altered in cardiovascular disease, such as that observed during obesity. Methods: Adult male SD rats were fed chow (control) or high fat (obese) diet. Control (536±12 g; n=15) or diet-induced obese (667±27 g, n=14, P less than 0.05) mesenteric arteries (4th order) were isolated and myogenic responses induced in a pressure myograph. SMC membrane potential (Em) was recorded using sharp microelectrodes and vessel diameter changes monitored using computer tracking (Diamtrak). Indomethacin (10 μM), L-NAME (100 μM) and ODQ (10 μM) were present to inhibit PGI2, NO synthase and guanylyl cyclase, respectively. Confocal immunohistochemistry was used to examine S/IKCa characteristics. Results: Arteries developed a graded myogenic constriction with an increase in pressure, from 40 to 80 mmHg (control: 93.5±3.1% resting vessel diameter (RVD), n=10; obese: 92.9±1.9 % RVD, n=17) to 80mmHg (control: 73.3±5.7 % RVD, n=10; obese: 72.6±3.2 % RVD, n=17). At 80 mmHg smooth muscle cell Em did not differ between control and obese vessels (-40.3±1.3 and -41.6±0.7 mV, respectively). ACh (1μM)-induced EDH-mediated SMC hyperpolarization was impaired in obese compared to control animals (-68.7±1.3 mV, n=10; -74.1 ±1.8 mV, n=10 obese and control respectively) and vasodilation to ACh was also reduced in obese arteries (control: 95.9±1.1 % RVD, LogEC50: -6.9±0.1, n=15; obese, 91.3±2.3 % RVD, LogEC50: -6.4±0.4, n=22, P less than 0.05). In both control and obese groups, hyperpolarization and relaxation was significantly reduced in the presence of apamin (50nM; control: -50.0±1.9 mV and 71.4±9.7 % RVD, n=5; obese, -53.6±2.4 mV and 84.4±4.9 % RVD, n=9) the remaining response being abolished with addition of TRAM-34. On the other hand, in obese arteries TRAM-34 alone abolished EDH (-42.7±1.2 mV and 72.7±3.5 % RVD, n=3), but only partially reduced the ACh-induced hyperpolarization (-54.7±2.7 mV) and relaxation (91.3±3.3 % RVD) in control arteries (n=4). SKCa (SK3) are accumulated to adjacent endothelial cell contacts, whilst IK (SK4) are abundant at myoendothelial contacts; the latter with altered expression in obese vessels. Arteries taken from obese rats also exhibit hypotrophic inward remodeling. Conclusion: These data suggest that activation of IKCa alone may account for EDH-mediated SMC hyperpolarization and relaxation in obese rat mesenteric arteries. Altered IKCa function may be related to its altered distribution. Restoration of normal KCa activity may represent a selective target to improve vasodilator function in cardiovascular disease, such as that observed in diet-induced obesity.

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