Impaired small‐conductance Ca2+‐activated K+ channel‐dependent EDHF responses in Type II diabetic ZDF rats

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Abstract
1 We have examined the relative contributions of small‐ and intermediate‐conductance Ca2+‐activated K+ channels (SKCa and IKCa) to the endothelium‐derived hyperpolarizing factor (EDHF) pathway response in small mesenteric arteries of Zucker Diabetic Fatty (ZDF) rats, before and after the development of Type II diabetes, together with Lean controls. 2 Smooth muscle membrane potential was recorded using sharp microelectrodes in the presence of 10 μM indomethacin plus 100 μM Nω‐nitro‐L‐arginine. SKCa was selectively inhibited with 100 nM apamin, whereas IKCa was blocked with 10 μM TRAM‐39 (2‐(2‐chlorophenyl)‐2,2‐diphenylacetonitrile). 3 Resting membrane potentials were similar in arteries from 17‐ to 20‐week‐old control and diabetic rats (approximately −54 mV). Responses elicited by 1 and 10 μM acetylcholine (ACh) were significantly smaller in the diabetic group (e.g. hyperpolarizations to −69.5±0.8 mV (ZDF; n=12) and −73.2±0.6 mV (Lean; n=12; PμM ACh). 4 The IKCa‐mediated components of the ACh responses were comparable between groups (hyperpolarizations to approximately −65 mV on exposure to 10 μM ACh). However, SKCa‐mediated responses were significantly reduced in the diabetic group (hyperpolarizations to −63.1±1.0 mV (ZDF; n=6) and −71.5±1.2 mV (Lean; n=6; PμM ACh. 5 Impaired ACh responses were not observed in arteries from 5‐ to 6‐week‐old (pre‐diabetic) animals. SKCa subunit mRNA expression was increased in the diabetic group. 6 The EDHF pathway, especially the SKCa‐mediated response, is impaired in Type II diabetic ZDF rats without a reduction in channel gene expression. These results may be particularly relevant to the microvascular complications of diabetes. The functional separation of SKCa and IKCa pathways is discussed. British Journal of Pharmacology (2006) 148, 434–441. doi:10.1038/sj.bjp.0706748

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