ENHANCED FUNCTION OF IKCa CHANNELS IN THE CORONARY VASORELAXATION OF INSULIN RESISTANT OBESE ZUCKER RATS

D Prieto, B Climent, C Contreras, A Sánchez, A García-Sacristán, L Rivera. Universidad Complutense de Madrid, Departamento de Fisiología, Facultad de Farmacia, 28040-Madrid, Spain

Obesity is associated with cardiovascular and metabolic risk factors such as insulin resistance, impaired glucose tolerance, hypertension and dyslipidemia, jointly termed metabolic syndrome (MS). Because each component of MS is an independent risk factor for cardiovascular disease, it is not surprising that MS increases morbidity and mortality to many cardiovascular-related diseases including stroke, coronary artery disease and myocardial infarction. The mechanisms involved in the altered endothelial function in MS-related cardiovascular disease are poorly understood. In particular, the role of large conductance Ca2+‑activated K+ (BKCa) channels in the impaired coronary microvascular function remains controversial (Borbouse et al., Am J Physiol Heart Circ Physiol 297:1629, 2009, Feher et al., Cardiovasc Res 87:732, 2010). Therefore, the current study aims to assess the relative contribution of Ca2+‑activated K+ (KCa) channels to coronary vasodilatation in a rat model of genetic obesity.

Intramyocardial arteries from male obese Zucker rats (OZR) and lean Zucker rats (LZR) were mounted in microvascular myographs and the effects of selective inhibitors of KCa channels were assessed. On coronary arteries precontracted with serotonin, acetylcholine (ACh) (100 nM-30 µM) elicited concentration-dependent relaxations not significantly different in arteries from LZR and OZR. Maximal relaxations (Emax) were 83 ± 3% and 89 ± 2%, and pEC50 values were 6.74 ± 0.08 (n=24) and 6.80 ± 0.14, (n=16) in LZR and OZR, respectively. The NO donor S-nitrosoacetyl-D,L-penicillamine (SNAP) (100 nM‑30 µM) induced relaxations of similar magnitude in both strains (Emax 90 ± 3%, n=16, and 86 ± 4 %, n=16; and pEC50 values were 6.14 ± 0.10, n=16, and 6.30 ± 0.15, n=16, in LZR and OZR, respectively).

Blockade of BKCa channels with iberiotoxin (100 nM) inhibited to a similar extent the ACh- and SNAP‑induced relaxations in LZR (Emax 58 ± 8% p<0.01 vs control, n=9; and 82 ± 3 % p<0.05 vs control n=8, respectively) and OZR (Emax 51 ± 7% p<0.001 vs control, n=10; and 79 ± 6% p<0.01 vs control n=8, respectively) However, in the presence of the inhibitor of intermediate conductance (IKCa) channels, TRAM‑34 (200 nM), the ACh-mediated vasorelaxation was right-shifted only in OZR (pEC50 6.56 ± 0.12, n=6 p<0.01 vs control). Moreover, incubation with TRAM-34 decreased the SNAP‑mediated vasorelaxation exclusively in OZR arteries (Emax 45 ± 10 %, n=8, p<0.01 vs control). In addition, the inhibitor of small conductance (SKCa) channels with apamin (0.5 µM) induced a rightwards shift of the ACh‑mediated vasorelaxation in OZR compared to LZR (pEC50 6.48 ± 0.13, p<0.05 vs OZR control, n=8).

The present results demonstrate that whereas BKCa channel contribution to the endothelium-dependent relaxations is preserved, there is an increased function of IKCa channel which might take place in the smooth muscle cell layer and probably accounts for the preserved coronary vasodilatation in coronary arteries from a rat model of genetic obesity.

This work has been supported by Grant nº SAF 2009-10448 from MCINN and grant nº BFU2007-67732/BFI from MEC, Spain