Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension

Department of Physiology, Medical College of Georgia, Augusta, Georgia Submitted 31 August 2006 ; accepted in final form 28 December 2006 Ca 2+ -activated K + channels (K Ca ), in particular, the small and intermediate K Ca (SK Ca and IK Ca , respectively) channels, are key players in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in small arteries. Hypertension is characterized by an endothelial dysfunction, possibly via reduced EDHF release and/or function. We hypothesize that during angiotensin II (14 days)-induced hypertension (ANG II-14d), the contribution of SK Ca and IK Ca channels in ACh-induced relaxations is reduced due to decreased expression of SK Ca and IK Ca channel proteins in rat small mesenteric arteries (MAs). Nitric oxide- and prostacyclin-independent vasorelaxation to ACh was similar in small MAs of sham-operated and ANG II-14d rats. Catalase had no inhibitory effects on these relaxations. The highly selective SK Ca channel blocker UCL-1684 almost completely blocked these responses in MAs of sham-operated rats but partially in MAs of ANG II-14d rats. These changes were pressure dependent since UCL-1684 caused a greater inhibition in MAs of 1-day ANG II-treated normotensive rats compared with ANG II-14d rats. Expression levels of both mRNA and protein SK3 were significantly reduced in MAs of ANG II-14d rats. The IK Ca channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) resulted in comparable reductions in the relaxation responses to ACh in MAs of sham-operated and ANG II-14d rats. Relative mRNA expression levels of IK1 were significantly reduced in MAs of ANG II-14d rats, whereas protein levels of IK1 were not but tended to be lower in MAs of ANG II-14d rats. The findings demonstrate that EDHF-like responses are not compromised in a situation of reduced functional activity and expression of SK3 channels in small MAs of ANG II-induced hypertensive rats. The role of IK1 channels is less clear but might compensate for reduced SK3 activity. calcium-activated potassium channels; endothelium Address for reprint requests and other correspondence: R. H. P. Hilgers, Dept. of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Univ. of Maastricht, Universiteitssingel 50, 6200 MD Maastrict, The Netherlands (e-mail: rhilgers{at}farmaco.unimaas.nl )