Obesity is an increasing problem worldwide leading to cardiovascular morbidity. Only limited information exists on the transcriptional regulation of arterial K+ and Ca2+ channels in obesity. We quantified, by real-time PCR, mRNA expression of K+ channels and L-type Ca2+ channels (LTCC) in small mesenteric (MA), middle cerebral (MCA), and left coronary arteries (LCA) of lean vs. obese rats and minipigs. Male Sprague Dawley rats were fed a high-fat (FAT; N=5), high-fructose (FRUC; N=7), high-fat/high-fructose (FAT/FRUC; N=7) or standard diet (STD; N=7-11) for 28 Weeks. FAT and FAT/FRUC became obese, whereas FRUC and STD were lean. Systolic blood pressure (SBP) averaged over 14 weeks was increased (P<0.001) in FRUC and FAT/FRUC but not in FAT. Kir, Kv1.2, Kv1.5, and Kv7.4 channels were up-regulated in FAT, whereas SKca and IKca channels were down-regulated in FAT/FRUC (P<0.05). There were no transcriptional changes in FRUC. Castrated male Göttingen minipigs with or without diabetes were fed a diet rich in fat, cholesterol and fructose (OB+DIAB; N=3 vs. OB; N=2, respectively) or a standard diet (STD; N=3) for 22-45 weeks. Body weight, total body fat content and plasma triglyceride levels were increased in OB and OB+DIAB. BKca, IKca, SKca and/or LTCC mRNA was up-regulated in LCA from OB and OB+DIAB (n.s.). Expression of BKca mRNA was increased, whereas IKca mRNA decreased in MCA from OB (n.s.). SKca mRNA was decreased in MA from OB (n.s.). Diet-induced obesity in rats and minipigs lead to complex changes in K+ and Ca2+ channel gene expression, which, in rats, did not seem to be linked with changes in SBP. These transcriptional changes may lead to disturbances in microvascular flow patterns in obesity.