Kv1.5 participates in forming voltage-gated K⁺ (Kv) channels in pulmonary artery smooth muscle cells (PASMC) and plays an important role in regulating membrane potential and vascular tone. Inhibited Kv channel expression and function have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that overexpression of the Kv1.5 gene (KCNA5) produced a 15 pS single channel current and a 4-AP-sensitive whole-cell current. Nicotine, bepridil, correolide, and endothelin-1 (ET-1) all reversibly reduced the Kv1.5 currents, while nicotine and bepridil also accelerate the inactivation kinetics of the currents. Furthermore, we sequenced KCNA5 from IPAH patients and identified 17 single nucleotide polymorphisms (SNPs); 7 are novel SNPs. There are 12 SNPs in the upstream 5' region, 2 of which may alter transcription factor binding sites in the promoter, 2 non-synonymous SNPs in the coding region, 2 SNPs in the 3'-untranslated region, and 1 SNP in the 3'-flanking region. Two SNPs may correlate with the nitric oxide-mediated decrease in pulmonary arterial pressure. Allele frequency of two other SNPs in patients with a history of fenfluramine and phentermine use is significantly different from patients who have never taken the anorexigens. These results suggest that a) Kv1.5 channels are modulated by various agonists, b) novel SNPs in KCNA5 are present in IPAH patients, and c) SNPs in the promoter and translated regions of KCNA5 may underlie the altered expression and/or function of Kv1.5 channels in PASMC from IPAH patients.