title: A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model.
abstract: SKA-31, an activator of endothelial KCa2.3 and KCa3.1 channels, reduces systemic blood pressure in mice and dogs, however, its effects in larger mammals are not well known. We therefore examined the hemodynamic effects of SKA-31, along with sodium nitroprusside (SNP), in anesthetized, juvenile male domestic pigs. Experimentally, continuous measurements of left ventricular (LV), aortic and inferior vena cava (IVC) pressures, along with flows in the ascending aorta, carotid artery, left anterior descending coronary artery and renal artery, were performed during acute administration of SKA-31 (0.1, 0.3, 1.0, 3.0 and 5.0mg/ml/kg) and a single dose of SNP (5.0 μg/ml/kg). SKA-31 dose-dependently reduced mean aortic pressure (mPAO), with the highest dose decreasing mPAO to a similar extent as SNP (-23 ± 3 and -28 ± 4 mmHg, respectively). IVC pressure did not change. Systemic conductance and conductance in coronary and carotid arteries increased in response to SKA-31 and SNP, but renal artery conductance was unaffected. There was no change in either LV stroke volume (SV) or heart rate (versus the preceding control) for any infusion. With no change in SV, drug-evoked decreases in LV stroke work (SW) were attributed to reductions in mPAO (SW vs. mPAO, r(2)=0.82, P<0.001). In summary, SKA-31 dose-dependently reduced mPAO by increasing systemic and arterial conductances. Primary reductions in mPAO by SKA-31 largely account for associated decreases in SW, implying that SKA-31 does not directly impair cardiac contractility.
authors.affiliation: Dept. of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; The Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Mishra
authors.affiliation: Dept of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Mitchell
authors.affiliation: Dept. of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Dept. of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; The Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada; Dept. of Biology, Ambrose University College, Calgary, Alberta, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Gibbons-Kroeker
authors.affiliation: Dept. of Pharmacology, University of California Davis, Davis, CA, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Dept. of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Dept. of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; The Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Israel
authors.initials: I
authors.lastname: Belenkie
authors.affiliation: Dept. of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Dept. of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; The Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: John V
authors.initials: JV
authors.lastname: Tyberg
authors.affiliation: Dept. of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; The Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. Electronic address: abraun@ucalgary.ca.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Braun
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects* / Q000502:physiology; D052160:Benzothiazoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D034421:Sus scrofa; D013552:Swine
chemical_list: D052160:Benzothiazoles; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496901:Kcnn3 protein, rat; D051640:Small-Conductance Calcium-Activated Potassium Channels; C535212:naphtho(1,2-d)thiazol-2-ylamine
keywords: Blood pressure; Conductance; Endothelium; Hemodynamics; KCa channel