A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model

Ramesh C. Mishra, Jamie R. Mitchell, Carol Gibbons-Kroeker, Heike Wulff, Israel Belenkie, John V. Tyberg, Andrew P. Braun

Research output: Contribution to journalArticle

12 Scopus citations

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 5.0 mg/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 mm Hg, 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, r2 = 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.

Original languageEnglish (US)
Pages (from-to)24-31
Number of pages8
JournalVascular Pharmacology
Volume79
DOIs
StatePublished - Apr 1 2016

Keywords

  • Blood pressure
  • Conductance
  • Endothelium
  • Hemodynamics
  • KCa channel

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Physiology

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