SKA-31, an activator of Ca2+-activated K+ channels, improves cardiovascular function in aging

Cini Mathew John, Rayan Khaddaj Mallat, Ramesh C. Mishra, Grace George, Vikrant Singh, Jeannine D. Turnbull, Channakeshava S. Umeshappa, Dylan J. Kendrick, Taeyeob Kim, Fazlin M. Fauzi, Frank Visser, Paul W.M. Fedak, Heike Wulff, Andrew P. Braun

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Abstract

Aging represents an independent risk factor for the development of cardiovascular disease, and is associated with complex structural and functional alterations in the vasculature, such as endothelial dysfunction. Small- and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacological activators of these channels induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of such compounds are unknown. In our study, we hypothesized that such treatment would ameliorate aging-related cardiovascular deficits. Aged (∼18 months) male Sprague Dawley rats were treated daily with either vehicle or the KCa channel activator SKA-31 (10 mg/kg, intraperitoneal injection; n = 6/group) for 8 weeks, followed by echocardiography, arterial pressure myography, immune cell and plasma cytokine characterization, and tissue histology. Our results show that SKA-31 administration improved endothelium-dependent vasodilation, reduced agonist-induced vascular contractility, and prevented the aging-associated declines in cardiac ejection fraction, stroke volume and fractional shortening, and further improved the expression of endothelial KCa channels and associated cell signalling components to levels similar to those observed in young male rats (∼5 months at end of study). SKA-31 administration did not promote pro-inflammatory changes in either T cell populations or plasma cytokines/chemokines, and we observed no overt tissue histopathology in heart, kidney, aorta, brain, liver and spleen. SKA-31 treatment in young rats had little to no effect on vascular reactivity, select protein expression, tissue histology, plasma cytokines/chemokines or immune cell properties. Collectively, these data demonstrate that administration of the KCa channel activator SKA-31 improved aging-related cardiovascular function, without adversely affecting the immune system or promoting tissue toxicity.

Original languageEnglish (US)
Article number104539
JournalPharmacological Research
Volume151
DOIs
StatePublished - Jan 2020

Keywords

  • Aging
  • Arteries
  • Ca-activated K channels
  • Heart
  • Immune system

ASJC Scopus subject areas

  • Pharmacology

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    John, C. M., Khaddaj Mallat, R., Mishra, R. C., George, G., Singh, V., Turnbull, J. D., Umeshappa, C. S., Kendrick, D. J., Kim, T., Fauzi, F. M., Visser, F., Fedak, P. W. M., Wulff, H., & Braun, A. P. (2020). SKA-31, an activator of Ca2+-activated K+ channels, improves cardiovascular function in aging. Pharmacological Research, 151, [104539]. https://doi.org/10.1016/j.phrs.2019.104539