Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism

Abstract

Cardiovascular disease is the world's leading cause of morbidity and mortality, with high blood pressure (BP) contributing to increased severity and number of adverse outcomes. Plasma membrane calcium ATPase 4 (PMCA4) has been previously shown to modulate systemic BP. However, published data are conflicting, with both overexpression and inhibition of PMCA4 in vivo shown to increase arterial contractility. Hence, our objective was to determine the role of PMCA4 in the regulation of BP and to further understand how PMCA4 functionally regulates BP using a novel specific inhibitor to PMCA4, aurintricarboxylic acid (ATA). Our approach assessed conscious BP and contractility of resistance arteries from PMCA4 global knockout (PMCA4KO) mice compared to wild‐type animals. Global ablation of PMCA4 had no significant effect on BP, arterial structure or isolated arterial contractility. ATA treatment significantly reduced BP and arterial contractility in wild‐type mice but had no significant effect in PMCA4KO mice. The effect of ATA in vivo and ex vivo was abolished by the neuronal nitric oxide synthase (nNOS) inhibitor Vinyl‐l‐NIO. Thus, this highlights differences in the effects of PMCA4 ablation and acute inhibition on the vasculature. Importantly, for doses here used, we show the vascular effects of ATA to be specific for PMCA4 and that ATA may be a further experimental tool for elucidating the role of PMCA4.

Kinetics of relaxation of rat myometrium in conditions of inhibition of plasma memb­rane calcium pump and systems of active Ca2+ transport of intracellular Ca2+-depot

“…As myometrium smooth muscle cells express similar isoforms of PMCA, one can use the material of the studies [10,11] for deeper understanding of processes in the myometrium tissue at the impact of a macrocyclic compound calixarene С-716. It is known that active PMCA molecules block the function of the constitutive isoforms of the nitric oxide synthase [9,19]. In our previous study it was found that blocking the synthesis of nitric oxide in rat uteric smooth muscles eliminates the effects of calixaren C-90 on their contractile function [24].…”

Genetic Variations In Human ATP2B4 Gene Alter Malaria Growth In Rbcs From Gambian Adults.

“…A key aim of malaria GWAS studies is to identify possible new targets for anti-malarial drug development [33]. As part of this effort and to provide proof of principle, we tested the PMCA4b inhibitor, aurinictricarboxylic acid (ATA), which is under investigation as a blood pressure modulator [34]. Our experiments reveal that the IC 50 value for parasite inhibition was over 100x higher than common drugs such as chloroquine and artemisinin.…”

PMCA4 inhibition does not affect cardiac remodelling following myocardial infarction, but may reduce susceptibility to arrhythmia

“…Overall these results demonstrate that PMCA4 ablation and inhibition do not significantly affect chronic outcomes in a model of permanent myocardial infarction, but may reduce the susceptibility to acute arrhythmia and sudden death. In addition, PMCA4 inhibition presents a promising target in a number of other cardiovascular areas including pressure overload induced cardiac hypertrophy 20 , the promotion of angiogenesis 22 , 26 and the reduction of blood pressure 25 . Further studies looking to develop PMCA4 inhibitors as a translational therapy may want to focus on these processes, along with alternative models such as ischaemia with reperfusion.…”

“…Through the development of a specific inhibitor 24 , we have shown PMCA4 to be a druggable candidate in a number of cardiovascular settings including the lowering of blood pressure 25 , promotion of angiogenesis 26 , the treatment of cardiac hypertrophy and the prevention of HF 20 . Our previous study found that PMCA4 inhibition reversed cardiac remodelling in mouse hearts subjected to pressure overload, through a paracrine mechanism involving the secretion of the Wnt inhibitor sFRP2 from cardiac fibroblasts 20 .…”