Table 1.

Effect of pharmacological interventions of BKCa α-subunit in various disease models.

Compound	(Disease) Model	Effect on BKCa	Effects in the Model	Potential Mechanisms	References
NS1619 and C-type natriuretic peptide	Normotensive rats	Activation	Enhanced endothelium-dependent PA ring dilation and PA pressure reduction ex vivo; hyperpolarised and increased NO production in PMVECs in vivo	Direct activation of the channel in PMVECs	[63]
Compound X	Monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model	Activation	Reduced pulmonary vascular remodelling, pulmonary flow resistance, RV hypertrophy and afterload in PAH model in vivo strongly vasodilated PA rings ex vivo	Direct activation of the channel in PASMCs	[64]
Docosahexaenoic acid (DHA)	IPAH patients normotensive rats chronic hypoxia-induced PH mouse model Kcnma1−/− mouse	Activation	Reduced RV pressure in the PH animal model to normal in vivo enhanced endothelium-dependent PA ring dilation and PA pressure reduction ex vivo; dose-dependently activated BKCa current and hyperpolarised human IPAH-PASMCs to normal in vivo	Direct activation of the channel in PASMCs	[57]
Dehydroepiandrosterone (DHEA)	Chronic hypoxia-induced PH rat model	Activation	Reduced RV pressure, RV wall thickness and PA remodelling in the PH animal model in vivo restored the PA-pressure response to acute hypoxia in the PH animal model in vivo. Decreased intracellular [Ca2+] under hypoxia in PASMCs in vitro Increased BKCa channel activity and expression in PA in the PH animal model in vitro	Dual effect: (i) Activation of the channel in PA by changing the redox balance toward a more oxidative state (ii) Upregulated BKCa mRNA and protein in PASMCs of the chronic hypoxic PH model	[60]
Echinacoside	Normotensive rats	Activation	Reduced noradrenaline-induced contraction of PA in extracellular [Ca2+]-dependent manner ex vivo	Activated NO-cGMP-PKG pathway with subsequent hyperpolarisation and decrease of intracellular free [Ca2+] in PASMCs	[59]
Forskolin and cAMP activators	Fawn-hooded rat employed in chronic hypoxia-induced PH rat model	Activation	Increased open probability of BKCa channels in fawn-hooded PH animal PASMCs in vitro	Direct activation of the channel in PASMCs	[50]
NS1619	Monocrotaline (MCT)-induced PAH rat model	Activation	Reduced RV pressure, carbon monoxide and improved oxygenation in the PAH animal model in vivo reduced PDGF-induced PASMC proliferation in vitro	Direct activation of the channel	[53]
JAK2 inhibitors	IPF patients bleomycin-induced lung fibrosis and PH rat model	Activation	Reduced RV pressure and PA Remodelling in vivo Reduced V/Q mismatch in animal model in vivo Promoted relaxant and anticontractile effects on IPF-PA ex vivo Inhibited effect of TGFβ1-induced loss of endothelial markers and upregulation of the PA remodelling markers in vitro Activated BKCa current in vitro	Unknown	[65]
Iloprost and treprostinil	Primary human PASMCs	Activation	Enhanced PA ring dilation ex vivo Enhanced BKCa current in vitro	(PKA)-induced phosphorylation of BKCa	[47]
NS1619	Chronic hypoxia-induced PH rat model	Activation	Enhanced NO-dependent PA pressure reduction ex vivo	Direct activation of the channel	[52]