This page lists medical journal articles discussing the association between cardiovascular issues and the mycotoxin known as penitrem A.
The Health Effects of Penitrem A page of the Paradigm Change site provides further information on the effects of this mycotoxin.
Khaddaj-Mallat R, Mathew John C, Braun AP. SKA-31, an activator of endothelial Ca2+-activated K+ channels evokes robust vasodilation in rat mesenteric arteries. Eur J Pharmacol. 2018 Jul 15;831:60-67. PMID: 29753043
Penitrem-A, an inhibitor of KCa1.1 channels, decreased vasodilatory responses to acetylcholine, sodium nitroprusside and NS-1619, but had little effect on the KCa channel activator SKA-31.
Sinharoy P, Bratz IN, Sinha S, Showalter LE, Andrei SR, Damron DS. TRPA1 and TRPV1 contribute to propofol-mediated antagonism of U46619-induced constriction in murine coronary arteries. PLoS One. 2017 Jun 23;12(6):e0180106. PMID: 28644897
Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs. Propofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice. We concluded that TRPA1 and TRPV1 appear to contribute to the propofol-mediated antagonism of U46619-induced constriction in murine coronary microvessels that involves activation of NOS and BKCa.
Kyle BD, Mishra RC, Braun AP. The augmentation of BK channel activity by nitric oxide signaling in rat cerebral arteries involves co-localized regulatory elements. J Cereb Blood Flow Metab. 2017 Dec;37(12):3759-3773. PMID: 28155571
Here, we investigate the cellular mechanisms underlying the enhancement of BK current in rat cerebral arteries by nitric oxide (NO) signaling. In isolated cerebral myocytes, BK current magnitude was reversibly increased by sodium nitroprusside (SNP, 100 μM) and sensitive to the BK channel inhibitor, penitrem-A (100 nM).
Mishra RC, Wulff H, Hill MA, Braun AP. Inhibition of Myogenic Tone in Rat Cremaster and Cerebral Arteries by SKA-31, an Activator of Endothelial KCa2.3 and KCa3.1 Channels. J Cardiovasc Pharmacol. 2015 Jul;66(1):118-27. PMID: 25815673
Endothelial KCa2.3 and KCa3.1 channels contribute to the regulation of myogenic tone in resistance arteries by Ca(2+)-mobilizing vasodilatory hormones. To define further the functional role of these channels in distinct vascular beds, we have examined the vasodilatory actions of the KCa channel activator SKA-31 in myogenically active rat cremaster and middle cerebral arteries. Penitrem-A, a blocker of BK(Ca) channels, did not alter SKA-31 evoked vasodilation but did reduce the inhibition of myogenic tone by ACh, the BKCa channel activator NS1619, and sodium nitroprusside.
Needham M, McGahon MK, Bankhead P, Gardiner TA, Scholfield CN, Curtis TM, McGeown JG. The role of K+ and Cl- channels in the regulation of retinal arteriolar tone and blood flow. Invest Ophthalmol Vis Sci. 2014 Apr 7;55(4):2157-65. PMID: 24609622
This study tested the role of K(+) and Cl(-) channels in the regulation of retinal blood flow. Voltage-activated K(+) current (IKv) was inhibited by correolide, large conductance (BK) Ca(2+)-activated K(+) current (IKCa) by Penitrem A, and Ca(2+)-activated Cl(-) current (IClCa) by disodium 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS). Intravitreal injections (10 μL) of DIDS (estimated intraocular concentration 10 mM) increased flow by 22%, whereas the BK-blockers Penitrem A (1 μM) and iberiotoxin (4 μM), and the IKv-inhibitor correolide (40 μM) all decreased resting flow by approximately 10%. Endothelin 1 (104 nM) reduced flow by approximately 65%. This effect was completely reversed by DIDS, but was unaffected by Penitrem A, iberiotoxin, or correolide.
Asano Shinichi, Bratz Ian N., Berwick Zachary C., Fancher Ibra S., Tune Johnathan D., Dick Gregory M.. Penitrem A as a tool for understanding the role of large conductance Ca(2+)/voltage-sensitive K(+) channels in vascular function. The Journal of pharmacology and experimental therapeutics. 2012;342:453–460. PMID: 22580348
Large conductance, Ca(2+)/voltage-sensitive K(+) channels (BK channels) are well characterized, but their physiological roles, often determined through pharmacological manipulation, are less clear. Thus, we characterized the effect of penitrem A, a tremorigenic mycotoxin, on BK channels and demonstrate its utility for studying vascularfunction in vitro and in vivo. Whole-cell currents from human embryonic kidney 293 cells transfected with hSlo α or α + β1 were blocked >95% by penitrem A (IC(50) 6.4 versus 64.4 nM; p < 0.05). Furthermore, penitrem A inhibited BK channels in inside-out and cell-attached patches, whereas iberiotoxin could not. Inhibitory effects of penitrem A on whole-cell K(+) currents were equivalent to iberiotoxin in canine coronary smooth muscle cells. As for specificity, penitrem A had no effect on native delayed rectifier K(+) currents, cloned voltage-dependent Kv1.5 channels, or native ATP-dependent K(ATP) current. Penitrem A enhanced the sensitivity to K(+)-induced contraction in canine coronary arteries by 23 ± 5% (p < 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 ± 11% (p < 0.05). Our data indicate that penitrem A is a useful tool for studying the role of BK channels in vascular function and is practical for cell and tissue (in vitro) studies as well as anesthetized animal (in vivo) experiments.
Namiranian Khodadad, Lloyd Eric E., Crossland Randy F., et al. Cerebrovascular responses in mice deficient in the potassium channel, TREK-1. American journal of physiology. Regulatory, integrative and comparative physiology. 2010;299. PMID: 20357027
We tested the hypothesis that TREK-1, a two-pore domain K channel, is involved with dilations in arteries. Because there are no selective activators or inhibitors of TREK-1, we generated a mouse line deficient in TREK-1. Alpha-linolenic acid or arachidonic acid increased whole cell currents in CVSMCs from both WT and TREK-1 KO mice. The selective blockers of large-conductance Ca-activated K channels, penitrem A and iberiotoxin, blocked the increased currents elicited by either alpha-linolenic or arachidonic acid.
Olanrewaju Hammed A., Gafurov B. S., Lieberman E. M.. Involvement of K+ channels in adenosine A2A and A2B receptor-mediated hyperpolarization of porcine coronary artery endothelial cells. Journal of cardiovascular pharmacology. 2002;40:43–49. PMID: 12072576
This study investigated the effects of adenosine agonists. 1-EB10, a selective opener of the maxi-KCa channel, hyperpolarized PCAECs, and the effect of 1-EB10 was completely blocked by a selective, irreversible blocker of the high conductance KCa (maxi-K) channels (penitrem A).
Asano Shinichi, Tune Johnathan D., Dick Gregory M.. Bisphenol A activates Maxi-K (K (Ca)1.1) channels in coronary smooth muscle. British journal of pharmacology. 2010;160:160–170.
Bisphenol A (BPA) is used to manufacture plastics, including containers for food into which it may leach. We tested the hypothesis that BPA activates Maxi-K channels through a mechanism that depends upon the regulatory beta1 subunit. BPA (10 microM) activated an outward current in smooth muscle cells that was inhibited by penitrem A (1 microM), a Maxi-Kblocker. Our data indicate that BPA increased the activity of Maxi-K channels and may represent a basis for some potential toxicological effects.
Borbouse Léna, Dick Gregory M., Payne Gregory A., et al. Contribution of BK(Ca) channels to local metabolic coronary vasodilation: Effects of metabolic syndrome. American journal of physiology. Heart and circulatory physiology. 2010;298. PMID: 20044440
This investigation was designed to examine the hypothesis that impaired function of coronary microvascular large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in metabolic syndrome (MetS) significantly attenuates the balance between myocardial oxygen delivery and metabolism at rest and during exercise-induced increases in myocardial oxygen consumption (MVo(2)). Data were collected under baseline/resting conditions and during graded treadmill exercise before and after selective blockade of BK(Ca) channels with penitrem A (10 microg/kg iv). We found that the exercise-induced increases in blood pressure were significantly elevated in MetS swine. Inhibition of BK(Ca) channels with penitrem A did not significantly affect blood pressure, heart rate, or the relationship between coronary venous Po(2) and MVo(2) in lean or MetS swine.
Borbouse Léna, Dick Gregory M., Payne Gregory A., et al. Metabolic syndrome reduces the contribution of K+ channels to ischemic coronary vasodilation. American journal of physiology. Heart and circulatory physiology. 2010;298. PMID: 20118408
This investigation tested the hypothesis that metabolic syndrome decreases the relative contribution of specific K(+) channels to coronary reactive hyperemia. Ca(2+)-activated (BK(Ca)), voltage-activated (K(V)), and ATP-dependent (K(ATP)) K(+) channels were investigated. Ischemic vasodilation was determined by the coronary flow response to a 15-s occlusion before and after cumulative administration of antagonists for BK(Ca) (penitrem A; 10 microg/kg iv), K(V) (4-aminopyridine; 0.3 mg/kg iv) and K(ATP) (glibenclamide; 1 mg/kg iv) channels. Inhibition of BK(Ca) channels had no effect on reactive hyperemia in either lean or metabolic syndrome swine. These data indicate that the metabolic syndrome impairs coronary vasodilation in response to cardiac ischemia via reductions in the contribution of K(+) channels to reactive hyperemia.
Borbouse Léna, Dick Gregory M., Asano Shinichi, et al. Impaired function of coronary BK(Ca) channels in metabolic syndrome. American journal of physiology. Heart and circulatory physiology. 2009;297. PMID: 19749164
The role of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in regulation of coronary microvascular function is widely appreciated, but molecular and functional changes underlying the deleterious influence of metabolic syndrome (MetS) have not been determined. MetS significantly impaired coronary vasodilation to the BK(Ca) opener NS-1619 in vivo (30-100 microg) and reduced the contribution of these channels to adenosine-induced microvascular vasodilation in vitro (1-100 microM). MetS reduced whole cell penitrem A (1 microM)-sensitive K(+) current and NS-1619-activated (10 microM) current in isolated coronary vascular smooth muscle cells.
Sones W. R., Leblanc N., Greenwood I. A.. Inhibition of vascular calcium-gated chloride currents by blockers of KCa1.1, but not by modulators of KCa2.1 or KCa2.3 channels. British journal of pharmacology. 2009;158:521–531. PMID: 19645713
Recent pharmacological studies have proposed there is a high degree of similarity between calcium-activated Cl(-) channels (CaCCs) and large conductance, calcium-gated K(+) channels (K(Ca)1.1). The goal of the present study was to ascertain whether blockers of K(Ca)1.1 inhibited calcium-activated Cl(-) currents (I(ClCa)) and if the pharmacological overlap between K(Ca)1.1 and CaCCs extends to intermediate and small conductance, calcium-activated K(+) channels. The selective K(Ca)1.1 blocker paxilline (1 microM) inhibited I(ClCa) by approximately 90%, whereas penitrem A (1 microM) and iberiotoxin (100 and 300 nM) reduced the amplitude of I(ClCa) by approximately 20%, as well as slowing channel deactivation.
McGahon Mary K., Dash Durga P., Arora Aruna, et al. Diabetes downregulates large conductance Ca2+-activated potassium beta 1 channel subunit in retinal arteriolar smooth muscle. Circulation research. 2007;100:703–711. PMID: 17293477
Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca(2+) release events (Ca(2+)-sparks), trigger the activation of large–conductance Ca(2+)-activated K(+)(BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension.
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