Endothelin-1, Delayed Rectifier K Channels, and Pulmonary Arterial Smooth Muscle

Salter, Katie J.; Wilson, C. M.; Kato, Koichi; Kozlowski, Roland Z.

doi:10.1097/00005344-199800001-00026

Cited by 17 publications

(9 citation statements)

References 4 publications

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“…For example, several earlier studies suggested that endothelin-1 inhibits K v channels in arterial myocytes (2,36,46,51,52). The contribution of this effect to endothelin-1-induced membrane depolarization is not clear, however.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Inward Cl − currents (due to Cl − efflux) are enhanced by α-adrenergic stimulation in rabbit portal vein myocytes (13), by endothelin-1 or angiotensin II in rat pulmonary artery myocytes (20,45,46), and by endothelin-1 or vasopressin in A7r5 cells (56). Furthermore, the stimulation of Cl − efflux has been implicated in the vasoconstrictor effects of endothelin-1 in rabbit basilar artery (10) and norepinephrine in rat resistance arteries (33) and aorta (32).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells

Brueggemann¹,

Moran²,

Barakat³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

121

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[Arg 8 ]-vasopressin (AVP), at low concentrations (10-500 pM), stimulates oscillations in intracellular Ca 2+ concentration (Ca 2+ spikes) in A7r5 rat aortic smooth muscle cells. Our previous studies provided biochemical evidence that protein kinase C (PKC) activation and phosphorylation of voltage-sensitive K + (K v ) channels are crucial steps in this process. In the present study, K v currents (I Kv ) and membrane potential were measured using patch clamp techniques. Treatment of A7r5 cells with 100 pM AVP resulted in significant inhibition of I Kv . This effect was associated with gradual membrane depolarization, increased membrane resistance, and action potential (AP) generation in the same cells. The AVP-sensitive I Kv was resistant to 4-aminopyridine, iberiotoxin, and glibenclamide but was fully inhibited by the selective KCNQ channel blockers linopirdine (10 μM) and XE-991 (10 μM) and enhanced by the KCNQ channel activator flupirtine (10 μM). BaCl 2 (100 μM) or linopirdine (5 μM) mimicked the effects of AVP on K + currents, AP generation, and Ca 2+ spiking. Expression of KCNQ5 was detected by RT-PCR in A7r5 cells and freshly isolated rat aortic smooth muscle. RNA interference directed toward KCNQ5 reduced KCNQ5 protein expression and resulted in a significant decrease in I Kv in A7r5 cells. I Kv was also inhibited in response to the PKC activator 4β-phorbol 12-myristate 13-acetate (10 nM), and the inhibition of I Kv by AVP was prevented by the PKC inhibitor calphostin C (250 nM). These results suggest that the stimulation of Ca 2+ spiking by physiological concentrations of AVP involves PKC-dependent inhibition of KCNQ5 channels and increased AP firing in A7r5 cells.Keywords potassium channel; signal transduction; membrane potential; calcium; vascular smooth muscle; M current Vasoconstrictor hormones cause contraction of vascular smooth muscle (VSM) cells by increasing cytosolic free Ca 2+ concentration ([Ca 2+ ] i ), which in turn activates the cells' contractile apparatus. Voltage-sensitive L-type Ca 2+ channels are known to be important in vasoconstrictor action (27), although the signaling pathways leading to activation of L-type channels are not well characterized. Influx of Ca 2+ via L-type channels is enhanced by NIH Public Access Author ManuscriptAm J Physiol Heart Circ Physiol. Author manuscript; available in PMC 2008 November 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript membrane depolarization, which may result from activation of nonselective cation currents (34,47,54) or Cl − currents (30). Alternatively, inhibition of outward K + currents could provide a depolarizing stimulus for activation of L-type Ca 2+ channels (38).We have previously demonstrated that concentrations of [Arg 8 ]-vasopressin (AVP) that may be found in the systemic circulation (10-500 pM) modulate the frequency of L-type Ca 2+ channel-dependent Ca 2+ spikes in A7r5 rat aortic smooth muscle cells. The stimulation of Ca 2+ -dependent action potentials, which underlie AVP-stimulated...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells

Brueggemann¹,

Moran²,

Barakat³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

121

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“…Acute up-regulation of gating by protein kinase A activated in response to isoprenaline or forskolin treatment (Aiello et al 1995(Aiello et al , 1998, and down-regulation of gating by vasoconstrictors, such as angiotensin II , endothelin-1 (Salter et al 1998), thromboxane-A 2 (Cogolludo et al 2003) acting via protein kinase C, uridine triphosphate via Rho kinase (Luykenaar et al 2004), and vasopressin via tyrosine kinase (Pyk-2) (Byron and Lucchesi 2002) have been demonstrated for VSM K DR channels. The responses are not necessarily observed in all vessels; for example, clear evidence of a vessel-specific modulation of K DR gating was obtained in experiments on cerebral arterial myocytes showing an absence of modulation by protein kinase C (PKC) activation (Luykenaar et al 2004) that is evident in cells from other vessels (Aiello et al 1996;Hayabuchi et al 2001;Cogolludo et al 2003).…”

Section: Acute Modulation Of K Dr Channel Gatingmentioning

confidence: 99%

Myogenic regulation of arterial diameter: role of potassium channels with a focus on delayed rectifier potassium current

Cole

Chen²,

Clément-Chomienne³

2005

Can. J. Physiol. Pharmacol.

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The phenomenon of myogenic constriction of arterial resistance vessels in response to increased intraluminal pressure has been known for over 100 years, yet our understanding of the molecular mechanisms involved remains incomplete. The focus of this paper concerns the potassium (K+) channels that provide a negative feedback control of the myogenic depolarization of vascular smooth muscle cells that is provoked by elevations in intraluminal pressure, and specifically, the contribution of delayed rectifier (KDR) channels. Our knowledge of the important role played by KDR channels, as well as their molecular identity and acute modulation via changes in gating, has increased dramatically in recent years. Several lines of evidence point to a crucial contribution by heteromultimeric KV1 subunit-containing KDR channels in the control of arterial diameter and myogenic reactivity, but other members of the KV superfamily are also expressed by vascular myocytes, and less is known concerning their specific functions. The effect of pharmacological modulation of KDR channels is discussed, with particular reference to the actions of anorexinogens on KV1- and KV2-containing KDR channels. Finally, the need for a greater understanding of the mechanisms that control KDR channel gene expression is stressed in light of evidence indicating that there is a reduced expression of KDR channels in diseases associated with abnormal myogenic reactivity and vascular remodelling.

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“…One alteration induced by chronic hypoxia involves activation of an ET-1 contractile pathway that is distinct from that which is activated during normoxia. Under normoxic conditions, ET-1 causes release of Ca 2ϩ from intracellular stores, PKC-dependent inhibition of voltage-gated K ϩ (K v ) channels, and subsequent membrane depolarization and Ca 2ϩ influx through voltage-dependent calcium channels (VDCCs) (30,33,34). This increase in intracellular calcium concentration ([Ca 2ϩ ] i ), due to both influx and release, activates myosin light chain kinase (MLCK), resulting in phosphorylation of myosin light chains and contraction (39,40).…”

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confidence: 99%

Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats

Weigand¹,

Sylvester²,

Shimoda³

2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Endothelin-1 (ET-1), a potent vasoconstrictor, is believed to contribute to the pathogenesis of hypoxic pulmonary hypertension. Previously we demonstrated that contraction induced by ET-1 in intrapulmonary arteries (IPA) from chronically hypoxic (CH) rats occurred independently of changes in intracellular Ca2+ concentration ([Ca2+]i), suggesting that ET-1 increased Ca2+ sensitivity. The mechanisms underlying this effect are unclear but could involve the activation of myosin light chain kinase, Rho kinase, PKC, or tyrosine kinases (TKs), including those from the Src family. In this study, we examined the effect of pharmacological inhibitors of these kinases on maximum tension generated by IPA from CH rats (10% O2 for 21 days) in response to ET-1. Experiments were conducted in the presence of nifedipine, an L-type Ca2+ channel blocker, to isolate the component of contraction that occurred without a change in [Ca2+]i. The mean change in tension caused by ET-1 (10(-8) M) expressed as a percent of the maximum response to KCl was 184.0+/-39.0%. This response was markedly inhibited by the Rho kinase inhibitors Y-27632 and HA-1077 and the TK inhibitors genistein, tyrphostin A23, and PP2. In contrast, staurosporine and GF-109203X, inhibitors of PKC, had no significant inhibitory effect on the tension generated in response to ET-1. We conclude that the component of ET-1-induced contraction that occurs without a change in [Ca2+]i in IPA from CH rats requires activation of Rho kinase and TKs, but not PKC.

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Endothelin-1, Delayed Rectifier K Channels, and Pulmonary Arterial Smooth Muscle

Cited by 17 publications

References 4 publications

Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells

Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells

Myogenic regulation of arterial diameter: role of potassium channels with a focus on delayed rectifier potassium current

Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats

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