Alpha‐2 adrenoceptors are present in rat aorta smooth muscle cells, and their action is mediated by ATP‐sensitive K<sup>+</sup> channels

Fauaz, Grasiele; Feres, Teresa; Borges, Antônio Carlos Romão; Paiva, Therezinha B.

doi:10.1038/sj.bjp.0703630

Cited by 17 publications

(18 citation statements)

References 17 publications

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“…The lack of an effect of TTX on the aortic resting tension, together with the fact that membrane depolarization induced by the addition of low concentrations of KCl (2–15 mmol/L) is required to unmask this component of contraction, reveals that Na v channels are closed at physiological RMPs. Our measurement of the RMP (−56 mV) is consistent with other reports [33], [34] and with the estimated activation threshold of the Na v 1.2 isoform; that is between −60 mV and −50 mV [35], [36]. Interestingly, the window current determined by the overlap of the steady-state activation and inactivation curves of the Na v 1.2 isoform is expected to generate a persistent influx of Na + between the activation threshold (between −60 mV and −50 mV) and −40 mV [35], [36].…”

Section: Discussionsupporting

confidence: 93%

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

et al. 2009

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BackgroundDespite increasing evidence for the presence of voltage-gated Na+ channels (Nav) isoforms and measurements of Nav channel currents with the patch-clamp technique in arterial myocytes, no information is available to date as to whether or not Nav channels play a functional role in arteries. The aim of the present work was to look for a physiological role of Nav channels in the control of rat aortic contraction.Methodology/Principal FindingsNav channels were detected in the aortic media by Western blot analysis and double immunofluorescence labeling for Nav channels and smooth muscle α-actin using specific antibodies. In parallel, using real time RT-PCR, we identified three Nav transcripts: Nav1.2, Nav1.3, and Nav1.5. Only the Nav1.2 isoform was found in the intact media and in freshly isolated myocytes excluding contamination by other cell types. Using the specific Nav channel agonist veratridine and antagonist tetrodotoxin (TTX), we unmasked a contribution of these channels in the response to the depolarizing agent KCl on rat aortic isometric tension recorded from endothelium-denuded aortic rings. Experimental conditions excluded a contribution of Nav channels from the perivascular sympathetic nerve terminals. Addition of low concentrations of KCl (2–10 mM), which induced moderate membrane depolarization (e.g., from −55.9±1.4 mV to −45.9±1.2 mV at 10 mmol/L as measured with microelectrodes), triggered a contraction potentiated by veratridine (100 µM) and blocked by TTX (1 µM). KB-R7943, an inhibitor of the reverse mode of the Na+/Ca2+ exchanger, mimicked the effect of TTX and had no additive effect in presence of TTX.Conclusions/SignificanceThese results define a new role for Nav channels in arterial physiology, and suggest that the TTX-sensitive Nav1.2 isoform, together with the Na+/Ca2+ exchanger, contributes to the contractile response of aortic myocytes at physiological range of membrane depolarization.

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Section: Discussionsupporting

confidence: 93%

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

et al. 2009

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“…In rat aorta smooth muscle, it has been recently reported that UK 14304 (1–30 n m ) and clonidine (0.1–3 n m ) produced relaxation in endothelium‐denuded aortic rings contracted with BaCl 2 , which was inhibited by yohimbine; whereas UK 14304 provoked contraction with higher concentrations (≥100 n m ), which was inhibited by prazosine [19]. The authors [19] concluded that low concentrations of α 2 ‐AR agonists (clonidine and UK 14304) induced relaxation activating smooth muscle α 2 ‐AR, whereas high concentrations may also activate α 1 ‐AR. On the contrary, our results obtained with serotonin‐ and PGF 2 α ‐contracted aortic tissues, clearly showed that low concentrations of clonidine and UK 14304 (≤100 n m ) did not produce relaxant responses, neither in the presence nor in the absence of endothelium.…”

Section: Discussionmentioning

confidence: 99%

Evidence against α₂‐adrenoceptors mediating relaxation in rat thoracic aortae: α₂‐agonists relaxation depends on interaction with α₁‐adrenoceptors

Castillo

Ortiz

López

et al. 2006

Fundamemntal Clinical Pharma

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In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.

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“…As augmentation of the twitch contractions induced by clonidine was inhibited by yohimbine, the augmenting action of clonidine involves α2 receptor stimulation of vascular smooth muscle cells. The presence of α2 receptors on smooth muscle cells of vascular muscle has been reported (Fauaz et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Clonidine is known to dilate various arteries and veins via both endothelium-dependent and -independent pathways (Angus et al, 1986;Thorin et al, 1998;Nishina et al, 1999;Lui et al, 2000;Fauaz et al, 2000). Figueroa et al (2001) reported that endothelial α2D subtype receptors were coupled to the NO synthetic pathway in the mesenteric artery of the rat.…”

Section: Introductionmentioning

confidence: 99%

Clonidine induced endothelium-dependent tonic contraction in circular muscle of the rat hepatic portal vein

Shimamura

Toba

Kimura

et al. 2006

J Smooth Muscle Res

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Clonidine, an α2-agonist, has been shown to be useful in the treatment of hepatic portal hypertension in cirrhosis. The mechanism has been attributed to a clonidineinduced decrease in sympathetic activity. While clonidine has been shown to stimulate the α2-adrenoceptors of blood vessels, there is limited knowledge of the effects of clonidine on the circular muscle of the hepatic portal vein which regulates its blood flow. To investigate clonidine-induced contraction of the circular muscle of the hepatic portal vein and to clarify the possible role of the endothelium in the contraction, we examined the effects of clonidine on the isometric contraction of endothelium-intact and -removed ring preparations of the rat hepatic portal vein. In endothelium-intact preparations, clonidine caused a concentration-dependent increase in the amplitude of contractions. Inhibition of NO synthesis with N ω -nitro-L-arginine (L-NNA) elevated the resting tone, and increased the amplitude of the clonidine-induced contractions. Inhibition of cyclooxygenase by diclofenac did not change the amplitude of the clonidine-induced contractions observed both in the presence and absence of L-NNA. Application of a single concentration of clonidine induced a clear increase in amplitude of both twitch and tonic contractions. Twitch and tonic contractions induced by clonidine were inhibited by yohimbine. When the endothelium was damaged by sodium deoxycholate, tonic contractions induced by clonidine were completely suppressed, whereas the increase in twitch contractions was not influenced by chemical damage of the endothelium. Neither SKF-96365, a nonselective cation channel blocker, nor superoxide dismutase, a free radical scavenger, in the presence of catalase, changed the tonic contraction induced by clonidine. These results indicate that stimulation of α2-adrenoceptors enhanced twitch contractions and induced tonic contractions in the circular muscle of the rat hepatic portal vein, especially in the absence of NO. The latter, but not the former, occurs through an endothelium-dependent pathway.

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Alpha‐2 adrenoceptors are present in rat aorta smooth muscle cells, and their action is mediated by ATP‐sensitive K⁺ channels

Cited by 17 publications

References 17 publications

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

Evidence against α₂‐adrenoceptors mediating relaxation in rat thoracic aortae: α₂‐agonists relaxation depends on interaction with α₁‐adrenoceptors

Clonidine induced endothelium-dependent tonic contraction in circular muscle of the rat hepatic portal vein

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Alpha‐2 adrenoceptors are present in rat aorta smooth muscle cells, and their action is mediated by ATP‐sensitive K+ channels

Cited by 17 publications

References 17 publications

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

Evidence against α2‐adrenoceptors mediating relaxation in rat thoracic aortae: α2‐agonists relaxation depends on interaction with α1‐adrenoceptors

Clonidine induced endothelium-dependent tonic contraction in circular muscle of the rat hepatic portal vein

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Alpha‐2 adrenoceptors are present in rat aorta smooth muscle cells, and their action is mediated by ATP‐sensitive K⁺ channels

Evidence against α₂‐adrenoceptors mediating relaxation in rat thoracic aortae: α₂‐agonists relaxation depends on interaction with α₁‐adrenoceptors