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Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery.

ABSTRACT: 1. The possibility that thromboxane (TXA(2)) receptor stimulation causes differential block of the SK(Ca) and IK(Ca) channels which underlie EDHF-mediated vascular smooth muscle hyperpolarization and relaxation was investigated in the rat isolated mesenteric artery. 2. Acetylcholine (30 nm-3 microm ACh) or cyclopiazonic acid (10 microm CPA, SERCA inhibitor) were used to stimulate EDHF-evoked smooth muscle hyperpolarization. In each case, this led to maximal hyperpolarization of around 20 mV, which was sensitive to block with 50 nm apamin and abolished by repeated stimulation of mesenteric arteries with the thromboxane mimetic, U46619 (30 nm-0.1 microm), but not the alpha(1)-adrenoceptor agonist phenylephrine (PE). 3. The ability of U46619 to abolish EDHF-evoked smooth muscle hyperpolarization was prevented by prior exposure of mesenteric arteries to the TXA(2) receptor antagonist 1 microm SQ29548. 4. Similar-sized smooth muscle hyperpolarization evoked with the SK(Ca) activator 100 microm riluzole was also abolished by prior stimulation with U46619, while direct muscle hyperpolarization in response to either levcromakalim (1 microm, K(ATP) activator) or NS1619 (40 microm, BK(Ca) activator) was unaffected. 5. During smooth muscle contraction and depolarization to either PE or U46619, ACh evoked concentration-dependent hyperpolarization (to -67 mV) and complete relaxation. These responses were well maintained during repeated stimulation with PE, but with U46619 there was a progressive decline, so that during a third exposure to U46619 maximum hyperpolarization only reached -52 mV and relaxation was reduced by 20%. This relaxation could now be blocked with charybdotoxin alone. The latter responses could be mimicked with 300 microm 1-EBIO (IK(Ca) activator), an action not modified by exposure to U46619. 6. An early consequence of TXA(2) receptor stimulation is a reduction in the arterial hyperpolarization and relaxation attributed to EDHF. This effect appears to reflect a loss of SK(Ca) activity.

SUBMITTER: Crane GJ

PROVIDER: S-EPMC1574933 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery.

Crane G J GJ Garland C J CJ

British journal of pharmacology 20040329 1

1. The possibility that thromboxane (TXA(2)) receptor stimulation causes differential block of the SK(Ca) and IK(Ca) channels which underlie EDHF-mediated vascular smooth muscle hyperpolarization and relaxation was investigated in the rat isolated mesenteric artery. 2. Acetylcholine (30 nm-3 microm ACh) or cyclopiazonic acid (10 microm CPA, SERCA inhibitor) were used to stimulate EDHF-evoked smooth muscle hyperpolarization. In each case, this led to maximal hyperpolarization of around 20 mV, whi ...[more]

PMID: 15051624

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Project description:Background and aimsThere are increasing reports on case series on spontaneous isolated mesenteric artery dissection, that is, dissections of the superior mesenteric artery and celiac artery, mainly due to improved diagnostic capacity of high-resolution computed tomography angiography performed around the clock. A few case-control studies are now available, while randomized controlled trials are awaited.Material and methodsThe present systematic review based on 97 original studies offers a comprehensive overview on risk factors, management, conservative therapy, morphological modeling of dissection, and prognosis.Results and conclusionsMale gender, hypertension, and smoking are risk factors for isolated mesenteric artery dissection, while the frequency of diabetes mellitus is reported to be low. Large aortomesenteric angle has also been considered to be a factor for superior mesenteric artery dissection. The overwhelming majority of patients can be conservatively treated without the need of endovascular or open operations. Conservative therapy consists of blood pressure lowering therapy, analgesics, and initial bowel rest, whereas there is no support for antithrombotic agents. Complete remodeling of the dissection after conservative therapy was found in 43% at mid-term follow-up. One absolute indication for surgery and endovascular stenting of the superior mesenteric artery is development of peritonitis due to bowel infarction, which occurs in 2.1% of superior mesenteric artery dissections and none in celiac artery dissections. The most documented end-organ infarction in celiac artery dissections is splenic infarctions, which occurs in 11.2%, and is a condition that should be treated conservatively. The frequency of ruptured pseudoaneurysm in the superior mesenteric artery and celiac artery dissection is very rare, 0.4%, and none of these patients were in shock at presentation. Endovascular therapy with covered stents should be considered in these patients.

Project description:(1) Vasorelaxation and hyperpolarization of endothelial cells by adenosine 5'-[beta-thio]diphosphate (ADPbetaS) and adenosine 5'-[gamma-thio]triphosphate (ATPgammaS) were studied in rat-isolated mesenteric artery. Effects from stimulation of P2X receptors were avoided by desensitization with alpha,beta-methylene adenosine triphosphate. (2) ADPbetaS caused concentration- and endothelium-dependent relaxations of methoxamine-precontracted small (third generation) and main mesenteric artery. These were inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME) or a combination of apamin plus charybdotoxin (inhibitors of Ca(2+)-activated K(+) channels); L-NAME, apamin and charybdotoxin applied together abolished the response. (3) ATPgammaS induced limited relaxation (35% of methoxamine-induced tone at 10 micro M) of small mesenteric artery, which was sensitive to L-NAME or endothelium denudation. However, it almost completely relaxed the main mesenteric artery over an extended concentration range (>6 orders of magnitude) in an endothelium-dependent manner. This relaxation was inhibited by either L-NAME or a combination of apamin with charybdotoxin, and abolished by a combination of all the three inhibitors. (4) The P2Y(1) receptor antagonist MRS 2179 (2'-deoxy-N(6)-methyladenosine 3',5'-bisphosphate; 0.3-3 micro M) caused parallel rightward shifts of the concentration/relaxation curve to ADPbetaS (pA(2)=7.1). However, MRS 2179 did not inhibit, but potentiated, relaxant responses to ATPgammaS. MRS 2179 did not affect the contractile responses ATPgammaS in small mesenteric artery; ATPgammaS did not contract the main mesenteric artery. (5) ADPbetaS hyperpolarized the endothelium of the main mesenteric artery in a concentration-dependent manner. This was unaffected by L-NAME but antagonized by MRS 2179. ATPgammaS also hyperpolarized the mesenteric artery endothelium in a concentration-dependent manner but, when ATPgammaS was applied at 10 micro M, its effect was potentiated by MRS 2179 (3 micro M). (6) It is concluded that both relaxation and hyperpolarization to ADPbetaS are mediated by P2Y(1) receptors and that the endothelial hyperpolarization is related to the L-NAME-resistant relaxation. Relaxation to the P2Y(2) agonist ATPgammaS shows regional variation along the mesenteric vasculature. The mechanisms for potentiation of relaxation and hyperpolarization by ATPgammaS are unknown, but may indicate interactions between P2Y receptor subtypes.

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Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery.

Publications

Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery.

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