Study of the mechanisms involved in adenosine‐5′‐O‐(2‐thiodiphosphate) induced relaxation of rat thoracic aorta and pancreatic vascular bed

Saiag, B.; Hillaire‐Buys, Dominique; Chapal, J; Petit, Pierre; Pape, Daniel J.; Rault, B; Allain, H.; Loubatières-Mariani, Marie-Madeleine

doi:10.1111/j.1476-5381.1996.tb15471.x

Cited by 27 publications

(28 citation statements)

References 46 publications

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“…Endothelium-dependent relaxation by ATP and other nucleotides has also been demonstrated in the rat aorta (Rapoport et al 1984;White et al 1985;Rose'Meyer and Hope 1990;Dainty et al 1991Dainty et al , 1994Dominiczak et al 1991;Frew et al 1993;Mombouli and Vanhoutte 1993;García-Velasco et al 1995;Saïag et al 1996). The rank order of agonist potency MeSATP > UTP = ATP García-Velasco et al 1995) is consistent with a mixed P2Y and P2U population .…”

Section: Introductionmentioning

confidence: 52%

Characterization by antagonists of P2-receptors mediating endothelium-dependent relaxation in the rat aorta

Hansmann

Bültmann

Tuluc

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The receptors through which 2-methylthio ATP (MeSATP), adenosine 5'-O-(2-thiodiphosphate) (ADP beta S), UTP and ATP elicit endothelium-dependent relaxation of noradrenaline-precontracted rings of the rat aorta were characterized by means of a series of antagonists. The acetylcholine-induced relaxation and the degradation of MeSATP, UTP and ATP were also studied. The potency of the nucleotides at producing relaxation decreased in the order MeSATP (EC50 0.24 microM) > ADP beta S (0.43 microM) > UTP (1.09 microM) > ATP (3.53 microM). MeSATP, ADP beta S and UTP did not cause relaxation when the endothelium had been destroyed; high concentrations of ATP still caused some relaxation. The relaxation by MeSATP, ADP beta S and UTP became very small after treatment of the rings with NG-nitro-L-arginine methyl ester; the relaxation by ATP was less affected. Pre-exposure to MeSATP (100 microM) abolished or almost abolished the relaxation normally elicited by MeSATP and ADP beta S, did not change that elicited by UTP and slightly enhanced the relaxation elicited by ATP. Of nine compounds examined as antagonists, six attenuated selectively the effect of some or all of the nucleotides (as compared to acetylcholine): suramin, reactive blue 2, pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS), pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), reactive red 2 and 5,5'-(1,1'-biphenyl-4,4'-diylbisazo)-bis-7-amino -6-hydroxy-naphthalene-1,4-disulphonate (NH05). Decreases of maximal relaxations and slopes different from unity in Schild plots often indicated non-competitive kinetics of the antagonism. For each of the six 'selective' antagonist, the apparent Kd values against MeSATP and against ADP beta S were similar: none of the six differentiated between MeSATP and ADP beta S. Also, for each of four 'selective' antagonists, the apparent Kd values against UTP and against ATP were similar: none of the four differentiated between these two nucleotides (two antagonists did not act against UTP and ATP in the 'selective' concentration range). On the other hand, for five of the six 'selective' antagonists (the exception being NH05), the apparent Kd values against MeSATP and ADP beta S were considerably lower than those against UTP and ATP. At the highest concentrations tested against agonist-evoked relaxations, the antagonists did not alter the removal from the incubation medium, by pieces of rat aorta, of MeSATP, UTP and ATP. It is concluded that nucleotides cause endothelium-dependent relaxation of the rat aorta through two sites: a P2Y-receptor and a P2U-receptor. The receptors may be pharmacologically similar to a bovine endothelial P2Y (P2Y1) and a cloned rat P2U (P2Y2) receptor, respectively. ATP acts mainly through the P2U-receptor. Suramin, reactive blue 2, iso-PPADS, PPADS and reactive red 2 are more potent at the P2Y- than the P2U-receptor. NH05 does not discriminate between the two receptors but is the most potent P2U antagonist so far described.

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Section: Introductionmentioning

confidence: 52%

Characterization by antagonists of P2-receptors mediating endothelium-dependent relaxation in the rat aorta

Hansmann

Bültmann

Tuluc

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Adenosine-59-(b-thio)-diphosphate, a P2Y 1 -selective agonist, caused endothelium-dependent vasodilatation of the rat isolated perfused pancreas, which was mediated partly by NO and PGI 2 but also through another mechanism that did not involve K ATP , SK Ca , and BK Ca channels (Saïag et al, 1996;HillaireBuys et al, 1998). P2X 1 , P2X 2 , P2Y 1 , and P2Y 2 receptor expression was shown using immunohistochemistry in small blood vessels of the rat pancreas (Coutinho- Silva et al, 2003).…”

Section: R Other Blood Vesselsmentioning

confidence: 99%

Purinergic Signaling and Blood Vessels in Health and Disease

2013

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“…Similarly, in rat mesenteric arteries, it has been reported that stimulation of the P 2Y receptors triggers endothelium-dependent relaxation, which was inhibited by the combination of iberiotoxin and apamin in the presence of L-NOARG and indomethacin [9]. Recent studies also suggests that activation of the P 2Y receptors induces endothelium-dependent vasodilation mediated by EDHF [10,11,14,15,18]. Therefore, it is suggested that ADP β S activates the P 2Y receptors to release EDHF from endothelial cells of the rabbit renal arteries.…”

Section: Discussionmentioning

confidence: 96%

“…Recent studies suggest that activation of the P 2Y receptors induces endothelium-dependent vasodilation mediated by EDHF [10,14,15,18]. In the rat mesenteric artery, P 2Y receptor-induced vasodilatation is antagonized by a combination of the K + channels inhibitors, charybdotoxin and apamin, which prevents hyperpolarization and relaxation mediated by EDHF in different blood vessels [3,9,20].…”

mentioning

confidence: 99%

Mechanisms of NO-Resistant Relaxation Induced by Acetylcholine in Rabbit Renal Arteries.

Kwon

2001

The Journal of Veterinary Medical Science

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ABSTRACT. The effects of K + channel blockers and P 2Y receptor agonist/antagonist on the vasorelaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) were investigated in the rabbit renal artery. Acetylcholine (ACh, 1 nM-10 µM) induced endotheliumdependent relaxation of arterial rings precontracted with norepinephrine (NE, 1 µM) in a concentration-dependent manner. N G -nitro-Larginine (L-NAME, 0.1 mM), an inhibitor of NO synthase, partially inhibited the ACh-induced endothelium-dependent relaxation. The ACh-induced relaxation was only partially inhibited by L-NAME whereas combined addition of L-NAME and 30 mM KCl completely inhibited the relaxation. The ACh-induced relaxation observed in the presence of L-NAME was significantly reduced by a combination of iberiotoxin (0.1 µM) and apamin (1 µM), and almost completely blocked by 4-aminopyridine (5 mM). The ACh-induced relaxation was antagonized by P 2Y receptor antagonist, cibacron blue (10 and 100 µM) in a concentration-dependent manner. Furthermore, ADP β S, a potent P 2Y agonist, induced the endothelium-dependent relaxation, and this relaxation was markedly reduced by either the combination of iberiotoxin and apamin or by cibacron blue alone. In conclusion, ACh may activate the release of ATP from endothelial cells which in turn activates a P 2Y receptor on the endothelial cells followed by a release of EDHF, resulting in a vasorelaxation via a mechanism that involves activation of both the voltage-gated K + channels and the Ca 2+ -activated K + channels. KEY WORDS: ATP, K + channel, rabbit renal artery.The vascular endothelial cells play an important role in maintaining the vascular homeostasis by liberating several vasodilator substances, including nitric oxide (NO), prostacyclin (PGI 2 ), and endothelium-derived hyperpolarizing factor (EDHF) [1]. EDHF is released by an increase in the Ca 2+ concentration within endothelial cells caused by agonists including acetylcholine (ACh), bradykinin, and ATP [7,10]. EDHF activates K + channels of smooth muscle cells, hyperpolarizes the cell membrane and thus causes the relaxation of smooth muscle [2]. There are several types of K + channels in vascular smooth muscle cells, and studies with various K + channel blockers have led to controversial conclusions on the identity of the K + channels involved in the EDHF-dependent vasorelaxation [8].As it is generally accepted that the P 2Y purinoceptors are located in vascular endothelial cells, the P 2Y -mediated relaxation is an endothelium dependent phenomenon [13]. Recent studies suggest that activation of the P 2Y receptors induces endothelium-dependent vasodilation mediated by EDHF [10,14,15,18]. In the rat mesenteric artery, P 2Y receptor-induced vasodilatation is antagonized by a combination of the K + channels inhibitors, charybdotoxin and apamin, which prevents hyperpolarization and relaxation mediated by EDHF in different blood vessels [3,9,20]. However, no study has provided direct evidence supporting that EDHF is released by activation of the endo...

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Study of the mechanisms involved in adenosine‐5′‐O‐(2‐thiodiphosphate) induced relaxation of rat thoracic aorta and pancreatic vascular bed

Cited by 27 publications

References 46 publications

Characterization by antagonists of P2-receptors mediating endothelium-dependent relaxation in the rat aorta

Characterization by antagonists of P2-receptors mediating endothelium-dependent relaxation in the rat aorta

Purinergic Signaling and Blood Vessels in Health and Disease

Mechanisms of NO-Resistant Relaxation Induced by Acetylcholine in Rabbit Renal Arteries.

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