| 11. |
- Malmsjö, Malin, et al.
(författare)
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P2X receptors counteract the vasodilatory effects of endothelium derived hyperpolarising factor
- 2000
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Ingår i: European Journal of Pharmacology. - 1879-0712. ; 390:1-2, s. 173-180
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Tidskriftsartikel (refereegranskat)abstract
- Dilatory responses of extracellular nucleotides were examined in the precontracted isolated rat mesenteric artery. Dilatation mediated by endothelium-derived hyperpolarising factor (EDHF) was studied in the presence of Nomega-nitro-L-arginine (L-NOARG) and indomethacin, and was most potently induced by the selective P2Y(1) receptor agonist adenosine 5'-O-thiodiphosphate (ADPbetaS), while 2-methylthioadenosine triphosphate (2-MeSATP) and adenosine triphosphate (ATP) were almost inactive. However, after P2X receptor desensitisation (with alphabeta-methylene-adenosine triphosphate, alphabeta-MeATP), 2-MeSATP and ATP potently stimulated EDHF-mediated dilatation. This can be explained by simultaneous activation of endothelial P2Y receptors that release EDHF, and depolarising P2X receptors on smooth muscle cells. Uridine triphosphate (UTP) also induced potent dilatation, suggesting EDHF release via P2Y(2)/P2Y(4) receptors. Uridine diphosphate (UDP) had only minor dilatory effects, and when pretreated with hexokinase it was almost inactive, suggesting a minor role for P2Y(6) receptors. The nitric oxide (NO) mediated dilatation was studied in the presence of charybdotoxin, apamin and indomethacin. ADPbetaS, 2-MeSATP, ATP and UTP were all potent relaxant agonists suggesting NO release via P2Y(1) and P2Y(2)/P2Y(4) receptors, while UDP was much less potent and efficacious. P2X receptor desensitisation had only minor effect on the NO-mediated dilatations. In conclusion, both EDHF and NO-mediated dilatation can be induced by activation of P2Y(1) and P2Y(2)/P2Y(4) receptors. P2X receptor stimulation of smooth muscle cells selectively counteracts the dilatory effect of EDHF.
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| 12. |
- Malmsjö, Malin, et al.
(författare)
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P2Y receptor-induced EDHF vasodilatation is of primary importance for the regulation of perfusion pressure in the peripheral circulation of the rat.
- 2002
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772. ; 174:4, s. 301-309
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium-derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre-contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine-5'-O-thiodiphosphate (ADPbetaS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5-7 and E(max)=40-70%), while uridine diphosphate (UDP) was ineffective. Endothelium-derived hyperpolarizing factor was studied in the presence of 0.5 mM Nvarpi-nitro-L-arginine (L-NOARG). ADPbetaS and UTP induced strong and potent EDHF-dilatations, while ATP only had a weak effect (E(max)=25%). After P2X1 receptor desensitization with 10 microM alphabeta-methylene-adenosine triphosphate, the ATP response was significantly increased (E(max)=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPbetaS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y(1) and P2Y(2)/P2Y(4) receptors, but not P2Y(6) receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.
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| 13. |
- Malmsjö, Malin, et al.
(författare)
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Potent P2Y6 receptor mediated contractions in human cerebral arteries
- 2003
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Ingår i: BMC Pharmacology. - : Springer Science and Business Media LLC. - 1471-2210. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extracellular nucleotides play an important role in the regulation of vascular tone and may be involved in cerebral vasospasm after subarachnoidal haemorrhage. This study was designed to characterise the contractile P2 receptors in endothelium-denuded human cerebral and omental arteries. The isometric tension of isolated vessel segments was recorded in vitro. P2 receptor mRNA expression was examined by RT-PCR. RESULTS: In human cerebral arteries, the selective P2Y6 receptor agonist, UDPbetaS was the most potent of all the agonists tested (pEC50 = 6.8 PlusMinus; 0.7). The agonist potency; UDPbetaS > alphabeta-MeATP > UTPgammaS > ATPgammaS > ADPbetaS = 0, indicated the presence of contractile P2X1 P2Y2, P2Y4 and P2Y6, but not P2Y1 receptors, in human cerebral arteries. In human omental arteries, UDPbetaS was inactive. The agonist potency; alphabeta-MeATP > ATPgammaS = UTPgammaS > ADPbetaS = UDPbetaS = 0, indicated the presence of contractile P2X1, and P2Y2 receptors, but not P2Y1 or P2Y6 receptors, in human omental arteries. RT-PCR analysis of endothelium-denuded human cerebral and omental arteries demonstrated P2X1, P2Y1, P2Y2 and P2Y6 receptor mRNA expression. There were no bands for the P2Y4 receptor mRNA in the omental arteries, while barely detectable in the cerebral arteries. CONCLUSIONS: P2Y6 receptors play a prominent role in mediating contraction of human cerebral arteries. Conversely, no such effect can be observed in human omental arteries and previous results confirm the absence of P2Y6 receptors in human coronary arteries. The P2Y6 receptor might be a suitable target for the treatment of cerebral vasospasm.
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| 14. |
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| 15. |
- Malmsjö, Malin, et al.
(författare)
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The stable pyrimidines UDPbetaS and UTPgammaS discriminate between the P2 receptors that mediate vascular contraction and relaxation of the rat mesenteric artery
- 2000
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 131:1, s. 51-56
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Tidskriftsartikel (refereegranskat)abstract
- The contractile and relaxant effects of the different P2 receptors were characterized in the rat isolated mesenteric artery by use of extracellular nucleotides, including the stable pyrimidines uridine 5'-O-thiodiphosphate (UDPbetaS) and uridine 5'-O-3-thiotriphosphate (UTPgammaS). The selective P2X receptor agonist, alphabeta-methylene-adenosine triphosphate (alphabeta-MeATP) stimulated a potent (pEC(50)=6.0) but relatively weak contraction (E:(max)=57% of 60 mM K(+)). The contractile concentration-response curve of adenosine triphosphate (ATP) was biphasic when added in single concentrations. The first part of the response could be desensitized by alphabeta-MeATP, indicating involvement of P2X receptors, while the second part might be mediated by P2Y receptors. The contractile P2Y receptors were further characterized after P2X receptor desensitization with 10 microM alphabeta-MeATP. Uridine diphosphate (UDP), uridine triphosphate (UTP) and ATP stimulated contraction only in high concentrations (1 - 10 mM). The selective P2Y(6) agonist, UDPbetaS, and the P2Y(2)/P2Y(4)-receptor agonists UTPgammaS and adenosine 5'-O-3-thiotriphosphate (ATPgammaS) were considerably more potent and efficacious (E:(max) approximately 250% of 60 mM K(+)). Adenosine 5'-O-thiodiphosphate (ADPbetaS) was inactive, excluding contractile P2Y(1) receptors. After precontraction with 1 microM noradrenaline, UTP, ADP and ATP induced relaxations with similar potencies (pEC(50) approximately 5.0). UTPgammaS, ADPbetaS and ATPgammaS were approximately one log unit more potent indicating the presence of endothelial P2Y(1) and P2Y(2)/P2Y(4) receptors. The P2Y(6) receptor agonist, UDPbetaS, had no effect. UDPbetaS and UTPgammaS are useful tools when studying P2 receptors in tissue preparations with ectonucleotidase activity. Contractile responses can be elicited by stimulation of P2Y(6) and, slightly less potently, P2Y(2)/P2Y(4) receptors. The P2X response was relatively weak, and there was no P2Y(1) response. Stimulation of P2Y(1) and P2Y(2)/P2Y(4) receptors elicited relaxation, while P2Y(6) did not contribute.
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| 16. |
- Nilsson, Torun, et al.
(författare)
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Forearm blood flow responses to neuropeptide Y, noradrenaline and adenosine 5'-triphosphate in hypertensive and normotensive subjects
- 2000
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Ingår i: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 9, s. 126-131
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY), noradrenaline (NA) and adenosine 5'-triphosphate (ATP) are important co-transmitters in the sympathetic nervous system, which has a central role in cardiovascular control. In order to evaluate if hypertension is associated with alterations in vascular responses to sympathetic co-transmitters we studied the effects of intra-arterial infusion of NPY, NA and ATP on forearm blood flow. Blood flow was measured by venous occlusion plethysmography in six hypertensive (mean arterial blood pressure (MAP) 113 +/- 4 mmHg) and six matched normotensive subjects (MAP 97 +/- 3 mmHg). NPY and NA significantly reduced forearm blood flow, while a powerful increase was seen with ATP. Forearm vascular resistance, calculated as MAP divided by forearm blood flow, was significantly increased by NPY and NA and strongly reduced by ATP. There was no difference between hypertensive and normotensive subjects in response to either transmitter. In conclusion, vascular reactivity to intra-arterial administration of NPY, NA and ATP seems to be intact in hypertensive patients without metabolic aberrations.
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| 17. |
- Olivecrona, Göran, et al.
(författare)
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Coronary artery reperfusion: The ADP receptor P2Y(1) mediates early reactive hyperemia in vivo in pigs.
- 2004
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Ingår i: Purinergic Signalling. - : Springer Science and Business Media LLC. - 1573-9546 .- 1573-9538. ; 1:1, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- The physiological mechanisms that regulate reactive hyperemia are not fully understood. We postulated that the endothelial P2Y(1) receptor that release vasodilatory factors in response to ADP might play a vital role in the regulation of coronary flow. Intracoronary flow was measured with a Doppler flow-wire in a porcine model. 2-MeSADP (10(-5) M), ATP (10(-4) M) or UTP (10(-4) M) alone or as co-infusion with a selective P2Y(1) receptor blocker, MRS 2179 (10(-3) M) was locally delivered through the tip of a coronary angioplasty balloon. In separate pigs the coronary artery was occluded with the balloon for 10 min. During the first and tenth minutes of coronary ischemia, 2.5 ml of MRS 2179 (10(-3) M) was delivered distal to the occlusion in 8 pigs, 10 pigs were used as controls. MRS 2179 fully inhibited the 2-MeSADP-mediated coronary flow increase (P < 0.05) with no effect on UTP, indicating selective P2Y(1) inhibition. ATP-mediated flow increase was significantly inhibited by MRS 2179. During reactive hyperemia following coronary occlusion, flow increased by nearly sevenfold. MRS 2179, however, reduced the post-ischemic hyperemia by a mean of 46% during the period 1-2.5 min following balloon deflation (P < 0.05), which corresponds to peak velocity flow during reperfusion. In conclusion, MRS 2179, a selective P2Y(1) receptor blocker, significantly reduces the increased coronary flow caused both by 2-MeSADP and reactive hyperemia in coronary arteries. Thus, ADP acting on the endothelial P2Y(1) receptor may play a major role in coronary flow during post-ischemic hyperemia.
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| 18. |
- Saetrum Opgaard, Ole, et al.
(författare)
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Endocardial expression and functional characterization of endothelin-1
- 2001
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Ingår i: Molecular and Cellular Biochemistry. - 0300-8177. ; 224:1-2, s. 151-158
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Tidskriftsartikel (refereegranskat)abstract
- Endothelin-1 (ET-1), a 21 amino acid peptide exerts a wide range of biological activities including vasoconstriction, mitogenesis and inotropic effects on the heart. In this study, we examined whether endocardial endothelial cells express ET-1 and evaluated its functional properties. Using immunofluorescence localization method, we demonstrated cytoplasmic staining of ET-1 in the human endocardial endothelial cells from the right atrium and left ventricle. Employing reverse transcriptase polymerase chain reaction (RT-PCR) expression of ET-1 mRNA and its receptors ET(A) and ET(B) mRNAs were found in human myocardial as well as in endocardial endothelial cells. Biological activity of endocardial endothelial cells derived ET-1 was established as the conditioned media obtained from cultured porcine endocardial endothelial cells induced a slowly developing, strong and long-lasting contraction of circular rat aortic segments, with similar characteristics to that obtained with exogenous ET-1. Furthermore, the selective endothelin-A receptor antagonist, FR 139317, blocked the conditioned media induced contractions. Our results suggest that endocardial endothelial cells express and release biologically active ET-1 which could play a pivotal role in the regulation of myocardial contractility as well as a circulatory peptide may further act in other peripheral target organs.
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| 19. |
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| 20. |
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