Uridine adenosine tetraphosphate (Up₄A) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for Up₄A in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of Up₄A on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X₁ receptor (P2X₁R) expression in isolated mouse coronary arteries. In vivo effects of Up₄A on coronary blood flow (CBF) were assessed using ultrasound. Infusion of Up₄A (10^-9-10^-5 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2X₁R antagonist MRS2159 restored Up₄A-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2X₁R expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2X₁R in ApoE KO + HFD mice. In contrast, Up₄A (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, Up₄A decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2X₁R. In contrast, Up₄A increases CBF in vivo regardless of the atherosclerotic model.

01 Dec 2016·Pharmacological ReportsQ4 · MEDICINE

Influence of P2X receptors on renal medullary circulation is not altered by angiotensin II pretreatment

Q4 · MEDICINE

Article

Author: Walkowska, Agnieszka ; Sadowski, Janusz ; Kuczeriszka, Marta ; Dobrowolski, Leszek

BACKGROUNDPurine P2X and P2Y receptors (P2-R) are involved in control of renal circulation, especially in the medulla, wherein they appear to interact with angiotensin II (Ang II). Our experimental approach enabled examination of interaction with Ang II per se, in the absence of blood pressure elevation. In this whole-kidney functional study we focused on the influence of P2X1-R on perfusion of the renal medulla.METHODSAcute experiments were conducted with normal rats, untreated or subjected to two weeks' infusion of Ang II (osmotic minipumps). Urethane was used for anesthesia because in Ang II-treated rats it normalized elevated blood pressure. MRS2159, a P2X1-R inhibitor, was infused intravenously or directly into the medulla. Renal blood flow (RBF, Transonic renal artery probe), perfusion of the outer and inner medulla (OM-BF, IM-BF; laser-Doppler fluxes), and sodium and water excretion and urine osmolality (U_osm) were measured.RESULTSIn untreated rats intravenous MRS2159 unexpectedly decreased RBF by 12±4% (p<0.02) and IM-BF by 7±2% (p<0.05). In Ang II-pretreated rats the inhibitor tended to increase RBF while OM-BF and IM-BF increased 14±5% and 12±2%, respectively (p<0.05 for both). Renal excretion was not affected, with or without Ang II treatment, while U_osm increased by about 150mosmol/kg H₂O (p<0.05). Intramedullary MRS2159 increased IM-BF only, by 21±5% in untreated and 16±3% in Ang II-treated rats (p<0.04 for both).CONCLUSIONSTonic activity of P2X1 receptors participates in control of renal medullary perfusion and of the tubular processes involved in urine concentration, neither effect is modified by Ang II pretreatment.

01 Oct 2015·Vascular PharmacologyQ3 · MEDICINE

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Q3 · MEDICINE

Article

Author: Tilley, Stephen L ; Mustafa, S Jamal ; Sun, Changyan ; Zhou, Zhichao

Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COXs). We and others demonstrated that activation of A1 or A3 adenosine receptors (ARs) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10(-9)-10(-5)M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non-selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A-induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3μM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3AR through an endothelium-dependent mechanism.

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