Differential effects of uridine adenosine tetraphosphate on purinoceptors in the rat isolated perfused kidney.

Charité- Universitätsmedizin Berlin, Medical. Klinik mit Schwerpunkt Nephrologie, Hindenburgdamm 30, 12203 Berlin, Germany.
British Journal of Pharmacology (Impact Factor: 5.07). 10/2010; 161(3):530-40. DOI: 10.1111/j.1476-5381.2010.00914.x
Source: PubMed

ABSTRACT Purinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up(4)A) as a novel and highly potent endothelial-derived contracting factor. Up(4)A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X(1) receptor activation. However, other purinoceptors are also involved and were analysed here.
The rat isolated perfused kidney was used to characterize vasoactive actions of Up(4)A.
After desensitization of the P2X(1) receptor by α,β-methylene ATP (α,β-meATP), Up(4)A showed dose-dependent P2Y(2)-mediated vasoconstriction. Continuous perfusion with Up(4)A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X(1) receptor desensitization. In addition, there is a long-lasting P2Y(2)-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up(4)A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X(1) receptor desensitization by α,β-meATP, and the remaining P2Y(2)-mediated vasoconstriction was only inhibited by suramin. The Up(4)A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y(1) and P2Y(2) receptor activation.
Up(4)A activated P2X(1) and P2Y(2) receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y(1/2) receptor activation. Up(4)A might be of relevance in the physiology and pathophysiology of vascular tone regulation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The dinucleotide uridine adenosine tetraphosphate (Up4A), which has both purine and pyrimidine moieties, was reported as a novel endothelium-derived contracting factor. Recently, growing evidence has suggested that Up4A plays an important role in regulation of the cardiovascular function. We previously demonstrated that Up4A-induced vasoconstrictions are altered in arteries from DOCA-salt hypertensive rats. We have assessed responses to Up4A shown by renal arteries from type 2 diabetic Goto-Kakizaki (GK) rats (42-46 weeks old) and identified the molecular mechanisms involved. Concentration-dependent contractions to Up4A were greater in renal arterial rings from the GK than age-matched control Wistar group. In both groups, the inhibition of nitric oxide synthase (with N (G)-nitro-L-arginine) increased the response to Up4A, whereas the inhibition of cyclooxygenase (COX) (with indomethacin) decreased the response. Specific inhibitors of COX-1 (valeroyl salicylate) and COX-2 (NS398), a thromboxane (TX) receptor (TP) antagonist (SQ29548), and P2 receptor antagonist (suramin) also decreased the response to Up4A. Protein expressions of COXs in renal arteries were greater in the GK than Wistar group. The production of TXB2 (a metabolite of TXA2) by Up4A did not differ between these groups. Concentration-dependent contractions to U46619, an agonist of the TP receptor, were greater in renal arteries from the GK than Wistar group. The expression of P2X1 and P2Y2 receptors did not differ between these groups. These results suggest that enhancement of the Up4A-induced contraction in renal arteries from GK rats may be attributable to the increased activation of COXs/TP receptor signaling.
    Pflügers Archiv - European Journal of Physiology 07/2013; · 4.87 Impact Factor
  • Source
    Acta Physiologica 01/2012; 204(1):3-5. · 4.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously demonstrated that uridine adenosine tetraphosphate (Up4A) exerts a potent vasodilator effect in the healthy porcine coronary vasculature. Since the coronary microvascular effects of Up4A after myocardial infarction (MI) are unknown, the present study investigated the response to Up4A in coronary microvessels from post-MI remodeled porcine myocardium, and the involvement of purinergic receptor subtypes. Coronary small arteries (diameter ∼150μm) were dissected from the apex of Sham-operated swine and swine in which MI had been produced 5 weeks earlier by transient (2hr) occlusion of the left circumflex coronary artery, and mounted on Mulvany wire myographs. Up4A (10-9-10-5M) produced coronary vasodilation that was reduced in MI as compared to Sham-operated swine. Up4A-induced vasodilation was reduced by P1 blockade with 8-phenyltheophylline in Sham-operated swine and to a lesser extent in MI, while the attenuation by the A2A receptor blocker SCH58261 was similar in Sham-operated and MI swine. Up4A-induced vasodilation remained unaffected by non-selective P2 receptor antagonist PPADS, but was attenuated by selective P2X1 and P2Y1 receptor antagonists MRS2159 and MRS2179, albeit to a similar extent in Sham-operated and MI swine. These responses were paralleled by similar mRNA expression levels of A2A, P2X1 and P2Y1 receptors in MI compared to slaughterhouse control swine; Finally, attenuation of Up4A-induced coronary vasodilation by nitric oxide synthase inhibition was not attenuated in MI as compared to Sham-operated swine. In conclusion, blunted coronary vasodilation in response to Up4A in MI swine is most likely due to reduced activation of P1, rather than P2, receptors and does not involve a loss of NO bioavailability.
    Pharmacological Research 08/2013; · 4.35 Impact Factor

Full-text (2 Sources)

Available from
Aug 6, 2014