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


METHODS
The rat isolated perfused kidney was used to characterize vasoactive actions of Up(4)A.


RESULTS
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.


CONCLUSIONS
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.
Tölle
Markus
M
Charité- Universitätsmedizin Berlin, Medical. Klinik mit Schwerpunkt Nephrologie, Hindenburgdamm 30, 12203 Berlin, Germany.
Schuchardt
Mirjam
M
Wiedon
Annette
A
Huang
Tao
T
Klöckel
Lars
L
Jankowski
Joachim
J
Jankowski
Vera
V
Zidek
Walter
W
van der Giet
Markus
M
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015226:Dinucleoside Phosphates / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D011983:Receptors, Purinergic / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D015226:Dinucleoside Phosphates; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D011983:Receptors, Purinergic; D014227:Triazines; C529314:uridine adenosine tetraphosphate; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C012842:Cibacron Blue F 3GA; D011732:Pyridoxal Phosphate; D013498:Suramin; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; C002630:alpha,beta-methyleneadenosine 5'-triphosphate