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Dual regulation of cerebrovascular tone by UTP: P 2U receptor‐mediated contraction and endothelium‐dependent relaxation
Author(s) -
Miyagi Yasushi,
Kobayashi Sei,
Nishimura Junji,
Fukui Masashi,
Kanaide Hideo
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15477.x
Subject(s) - uridine triphosphate , contraction (grammar) , endothelium , agonist , chemistry , extracellular , medicine , endocrinology , vasodilation , muscle contraction , receptor , biophysics , purinergic receptor , biology , biochemistry , nucleotide , gene
1 The mechanisms of vascular tone regulation by extracellular uridine 5′‐triphosphate (UTP) were investigated in bovine middle cerebral arterial strips. Changes in cytosolic Ca 2+ concentration ([Ca 2+ ] i ) and force were simultaneously monitored by use of front‐surface fluorometry of fura‐2. 2 In the arterial strips without endothelium, UTP (0.1 μ m ‐1 mM) induced contraction in a concentration‐dependent manner. However, when the endothelium was kept intact, cumulative application of UTP (0.1–100 μ m ) (and only at 1 mM) induced a modest phasic contraction in arterial strips. This endothelium‐dependent reduction of the UTP‐induced contraction was abolished by 100 μ m N ω ‐nitro‐L‐arginine (L‐NOARG) but not by 10 μ m indomethacin. In the presence of intact endothelium, UTP (30 μ m ) induced a transient relaxation of the strips precontracted with 30 nM U‐46619 (a stable analogue of thromboxane A 2 ), which was completely inhibited by pretreatment with L‐NOARG but not with indomethacin. 3 In the endothelium‐denuded strips, the contractile response to UTP was abolished by desensitization to either ATPγS or ATP (P 2U receptor agonists), but not by desensitization to α, β‐methylene‐ATP (P 2X receptor agonist) or to 2‐methylthio‐ATP (P 2Y receptor agonist). Desensitization to UTP abolished the contractile response to ATP. 4 In the endothelium‐denuded artery, a single dose application of UTP induced an initial transient, and subsequently lower but sustained increase in [Ca 2+ ] i and force. In the absence of extracellular Ca 2+ , UTP induced only the initial transient increases in [Ca 2+ ] i and force, while the sustained increases in [Ca 2+ ] i and force were abolished. UTP (1 mM) had no effect on the basic [Ca 2+ ] i ‐ force relationship obtained on cumulative application of extracellular Ca 2+ at steady state of 118 mM K + ‐depolarization‐induced contraction. 5 We conclude that in the presence of an intact endothelium, UTP‐induced relaxation of pre‐constricted middle cerebral artery is mainly mediated indirectly, by the production of an endothelium‐derived relaxing factor, but at high doses of UTP, vascular smooth muscle contraction is mediated directly via activation of P 2U purinoceptor and [Ca 2+ ] i elevation without Ca 2+ ‐sensitization of the contractile apparatus. UTP may thus exert a dual regulatory effect upon cerebrovascular tone, but in cases where the endothelium is impaired, it may also act as a significant vasoconstrictor.