Role of Nitric Oxide towards Vasodilator Effects of Substance P and ATP in Human Forearm Vessels

Shiramoto, Masanari; Imaizumi, Tsutomu; Hirooka, Yoshitaka; Endo, Toshihiko; Namba, Takashi; Oyama, Jun Ichi; Hironaga, Kiyoshi; Takeshita, Akira

doi:10.1042/cs0920123

Cited by 22 publications

(21 citation statements)

References 9 publications

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“…The findings from the present study add to the growing body of knowledge regarding the potential mechanisms of vasodilation to exogenous ATP infusions in humans (24,28,32,37). The independent roles of NO and PGs in ATP-mediated vasodilation have been addressed in separate studies by Rongen and colleagues (28,37) in an experimental forearm model similar to that used in the present study.…”

Section: Exogenous Atp-mediated Vasodilation In the Human Vasculaturementioning

confidence: 82%

“…It is well established that endothelial-derived vasodilation occurs through the production of 1) nitric oxide (NO); 2) prostacyclin, the predominant vasodilatory prostaglandin (PG); or 3) other endothelial-derived factors that result in smooth muscle cell hyperpolarization (15). Limited studies have addressed the role of these pathways in ATP-mediated vasodilation in humans, and the results are conflicting, some showing no significant role for NO or PGs (28,32,37) and others claiming these pathways are involved in ATP vasodilation (24).…”

mentioning

confidence: 99%

“…Second, the majority of studies in humans have not tested for interactions between NO and PGs in ATP-mediated vasodilation (28,32,37). Intracellular endothelial cell calcium release events and calcium concentrations are a point of crossover in the stimulus for the synthesis of NO, PGs, and hyperpolarizing factors (38), and in fact, a portion of PG-mediated vasodilation may be dependent on NO (27).…”

mentioning

confidence: 99%

“…Thus, when taken together, it seems plausible to speculate that low doses of ATP may be more dependent on NO and PGs to evoke vasodilation compared with high doses. Second, the majority of studies in humans have not tested for interactions between NO and PGs in ATP-mediated vasodilation (28,32, 37). Intracellular endothelial cell calcium release events and calcium concentrations are a point of crossover in the stimulus for the synthesis of NO, PGs, and hyperpolarizing…”

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confidence: 99%

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Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

Crecelius

Kirby

Richards

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Crecelius AR, Kirby BS, Richards JC, Garcia LJ, Voyles WF, Larson DG, Luckasen GJ, Dinenno FA. Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins. Am J Physiol Heart Circ Physiol 301: H1302-H1310, 2011. First published July 22, 2011; doi:10.1152/ajpheart.00469.2011.-ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n ϭ 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthaseand cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P ϭ 0.22-0.99). In protocol 2 (n ϭ 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n ϭ 8)-and high-dose (n ϭ 8) ATP for 5 min evoked a significant increase in FVC above baseline (low ϭ 198 Ϯ 24%; high ϭ 706 Ϯ 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low-and high-dose ATP (P Ͻ 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (⌬FVC ϭ Ϫ31 Ϯ 11%)-and high-dose ATP (⌬FVC Ϫ25 Ϯ 11%; P ϭ 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular responses. Importantly, the majority of ATP-mediated vasodilation is independent of these putative endothelium-dependent pathways in humans. endothelium dependence; purine; adenosine triphosphate ADENOSINE TRIPHOSPHATE (ATP) is an important nucleotide with various functions including diverse effects on the cardiovascular system (3). With respect to the control of vascular tone, ATP can be released as a cotransmitter with norepinephrine from sympathetic nerve endings, bind to P 2X receptors on smooth muscle cells, and evoke subsequent vasoconstriction (4). In contrast, circulating ATP can bind to P 2Y receptors on the vascular endothelium, which results in vasodilation, the magnitude of which can reach levels observed during exercise in the peripheral circulation (3, 16). Accumulati...

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Section: Exogenous Atp-mediated Vasodilation In the Human Vasculaturementioning

confidence: 82%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

Crecelius

Kirby

Richards

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…This is further supported by the fact that the P1-purinoceptor antagonist theophylline did not affect the vasodilator response to ATP (Rongen et al, 1994). It was shown previously that ATP-induced vasodilation in the human forearm cannot be inhibited by the competitive NO-synthase antagonist N G -monomethyl-L-arginine (L-NMMA) (Rongen et al, 1994;Shiramoto et al, 1997). Finally, previous experiments by our group have demonstrated that the vasodilator response to intra-arterial ATP in the forearm is not limited by any vasoconstrictor action, including vasoconstriction that could theoretically have resulted from P2x receptor stimulation on vascular smooth muscle cells (Rongen et al, 1994).…”

Section: Introductionmentioning

confidence: 80%

ATP‐induced vasodilation in human skeletal muscle

Ginneken

Meijer

Verkaik

et al. 2004

British J Pharmacology

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1 The purine nucleotide adenosine-5 0 -triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2 Adenosine 5 0 -triphosphate (0.2, 0.6, 6 and 20 nmol dl À1 forearm volume min À1 ) evoked a dosedependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 mg dl À1 min À1 , n ¼ 10), the blocker of Na þ /K þ -ATPase ouabain (0.2 mg dl À1 min À1 , n ¼ 8), the blocker of K Ca channels tetraethylammonium chloride (TEA, 0.1 mg dl À1 min À1 , n ¼ 10), nor by the K ATP -channel blocker glibenclamide (2 mg dl À1 min À1 , n ¼ 10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and L-NMMA (n ¼ 6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 4875, 6773, 8872, and 9272% in the absence and 2377, 6274, 8972, and 9371% in the presence of the combination of TEA, indomethacin and L-NMMA (Po0.05, repeated-measures ANOVA, n ¼ 6). A similar inhibition was obtained for sodium nitroprusside (SNP, Po0.05 repeated-measures ANOVA, n ¼ 6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3 ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and L-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.

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Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity

et al. 2001

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Role of Nitric Oxide towards Vasodilator Effects of Substance P and ATP in Human Forearm Vessels

Cited by 22 publications

References 9 publications

Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

ATP‐induced vasodilation in human skeletal muscle

Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity

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