A Beta-adrenoceptor Agonist Evokes a Nitric Oxide-cGMP Relaxation Mechanism Modulated by Adenylyl Cyclase in Rat Aorta

Iranami, Hiroshi; Hatano, Yoshio; Tsukiyama, Yoshi; Maeda, Hiroshi; Mizumoto, Kazuhiro

doi:10.1097/00000542-199611000-00022

Cited by 25 publications

(12 citation statements)

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“…22,25,33,34 In the present study, dideoxyadenosine blocked the effects of forskolin and isoproterenol on NO formation but did not affect nitrite release induced by 8-bromo-cAMP, indicating a specific inhibitory effect of dideoxyadenosine on adenylyl cyclase. These results suggest that forskolin or isoproterenol promotes NO production through activation of adenylyl cyclase.…”

Section: Discussionsupporting

confidence: 48%

cAMP Signal Transduction Cascade, a Novel Pathway for the Regulation of Endothelial Nitric Oxide Production in Coronary Blood Vessels

Zhang

Hintze

2001

ATVB

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Abstract-The aim of this study was to determine whether cAMP signal transduction plays a role in the regulation of endothelial nitric oxide (NO) production. Canine coronary blood vessels were isolated, and nitrite, the hydration product of NO, from these vessels was quantified by using the Griess reaction. Forskolin (10 Ϫ4 mol/L), 8-bromo-cAMP (10 Ϫ2 mol/L), or isoproterenol (10 Ϫ4 mol/L) significantly increased nitrite release to 168Ϯ10, 162Ϯ13, or 149Ϯ13 pmol/mg, respectively, from isolated coronary microvessels (all PϽ0.05; control, 86Ϯ3 pmol/mg). Adrenomedullin and calcitonin gene-related peptide (CGRP), both potent vasodilator peptides, also increased coronary microvascular nitrite production. N -nitro-L-arginine methyl ester, a competitive inhibitor of NO synthase, or Rp-cAMP, a protein kinase A inhibitor, markedly blocked the nitrite release induced by these agents. Forskolin and adrenomedullin also potentiated coronary NO production induced by bradykinin. In large coronary arteries, removal of the endothelium eliminated nitrite production to both forskolin and acetylcholine. Our data demonstrate that stimulation of cAMP signal transduction can substantially increase coronary NO production, indicating that there is a cAMP-mediated, endothelial NO-forming system in coronary blood vessels. Because the cAMP signal cascade can be activated by CGRP or adrenomedullin and enhance kinin-mediated nitrite production, the cAMP-NO pathway may play an important role in the regulation of cardiovascular function. Key Words: cAMP Ⅲ nitric oxide Ⅲ endothelium Ⅲ protein kinase B Ⅲ coronary blood vessels ␤ -Adrenoceptor agonists and adenosine have been regarded as "archetypal" endothelium-independent vasodilators that cause vasodilation by increasing intracellular cAMP, with subsequent activation of protein kinase A (PKA) and myosin light-chain kinase within smooth muscle cells. [1][2][3][4][5][6] However, recent studies have challenged this concept. Growing evidence indicates that a number of classic endotheliumindependent vasodilator drugs also cause endotheliumdependent vasodilation, and this process seems to be related to endothelial NO production. [7][8][9][10][11][12][13][14][15][16][17][18][19] These include (1) the inhibition of isoprenaline-induced vasorelaxation in rat aorta by hemoglobin and methylene blue 11,12 ; (2) the inhibition of prostacyclin-and forskolin-induced vasorelaxation in pig coronary artery in vitro by hemoglobin and methylene blue 13 ; (3) the inhibition of salbutamol-and epinephrine-induced vasorelaxation in vivo and in vitro in the rat by the NO synthase (NOS) inhibitor N -nitro-L-arginine methyl ester (L-NAME); 14 -16 (4) the inhibition of isoproterenol-induced resistance coronary vessel dilation in the conscious dog by L-NAME 17,18 ; and (5) the inhibition of isoproterenol-induced vasodilation in human forearm by N -monomethyl-Larginine. 19 These results indicate that in blood vessels, there is an NO component to the vasorelaxant response to all of See page 729 these agonists. This may be of...

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Section: Discussionsupporting

confidence: 48%

cAMP Signal Transduction Cascade, a Novel Pathway for the Regulation of Endothelial Nitric Oxide Production in Coronary Blood Vessels

Zhang

Hintze

2001

ATVB

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“…The NO-cGMP pathway is responsible, at least in part, for the vascular smooth muscle relaxation produced by many agents, including nitrovasodilators (Kelly and Smith, 1996;Van Riper et al, 1997), histamine (Pussard et al, 1995), acetylcholine (Pussard et al, 1995;Iranami et al, 1996), estrogens (White et al, 1995;Rosenfeld et al, 1996), insulin (Trovati et al, 1995;Trovati et al, 1996), and corticotrophin-releasing hormone (Clifton et al, 1995). These agents stimulate the endothelial cell to produce and release NO, which in turn acts on the SMC to increase cGMP production.…”

Section: Guanylate Cyclasesmentioning

confidence: 99%

Molecular mechanism of cGMP-mediated smooth muscle relaxation

et al. 2000

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Contraction and relaxation of smooth muscle is a tightly regulated process involving numerous endogenous substances and their intracellular second messengers. We examine the key role of cyclic guanosine monophosphate (cGMP) in mediating smooth muscle relaxation. We briefly review the current art regarding cGMP generation and degradation, while focusing on the recent identification of the molecular mechanisms underlying cGMP-mediated smooth muscle relaxation. cGMP-induced SM relaxation is mediated mainly by cGMP-dependent protein kinase activation. It involves several molecular events culminating in a reduction in intracellular Ca(2+) concentration and a decrease in the sensitivity of the contractile system to Ca(2+). We propose that the cGMP-induced decrease in Ca(2+) sensitivity is a strategic way to achieve "active relaxation" of the smooth muscle. In summary, we present compelling evidence supporting a key role for cGMP as a mediator of smooth muscle relaxation in physiological and pharmacological settings.

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“…Recent work indicates that PI3-K is also activated by adrenergic receptor signaling in vascular smooth muscle cells (VSMC) (2) and by G-protein ␤␥ subunits in myeloid-derived cell (3). Both insulin and IGF-1 mediate vascular relaxation, in part, through PI3-K mediate increases in NO production (4,5). Isoproterenol (Iso), a beta (␤)-adrenergic agonist, relaxes arteries by stimulating endothelium-derived NO (5, 6) but, the signal transduction pathways responsible for this action are poorly understood.…”

mentioning

confidence: 99%