(Hypertension. 1998;31:296.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Cyclic AMP-Adenosine Pathway Induces Nitric Oxide Synthesis in Aortic Smooth Muscle Cells
From the Center for Pharmacology, Departments of Medicine (R.K.D., D.G.G.) and Pharmacology (E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, PA.
Correspondence to Dr. Raghvendra K. Dubey, Center for Clinical Pharmacology, Department of Medicine, 623 Scaife Hall, 200 Lothrop Street, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582. E-mail: dubey{at}novell2.dept-med.pitt.edu
The main purpose of this investigation was to evaluate whether the cyclic AMP-adenosine pathway, ie, the conversion of cAMP to AMP and, hence, to adenosine, is involved in the regulation of nitric oxide (NO) synthesis by vascular smooth muscle cells (SMCs). Treatment of confluent monolayers of SMCs with adenosine, 2-chloroadenosine (stable analog of adenosine), and agents that elevate endogenous (SMC-derived) adenosine (EHNA and iodotubericidin) increased nitrite/nitrate (stable metabolites of NO) levels in the medium and enhanced the conversion of 3H-L-arginine to 3H-L-citrulline by cytosolic extracts obtained from the pretreated SMCs. The stimulatory effects of adenosine were not mimicked by low (1 to 100 nmol/L) concentrations of CGS21680, an A2A receptor agonist, or CPA, a selective A1 receptor agonist. The stimulatory effects of 2-chloroadenosine and EHNA plus iodotubericidin were significantly inhibited by KF17837, a selective A2 receptor antagonist, and by DPSPX, and A1/A2 receptor antagonist, but not by DPCPX, a selective A1 receptor antagonist. DDA (adenylyl cyclase inhibitor) and Rp-cyclic AMP (protein kinase A inhibitor) did not block the effects of adenosine on NO synthesis. Incubation of SMCs with exogenous cyclic AMP, at concentrations previously shown to elevate levels of adenosine in the medium, also increased nitrite/nitrate levels and 3H-L-citrulline formation, and the effects of cyclic AMP on NO synthesis were blocked by DPSPX and KF17837, but not by DPCPX. These findings provide evidence that exogenous and SMC-derived adenosine induce NO synthesis via A2B receptors linked to a pathway not involving adenylyl cyclase/protein kinase A. Moreover, extracellular cyclic AMP induces NO synthesis via conversion to adenosine and activation of A2B adenosine receptors. The cyclic AMP-adenosine pathway may be importantly involved in the vascular production of NO.
Key Words: cyclic AMP • adenosine • nitric oxide • smooth muscle cells • A2 adenosine receptors • vasculature
Abbreviations: BME = basal medium Eagle’s • FCS = fetal calf serum • DMEM = Delbucco’s modified Eagle medium • HBSS = Hanks balanced salt solution • IDO = iodotubericidin • LPS = lipopolysaccharide • MEM = minimum essential medium • NO = nitric oxide • NOS = nitric oxide synthase • SMC = smooth muscle cells
This article has been cited by other articles:
 |
|
 |
|
  E. K. Jackson, J. Ren, and Z. Mi Extracellular 2',3'-cAMP Is a Source of Adenosine J. Biol. Chem., November 27, 2009; 284(48): 33097 - 33106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Jackson and Z. Mi Regulation of Renovascular Adenosine 3',5'-Cyclic Monophosphate in Spontaneously Hypertensive Rats Hypertension, August 1, 2009; 54(2): 270 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Xu, J. Pang, H. Yin, M. Li, W. Hao, C. Chen, and J.-M. Cao Hexarelin suppresses cardiac fibroblast proliferation and collagen synthesis in rat Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2952 - H2958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Jackson, Z. Mi, L. C. Zacharia, S. P. Tofovic, and R. K. Dubey The Pancreatohepatorenal cAMP-Adenosine Mechanism J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 799 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, Z. Mi, and E. K. Jackson Adenosine Inhibits PDGF-Induced Growth of Human Glomerular Mesangial Cells Via A2B Receptors Hypertension, September 1, 2005; 46(3): 628 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-J. Teng and Q. Lu Bile Leakage during Transjugular Intrahepatic Portosystemic Shunt Creation: In Vitro Effect of Bile on Growth and Function of Human Umbilical Vein Endothelium Radiology, June 1, 2005; 235(3): 867 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xu, S.-S. Park, R. A. Mueller, R. C. Bagnell, C. Patterson, and P. G. Boysen Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes Cardiovasc Res, March 1, 2005; 65(4): 803 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kousai, R. Mizuno, F. Ikomi, and T. Ohhashi ATP inhibits pump activity of lymph vessels via adenosine A1 receptor-mediated involvement of NO- and ATP-sensitive K+ channels Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2585 - H2597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.R.R. Gangula, P. Lanlua, R.D. Bukoski, S.J. Wimalawansa, and C. Yallampalli Mesenteric Arterial Relaxation to Calcitonin Gene-Related Peptide Is Increased During Pregnancy and by Sex Steroid Hormones Biol Reprod, November 1, 2004; 71(5): 1739 - 1745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Cometti, R. K. Dubey, B. Imthurn, E. K. Jackson, and M. Rosselli Oviduct Cells Express the Cyclic AMP-Adenosine Pathway Biol Reprod, September 1, 2003; 69(3): 868 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, and E. K. Jackson A2B Adenosine Receptors Stimulate Growth of Porcine and Rat Arterial Endothelial Cells Hypertension, February 1, 2002; 39(2): 530 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Jackson and R. K. Dubey Role of the extracellular cAMP-adenosine pathway in renal physiology Am J Physiol Renal Physiol, October 1, 2001; 281(4): F597 - F612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jacoby, R. E Sims, and N. A Hartell Nitric oxide is required for the induction and heterosynaptic spread of long-term potentiation in rat cerebellar slices J. Physiol., September 15, 2001; 535(3): 825 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, Z. Mi, and E. K. Jackson Endogenous Cyclic AMP-Adenosine Pathway Regulates Cardiac Fibroblast Growth Hypertension, April 1, 2001; 37(4): 1095 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, L. C. Zacharia, Z. Mi, and E. K. Jackson A2B Receptors Mediate the Antimitogenic Effects of Adenosine in Cardiac Fibroblasts Hypertension, February 1, 2001; 37(2): 716 - 721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Rubin, L. R. Johnson, J. R. Dodam, A. K. Dhalla, L. Magliola, M. H. Laughlin, and A. W. Jones Selective transport of adenosine into porcine coronary smooth muscle Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1397 - H1410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, Z. Mi, and E. K. Jackson Cardiac Fibroblasts Express the cAMP-Adenosine Pathway Hypertension, September 1, 2000; 36(3): 337 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gao, T. A. Christopher, B. L. Lopez, E. Friedman, G. Cai, and X. L. Ma Mechanism of decreased adenosine protection in reperfusion injury of aging rats Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H329 - H338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Shin, Y. W. Shin, and K. W. Hong Role of adenosine A2B receptors in vasodilation of rat pial artery and cerebral blood flow autoregulation Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H339 - H344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-L. Peyot, A.-P. Gadeau, F. Dandre, I. Belloc, F. Dupuch, and C. Desgranges Extracellular Adenosine Induces Apoptosis of Human Arterial Smooth Muscle Cells via A2b-Purinoceptor Circ. Res., January 7, 2000; 86(1): 76 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, Z. Mi, M. Rosselli, P. J. Keller, and E. K. Jackson Estradiol Inhibits Smooth Muscle Cell Growth in Part by Activating the cAMP-Adenosine Pathway Hypertension, January 1, 2000; 35(1): 262 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, H. Shue, and E. K. Jackson A2B Receptors Mediate Antimitogenesis in Vascular Smooth Muscle Cells Hypertension, January 1, 2000; 35(1): 267 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. GALEA and D. L. FEINSTEIN Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP FASEB J, December 1, 1999; 13(15): 2125 - 2137. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Mi and E. K. Jackson Effects of alpha - and beta -Adrenoceptor Blockade on Purine Secretion Induced by Sympathetic Nerve Stimulation in the Rat Kidney J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 295 - 301. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Mi and E. K. Jackson Evidence for an Endogenous cAMP-Adenosine Pathway in the Rat Kidney J. Pharmacol. Exp. Ther., December 1, 1998; 287(3): 926 - 930. [Abstract] [Full Text]
|
|