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Vol. 295, Issue 1, 23-28, October 2000

Preglomerular Microcirculation Expresses the cAMP-Adenosine Pathway1

Edwin K. Jackson and Zaichuan Mi

Center for Clinical Pharmacology, Departments of Pharmacology and Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

The purpose of this study was to investigate whether the extracellular cAMP-adenosine pathway (i.e., transport of cAMP out of cells followed by extracellular conversion of cAMP to adenosine) exists in preglomerular microvessels (PGMVs). Incubation of PGMVs for 1 h with 30 µM cAMP increased the amount of extracellular adenosine from 163 ± 18.6 (n = 18) to 9810 ± 604 (n = 12) pmol/mg of protein (P < 10-6). The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX; 1 mM; n = 6) and the ecto-phosphodiesterase inhibitor 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX; 1 mM; n = 6) significantly (P < 10-6 and P < 10-5, respectively) reduced the cAMP-induced increase in extracellular adenosine. Incubation of PGMVs for 1 h with isoproterenol (beta -adrenoceptor agonist; 1 µM) + IBMX (0.1 mM) increased the amount of extracellular cAMP from 0.800 ± 0.047 to 22.3 ± 2.20 pmol/mg of protein (P < 10-6; n = 41). In PGMVs incubated with isoproterenol (1 µM) + IBMX (0.1 mM) for 1 h, there was a significant (P < 10-4) linear (r2 = 0.6) relationship between intracellular and extracellular cAMP levels. Incubation of PGMVs for 1 h with 1 µM isoproterenol increased the amount of extracellular adenosine from 163 ± 18.6 (n = 18) to 297 ± 38.3 (n = 12) pmol/mg of protein (P = .002). Propranolol (beta -adrenoceptor antagonist; 1 µM; n = 7), IBMX (1 mM; n = 14), and DPSPX (1 mM; n = 12) blocked (P = .037, P = .015, and P = .026, respectively) isoproterenol-induced increases in extracellular adenosine. Conclusions: PGMVs transport endogenous cAMP to the extracellular compartment and metabolize extracellular cAMP to adenosine. This pathway can increase extracellular levels of adenosine during beta -adrenoceptor activation of adenylyl cyclase.

1 This study was supported by National Institutes of Health Grants HL55314 and HL35909.

0022-3565/00/2951-0023$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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