Edwin K Jackson1, Zaichuan Mi. 1. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219-3130, USA. edj@pitt.edu
Abstract
UNLABELLED: The naturally occurring purine 2',3'-cAMP is metabolized in vitro to 2'-AMP and 3'-AMP, which are subsequently metabolized to adenosine. Whether in vivo 2',3'-cAMP, 2'-AMP, or 3'-AMP are rapidly converted to adenosine and exert rapid effects via adenosine receptors is unknown. To address this question, we compared the cardiovascular and renal effects of 2',3'-cAMP, 2'-AMP, 3'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine in vivo in the rat. Purines were infused intravenously while monitoring mean arterial blood pressure (MABP), heart rate (HR), cardiac output, and renal and mesenteric blood flows. Total peripheral (TPR), renal vascular (RVR), and mesenteric vascular (MVR) resistances were calculated. Urine was collected for determination of urine excretion rate [urine volume (UV)]. When sufficient urine was available, the sodium excretion rate (Na(+)ER) and glomerular filtration rate (GFR) were determined. 2',3'-cAMP, 2'-AMP, and 3'-AMP dose-dependently and profoundly reduced MABP, HR, TPR, and MVR with efficacy and potency similar to adenosine and 5'-AMP. These effects of 2',3'-cAMP, 2'-AMP, and 3'-AMP were attenuated by blockade of adenosine receptors with 1,3-dipropyl-8-(p-sulfophenyl)xanthine. 2',3'-cAMP, 2'-AMP, 3'-AMP, adenosine, and 5'-AMP variably affected RVR, but profoundly (nearly 100%) decreased UV at higher doses. GFR and Na(+)ER could be measured at the lower doses and were suppressed by 2',3'-cAMP, 2'-AMP, and 3'-AMP, but not by adenosine or 5'-AMP. 2',3'-cAMP increased urinary excretion rates of 2'-AMP, 3'-AMP, and adenosine. 3',5'-cAMP exerted no adverse hemodynamic effects yet increased urinary adenosine as efficiently as 2',3'-cAMP. CONCLUSIONS: In vivo 2',3'-cAMP is rapidly converted to adenosine. Because both cAMPs increase adenosine in the urinary compartment, these agents may provide unique therapeutic opportunities.
UNLABELLED: The naturally occurring purine2',3'-cAMP is metabolized in vitro to 2'-AMP and 3'-AMP, which are subsequently metabolized to adenosine. Whether in vivo 2',3'-cAMP, 2'-AMP, or 3'-AMP are rapidly converted to adenosine and exert rapid effects via adenosine receptors is unknown. To address this question, we compared the cardiovascular and renal effects of 2',3'-cAMP, 2'-AMP, 3'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine in vivo in the rat. Purines were infused intravenously while monitoring mean arterial blood pressure (MABP), heart rate (HR), cardiac output, and renal and mesenteric blood flows. Total peripheral (TPR), renal vascular (RVR), and mesenteric vascular (MVR) resistances were calculated. Urine was collected for determination of urine excretion rate [urine volume (UV)]. When sufficient urine was available, the sodium excretion rate (Na(+)ER) and glomerular filtration rate (GFR) were determined. 2',3'-cAMP, 2'-AMP, and 3'-AMP dose-dependently and profoundly reduced MABP, HR, TPR, and MVR with efficacy and potency similar to adenosine and 5'-AMP. These effects of 2',3'-cAMP, 2'-AMP, and 3'-AMP were attenuated by blockade of adenosine receptors with 1,3-dipropyl-8-(p-sulfophenyl)xanthine. 2',3'-cAMP, 2'-AMP, 3'-AMP, adenosine, and 5'-AMP variably affected RVR, but profoundly (nearly 100%) decreased UV at higher doses. GFR and Na(+)ER could be measured at the lower doses and were suppressed by 2',3'-cAMP, 2'-AMP, and 3'-AMP, but not by adenosine or 5'-AMP. 2',3'-cAMP increased urinary excretion rates of 2'-AMP, 3'-AMP, and adenosine. 3',5'-cAMP exerted no adverse hemodynamic effects yet increased urinary adenosine as efficiently as 2',3'-cAMP. CONCLUSIONS: In vivo 2',3'-cAMP is rapidly converted to adenosine. Because both cAMPs increase adenosine in the urinary compartment, these agents may provide unique therapeutic opportunities.