In Vivo Cardiovascular Pharmacology of 2′,3′-cAMP, 2′-AMP, and 3′-AMP in the Rat

Abstract

The naturally occurring purine 29,39-cAMP is metabolized in vitro to 29-AMP and 39-AMP, which are subsequently metabolized to adenosine. Whether in vivo 29,39-cAMP, 29-AMP, or 39-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 29,39-cAMP, 29-AMP, 39-AMP, 39,59-cAMP, 59-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 1 ER) and glomerular filtration rate (GFR) were determined. 29,39-cAMP, 29-AMP, and 39-AMP dose-dependently and profoundly reduced MABP, HR, TPR, and MVR with efficacy and potency similar to adenosine and 59-AMP. These effects of 29,39-cAMP, 29-AMP, and 39-AMP were attenuated by blockade of adenosine receptors with 1,3-dipropyl-8-(p-sulfophenyl)xanthine. 29,39-cAMP, 29-AMP, 39-AMP, adenosine, and 59-AMP variably affected RVR, but profoundly (nearly 100%) decreased UV at higher doses. GFR and Na 1 ER could be measured at the lower doses and were suppressed by 29,39-cAMP, 29-AMP, and 39-AMP, but not by adenosine or 59-AMP. 29,39-cAMP increased urinary excretion rates of 29-AMP, 39-AMP, and adenosine. 39,59-cAMP exerted no adverse hemodynamic effects yet increased urinary adenosine as efficiently as 29,39-cAMP. Conclusions: In vivo 29,39-cAMP is rapidly converted to adenosine. Because both cAMPs increase adenosine in the urinary compartment, these agents may provide unique therapeutic opportunities.

CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production

“…In this sense, CNPase represents as novel “energy” therapy target for heart failure beyond the traditional neurohumoral and hemodynamic modulation approaches. The CNPase-2′,3′-cyclic nucleotide system is present in the circulating system, and cardiomyopathy could increase the formation of 2′,3′-cyclic nucleotides through mRNA degradation [ 19 ]. AAV9-mediated CNPase myocardial expression alleviated the pressure overload-induced hypertrophic response and improved heart function ( Figure 3 and Figure 4 ), possibly by CNPase metabolizing 2′,3′-cyclic nucleotides into adenosine to exert beneficial physiological effects [ 19 , 20 ].…”

“…The CNPase-2′,3′-cyclic nucleotide system is present in the circulating system, and cardiomyopathy could increase the formation of 2′,3′-cyclic nucleotides through mRNA degradation [ 19 ]. AAV9-mediated CNPase myocardial expression alleviated the pressure overload-induced hypertrophic response and improved heart function ( Figure 3 and Figure 4 ), possibly by CNPase metabolizing 2′,3′-cyclic nucleotides into adenosine to exert beneficial physiological effects [ 19 , 20 ]. Our study also explains the binding affinity of CNPase proteins with cyclic nucleotide positional isomers ( Figure 5 ), concluding that CNPase does not interfere with PDE 3′-5′-cyclic nucleotide pathways.…”

A Novel Adenosine Precursor 2′,3′-Cyclic Adenosine Monophosphate Inhibits Formation of Post-surgical Adhesions

“…Adenosine would reverse the initial event of microvascular ischemia induced by surgical trauma via vasodilatation through activation of adenosine receptors. Indeed, our recently published studies show that in vivo 2′,3′-cAMP causes vasodilation via activation of adenosine receptors [ 30 ]. In addition to vasodilation, 2′,3′-cAMP, via adenosine, stimulates the proliferation of vascular endothelial cells, which would accelerate vascular repair [ 41 ].…”

“…We hypothesize that administration of a non-cell-membrane permeable adenosine prodrug would provide more sustained levels in the abdominal cavity and would avoid potential toxicity on other organs. In this regard, our recent studies show that 2′,3′-cyclic adenosine monophosphate (2′,3′-cAMP), a positional isomer of 3′,5′-cyclic adenosine monophosphate (3′,5′-cAMP) and formed from the metabolism of mRNA, is metabolized extracellularly to adenosine by organ systems [ 21 – 30 ]. Because 2′,3′-cAMP is even more hydrophilic than 3′,5′-cAMP [ 31 ], the absorption of 2′,3′-cAMP would be limited because of lack of diffusion across cell membranes.…”

A Facile and Sensitive Method for Quantification of Cyclic Nucleotide Monophosphates in Mammalian Organs: Basal Levels of Eight cNMPs and Identification of 2',3'-cIMP

“…2',3'-cAMP was first detected in perfused rat kidney using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) [ 17 ]. Additional studies have suggested that tissue injury triggers mRNA degradation, leading to production of 2',3'-cAMP that is converted through the action of the enzyme 2',3'-cyclic nucleotide phosphodiesterase to endogenous adenosine, which upon binding to various adenosine receptors can protect against acute organ injury, as well as have profound effects on the cardiovascular system [ 8 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Recently, 2',3'-cAMP and cGMP have been shown to correlate with leaf wounding stress in Arabidopsis , further suggesting that these nucleotides may be important in post-injury mechanisms [ 25 ].…”