Tadalafil inhibits the cAMP stimulated glucose output in the rat liver

The purpose of the present work was to verify if tadalafil affects hepatic glucose output, one of the primary targets of cAMP, in the isolated perfused rat liver. No effects on glycogen catabolism and oxygen uptake were found under basal conditions for tadalafil concentrations in the range between 0.25 and 10 mu M. However, tadalafil had a clear and time-dependent inhibitory effect on the cAMP- and glucagon-stimulated glucose release. Constant infusion of tadalafil in the range between 0.25 and 10 mu M eventually abolished 100% of the stimulatory action of those effectors. The tadalafil concentrations producing half-maximal rates of inhibition of the cAMP and glucagon stimulated glycogenolysis were 0.46 +/- 0.04 and 1.07 +/- 0.16 mu M, respectively. These concentrations are close to the plasma peak concentrations in patients after ingestion of 20 mg tadalafil. The drug also diminished the activity of glycogen phosphorylase a and increased the activities of glucose 6-phosphatase, glucokinase, pyruvate kinase and glucose 6-phosphate dehydrogenase. These actions occurred only in the cellular environment. Tadalafil did not affect binding of cAMP to protein kinase A. Diminution of cAMP-stimulated glucose output is the opposite of what can be expected from a phosphodiesterase inhibition, the most common effect attributed to tadalafil. Diminution of glucose output by tadalafil can be attributed (a) to an interference with glycogen phosphorylase stimulation and (b) to an increased futile cycling of glucose 6-phosphate and glucose with a concomitant increased flow of hexose units into cellular metabolic pathways. The effects described in the present work may prove to represent important side effects of tadalafil. (C) 2014 Elsevier Ireland Ltd. All rights reserved.