Misoprostol and the Sildenafil analog (PHAR-0099048) Modulate Cellular Efflux of cAMP and cGMP Differently - Pharmacology & Pharmacy

PP > Vol.4 No.1, January 2013

Pharmacology & Pharmacy

Volume 4, Issue 1 (January 2013)

ISSN Print: 2157-9423 ISSN Online: 2157-9431

Google-based Impact Factor: 0.67 Citations

Misoprostol and the Sildenafil analog (PHAR-0099048) Modulate Cellular Efflux of cAMP and cGMP Differently ()

HTML XML

Download as PDF (Size: 248KB) PP. 104-109

DOI: 10.4236/pp.2013.41015 3,745 Downloads 6,437 Views Citations

Author(s)

Elin Ørvoll, Roy A. Lysaa, Aina W. Ravna, Georg Sager

Affiliation(s)

Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Troms?, Troms?, Norway.

ABSTRACT

In the present study we have characterized ATP-dependent transport of cAMP and cGMP in physiological, but also supraphysiological concentrations. The uptake into inside-out vesicles from human erythrocytes could be dissected into two components with high and low affinity. The respective K_m-values were 30.8 ± 5.2 and 352 ± 26 μM for cAMP and 2.6 ± 0.4 and 260 ± 15 μM for cGMP. The two cyclic nucleotides were unable to mutually inhibit cellular efflux for concentrations up to about 100 μM. At higher concentrations the inhibition curve showed a steep fall. The IC₅₀-value for cAMP reduction of high affinity [³H]-cGMP transport was 695 ± 9 μM. The respective value for cGMP inhibition of [³H]-cAMP efflux was 284 ± 20 μM. These observations are compatible with two selective high affinity transport systems. Other endogenous substances such as prostaglandins did not discriminate between cyclic nucleotide transport. The IC₅₀ values for inhibition of [³H]-cAMP and [³H]-cGMP were 4.1 and 4.2 μM for PGE₁, 2.7 and 4.4 μM for PGE₂, respectively. However, the prostaglandin analog misoprostol discriminated distinctly between cAMP and cGMP transport with respective IC₅₀-values of 4.5 and 24 μM. The assumption that the specific PDE5-inhibitor sildenafil could distinguish between the two cyclic nucleotides was disproved with respective IC₅₀ values of 3.8 and 2.9 μM for inhibition of [³H]-cAMP and [³H]-cGMP, respectively. However, at least one sildenafil analog (PHAR0099048) showed a clear difference with respective IC₅₀ values of 2.0 and 0.52 μM. The other tested sildenafil analogs showed no or minor ability to discriminate with IC₅₀ values of 0.16 and 0.17 μM for IS-39213, and 0.35 and 0.16 μM for IS-60049, respectively. In agreement with previous reports, the present study shows that proteins responsible for cyclic nucleotide transport are multiorganic anion pumps. However, the observation that drug analogs may discriminate between these two efflux systems makes them potential drug targets.

KEYWORDS

ABC-Transporters; cAMP; cGMP; Misoprostol; Sildenafil

Share and Cite:

Ørvoll, E. , Lysaa, R. , Ravna, A. and Sager, G. (2013) Misoprostol and the Sildenafil analog (PHAR-0099048) Modulate Cellular Efflux of cAMP and cGMP Differently. Pharmacology & Pharmacy, 4, 104-109. doi: 10.4236/pp.2013.41015.

Cited by

[1]	Pharmacodynamic properties for inhibition of cAMP-and cGMP elimination by pentoxifylline remain unaltered in vitro during hypothermia
	Scandinavian Journal of …, 2022

[2]	Inhibition of ABCC5-mediated cGMP transport by progesterone, testosterone and their analogues
	The Journal of Steroid …, 2021

[3]	Treatment of Cardiovascular Dysfunction With PDE5-Inhibitors–Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP
	Frontiers in …, 2021

[4]	Identification and experimental confirmation of novel cGMP efflux inhibitors by virtual ligand screening of vardenafil-analogues
	2020

[5]	MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine cAMP binding sites as a tool for drug design
	2018

[6]	Inhibition of PDE5A1 guanosine cyclic monophosphate (cGMP) hydrolysing activity by sildenafil analogues that inhibit cellular cGMP efflux
	Journal of Pharmacy and Pharmacology, 2017

[7]	The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes
	Journal of cellular physiology, 2017

[8]	Inhibition of PDE 5A1 guanosine cyclic monophosphate (cGMP) hydrolysing activity by sildenafil analogues that inhibit cellular cGMP efflux
	Journal of Pharmacy and Pharmacology, 2017

[9]	The Effect of MRP5-Expression on Human Erythroleukemia (HEL) Cell Growth and cGMP Levels
	Pharmacology & Pharmacy, 2016

[10]	Cyclic nucleotide dependent ATPase activity in inside out vesicles from human erythrocytes
	2015

[11]	Modulation of high affinity ATP-dependent cyclic nucleotide transporters by specific and non-specific cyclic nucleotide phosphodiesterase inhibitors
	European journal of pharmacology, 2014

Journals Menu

Follow SCIRP

	customer@scirp.org
	+86 18163351462(WhatsApp)
	1655362766

	Paper Publishing WeChat

Journals Menu

Home

About SCIRP

Service

Policies