PDE4 and PDE5 regulate cyclic nucleotides relaxing
effects in human umbilical arteries
António José Santos-Silva
a
, Elisa Cairrão
a,b
, Manuel Morgado
a,b
,
Ezequiel Álvarez
a
, Ignacio Verde
a,
⁎
a
CICS — Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
b
Centro Hospitalar da Cova da Beira E.P.E. Quinta do Alvito, 6200-251 Covilhã, Portugal
Received 27 July 2007; received in revised form 21 November 2007; accepted 16 December 2007
Available online 28 December 2007
Abstract
Cyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and
degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT;
1 μM) and histamine (10 μM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and
5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We
investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery
smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The
unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 μM) relaxed histamine-contracted human umbilical artery on 47.4±7.2%. This
effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 μM)
and the PDE5 inhibitors (dipyridamole and T0156; 3 μM and 1 μM respectively) induced significant relaxation (39.0 ±8.7, 30.4 ± 6.0 and 36.3±
2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of
IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by
histamine (92.5±4.9 and 90.9±4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this,
because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after
sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3
inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP
induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the
increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed
in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation
of the relaxation associated to cAMP and cGMP, respectively.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Cyclic nucleotide; Phosphodiesterase; Human umbilical artery; Smooth muscle
1. Introduction
Human umbilical artery is involved in fetoplacental circula-
tion. The mechanisms that regulate the contractile state of this
artery are very important for optimum gas and nutrient exchange
between the foetus and the placenta. Since the umbilical blood
vessels are not innervated, the control of umbilical blood flow
depends entirely on vasoactive substances either released locally
or existing in the circulation (Leung et al., 2006). The un-
derstanding of the intracellular mechanisms modulating human
umbilical artery contractility may offer therapeutic value for the
treatment of some pathologies as pre-eclampsia. Cyclic nucleo-
tides (cAMP and cGMP) are the main second messengers linked
to vasodilatation. The intracellular levels of these second messen-
gers are regulated by adenylate cyclase and guanylate cyclase,
Available online at www.sciencedirect.com
European Journal of Pharmacology 582 (2008) 102 – 109
www.elsevier.com/locate/ejphar
⁎
Corresponding author. Tel.: +351 275 329049; fax: +351 275 329099.
E-mail address: iverde@fcsaude.ubi.pt (I. Verde).
0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2007.12.017