Biology Reference
In-Depth Information
Eleven families of PDE isoenzymes can be distinguished: Ca
2+
/calmodulin-
stimulated PDE (PDE1), cGMP-stimulated PDE (PDE2), cGMP-inhibited PDE
(PDE3), cAMP-specific PDE (PDE4), cGMP-binding, cGMP-specific PDE (PDE5),
and the cGMP-binding, cGMP-specific PDE of mammalian rods and cones (PDE6).
While PDE7 (which has high affinity and specificity for cAMP) and PDE8 (IBMX-
insensitive) have preferred selectivity for cAMP, PDE9 exclusively degrades
cGMP. PDEs 10 and 11 can inactivate both cAMP and cGMP (Michaeli et al.
1994
; Han et al.
1997
; Fisher et al.
1998a
; Fisher et al.
1998b
; Loughney et al.
1999
;
Fawcett et al.
2000
). Some of these isoenzyme families consist of more than one
gene (isogenes) and some genes are alternatively spliced so that, to date, more than
50 isoenzymes or variants have been described (Conti and Jin
1999
; Essayan
2001
).
Some PDE genes are also variably expressed in different tissues. For example,
PDE2 is predominantly found in vascular smooth muscle. Expression of PDE5 in
the corpus cavernosum and the cGMP-mediated relaxation of the cavernous smooth
muscle during sexual stimuli have made inhibition of this enzyme a clinical benefit
in the management of erectile dysfunction (ED). PDE7 is abundant in skeletal
muscle and is also present in the human kidney. Although expressed in other
tissues, high levels of PDE8, -10, and -11 are found in the testis, and PDE9 is
expressed in intestinal smooth muscle, skeletal (striated) muscle, and brain
(Rybulkin et al.
2003
; Maurice et al.
2003
). To date, 6 out of these 11 isoenzymes
(PDE1, -2, -3, -4, -5, and -11) have been proven to be of pharmacological impor-
tance. Since the distribution and functional significance of PDE isoenzymes can
vary in different tissues, isoenzyme-selective inhibitors have the potential to exert
specific effects on the target tissue.
2 PDE5 Inhibitors in Male Erectile Dysfunction
Due to the demographic development in the populations of industrialized countries,
the prevalence of ED has dramatically increased. While, in 1995, ~152 million men
worldwide reported that they suffered from ED, in 2005, it has been estimated that
320 million men will report this as a medical problem by the year 2025. Since the
early 1980s, the mechanisms of erectile physiology and pathophysiology have been
clarified in detail and extensive coverage was made on the nitric oxide (NO)-cGMP
pathway and its role in the initiation and maintenance of penile erection (Holmquist
et al.
1991
; Rajfer et al.
1992
) The discovery of NO and cGMP as the major
effectors in penile smooth muscle relaxation was a landmark and has led to the
identification of certain drugs that can foster elevation of intracellular levels of
cGMP. Among these agents are the nitric oxide donor drugs such as sodium
nitroprusside, nitroglycerin and linsidomine (SIN-1), and selective inhibitors of
PDE5 (Truss et al.
1994
; Heaton and Morales
1990
; Uckert et al.
2001a
). Espe-
cially, the use of selective PDE5 inhibitors in the treatment of ED has gained
widespread acceptance in the field of urology and persists as an important topic.
Sildenafil, vardenafil, and tadalafil are nonhydrolysable analogs of cGMP that
