Biology Reference
In-Depth Information
smooth muscle tone has become the most promising strategy to modulate tissue and
organ function. Since the concept of taking a pill to relieve symptoms of lower
urinary tract dysfunction is now widely accepted following the successes of phos-
phodiesterase 5 (PDE5) inhibitor treatment of erectile dysfunction, the treatment of
urological diseases has focused on orally available drugs acting via influencing
intracellular signaling pathways, thereby combining a high response rate with the
advantage of an on-demand intake. Specifically, the use of isoenzyme-selective
PDE inhibitors offers great opportunities in the medical treatment of various
genitourinary diseases. These agents are regarded to be safe and to be efficacious,
i.e., having a fast onset of drug action and an improved effect-to-side-effect ratio.
As experience with this class of compounds and their use in urology is rapidly
growing, basic and clinical research in this field will most likely expand the
pharmacological armamentarium of innovative treatment options in the next few
years. The purpose of this review is to summarize current, as well as potential,
upcoming indications for the use of PDE inhibitors in the pharmacotherapy of male
erectile dysfunction and lower urinary tract symptoms.
Keywords Lower urinary tract symptoms
Male erectile dysfunction
Oral phar-
macotherapy
Phosphodiesterase (PDE) inhibitors
1
Introduction
Cyclic nucleotide monophosphates cyclic AMP (cAMP) and cyclic GMP (cGMP)
are important intracellular mediators of several processes, including smooth muscle
motility, electrolyte homeostasis, neuroendocrine signals, and retinal phototrans-
duction (Antoni
2000
; Lucas et al.
2000
). Following a physiological signal, e.g., the
release of nitric oxide (NO) from nonadrenergic, noncholinergic nerve terminals or
activation of specific G-protein-coupled receptors on the outer cell surface, cyclic
nucleotides are synthesized from their corresponding nucleoside triphosphate by
the activity of adenylyl and guanylyl cyclases. This increase in cAMP or cGMP
triggers a signal transduction cascade, which encompasses the activation of cyclic
nucleotide-dependent protein kinases (cAK, cGK), subsequent phosphorylation of
the actin-myosin system, as well as Ca
2+
channels and ATP-driven Ca
2+
pumps
located in the outer cell membrane or the membrane of the sarcoplasmatic reticu-
lum. This cascade leads to a reduction in cytosolic Ca
2+
and, finally, to smooth
muscle relaxation. Cyclic nucleotides are degraded by phosphodiesterase (PDE)
isoenzymes, a heterogeneous group of hydrolytic enzymes. It is because of their
central role in smooth muscle tone regulation that PDEs have become an attractive
target for drug development. PDEs are classified according to their preference or
affinity for cAMP or/and cGMP, kinetic parameters of cyclic nucleotide hydrolysis,
relative sensitivity to inhibition by various compounds, allosteric regulation by
other molecules, amino acid sequences, and chromatographic behavior on anion
exchange columns.
