Our group has been working on several aspects
of male and female sexual function and dysfunction and of neuronal
regulation of the urogenital tract.
The interaction between the nitrergic and
noradrenergic systems regulates penile erection. We have shown
that this interaction happens in smooth muscle, suggesting a
physiological antagonism (1). We believe that the key element
in this interaction is intracellular calcium in the smooth muscle,
which causes the nitrergic pathway to predominate (2). We have
shown that phosphodiesterase type-5 inhibitors can enhance and
prolong nitrergic control of noradrenergic responses, and such
compounds could be used to treat impotence, in which defective
nitrergic transmission is accompanied by increased noradrenergic
In rats with diabetes, we have shown that
nitrergic nerves undergo selective degeneration in the penis,
whereas noradrenergic nerves are not affected, leading to reduced
erectile function (3). We have recently shown that this selective
degenerative process is bi-phasic (4). Delayed insulin treatment
can reverse the effects of diabetes on the autonomic nerves
up to a certain time point. After that point, the damage becomes
irreversible. The irreversible damage is due to accumulation
of advanced glycation endproducts in the blood and organs which
cannot be reversed with insulin treatment. These results emphasize
the importance of blood glucose control in prevention of diabetic
complications. We aim to understand further the relation between
diabetes, autonomic neuropathy, the function of nitrergic nerves,
and erectile dysfunction.
We are investigating the effects of soluble
guanylate cyclase activators, NO - releasing agents, and Rho-kinase
inhibitors on animal and human penile cavernosal smooth muscle
Enlargement of the prostate (BPH) affects approximately 85%
of men over the age of 50. The current drugs available for the
treatment of BPH aim either to relax the prostate or to reduce
its size, as two separate actions. We have recently shown that
Rho-kinase inhibitor is able both to reduce the size of the
prostate and to stop it from growing (6).
here to read the press release about Rho-kinase inhibitor
and BPH (available November).
We have also been working on the identification of neurotransmission
pathways in female sexual dysfunction and female sexual arousal
disorder. We have shown that NO is the major relaxant neurotransmitter
in the clitoral cavernous body, (7), whereas in the vaginal
wall NO accounts for only 30% of the relaxation response. The
remainder seems to be mediated by an unknown neurotransmitter
(8), which we aim to identify.
2. Cellek S. Nitrergic-noradrenergic interaction
in penile erection: a new insight into erectile dysfunction. Drugs
Today 2000; 36: 135-146.
3. Cellek S, Rodrigo J, Lobos E, Fernández P, Serrano J,
Moncada S. Selective nitrergic neurodegeneration in diabetes mellitus:
a nitric oxide-dependent phenomenon. Br J Pharmacol 1999; 128:
4. Cellek S, Foxwell NA, Moncada S. Two phases of nitrergic neuropathy
in streptozotocin-induced diabetic rats. Diabetes 2003; 52: 2353-2362.
5. Cellek S, Rees RW, Kalsi JS. A Rho-kinase
inhibitor, soluble guanylate cyclase activator and nitric oxide-releasing
PDE5 inhibitor: novel approaches to erectile dysfunction. Expert
Opin Investig Drugs 2002; 11: 1563-1573.
6. Rees RW, Foxwell NA, Ralph DJ, Kell PD, Moncada
S, Cellek S. Y-27632, a Rho-kinase inhibitor, inhibits proliferation
and adrenergic contraction of prostatic smooth muscle cells. J
Urol 2003; IN PRESS.
7. Cellek S, Moncada S. Nitrergic neurotransmission
mediates the non-adrenergic non-cholinergic responses in the clitoral
corpus cavernosum of the rabbit. Br J Pharmacol 1998; 125: 1627-1629.
8. Ziessen T, Moncada S, Cellek S. Characterization
of the non-nitrergic NANC responses in the rabbit vaginal wall.
Br J Pharmacol 2002; 135: 546-554.