WIBR members only!!!













back to previous page

 

Neuro-Urology

Our group has been working on several aspects of male and female sexual function and dysfunction and of neuronal regulation of the urogenital tract.

Nitrergic - noradrenergic interactions

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 activity (2,3).

Diabetes mellitus and male erectile dysfunction (MED)

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.

Novel therapeutic approaches to MED

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 (5).

Novel therapeutic approaches to benign prostatic hyperplasia (BPH)

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).
Click here to read the press release about Rho-kinase inhibitor and BPH (available November).

Female sexual dysfunction

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.




 

Selected Publications

1. Cellek S, Moncada S. Nitrergic control of peripheral sympathetic responses in the human corpus cavernosum: a comparison with other species. Proc Natl Acad Sci USA 1997; 94: 8226-8231.

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: 1804-1812.

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.

back to previous page