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significantly reduced the relaxation response. However, no effects of the NOS-
inhibitor L-NORAG were observed on the relaxation induced by means of EFS.
Immunohistochemistry revealed NOS-containing neuronal axons as well as nerve
endings in the muscular layers of the ureter (Stief et al.
1996
). Taher et al. (
1994
)
reported the presence of the cGMP PDE type 5 (PDE5), cAMP/cGMP PDE1, and
cAMP PDE2 and PDE4 in cytosolic supernatants prepared from human ureteral
tissue. Using the organ bath technique, they demonstrated the potency of the PDE4
inhibitor rolipram and dual PDE5/PDE1 inhibitor zaprinast to reverse the tension
induced by KCl of circular ureteral segments (Taher et al.
1994
). Kuhn et al. (
2000
)
later confirmed the relaxing properties of inhibitors of PDE4 (rolipram) and PDE5 (E
4021, MSPP) on isolated human ureteral smooth musculature and showed that these
effects were paralleled by an elevation in intracellular levels of cAMP or cGMP,
respectively. Based on the results from the experiments on the effects of the NO-donor
drugs sodium nitroprusside and SIN-1, and the PDE5 inhibitor zaprinast on the
tension induced by KCl of proximal segments of the human ureter, Saighi et al.
(
2000
) concluded that cGMP is an important second messenger in the signaling
pathway leading to the relaxation of the ureteral smooth muscle. In contrast, Gratzke
et al. (
2007
) registered marginal effects of PDE5 inhibitors (vardenafil, sildenafil, and
tadalafil) on the tension induced by KCl of human ureteral tissue. Although the
responses were paralleled by a three- to fourfold increase in tissue level of cGMP,
the maximum relaxation (
R
max
) induced by the drugs ranged from only 23 to 6.0%
(Gratzke et al.
2007
). In an in vivo rabbit model, Becker et al. (
1998
) examined the
potential of the PDE4 inhibitor rolipram in comparison to nonselective PDE inhibitors
(papaverine and theophylline) and the muscarinic antagonist scopolamine to induce
ureteral relaxation. They found that only rolipram induced pronounced decreases in
intraluminal (intraureteral) pressure as well as in the amplitude and frequency of the
phasic (peristaltic) contractions of the ureter. No considerable effects on the systemic
circulation were observed, whereas the application of scopolamine, papaverine, or
theophylline exerted no or only short-lasting effects on the ureter but significantly
affected systemic blood pressure of the animals (Becker et al.
1998
). It was concluded
from these findings that the application of PDE inhibitors, especially those of cAMP
PDE4, seems promising to facilitate effectively and with minimal side effects the
spontaneous passage of distal ureteral stones and relieve ureteral colic pain.
9 Conclusion
Based on the knowledge of the physiological mechanisms regulating the male and
female genitourinary tract, the use of selective PDE inhibitors has been suggested to
be a logical approach for the treatment of various urological diseases. The unending
charge to conceive first-line treatments demonstrating advanced efficacy over
previous options offers a promising future for the use of PDE inhibitors in the
therapy of diseases of the urinary tract and reproductive tissues. Although some
approaches are likely to involve the NO/cGMP-cascade, other strategies should also
