Biology Reference
In-Depth Information
The most innovative example of the NO/cGMP pathway with therapeutic
and lifestyle implications was discovered by Ignarro when he determined that NO
was the mediator for penile erection. NO is released by electric stimulation from
nitrergic nerves in corpus cavernosum and thereby relaxes arterial and trabecular
tone in this muscular organ (Ignarro et al.
1990
). NO again stimulates cGMP pro-
duction, and this local concentration may be amplified in the presence of PDE5
inhibitors. The potentiation of NO signalling by PDE5 inhibitors in the corpus
cavernosum was described and became the standard preparation for PDE5 inhi-
bitors for fast-onset and long duration penile erection (Knispel et al.
1992
).
3.3.3 Additive Contribution by Several Different PDE Inhibitors
In asthma, a reversible contraction of large and medium airways is evoked by
irritants, and mediators such as histamine, ACh, thromboxane, leukotrienes or
allergens. Other mediators such as VIP, NO and PGE2 and pharmacological agents
such as ß2-mimetic drugs counteract this constriction and relieve the dyspnea
attack. This function is mimicked in vitro in isolated tracheal rings from the guinea
pig which were the technical improvements of the tracheal muscles from larger
animals such as the cow or dog. These rings develop a spontaneous contraction
which can be further enhanced by agonists such as histamine, leukotrienes or
carbachol (Torphy et al.
1988
). The unselective PDE inhibitor theophylline at
100
m
mol/l evokes a complete relaxation of these rings comparable to that achieved
by treatment with isoproterenol. Partially selective PDE inhibitors, such as PDE3
inhibitor CI930, start relaxing at much lower concentrations but a flat and some-
times biphasic concentration-response curve is obtained which does not allow
determination of exact ED50 values. It was Harris et al. (
1989
) who finally solved
this problem elegantly by comparing the substance activities in the mechanical and
biochemical assessment. He chose CI930 and rolipram which inhibit PDE3
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PDE4 and PDE4
PDE3, respectively, both exhibit an approximately 100-fold
selectivity ratio for inhibition of these PDEs in isolated PDE fractions from guinea
pig trachea. He then determined the threshold concentrations for complete inhibi-
tion of PDE3 by CI930 and PDE4 by rolipram. In the pharmacological experiment,
he then pretreated the tracheal preparation with these threshold concentrations,
thereby blocking the action of one of these PDEs, and then measured a concentra-
tion- response curve for the other inhibitor. From the resulting monophasic curves,
correct ED50 values for these (not completely) selective compounds could be
evaluated. Thus, he answered two questions (1) the contribution of two different
PDEs in one tissue to relaxation and (2) the additive fractional efficacy of PDE3 and
PDE4 inhibition of dual-selective inhibitors, which may offer therapeutical benefit
by bronchorelaxation.
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