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effects, but it was equally effective in each system studied. These early observations
of the different pharmacological and biochemical profiles of the PDE inhibitors was
observed by several authors (e.g. Poech and Kukovetz
1971
) and gave rise to the
view that there must be multiple PDE enzymes and that different tissues may
contain different PDEs.
3.2 Column Chromatography Profiles of PDEs and Development
of the First Generation of PDE Inhibitors
Up to 1985, a variety of pharmacological models for PDE inhibitor research had
been established, and the prominent ones are listed in Table
3
. In order to under-
stand the interference of the available old and new substances, a biochemical
analysis clarifying PDE content and diversity of all these models appeared to be
inevitable. Thompson and Appleman provided key pioneering experiments by
successfully using anion-exchange chromatography for separation of a number of
Table 3 Isolated organs and tissues available in 1985 for investigation of functions of PDEs 3, 4, 5
Preparation
Pretreatment
Response
PDE
Aorta, rat
L
-Phe
Relaxation
Intact
PDE5
PDE4
>
Denuded
PDE3
PDE5
>
Pulmonary artery, rat
L
-Phe
Relaxation
Intact
PDE5
Denuded
PDE5
Coronary artery, gp
L
-Phe
Relaxation
Intact
PDE5
Denuded
PDE5
Perfused heart, gp
Spontaneous
Contractility dp/dt
PDE3
Coronary flow
PDE5
>
PDE3
Heart rate
PDE3
LV pressure
PDE3
Left atrium, gp
Electrical stimulation
Force of contraction
PDE3
Tracheal rings, gp
Untreated Spontaneous PDE3, 4, 3/4
Sensitised OVA challenge PDE4
Lung strips, gp Histamine, carbachol Relaxation PDE3
Isolated organ and tissue preparations have been developed from the end of the nineteenth century.
Functional analysis was based on isometric force transduction for either contraction or relaxation.
The preferred species for each preparation is mentioned (gp
guinea pig) and the pre-treatment to
reach a contracted state ready for relaxation by PDE inhibitors is given
OVA
ovalbumin,
L
-Phe
L
-phenylephrine
ΒΌ
