Biology Reference
In-Depth Information
direct interaction with agonists at the receptor, (2) apparently acting intracellularly
and (3) potentiating relaxation by adrenaline, histamine, adenosine, vasoactive
intestinal peptide (VIP) or dopamine. This agonist-potentiating effect became
a characteristic mechanism of PDE inhibitors, which amplify physiological signals
and thus might be therapeutically relevant.
The new PDE3 inhibitors such as amrinone and milrinone showed the same
inotropic spectrum of changes in contractility especially on the force development
and with minor effects on rate of contraction (Honerjager et al.
1981
). With
time, the isolated perfused heart preparation was established as the preparation
to detect PDE3 inhibitor efficacy, and additionally, later demonstration of
PKA activation gave further evidence for the interference with the cAMP-
mediated dilatory pathway(EnglandandShahid
1987
). In contrast, coronary
flow in constant-pressure perfused heart preparations was enhanced by the
PDE5 inhibitor zaprinast (M&B 22,948), and its potentiation by addition of nitric
oxide (NO)-donating agents was described in 1979 by Kukovetz and later by
Lorenz and Wells (Kukovetz et al.
1979
; Lorenz and Wells
1982
). Katsuki had
demonstrated in 1977 that nitroglycerin stimulated guanylate cyclase (GC) fol-
lowed by cellular increase of cGMP whereby elevated cGMP relaxed coronary
and pulmonary artery smooth muscle tension (Katsuki et al.
1977
). Therefore, it
was reasonable that inhibition of cGMP-degrading PDE5 evoked relaxation in
these vascular preparations. In 1993, human pulmonary artery smooth muscle was
showntocontainPDE3andPDE5aspredominantPDEactivities,andthe
efficacies of PDE3 and PDE5 inhibitors were additive (Rabe et al.
1994
). This
synergywithagonistsofcyclasesandadditivity of different PDE inhibitors was
showninavarietyofsmoothmusclepreparations and cells. The synergism of NO
with zaprinast in lowering pulmonary artery pressure (PAP) in lambs with pul-
monary hypertension (PHT) was shown (Thusu et al.
1995
), and these in vitro and
in vivo observations provided the first allusion for applying PDE5 inhibitors in
treatment of PHT.
3.3.2 Even Isolated Organs Can Be Denuded
Another lesson taught by isolated organs was the discovery of the effects of
“denudation” of vascular preparations. Acetylcholine (ACh)-induced relaxation
of pulmonary artery was abolished after removal of the endothelium. Furthermore,
the archetypical GC inhibitor, methylene blue inhibited relaxation of the denuded
muscle to NO-releasing agents. These results demonstrated that upon ACh stimu-
lation the endothelium releases NO [also known at the time as endothelium-derived
relaxing factor (EDRF)], which in turn activated GC. GC was inhibited by methy-
lene blue and no longer stimulated the cGMP pathway (Gruetter et al. 1980).
Thus, different mechanisms underlying relaxation mediated by changes in the
endothelium and those mediated by events in the target organ need to be discriminated
since complete and denuded preparations differ in sensitivity towards different PDE
inhibitors (Table
3
).
