Biology Reference
In-Depth Information
theophylline show massive deviations among individuals. The Ohta study which
included nearly 3,800 patients underlined this unusually shaky ratio, and no signifi-
cant relation between dose and AEs could be found (Ohta et al.
2004
). Conse-
quently, in clinical studies patients had to be preselected for AEs, and for the
practitioner, theophylline had to be individually dosed after measuring blood
concentrations (Wilkens et al.
1984
) and even then the probability of AEs was high.
2.5 Theophylline as Tool for PDE Research
The identification of theophylline as a PDE inhibitor emerged in the initial experi-
ments of Sutherland and Rall in 1957 when they opened the world of cAMP
signalling (Rall and Sutherland
1958
). They investigated hormone action on gly-
cogenolysis in broken cell preparations and found that caffeine inhibited the basal,
non-activated form of glycogen phosphorylase. They reasoned that addition of
caffeine to the adrenaline-stimulated interconversion test might improve the detec-
tion of the activated phosphorylase. In contrast to their expectation, they observed a
synergy of caffeine with adrenaline or glucagon in activating phosphorylase. From
this result, they consequently hypothesised that caffeine might inhibit either the
activity of the agent that destroyed their “heat-stable factor” or the phosphorylase-
phosphatase (Butcher
1984
). Later, when this heat-stable factor was identified as
cAMP - the “golden bullet” for second messenger signalling - the enzymatic activity
for breakdown was determined to be “phosphodiesterase activity” and concomitantly,
caffeine and theophylline became the first recognised PDE inhibitors (Rall and
Sutherland
1958
). In the following years, the potentiation of adrenaline effects was
shown in pharmacological and biochemical assay systems: inotropic responses in
isolated perfused hearts (Rall and West
1963
) and likewise in other tissues.
3 Pharmacological Models Need to Be Analysed Biochemically
3.1 Different Inhibitory Profile Indicate Multiple Enzymes
Papaverine was isolated in 1848 and introduced as the second PDE inhibitor after
the xanthines. Pharmacological activity of both types of compounds were compared
in a variety of contractile preparations including heart, vascular and intestinal
smooth muscle, isolated bronchi and also in metabolic functions such as lipolysis
of isolated fat cells or glycogenolysis in liver tissue. Papaverine functioned as
an efficacious smooth muscle relaxant and was denominated a “direct vasodilator”,
but it showed comparably less inotropic activity in the heart or enhancement of
lipolysis or glycogenolysis. Theophylline was weaker in potency and in vascular
and intestinal muscular preparations where it predominantly potentiated adrenaline
