synthesis and in vitro pharmacology of a series of histamine h2 ...

Chapter 1
Calcium homeostasis in the cell is influenced by modification of cellular calciumbinding
proteins that regulate calcium metabolism.
There are two types of calcium-binding proteins 11
:
- calcium-transporting proteins integrated in the cell wall or integrated in
membranes of intracellular organelles.
- calcium-modulated proteins which are freely dissolved in the cell or are part of
a nonmembranous intracellular structure like troponin or calmodulin.
Drugs affecting cardiac calcium-binding proteins can therefore act on calciumtransporting
proteins or calcium-modulating proteins by direct binding to the protein
or by modification of the binding through drug-receptor interaction.
As mentioned before, calcium homeostasis is regulated by Ca 2+
-influx and efflux
processes. Indirectly, the intracellular calcium concentration is also influenced by the
Na +
/K +
-exchange process. Interferences of Na +
/K +
-pump disturbs the steady state
concentration of sodium and hence via the Na +
/Ca 2+
-pump also the intracellular
calcium concentration.
2.3 Contractility
The heart exerts its work by rhythmic contraction (systole) and relaxation (diastole).
Contraction of the cardiac muscle at constant ventricular volume causes a rise in
ventricular pressure. When this ventricular pressure exceeds the actual aortic
pressure, the ventricular valve will be opened and the blood flows into the aorta. The
stroke volume is about 70 ml and a rest volume of about 70 ml remains in the
ventricle. With the decrease in ventricular pressure, the aortic valve is closed and the
atrio-ventricular valve is opened when the aortic pressure is higher then the
ventricular pressure. The influx of blood into the atrium and ventricle takes place via
a passive mechanism.
The contractile process of the cardiac myocytes is regulated by biochemical factors
such as ATP and intracellular calcium and hence depends on Ca 2+
-entry across the
cell membrane. The slow inward Ca 2+
-current promotes the release of a much larger
2 +
amount of Ca
from the sarcoplasmic reticulum. The increased intracellular Ca 2+
-
concentration unblocks the effects of troponin and tropomyosin, which then in turn
allows actin and myosin to interact with the muscle fiber filaments to contract.
The contractile activity in smooth muscle is also regulated by the free intracellular
Ca 2+
-concentration and Ca 2+
-sensitivity of the contractile proteins. Upon stimulation,
the intracellular Ca 2+
-concentration is increased from about 10~ 7
M to 10~ 5
M, by
2 +
influx of extracellular Ca and from release M Ca 2+
from intracellular stores. In the
cytosol, the increased Ca 2+
-concentration allows calcium to interact with specific
binding sites on calmodulin. Calmodulin is an intracellular protein involved in several
activation processes of target enzymes. This protein is the mediator of the excitationcontraction
coupling in smooth muscle. The calcium-calmodulin complex interacts
with another protein, the myosin light chain kinase. This newly formed complex then
phosphorylates a smooth muscle myosin light chain which, in its phosphorylated
form, interacts with actin leading to shortening (contraction) of the myofilaments.
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