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

Chapter 1
spontaneous rhythm. This is called the intrinsic rhythm of the heart showing a
frequency of about 70 beats per minute. As a result of an electrical or chemical
stimulus, the transmembrane action potential of a cardiac muscle cell changes. This
cardiac transmembrane action potential, manifested as a propagating wave of
transient depolarisation, can be divided into several phases (fig. 1).
At resting potential, cardiac ventricular cells maintain a transmembrane potential
varying from -80 to -95 mV. The resting potential is maintained by the concentration
of intra- and extracellular potassium and is determined by K +
-permeability of the cell
membrane and a Na +
/K +
-ATPase which exchanges three sodium ions for two
potassium ions.
At phase 0, a rapid depolarisation occurs by opening of Na +
-channels leading to a
fast inward Na +
-current.
At phase 1, a partial repolarisation takes place, known as the transient outward
current caused almost exclusively by K +
-efflux 2
' 3
.
At phase 2, a plateau region exists as a result of reduced K +
-efflux and a slow influx
of Na +
2 +
and Ca leading to a net slow inward current.
At phase 3, a rapid repolarisation takes place because of the closure of Na +
- and Ca 2+
-
channels and activation of one or more fast outward K +
-channels.
This eventually leads to phase 4 in which the resting potential is reached. The K +
-
concentration is restored via the Na +
/K +
-pump and by K +
-permeability of the cell
membrane.
+30 to +40 mV
•80 to -95 mV
b
0 100 200 300 400 ms
a) phase 0;fast inward Na+-current
b) phase 1; partial repolarisation by K+-efflux
c) phase 2; reduced K+-efflux and slow Na +
- and Ca 2
* -influx
d) phase 3; closure ofNa+- and Ca*+-channels, fast outward K +
-current
e) phase 4; resting potential, K+-concentration is restored via the Na+IK+-pump and by
the K+-permeability of the cell membrane
Figure 1: Action potential curve
This intrinsic rhythm, however, is not the only factor influencing heart rate. Also the
sympathetic nervous system, which accelerates heart beating and the para­
sympathetic nervous system, which slows heart beating, play a role.
2