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

Chapter 1
Figure 7: Direct acting vasodilators
3.4.3 Modulators of the renin-angiotensin system
The renin-angiotensin system is one of the hormonal mechanisms involved in cardiac
regulation and control of blood pressure 46
. In the coronary circulation the endocrine
and paracrine renin-angiotensin system modulates the vasoconstrictor tone. In
myocytes it increases contractility partly because of the facilitation of noradrenaline
release 47
. An historical overview of the development of renin-angiotensin system
modulators is given by Menard 48
.
Angiotensin is enzymatically formed from
angiotensinogen, an a 2-globulin. The
enzyme renin cleaves angiotensinogen to
afford the decapeptide angiotensin I.
Another cleavage of two amino acid
residues by the angiotensin-converting
enzyme (ACE) gives the octapeptide
angiotensin II. By several peptidases
angiotensin II is degraded to angiotensin
HI and further to inactive peptide
fragments.
AO
AI
All
AMI
angiotensinogen
^ renin
angiotensin-l
J ACE
angiotensin-l I
^ aminopeptidase
angiotensin-lll
I peptidase
inactivé fragments
Figure 8. The renin-angiotensin system
Angiotensin II is a potent vasoconstrictor, it stimulates aldosteron secretion, increases
sympathetic nervous system activity, and has a positive inotropic activity. Production
of angiotensin II results in an increase in systemic blood pressure. Angiotensinconverting
enzyme inhibitors (ACE-inhibitors: Captopril 37, enalapril 38, lisinopril 39;
fig. 9a) show side effects which are thought to be due to inhibited breakdown of the
inflammatory peptide bradykinin 49
. Bradykinin accumulation near the endothelial
cells stimulates the nitric oxide synthase and induces vasodilation causing an increase
in coronary flow 50
.
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