5.20.2 GlucagonGlucagon, the second pancreatic hormone, was discovered as an impurity in early
insulin preparations. It is a peptide containing 29 amino acids and is biosynthesized as
proglucagon (160 residues) which is cleaved to produce glicentin, which in turn is
cleaved to yield glucagon. The hormone activates receptors in liver cell membranes and
acts through adenylate cyclase and cAMP. It triggers glycogenolysis and thus elevates
blood glucose levels, and also activates protein phosphorylation in cell organelles. The
glucagon receptor has been characterized.
The hyperglycemic action of glucagon is believed to play a role in diabetes. The hor-
mone is produced by the αcells of the islets of Langerhans, which are not impaired in
diabetes. Animal studies employing antibodies against glucagons suggest that glucagon
plays a role in maintaining elevated blood glucose. It is possible that therapies that
block glucagon may provide a significant advance in the management of Type II dia-
betes mellitus. Due to this promising potential for therapeutic utility, balanced against
the shortcomings of peptides as drugs, the search for non-peptidic glucagon receptor
modulators has been an active research area for the past decade. Moreover, successful
cloning and expression of the glucagon receptor has enabled research groups to search
for new chemical entities as novel ligands for this receptor. Since 1992, various families
of quinoxalines, acyl hydrazides, and pyrimidones have been evaluated as glucagon
agonists and antagonists. This work has been greatly facilitated by X-ray crystallo-
graphy and molecular modeling calculations.
5.21 PEPTIDE HORMONES OF THE KIDNEY
(RENIN–ANGIOTENSIN SYSTEM)
Blood pressure is regulated by a multitude of interrelated factors involving neural,
hormonal, vascular, and volume-related effects. Two of these factors have been dealt
with in preceding chapters in sections on the adrenergic neuronal system and the hypo-
thalamic hormone vasopressin. Another group of peptide hormones involved in blood
pressure regulation, the angiotensins, was recognized many years ago through the
enzyme that activates some of them. Since this enzyme is produced in the kidneys, it
was named renin.
The renin–angiotensin system regulates blood pressure through several feedback
mechanisms. A decrease in blood pressure due to blood loss, sodium loss, or caused
experimentally by clamping of the renal artery, stimulates the juxtaglomerular cells of
the kidney to secrete renin, a proteolytic enzyme. This enzyme acts on a circulating
protein, angiotensinogen, cleaving off angiotensin I, which is then further cleaved in
the lung and kidneys by angiotensin-converting enzyme to yield angiotensin II. This
hormone has a powerful constricting action on arterioles, and elevates the blood
pressure instantly. Long-range effects are also achieved, either by angiotensin II or
its cleavage product, angiotensin III. One or both trigger aldosterone release, causing
Na+retention and an increase in fluid volume (i.e., antidiuresis), which results in
elevation of the blood pressure. Since the angiotensins are quickly hydrolyzed, their
effect is transitory and therefore suitable for continuous homeostatic regulation of the
blood pressure.
HORMONES AND THEIR RECEPTORS 371