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1 Max Planck Institute for Physiological and Clinical Research, W. G. Kerckhoff Institute, 61231 Bad Nauheim, Germany; and 2 Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
Amylin is secreted
with insulin from the pancreas during and after food intake. One of the
most potent actions of amylin in vivo is its anorectic effect, which is
directly mediated by the area postrema (AP), a circumventricular organ
lacking a functional blood-brain barrier. As we recently demonstrated,
amylin also stimulates water intake most likely via its excitatory
action on subfornical organ (SFO) neurons. Neurons investigated under equal conditions in an in vitro slice preparation of the rat AP were
15-fold more sensitive to amylin than SFO neurons. Amylin (10
11-108 M) excited 48% of 94 AP
neurons tested; the remaining cells were insensitive. The average
threshold concentration of the excitatory response was
1010 M and, thus, close to physiological plasma
concentrations. Coapplication of the amylin receptor antagonist AC-187
reduced amylin's excitatory effect. Amylin-mediated activation of AP
neurons and antagonistic action of AC-187 were confirmed in vivo by
c-fos studies. Peripherally applied amylin stimulated cGMP
formation in AP and SFO neurons, as shown in immunohistochemical
studies. This response was independent of nitric oxide (NO) formation
in the AP, while coapplication of the NO synthase inhibitors
N-monomethyl-L-arginine (100 mg/kg) and
nitro-L-arginine methyl ester (50 mg/kg) blocked cGMP
formation in the SFO. In contrast to the SFO, where NO-dependent cGMP
formation seems to represent a general inhibitory transduction pathway, cGMP acts as an excitatory second messenger in the AP, since the membrane-permeable analog 8-bromo-cGMP stimulated 65% of all neurons tested (n = 17), including seven of nine
amylin-sensitive neurons (77%). The results indicate that the
anorectic effect of circulating amylin is based on its excitatory
action on AP neurons, with cGMP acting as a second messenger.
food intake; water intake; electrophysiology; nitric oxide; subfornical organ
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