PHYSIOLOGY OF ATRIAL NATRIURETIC FACTOR IN TRANSGENIC MI

Project: Research project

Description

ANF is released into the circulation in response to volume expansion, and
elicits numerous physiological effects which act in a combinatorial fashion
to reduce blood pressure. The physiological responses of ANF include
vasodilation, natriuresis, diuresis, inhibition of the renin-angiotensin-
aldosterone axis, inhibition of AVP secretion and modulation of neural
activity. While the effects of acute ANF administration are well
characterized, the chronic role of the hormone in cardiovascular
homeostasis has remained controversial. In an effort to directly address
this issue, we have generated a transgenic model system which exhibits
chronically elevated levels of ANF in the systemic circulation. These
transgenic animals, designated TTR-ANF, have immuno-reactive plasma ANF
levels which are approximately 10 fold elevated as compared to their non-
transgenic litter mates. Moreover, the TTR-ANF mice have a mean arterial
blood pressure (as determined in conscious resting mice with indwelling
annulus) of 75.5 plus/minus 9.9 mm Hg as compared to 103.9 plus/minus 2.0
for the non-transgenic litter mates. This study clearly demonstrates that
chronically elevated levels of ANF can induce a sustained hypotensive
response. In this proposal, we will continue to expand on our transgenic
model. Specifically, we will: (1) Further assess the physiological
consequences of elevated ANF levels in the TTR-ANF transgenic mice. These
studies will include a detailed analysis of kidney function (nephron
puncture and micro-catheterization analyses), assessment of baroreceptor
gain, characterization of the response of the various ANF receptors, and
assessment of the resistance of the transgenic animals to experimentally
induced hypertension. (2) Generate transgenic mice in which an "activated"
ANF receptor is expressed in the cell types which are responsive to the
hormone. Studies by other groups have demonstrated that deletion of the
kinsae domain in the ANF-A receptor results in constitutive guanylate
cyclase activity. Expression of such a "trans-dominant" ANF receptor can
be targeted to specific cell types which are responsive to ANF. This
approach will allow us to experimentally establish correlates between
specific target tissue activation and physiological response in intact
animals. (3) Generate transgenic models with chronically elevated ANF
levels in the central nervous system. Numerous studies have shown that ANF
cannot breach the blood brain barrier, and that intra-cerebral injection of
ANF can elicit discrete physiological responses. We will generate a
transgenic model system in which ANF is specifically secreted into the
cerebrospinal fluid in order to assess the consequences of chronically
elevated hormone levels in the CNS. (4) Generate transgenic animals which
do not synthesize ANF. Recent advances in mouse embryology have made it
possible to genetically inactivate specific genes in embryonic stem (ES)
cells. These cells retain a certain degree of pluripotency, and have been
used to generate chimeric animals in which cells that carry the mutated
allele have populated the germline. These chimeric animals have
subsequently passed the mutation on to progeny mice. We will use this
approach to generate animals which fail to express ANF. All of the
transgenic models will be subjected to comprehensive molecular and
physiological analyses to assess the consequences or altered ANF expression
(or the consequences of altered activity of the ANF signal transduction
pathway). These experiments will enable us to understand the physiological
role that ANF exerts in chronic cardiovascular regulation.
StatusFinished
Effective start/end date9/1/906/30/95

Funding

  • National Institutes of Health: $160,568.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $173,029.00
  • National Institutes of Health: $171,976.00

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Atrial Natriuretic Factor
Atrial Natriuretic Factor Receptors
Genetically Modified Animals
Transgenic Mice
Hormones
Natriuresis
Embryology
Diuresis
Angiotensins
Embryonic Stem Cells
Aldosterone
Blood-Brain Barrier
Renin
Catheterization

ASJC

  • Medicine(all)