Biomedical Engineering Reference
In-Depth Information
At least in guinea pig sinoatrial nodes, NP
1
and NP
2
are synthesized. Both
BNP and CNP facilitate vagal neurotransmission and bradycardia possibly via a
cGMP-PDE3 pathway that activates the cAMP-PKA pathway, hence supporting
phosphorylation of presynaptic Ca
V
2.2 channels.
Hormones BNP and CNP heighten vagal neurotransmission, as they increases the
release of acetylcholine via a presynaptic cGMP-dependent pathway. Acetylcholine
binds to postsynaptic muscarinic M
2
receptors on sinoatrial node pacemaker cells
to decrease the cardiac frequency following effects on several pacemaking currents
(calcium, hyperpolarization-activated, and ACh-sensitive potassium currents).
In addition, natriuretic peptides can directly augment the cardiac frequency
independently of the autonomic nervous system via particulate guanylate cyclase
NP
2
, cGMP-primed inhibition of PDE3, hence elevated cAMP level. Messenger
cAMP acts directly on the hyperpolarization-activated cyclic nucleotide-gated
channel, shifting its activation to more positive potentials [
400
]. The tachycardia
triggered by CNP can also result from a rise of the rate of diastolic depolarization.
cGMP-Independent Signaling of Guanylate Cyclase-A
Whereas the cGMP-dependent signaling pathway counteracts the Ca
2
+
-enhancing
action of hypertrophic factors such as angiotensin-2, in chronic cardiac hypertrophy,
when ANP level increases and GC2a receptor is desensitized, ANP binds to
GC2a and stimulates a cGMP-independent signaling pathway. This signaling is
characterized by an abnormally elevated cytosolic Ca
2
+
concentration that result
from activation of TRPC3 and TRPC6 cation channels by GCa receptor [
399
].
The resulting cation influx through TRPC channels within a pre-existing stable
GC2a-TRPC complex stimulates Ca
V
1.2 channels.
5.6.1.2
Prohormones and Active Natriuretic Peptides
Cardiac natriuretic peptides constitute a family of peptides that are synthesized from
different genes and then stored as distinct prohormones (Table
5.6
), in particular:
126-amino acid atrial (A-type; proANP; ANP
1
−−
126
), 108-amino acid brain (B-
type; proBNP; BNP
1
−−
108
), and 103-amino acid C-type (proCNP; CNP
1
−−
103
)
natriuretic peptide prohormones.
The natriuretic peptide family consists of 5 known peptides (Table
5.7
):
A-type
(atrial; ANP [ANP
99
−−
126
)
], or cardiodilatin; plasma concentration
∼
10 fmol/ml
[
402
]);
B-type
(brain; BNP; plasma concentration
1 fmol/ml; 3.5 pg/ml);
C-
type
(CNP); and
D-type
(DNP) natriuretic peptides; as well as
urodilatin
,or
ANP
95
−−
126
)
.
Both ANP and urodilatin are produced from the same type of precursor (prepro-
hormone) itself cleaved into ANP
1
−−
126
prohormone, stored in membrane-bound
secretory granules in the atria. Urodilatin targets NP
1
in renal tubules and vascular
∼
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