Mlk. Debold, ATRIAL-NATRIURETIC-FACTOR AND BRAIN NATRIURETIC PEPTIDE GENE-EXPRESSION IN THE SPONTANEOUS HYPERTENSIVE RAT DURING POSTNATAL-DEVELOPMENT, American journal of hypertension, 11(8), 1998, pp. 1006-1018
The increase in natriuretic peptides (NP), atrial natriuretic factor (
ANF), and brain natriuretic peptide (BNP) production and release by ca
rdiocytes that occurs in hypertension has been considered to be a comp
ensatory mechanism against ventricular overload. Studies on NP product
ion in the spontaneously hypertensive rat (SHR), an experimental model
of human hypertension, have produced controversial results and were c
arried out when hypertension was already established (> 17 weeks). At
this time, age-related physiologic and molecular changes in cardiac mu
scle are difficult to separate from those related to hypertension, ie,
increased ANF production and plasma levels. In addition, most of the
studies used male rats because the rate of increase in arterial blood
pressure-as well as the level to which it rises-is greater in males th
an in females. Studies of a similar nature using female SHR are not av
ailable. The aim of this work was to determine 1) whether ANF and BNP
production and secretion increase with the development of hypertension
in genetically hypertensive rats; 2) whether a sexual dimorphism in A
NF and BNP production and secretion is present in the genetically hype
rtensive rat during the development of hypertension; and 3) whether th
e demand for ANF and BNP is the same from each chamber of the heart un
der these experimental conditions. Age-matched male and female SHR, Wi
star-Kyoto (WKY), and Sprague Dawley (SD) rats at 2, 4, and 8 weeks of
age were used. The normotensive SD were included to provide a wider b
asis for baseline findings, as WKY rats are not always a suitable cont
rol for SHR due to genetic variations. Natriuretic peptide plasma leve
ls and tissue content were measured by radioimmunoassay. ANF, BNP, as
well as (alpha- and beta-myosin heavy chain (MHC) mRNA were estimated
by Northern blot analysis. Blood pressure (BP) of more than 150 mm Hg
was found only in 8-week-old male SHR. Plasma immunoreactive (ir)ANF a
nd irBNP increased significantly at puberty (8 weeks) in both male and
female SHR. The earliest molecular change encountered during the deve
lopment of hypertension was a significant increase in BNP mRNA in the
right and left atria from both male and female 8-week-old SHR. In the
ventricles from both male and female SHR, there was no increase in the
ratio of left ventricular wet weight/body weight, no increase in vent
ricular ANF mRNA transcripts, and no myosin heavy chain isoform switch
(a protein marker of hypertrophy). irBNP ventricular concentration, h
owever, increased significantly in both male and female SHR, but only
in female SHR was there a concomitant increase in BNP mRNA. These resu
lts suggest that 1) ANF and BNP production are not coordinated in all
cardiac compartments during the development of hypertension; 2) upregu
lation of BNP in the atria from male and female SHR is the earliest ev
ent detected at 8 weeks; 3) the prehypertensive stage, in the genetica
lly hypertensive female rats, is associated with an increase in ventri
cular irBNP concentration and BNP mRNA; 4) there is a dissociation bet
ween BF and plasma levels of NP; and 5) as well, there is a dissociati
on between NP gene expression and MHC isoform switch. The regulation o
f NP is not coordinated in either gender during the development of hyp
ertension. The activation of the BNP gene in female SHR suggests that
BNP might play an important role at the onset of hypertension. Am J Hy
pertens 1998;11:1006-1018 (C) 1998 American Journal of Hypertension, L
td.