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Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
This
study evaluated the contribution of angiotensin peptides acting at
various receptor subtypes to the arterial pressure and heart rate of
adult 9-wk-old male conscious salt-depleted spontaneously hypertensive
rats (SHR). Plasma ANG II and ANG I in salt-depleted SHR were elevated
sevenfold compared with peptide levels measured in sodium-replete SHR,
whereas plasma ANG-(1-7) was twofold greater in
salt-depleted SHR compared with salt-replete SHR. Losartan (32.5 µmol/kg), PD-123319 (0.12 µmol · kg
1 · min1),
[D-Ala7]ANG-(1-7) (10 and
100 pmol/min), and a polyclonal ANG II antibody (0.08 mg/min) were
infused intravenously alone or in combination. Combined blockade of
AT2 and AT(1-7) receptors
significantly increased the blood pressure of losartan-treated SHR
(+15 ± 1 mmHg; P < 0.01); this change did not
differ from the blood pressure elevation produced by the sole blockade
of AT(1-7) receptors (15 ± 4 mmHg).
On the other hand, sole blockade of AT2 receptors in
losartan-treated SHR increased mean arterial pressure by 8 ± 1 mmHg (P < 0.05 vs. 5% dextrose in water as vehicle),
and this increase was less than the pressor response produced by
blockade of AT(1-7) receptors alone or
combined blockade of AT(1-7) and
AT2 receptors. The ANG II antibody increased blood pressure to the greatest extent in salt-depleted SHR pretreated with only losartan (+11 ± 2 mmHg) and to the least extent in salt-depleted SHR previously treated with the combination of losartan, PD-123319, and
[D-Ala7]ANG-(1-7) (+7 ± 1 mmHg; P < 0.01). Losartan significantly increased heart rate, whereas other combinations of receptor antagonists or the
ANG II antibody did not alter heart rate. Our results demonstrate that
ANG II and ANG-(1-7) act through non-AT1
receptors to oppose the vasoconstrictor actions of ANG II in
salt-depleted SHR. Combined blockade of AT2 and
AT(1-7) receptors and ANG II
neutralization by the ANG II antibody reversed as much as 67% of the
blood pressure-lowering effect of losartan.
angiotensin II; angiotensin-(1-7); angiotensin receptor antagonists; hypertension; losartan; PD-123319; salt depletion; spontaneously hypertensive rats
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