P. Gohlke et al., AT(2) RECEPTOR STIMULATION INCREASES AORTIC CYCLIC-GMP IN SHRSP BY A KININ-DEPENDENT MECHANISM, Hypertension, 31(1), 1998, pp. 349-355
In the present study we tested the hypothesis whether an angiotensin A
T(2) receptor-mediated stimulation of the bradykinin (BK)/nitric oxide
(NO) system can account for the effects of AT(1) receptor antagonism
on aortic cGMP described previously in SHRSP. Adult SHRSP were treated
for 4 hours with angiotensin II (ANG II) (30 ng/kg per min IV) or veh
icle (0.9% NaCl IV). Animals were pretreated with vehicle, losartan (1
00 mg/kg PO), PD 123319 (30 mg/kg IV), losartan plus PD 123319, icatib
ant (500 mu g/kg IV), N-G-nitro-L-arginine methyl ester (L-NAME; 1 mg/
kg IV), or minoxidil (3 mg/kg IV). Mean arterial blood pressure (MAP)
was continuously monitored over the 4-hour experimental period, and pl
asma ANG II and aortic cGMP were measured by RIA at the end of the stu
dy. ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losarta
n alone or losartan plus ANG II as well as minoxidil plus ANG II marke
dly reduced blood pressure when compared to vehicle-treated or ANG II-
treated animals, respectively. Plasma levels of ANG II were increased
2-fold by ANG II infusion alone or by ANG II in combination with icati
bant, L-NAME, or minoxidil. The increase in plasma ANG II levels was e
ven more pronounced after losartan treatment. Aortic cGMP content was
significantly increased by ANG II, losartan, losartan plus ANG II, and
minoxidil plus ANG II by 60%, 45%, 68%, and 52%, respectively (P<.05)
. The effects of ANG II and of losartan plus ANG II on aortic cGMP con
tent were both blocked by cotreatment with the AT(2) receptor antagoni
st PD 123319. Icatibant and L-NAME abolished the effects of ANG II on
aortic cGMP. Our results demonstrate the following: (1) ANG II increas
es aortic cGMP by an AT(2) receptor-mediated action because the effect
could be prevented by an AT(2) receptor antagonist; (2) the effect of
ANG II was not secondary to blood pressure increase because it remain
ed under reduction of MAP with minoxidil; (3) losartan increased aorti
c cGMP most likely by increasing plasma ANG II levels with a subsequen
t stimulation of AT(2) receptors; and (4) the effects of AT(2) recepto
r stimulation are mediated by BK and, subsequently, NO because they we
re abolished by B-2 receptor blockade as well as by NO synthase inhibi
tion.