(Hypertension. 1996;27:19-24.)
© 1996 American Heart Association, Inc.
Articles |
Nitric Oxide and the Depressor Response to Angiotensin Blockade in Hypertension
From the Departments of Pharmacology and Physiology, New York Medical College, Valhalla, NY.
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Abstract |
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Abstract We investigated the contribution of nitric oxide to the short-term blood pressure reduction caused by interruption of the renin-angiotensin system in angiotensin-dependent hypertension. The blood pressure of rats made hypertensive by coarctation of the aorta between the renal arteries at their origin fell after administration of the angiotensin-converting enzyme inhibitor ramiprilat (2 mg/kg IV; -75±5 mm Hg) or the angiotensin II antagonist losartan (30 mg/kg IV; -79±6 mm Hg). But the antihypertensive effect of these agents was attenuated in rats pretreated with NG-nitro-L-arginine methyl ester (10 mg/kg IV) to inhibit nitric oxide synthesis (ramiprilat, -23±7 mm Hg; losartan, -37±5 mm Hg). In rats made hypertensive by long-term infusion of angiotensin II (60 ng/min IV, 6 to 7 days), the vasodepressor response to discontinuation of the angiotensin II infusion also was attenuated by pretreatment with the nitric oxide synthesis inhibitor (-52±7 versus -31±7 mm Hg); this attenuation was not demonstrable in rats receiving sodium nitroprusside (1 µg·kg -1·min -1 IV) to replace the loss of endogenous nitric oxide (-72±9 mm Hg). Pretreatment with NG-nitro-L-arginine methyl ester did not interfere with the vasodepressor effect of sodium nitroprusside or prazosin in rats with aortic coarctation–induced hypertension or with the blood pressure reduction caused by discontinuation of an infusion of phenylephrine in rats made hypertensive by long-term administration of this drug. These data suggest a contribution of nitric oxide to the blood pressure reduction caused by interruption of the renin-angiotensin system in models of established angiotensin-dependent hypertension.
Key Words: antihypertensive agents • experimental hypertension • losartan • nitric oxide • renin-angiotensin system • angiotensin-converting enzyme inhibitors
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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NO activates soluble guanylate cyclase in vascular smooth muscle, increasing the cellular content of cGMP and promoting vasodilation.1 Endothelial cells are the primary site of NO synthesis in blood vessels,2 3 which is catalyzed by a constitutively expressed enzyme both under basal conditions and during stimulation by various vasoactive hormones.4 Increasing evidence suggests that interactions among NO and vasoconstrictor and vasodilator hormones have a major impact on the regulation of vascular functions.1 4 5
Recent studies have established that angiotensin peptides stimulate synthesis of NO in endothelial cells and coronary vessels.6 7 It has also been documented that treatment with inhibitors of NO synthesis heightens the pressor and vasoconstrictor responsiveness to Ang II,8 9 that a mechanism of vasodilation mediated by NO is preferentially manifested in rats with angiotensin-dependent hypertension,10 11 12 13 and that pharmacological blockade of Ang II formation or actions greatly attenuates the development of hypertension in rats undergoing long-term treatment with inhibitors of NO synthesis.14 15 16 These observations support the concept that NO and Ang II function as antagonistic regulators of blood pressure, with NO serving as a counterregulatory influence on the vascular actions of Ang II.8 9 10 NO also may subserve mechanisms that control renin release, but the precise nature of the regulatory influence, inhibitory or stimulatory, is the subject of conflicting reports.17 18 19 All in all, there is compelling evidence that the L-arginine–NO and the renin-angiotensin systems are interactive at various levels and that the interactions impinge on blood pressure regulation.
We reported that the antihypertensive effect of losartan, a blocker of AT1 receptors, in spontaneously hypertensive rats is substantially attenuated by pretreatment with NG-monomethyl-L-arginine, an inhibitor of NO synthesis.20 This unexpected finding may be indicative of another type of interaction between NO and the renin-angiotensin system, one that links NO to the mechanism underlying the antihypertensive response to interruption of the renin-angiotensin system in models of angiotensin-dependent hypertension. Accordingly, the present studies were undertaken to investigate the participation of NO in the implementation of antihypertensive responses to treatment with an inhibitor of ACE or blockers of AT1 receptors in rats with aortic coarctation–induced hypertension. We also examined the role of NO in the blood pressure–lowering response to cessation of Ang II infusion in rats previously made hypertensive by long-term infusion of the peptide.
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Methods |
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Drugs and Solutions
Ramiprilat was obtained from Hoechst-Roussel Pharmaceuticals, losartan from E.I. duPont de Nemours & Co, CL329167 from Lederle Laboratories, and flavin adenine dinucleotide and nitrate reductase from Boehringer Mannheim Biochemical. All other drugs and chemicals were obtained from Sigma Chemical Co.
All the drug solutions were prepared at the time of use. Ramiprilat was dissolved in 50 mmol/L Na2CO3. Prazosin was dissolved in deionized water. All other drugs were dissolved in saline (NaCl, 0.15 mol/L).
Protocols
Experiments were conducted on male Sprague-Dawley
rats
(Charles River, Wilmington, Mass) weighing 300 to 375 g. The animals
were housed in group cages or in individual cages as appropriate, were
given tap water to drink, and were fed a standard chow (Ralston Purina)
unless indicated otherwise. All protocols were approved by the
Institutional Animal Care and Use Committee.
Protocols 1 through 4 were executed in rats with aortic coarctation–induced hypertension. Aortic coarctation was produced in rats anesthetized with pentobarbital sodium (60 mg/kg IP) by complete ligation of the abdominal aorta at a point below the right but above the left renal artery.21 On the day of the experiment, 7 to 14 days after aortic coarctation, the animals were anesthetized with methoxyflurane (Pitman-Moore, Inc), and polyethylene cannulas (PE-50) were inserted into the right carotid artery for blood sampling and/or measurement of blood pressure. The indwelling cannulas, filled with saline, were exteriorized at the nape of the neck. Blood pressure was continuously measured with a transducer (model P23ID, Statham Division, Gould Inc) and recorded on a polygraph (model 7D, Grass Instruments Co). Animals were allowed 4 hours to recover from the anesthesia before the beginning of the experiments, and they were awake and unrestrained in their cages during the experiments.
Protocol 1 was designed to contrast the blood pressure response to pharmacological blockade of Ang II actions or synthesis in hypertensive rats pretreated or not pretreated with L-NAME, an inhibitor of NO synthase.22 To this end, L-NAME (10 mg/kg) or saline vehicle was given intravenously to rats with aortic coarctation–induced hypertension, followed 10 minutes later by intravenous injections of either an antagonist of AT1 receptors, losartan (30 mg/kg) or CL329167 (4 mg/kg); the ACE inhibitor ramiprilat (2 mg/kg); or saline vehicle only. In a complementary study, rats with aortic coarctation–induced hypertension first received an intravenous injection of D-NAME (10 mg/kg), an enantiomer of L-NAME that does not inhibit NO synthase, followed 10 minutes later by intravenous injections of losartan (30 mg/kg) or ramiprilat (2 mg/kg).
Protocol 2 was designed to contrast the blood
pressure response to
sodium nitroprusside, a donor of NO, and prazosin, a blocker of
1-adrenergic receptors, in hypertensive rats pretreated
or not pretreated with L-NAME. L-NAME (10 mg/kg) or saline vehicle was
given intravenously to rats with aortic
coarctation–induced hypertension, followed 10 to 20 minutes later
by an intravenous infusion of sodium nitroprusside (5
µg·kg-1·min-1)
or an intravenous injection of prazosin (0.1 mg/kg).
In protocol 3, carotid arterial blood (0.3 to 0.4 mL) was sampled before and 1 hour after intravenous injection of L-NAME (10 mg/kg) or vehicle to rats with aortic coarctation–induced hypertension; the blood volume was restored by the administration of an equivalent amount of blood obtained from nephrectomized rats. After centrifugation of the blood sample, the plasma was assayed for renin activity by radioimmunoassay of Ang I generated during incubation of the plasma (1 hour, 37°C, pH 6.5) in the presence of angiotensinase inhibitors (Na2EDTA, 5 mmol/L; 2,3-dimercapto-1-propanol, 5 mmol/L; and phenylmethylsulfonyl fluoride, 1.5 mmol/L). Renin activity is expressed as nanograms of Ang I generated per milliliter of plasma per hour of incubation. The radioimmunoassay of Ang I was performed with reagents purchased from DuPont-NEN.
Protocol 4 was designed to examine the effect of losartan on cGMP content of the thoracic aorta and the plasma level of nitrate in hypertensive rats. For this purpose, losartan (30 mg/kg) or saline vehicle was given intravenously to rats with aortic coarctation–induced hypertension, followed 30 minutes later by removal of the thoracic aorta under pentobarbital anesthesia (45 mg/kg) for measurement of aortic cGMP or, in awake rats, sampling of carotid arterial blood (3 to 4 mL) for measurement of plasma nitrate. cGMP in aortas was measured according to a published procedure,23 with some modifications. Thoracic aortas were snap-frozen in liquid nitrogen and subsequently homogenized in ice-cold trichloroacetic acid (10 g/100 mL). Homogenates were extracted with diethyl ether, and the aqueous phase was evaporated under vacuum. After reconstitution with deionized water, cGMP was measured by radioimmunoassay using reagents purchased from Advanced Magnetics. Plasma nitrate content was measured, after sequential conversion to nitrite and NO, with an NO chemiluminescence detector (model 207B, Sievers Research, Inc) as described24 with a minor modification to increase the degree of conversion of nitrite to NO by replacement of HCl with a solution containing (in mol/L): H2SO4 0.1, Na2SO4 0.15, and NaI 0.1.
Protocol 5, executed in rats made hypertensive by long-term infusion of Ang II or phenylephrine, was designed to contrast the blood pressure response to discontinuation of pressor agent infusion in rats either with or without L-NAME pretreatment. To measure blood pressure, a polyethylene cannula (PE-50) was introduced via a femoral artery into the abdominal aorta of rats anesthetized with sodium pentobarbital (60 mg/kg); two additional cannulas were introduced into the right external jugular vein for separate administration of the pressor agent and other drugs. The cannulas, filled with saline containing heparin (1000 U/mL), were tunneled subcutaneously to an exit point between the scapulae, placed on a protective metal spring fastened to a plastic plate sutured to the back of the rats, and attached to a three-channel swivel (Spalding Medical Products) that allows freedom of movement. After the anesthesia had worn off, animals began receiving either Ang II (60 ng/min) or phenylephrine (4 µg/min) intravenously by means of a syringe infusion pump (SAGE model 341B, Orion Research Inc). The experiments were conducted 6 to 7 days after the onset of Ang II or phenylephrine infusion. To this end, rats with Ang II– or phenylephrine-induced hypertension of 6 to 7 days' duration were injected intravenously with L-NAME (10 mg/kg) or saline vehicle only, followed 10 minutes later by discontinuation of the pressor agent infusion. In complementary experiments, the blood pressure response to discontinuation of Ang II infusion in hypertensive rats pretreated with L-NAME was examined after the pressor effect of the NO synthesis inhibitor was offset by the intravenous administration of sodium nitroprusside (1 µg·kg-1·min-1), an NO donor, or diazoxide (10 mg/kg), an activator of potassium channels.
Protocol 6 examined whether pretreatment with L-NAME of rats made hypertensive by short-term infusion of Ang II affects the blood pressure response to discontinuation of the angiotensin infusion. Rats instrumented with arterial and venous cannulas as described above were infused with Ang II at 60 ng/min IV. L-NAME (10 mg/kg) or saline vehicle was injected intravenously 30 minutes after the onset of Ang II infusion. The infusion of Ang II was discontinued 10 minutes after the administration of L-NAME or vehicle.
Protocol 7 examined whether pretreatment with L-NAME affects the blood pressure response to blockade of Ang II receptors in normotensive rats fed a sodium-deficient diet to activate the renin-angiotensin system. Rats fed a sodium-deficient diet (ICN Biomedicals) for 10 to 15 days were instrumented with arterial and venous cannulas as described for protocols 1 through 4. The animals were allowed at least 4 hours for the anesthesia to wear off before they were given an intravenous injection of L-NAME (10 mg/kg) or saline vehicle, followed 10 minutes later by the administration of losartan (30 mg/kg IV).
Statistical Analysis
Results are expressed as
mean±SEM; n indicates the number of
experiments. Single-variable comparisons were made with a
paired or unpaired Student's t test, and all other data
were analyzed by one- or two-way ANOVA, as appropriate. If
differences were noted, the Newman-Keuls modified t test was
used to make specific comparisons. The null hypothesis was rejected
when the probability value was less than .05.
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Results |
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Values of MAP and plasma renin activity in rats with aortic coarctation–induced hypertension (n=6) averaged 173±4 mm Hg and 52±10 ng·mL-1·h-1, respectively, at 7 to 14 days after coarctation. L-NAME (10 mg/kg IV) did not significantly change plasma renin activity (67±16 ng·mL-1·h-1) measured 1 hour after treatment but increased blood pressure rapidly to a plateau level of 194±4 mm Hg (P<.01), which was reached within the first 10 minutes after L-NAME administration and remained constant throughout the 1-hour observation period. Neither blood pressure (177±3 versus 177±2 mm Hg) nor plasma renin activity (65±12 versus 93±18 ng·mL-1·h-1) was significantly affected by the administration of L-NAME vehicle only (n=6).
Fig 1
illustrates the effect of agents that inhibit the
synthesis of Ang II or its actions on the blood pressure of rats with
aortic coarctation–induced hypertension pretreated with L-NAME or
vehicle only. Sixty minutes after the onset of treatment, the ACE
inhibitor ramiprilat (2 mg/kg IV) reduced the
blood pressure of vehicle-pretreated rats from 184±6 to 109±8 mm
Hg (P<.001; n=6) and that of L-NAME–pretreated rats
from
194±4 to 171±9 mm Hg (P<.01; n=7). The Ang II
receptor
antagonist losartan (30 mg/kg IV) decreased the
blood pressure of rats pretreated with vehicle from 196±7 to
117±8 mm
Hg (P<.001; n=6) and that of L-NAME–pretreated rats
from
192±5 to 155±15 mm Hg (P<.01; n=8).
Similarly, another
Ang II antagonist, CL329167 (4 mg/kg IV), lowered the blood
pressure of rats pretreated with vehicle from 175±3 to 105±14 mm
Hg
(P<.001; n=6) and that of rats pretreated with L-NAME from
189±3 to 153±6 mm Hg (P<.01; n=6). Clearly,
as shown in
Fig 1, the blood pressure–lowering effects of the ACE
inhibitor and of both blockers of Ang II receptors were
greatly attenuated in hypertensive rats pretreated with the
inhibitor of NO synthesis. In contrast, pretreatment of
rats with aortic coarctation–induced hypertension with D-NAME (10
mg/kg IV) did not attenuate the blood pressure–lowering effect of
either losartan (from 188±7 to 92±10 mm Hg,
P<.001; n=4) or ramiprilat (from 162±6 to
99±10 mm Hg, P<.001; n=4).
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Although pretreatment with L-NAME was found to minimize the antihypertensive effect of losartan in rats with aortic coarctation–induced hypertension, the plasma level of nitrate in hypertensive rats given losartan (11.2±3 µmol/L; n=5) was similar to that in vehicle-treated controls (9.3±3 µmol/L; n=6). The content of cGMP in the thoracic aorta also was similar in vehicle- and losartan-treated hypertensive rats (352±50 versus 363±95 fmol/mg protein; n=5).
Fig 2 depicts the effects of sodium nitroprusside and
prazosin on arterial blood pressure of rats with aortic
coarctation–induced hypertension pretreated or not pretreated with
L-NAME. Sodium nitroprusside infused intravenously (5
µg·kg-1·h-1)
lowered the blood pressure of rats with and without L-NAME
pretreatment. This effect of the NO donor in rats pretreated with
L-NAME surpassed (P<.01) that in vehicle-pretreated
rats in the early but not the late stage of sodium nitroprusside
infusion. The blood pressure–lowering response to an
intravenous injection of prazosin (0.1 mg/kg) in
hypertensive rats pretreated with vehicle only (from 172±4 to
117±10
mm Hg, P<.001; n=6) was comparable to that obtained in rats
pretreated with L-NAME (from 187±7 to 132±13 mm Hg,
P<.001; n=5).
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Fig 3 (top) illustrates the blood pressure response to
discontinuation of Ang II infusion in rats with acute Ang II–induced
hypertension pretreated or not pretreated with L-NAME. The blood
pressure of rats infused with Ang II at 60 ng/min for 30 minutes was
154±3 mm Hg. Within 10 minutes after administration of L-NAME (10
mg/kg IV), the blood pressure of these rats increased to a plateau
level of 171±3 mm Hg (P<.01; n=7). As shown in Fig
3,
discontinuation of the short-term infusion of Ang II elicited a
similar blood pressure–lowering response in rats pretreated with
L-NAME (from 171±3 to 136±3 mm Hg, P<.001;
n=7) and in
rats pretreated with vehicle only (from 153±4 to 109±5 mm Hg,
P<.001; n=6).
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Fig 3
(bottom) illustrates the blood pressure response to
discontinuation of Ang II infusion in rats with chronic Ang II–induced
hypertension pretreated or not pretreated with L-NAME. The average MAP
of rats receiving an intravenous infusion of Ang II at 60
ng/min for 6 to 7 days was 165±7 mm Hg. L-NAME given
intravenously (10 mg/kg) increased the blood pressure of
these rats to a plateau level of 185±7 mm Hg (P<.01),
which was reached within 10 minutes after the onset of drug
administration. Discontinuation of the long-term infusion of Ang II
resulted in a protracted and less intense blood pressure–lowering
response in the rats pretreated with L-NAME (from 185±7 to 154±8
mm
Hg, P<.001; n=6) than in the rats pretreated with vehicle
only (from 167±2 to 115±8 mm Hg, P<.001;
n=6).
Importantly, as shown in Fig 4, the
inhibitory influence of L-NAME pretreatment on the
hypotensive response to ending the long-term infusion of Ang II was
not apparent in rats undergoing an infusion of the NO donor sodium
nitroprusside at a dosage (1
µg·kg-1·min-1
IV) just sufficient to reverse the blood pressure increase elicited by
the inhibitor of NO synthesis. In contrast, the
inhibitory influence of L-NAME pretreatment on the
hypotensive response to discontinuation of Ang II was well expressed in
rats injected with the potassium channel activator
diazoxide at a dosage (10 mg/kg IV) sufficient to offset the pressor
effect of L-NAME.
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The average MAP of rats undergoing an intravenous infusion of phenylephrine at 4 µg/min for 6 to 7 days was 165±3 mm Hg. L-NAME given intravenously (10 mg/kg) increased the blood pressure of these rats to a plateau level of 194±5 mm Hg (P<.005), which was reached within 10 minutes after its administration. Discontinuation of the long-term infusion of phenylephrine elicited a similar blood pressure–lowering response in rats pretreated with L-NAME (from 194±5 to 137±11 mm Hg, P<.001; n=5) and in rats pretreated with vehicle only (from 160±6 to 102±9 mm Hg, P<.001; n=5).
Fig 5 illustrates the effect of losartan on
blood pressure of sodium-deficient normotensive rats pretreated or
not pretreated with L-NAME. The average MAP of rats fed a
sodium-deficient diet for 10 to 15 days was 111±5 mm Hg. L-NAME
(10 mg/kg IV) increased the blood pressure of these rats to a plateau
of 153±8 mm Hg (P<.001). The intravenous
administration of losartan (30 mg/kg) elicited a comparable
reduction of blood pressure in sodium-deficient rats pretreated
with vehicle (from 114±4 to 62±5 mm Hg, P<.001;
n=5) and
in sodium-deficient rats pretreated with L-NAME (from 153±8 to
95±14 mm Hg, P<.001; n=5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In rats, complete occlusion of the abdominal aorta between the renal arteries at their origin increases plasma renin activity and elicits hypertension, which is readily reversed by pharmacological or immunologic blockade of the renin-angiotensin system.25 26 The present study demonstrates that pretreatment of these hypertensive rats with the NO synthesis inhibitor L-NAME greatly attenuates the antihypertensive effects of the ACE inhibitor ramiprilat and of the Ang II receptor blockers losartan and CL329167. These findings are in keeping with reports that pretreatment with inhibitors of NO synthesis reduces the magnitude of the blood pressure reduction produced by short-term administration of losartan,20 27 ramiprilat,20 or lisinopril27 in spontaneously hypertensive rats and by losartan and lisinopril in the third week after the onset of two-kidney, one clip hypertension in dogs.13
In our study, L-NAME did not significantly reduce plasma renin activity in rats with aortic coarctation–induced hypertension, in contrast to reports that it does so in normotensive rats.19 This finding argues against the possibility that the decreased antihypertensive effectiveness of ramiprilat, losartan, and CL329167 in hypertensive rats pretreated with L-NAME is brought about by reductions in plasma renin activity that lessen the dependency of the hypertension on the activity of the renin-angiotensin system. Moreover, in rats made hypertensive by long-term infusion of Ang II, in which increased levels of Ang II are independent of plasma renin, the blood pressure–lowering response to discontinuation of the Ang II infusion also was attenuated by pretreatment with L-NAME.
The possibility that L-NAME decreases vasodepressor responsiveness in a nonspecific manner merits consideration, since in a recent study, pretreatment with L-NAME was found to abolish the blood pressure–lowering response to unclipping of the renal artery in rats with two-kidney, one clip hypertension.28 However, several of our findings make this possibility unlikely. First, pretreatment with L-NAME did not decrease the vasodepressor responsiveness to prazosin or sodium nitroprusside in rats with aortic coarctation–induced hypertension. Second, L-NAME pretreatment of rats made hypertensive by long-term infusion of phenylephrine did not attenuate the blood pressure–lowering response to discontinuation of the phenylephrine infusion. Third, L-NAME pretreatment did not minimize the hypotensive effect of losartan in normotensive rats fed a sodium-deficient diet to activate the renin-angiotensin system. Fourth, L-NAME pretreatment of rats made hypertensive by short-term infusion of Ang II did not impede the blood pressure–lowering response to discontinuation of the Ang II infusion. Accordingly, it would appear that L-NAME interferes only with the expression of vasodepressor responses elicited by interventions that block the vascular actions or decrease the levels of Ang II in models of established angiotensin-dependent hypertension.
In our study, the antihypertensive effects of losartan and ramiprilat in rats with aortic coarctation–induced hypertension were unaffected by pretreatment with D-NAME. This finding alerts us to the possibility that the inhibitory action of L-NAME on NO synthesis confers upon L-NAME the ability to blunt the vasodepressor effect of interventions that decrease the activity of the renin-angiotensin system in models of established angiotensin-dependent hypertension. It is plausible that inhibitors of NO synthesis interfere with the expression of antihypertensive responses to interruption of the renin-angiotensin system by limiting the contribution of NO to such responses. However, L-NAME did not reduce the magnitude of the blood pressure–lowering effect of losartan in sodium-deprived rats or of discontinuation of Ang II infusion in rats with acute angiotensin-induced hypertension. Accordingly, it would appear that only in models of established angiotensin-dependent hypertension does NO participate in the implementation of vasodepressor responses to interruption of the renin-angiotensin system. The combination of increased activity of the renin-angiotensin system and prolonged hypertension may create conditions that favor involvement of NO in mediation of vasodepressor responsiveness to interruption of the renin-angiotensin system in rats with aortic coarctation–induced hypertension and rats made hypertensive by long-term Ang II infusion. Such conditions may not be obtained in sodium-deprived rats or rats with acute angiotensin-induced hypertension, which would explain the inability of L-NAME pretreatment of these animals to interfere with vasodepressor responses elicited by losartan and discontinuation of the Ang II infusion, respectively.
A priori, the contribution of NO to the antihypertensive effect of interventions that arrest the activity of the renin-angiotensin system may be linked to increased production of NO with attendant elevation of NO levels and promotion of cGMP-mediated vasodilation. It also may be linked to decreased degradation of NO consequent to diminished vascular generation of superoxide, which is stimulated by Ang II.29 30 One argument against these notions is that neither plasma nitrate levels nor cGMP levels in the thoracic aorta were increased by losartan in rats with aortic coarctation–induced hypertension. Yet, one cannot exclude the possibility that augmentation of NO levels at microvascular sites contributes to the blood pressure–lowering effect of interventions that block the renin-angiotensin system in angiotensin-dependent hypertension, since levels of plasma nitrate and aortic cGMP may not be appropriate indexes of the activity of dilator mechanisms mediated by NO in resistance vessels.
Another possibility is that NO, even at basal levels, is needed to abate a pressor mechanism that is not readily deactivated by interruption of the renin-angiotensin system in rats with established angiotensin-dependent hypertension. This view derives support from our finding that L-NAME pretreatment of rats made hypertensive by long-term infusion of Ang II did not attenuate the blood pressure–lowering response to discontinuation of the Ang II infusion in animals receiving sodium nitroprusside to replace the loss of endogenous NO. In this regard, we recently reported that endogenous NO serves as a counterregulatory influence to a protein kinase C–dependent mechanism of vascular contraction, overexpressed in rats with aortic coarctation–induced hypertension, which is not readily deactivated by losartan.10 31 Hence, in models of established angiotensin-dependent hypertension, the vasodepressor response to interruption of the renin-angiotensin system may be weakened after NO synthesis inhibition because of continual operation of a vasoconstrictor mechanism that lingers in the absence of NO.
In summary, we found that L-NAME pretreatment of rats with established angiotensin-dependent hypertension greatly attenuates the antihypertensive response to interventions that either reduce the levels or block the actions of Ang II. The study documents a novel and important interaction between NO and the renin-angiotensin system, one that links NO to the mechanisms underlying the antihypertensive effect of ACE inhibitors and Ang II receptor blockers.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by US Public Health Service grants HL-18579, HL-31069, and HL-43023. We thank Jennifer Brown for secretarial assistance.
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Footnotes |
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Reprint requests to Alberto Nasjletti, MD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595.
Received June 14, 1995; first decision August 7, 1995; accepted September 26, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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