| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1996;27:672-678.)
© 1996 American Heart Association, Inc.
Articles |
Nitric Oxide Release From Kidneys of Hypertensive Rats Treated With Imidapril
From The Second Department of Internal Medicine (Y.H., H.H., M.K., A.T., E.S., K. Kimura, A.G., M.O.) and Department of Pharmaceutical Sciences (K. Kikuchi, T.N., M.H.), University of Tokyo, Japan.
Correspondence to Yasunobu Hirata, MD, The Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail hirata-2im@h.u-tokyo.ac.jp.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)–salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescence assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10-8 mol/L) of both renal perfusion pressure (stroke-prone SHR 42±4% versus Wistar-Kyoto rats [WKY] 58±4% [mean±SE], P<.01) and nitric oxide release (stroke-prone SHR +7.6±2.1 versus WKY +29.7±9.7 fmol/min per gram of kidney wt, P<.01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56±3%; nitric oxide release, +27.1±6.4 fmol/min per gram of kidney wt; both P<.01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA–salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA–salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.
Key Words: rats, inbred, SHR • desoxycorticosterone • nitric oxide • endothelium • vasodilation
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Endothelium-dependent vasodilation is attenuated in human and experimental hypertension,1 2 3 and this phenomenon may be due in great part to decreased release or activity of NO. Since NO is a potent vasodilator molecule that accounts for an endothelium-derived relaxing factor,4 5 a decrease in NO results in an elevation of blood pressure. Administration of NO synthesis inhibitors can produce chronic hypertension in rats.6 7 Thus, elucidation of the mechanisms for reduced NO activity may in turn provide important clues to clarify the pathogenesis of hypertension, in particular genetic hypertension, including SHR. However, attenuated endothelium-dependent vasodilation is not always associated with decreases in NO release in SHR. Lüscher et al8 did not find any difference in the vasodilatory response of the bioassay vessels to ACh-stimulated superfusate from SHR and normotensive WKY. Hemodynamic responses to NOS inhibitors were not reduced in SHR.9 Furthermore, agonist-induced increases of cGMP in vascular smooth muscle cells from SHR were somewhat greater than in those from WKY.10 11 We have also reported that the levels of NO metabolites12 and NO itself13 in the perfusate of isolated kidneys from SHR and WKY were comparable.
SHRSP, in which hypertensive organ damage is more marked than in SHR, have been regarded as an experimental model for human malignant hypertension.14 15 Also, endothelium-dependent vasodilation is depressed in this strain of rats.16 17 Recently, Malinski et al18 measured bradykinin-induced NO release from cultured endothelial cells of SHRSP using a porphyrinic electrode19 and found it decreased compared with that from cells of WKY. They suggested that these changes were genetic rather than acquired because the cells were passaged.
In the present study, we administered imidapril, an ACE inhibitor,20 to SHRSP or DOCA–salt hypertensive rats, to examine whether a decrease in NO release in SHRSP is a defect that is primary or secondary to hypertension, and the effects of imidapril on endothelium-dependent vasodilation in the isolated perfused kidneys were investigated. Furthermore, we directly determined NO release in the perfusate using a sensitive chemiluminescence assay and examined its origin by immunohistochemical analysis of NOS.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
SHRSP at 8 weeks of age were divided into three groups. They received 1 or 10 mg/d of imidapril (Tanabe Pharmaceutical Co) or vehicle. The agent was dissolved in sterile 0.9% saline and given subcutaneously with the use of an osmotic minipump (Alzet 2ML4, Alza Co). With the rats under light ether anesthesia, we implanted the pump subcutaneously into their backs. Similarly, WKY were given vehicle. Each group consisted of six rats.
After 4 weeks of imidapril, systolic blood pressure was measured by the tail-cuff method. Rats were then anesthetized with pentobarbital (30 mg/kg IP). The right kidney was isolated and perfused as previously described.21 In brief, the superior mesenteric artery was punctured with an 18-gauge needle, and the tip of the needle was introduced into the right renal artery across the abdominal aorta. Perfusion with Krebs-Henseleit buffer was started without ischemia. The renal vein was also cannulated and the venous effluent was continuously introduced with a double-plunger head pump into a chemiluminescence detector via a rotating mixer. RPP was monitored at the renal artery with a pressure transducer. The perfusion buffer was saturated with 95% O2/5% CO2 at 37°C and contained 10-6 mol/L phenylephrine and 10-5 mol/L indomethacin. Renal perfusion flow was maintained at a rate of 5 mL/min throughout the study. NO concentration in the perfusate was determined by a sensitive chemiluminescence assay as previously described.22 23 24 The venous effluent was drained at 2 mL/min with the pump and mixed with a chemiluminescence probe. The rest of the effluent overflowed through a three-way needle. The probe consisted of 2 mmol/L H2O2, 18 µmol/L luminol, 2 mmol/L potassium carbonate, and 150 mmol/L desferrioxamine and was introduced into the mixer at 0.5 mL/min. RPP and the chemiluminescence signal were simultaneously monitored with a polygraph recorder. The NO concentration in the perfusate was calibrated by use of an authentic NO solution of known concentration determined by the oxyhemoglobin method or a horseradish-peroxidase solution that produced signals corresponding to the calibrated NO solution.
After a 60-minute equilibrium period, we sequentially infused vehicle and 10-9 mol/L, 10-8 mol/L, and 10-7 mol/L ACh into the isolated kidney at 0.25 mL/min through a three-way stopcock at 10-minute intervals. Finally, 10-4 mol/L L-NMMA, an NOS inhibitor, was added to 10-7 mol/L ACh. The effects of these agents on NO release and RPP were compared among rat groups. The left kidney was used for histological examination. Interlobular arteries were observed under a light microscope after elastica-Van Gieson staining. Lumen diameters and wall thickness of the interlobular arteries were determined with the use of a microscopic videoanalyzer. At least three samples from each kidney were analyzed, and the wall-to-lumen ratios were averaged in each group.
We also examined the response to ACh at perfusion pressures similar to those measured just before kidney isolation. Given the systolic blood pressures of SHRSP after administration of vehicle, 1 mg/d imidapril, or 10 mg/d imidapril, the RPP was adjusted with phenylephrine to approximately 160, 130, and 100 mm Hg, respectively. After the equilibrium periods, the responses of RPP and NO to ACh were determined.
The effects of imidapril on the kidneys of DOCA–salt hypertensive rats were also examined. Male WKY were unilaterally nephrectomized at 4 weeks of age, and 200 mg/kg DOCA-containing silicone pellets were implanted subcutaneously. Rats were given 0.9% saline as drinking water for 4 weeks. Imidapril at 10 mg/d or vehicle was then administered to DOCA salt–treated rats for 4 weeks as described above. The effects of ACh on RPP and NO release were examined in these rats.
The acute effects of imidapril on ACh-induced and bradykinin-induced changes in RPP and NO release were also examined in male WKY. ACh (10-8 or 10-7 mol/L) or bradykinin (10-8 or 10-7 mol/L) was infused during infusion of 10-6 mol/L imidaprilat, an active metabolite of imidapril, or vehicle (n=5 each).
Immunohistochemistry
The immunoreactivity of NOS was examined
in renal tissue, as
previously reported.25 In brief, two rats from each group
(SHRSP, WKY, and DOCA–salt hypertensive rats treated with imidapril or
vehicle as described above) were anesthetized with
pentobarbital. The abdominal aorta was cannulated and the kidneys were
perfused and fixed with
paraformaldehyde-lysine-periodate. The kidneys
were sliced and the slices were embedded in wax (polyethylene glycol
400 disterate, Polysciences Inc). Then, 3-µm wax sections were
prepared and stained with primary antisera raised against EC NOS, brain
NOS, and macrophage-type inducible NOS (Transduction
Laboratories) according to the labeled streptavidin-biotin method.
A section incubated with 1% bovine serum albumin served as the
negative control. EC NOS was stained by use of the
avidin-biotin–horseradish peroxidase complex technique for
light microscopic immunohistochemical observation. The other kidney
slices were used for histochemical detection of NADPH
diaphorase activity. Fifty-micrometer
sections were incubated with 1 mmol/L reduced ß-NADPH, 0.2 mmol/L
nitro blue tetrazolium, and 0.2% Triton X-100 for 45 minutes at 37°C
and then examined under a light microscope.
Statistical Analysis
Values are given as mean±SE. The
effects of ACh were assessed
by one-way ANOVA for repeated measures followed by the Dunnett's
test. Differences among the groups of SHRSP, WKY, and DOCA–salt
hypertensive rats were also compared by one-way ANOVA. A value of
P<.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The Table
lists the values of measured
variables. Systolic blood pressure was much higher in
vehicle-treated SHRSP than in WKY. Imidapril decreased blood
pressure dose dependently in SHRSP, and 10 mg/d imidapril lowered blood
pressure in SHRSP to a level comparable to that in WKY. The decrease in
heart weight paralleled that in blood pressure, whereas kidney
weight was not affected by imidapril. Fig 1 shows
representative tracings of RPP and NO signal during
administration of ACh and L-NMMA in WKY and SHRSP treated with vehicle
or imidapril. In WKY, ACh decreased RPP in a dose-dependent manner
and L-NMMA increased it. On the other hand, NO release was increased by
ACh but decreased by L-NMMA. The effects of
10-4 mol/L L-NMMA were restored by the
addition of 10-3 mol/L
L-arginine (data not shown). In vehicle-treated SHRSP,
the responses of RPP and NO signals to ACh were obviously reduced,
whereas in SHRSP treated with 10 mg/d imidapril, the responses were
similar to those of WKY. As summarized in Fig 2, the
ACh-induced reduction in RPP and increase in NO release were
significantly attenuated in SHRSP compared with WKY. Imidapril at 10
mg/d significantly increased the response to Ach of both RPP and NO
release. As a result, no differences in the effects of ACh were
observed between WKY and SHRSP treated with 10 mg/d imidapril.
Histological studies confirmed the effects of
imidapril. Treatment with 10 mg/d imidapril significantly reduced wall
thickening of the interlobular arteries in SHRSP, resulting in a
decrease in the wall-to-lumen ratio (Table).
|
|
|
P<.01,
P<.001 vs WKY; §P<.05,
P<.01, ¶P<.001 vs
SHRSP/vehicle.
When kidneys were perfused with
10-6 mol/L
phenylephrine-containing buffer, the baseline RPP was
100 mm Hg in all groups of rats. When RPP was maintained close to
the blood pressure level measured before renal isolation, the
phenylephrine concentrations required were
3.3±0.3x10-6 mol/L for
vehicle-treated,
1.9±0.2x10-6 mol/L for 1 mg/d
imidapril-treated, and 10-6 mol/L for
10 mg/d imidapril-treated SHRSP. ACh-induced changes of
RPP and NO release were again significantly smaller in
vehicle-treated SHRSP than in SHRSP treated with 10 mg/d imidapril
even when the baseline RPP in vehicle-treated SHRSP was elevated
(Fig 3).
|
DOCA salt–treated rats also showed marked hypertension
(Table
).
Imidapril treatment changed neither systolic blood pressure nor
heart weight. The renal perfusion study revealed that the kidneys of
DOCA–salt hypertensive rats were markedly hyporesponsive to ACh with
respect to both RPP and NO release. Imidapril-treated rat kidneys
were also hyporesponsive, and there were no differences in
ACh-induced decreases in RPP or increases in NO release between
DOCA–salt hypertensive rats treated with vehicle and those treated
with imidapril (Fig 4). The wall-to-lumen ratio
of the interlobular arteries in the kidneys did not differ between
these two groups of DOCA–salt hypertensive rats (Table).
|
Imidaprilat infusion per se did not change RPP in this preparation.
Acute administration of imidaprilat influenced neither ACh- nor
bradykinin-induced renal vasodilation. As illustrated in Fig 5,
NO release was not altered by imidapril either.
|
To examine the origin of NO released in the perfusate, the
immunoreactivity of NOS was evaluated by use of immunohistochemical
techniques. The antibody for EC NOS stained the
endothelium in the renal vasculature, and the antibody
for brain NOS specifically labeled the macula densa cells in the
kidneys of SHRSP (Fig 6). The negative control incubated
with 1% bovine serum albumin did not show any staining. The
localization of NOS isoforms was consistent with previous
reports.25 26 The intensity of immunoreactivity for
both
NOS isoforms was similar among WKY and SHRSP whether treated with
imidapril or not. On the other hand, the intensity of immunoreactivity
for both NOS isoforms was significantly weaker in DOCA–salt
hypertensive rats. Immunoreactivity for inducible NOS was barely
detected in the glomeruli and vessels of any rats studied. The
localization and intensity of NADPH diaphorase activity
were also consistent with the results of the
immunohistochemical examination (Fig 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
ACh-induced renal vasodilation and NO release were increased in SHRSP after 4 weeks of treatment with imidapril. These effects appeared to be correlated with its antihypertensive action because both the blood pressure reduction and NO release increment caused by imidapril were dose dependent. These findings suggest that the impaired NO release observed in the kidneys of SHRSP may be closely related to the hypertensive state rather than the consequence of a genetic defect.
The question of whether normalization of blood pressure results in improvement of endothelium-dependent vasodilation in human and experimental hypertension is controversial. Panza et al27 reported that antihypertensive treatment with various drugs for longer than 5 years in patients with essential hypertension did not change the response of the brachial artery to ACh. This may have been due to irreversible endothelial damage. However, Hirooka et al28 showed an acute potentiation of ACh-induced vasodilation within 60 minutes after administration of captopril, whereas nifedipine did not exert such effects. Such controversy may be attributable to the mechanisms of action of the antihypertensive agents administered. Clozel et al29 reported that cilazapril and hydralazine lowered blood pressure in SHR to a similar extent; however, they found that endothelium-dependent vasodilation was increased only by cilazapril. These findings suggest that ACE inhibitors may exert some vascular protective effect and that this effect is sometimes exerted independently of whether blood pressure reduction is attained. This effect of ACE inhibitors may be attributable to inhibition of kininase II, which may potentiate bradykinin-mediated NO release. In fact, captopril and cilazapril acutely augmented bradykinin-induced vasodilation in the normal human brachial artery and in the cerebral arteries of SHRSP, respectively.30 31
However, Creager and Robby32 recently showed that administration of captopril or enalapril for 8 weeks lowered blood pressure to normal levels but did not increase endothelium-dependent vasodilation of the brachial artery in patients with essential hypertension. Furthermore, a Ca2+ antagonist, an angiotensin receptor antagonist, and an ACE-inhibitor lowered blood pressure equally and increased endothelium-dependent vasorelaxation in the coronary artery of SHR to a similar extent.33 In the present study, imidapril infusion did not acutely potentiate the effects of bradykinin. It also has been reported that only ACE inhibitors with a sulfhydryl group, such as captopril but not enalapril, potentiate endothelium-dependent vasodilation.34 35 However, despite a sulfhydryl group–free ACE inhibitor,20 imidapril actually increased NO release. Imidapril lowered blood pressure in SHRSP but not in DOCA–salt hypertensive rats in which renin-angiotensin activity is markedly suppressed, suggesting that the effects of imidapril may be exerted mainly through inhibition of the generation of angiotensin II.
We examined the renal response to ACh at the pressures attained with 10-6 mol/L phenylephrine and those measured just before renal isolation by increasing the concentration of phenylephrine. It is possible that baseline RPP and the concentration of phenylephrine modify the renal response to ACh. We have already reported that adjustments of RPP to blood pressure by changing the renal perfusion flow did not alter the hyporesponsiveness of kidneys to ACh in DOCA–salt hypertensive rats.36 Although changes in perfusion flow and phenylephrine concentration may influence shear stress, and strict comparison of the response to ACh at different perfusion pressures is difficult, the response to ACh was substantially greater in imidapril-treated SHRSP, suggesting that imidapril improves NO-releasing activity.
We have already reported that 8-week administration of L-arginine improved ACh-induced NO release in DOCA–salt hypertensive rats.36 Furthermore, when the response to ACh was examined in rats 2 weeks after the DOCA implantation, ACh-induced NO release and vasodilation were not impaired. These rats showed marginally normal blood pressure (Hirata et al, 1995, unpublished observation). These findings suggest that endothelial dysfunction in DOCA–salt hypertensive rats is reversible and that the decrease of NO release is not due to DOCA itself. Therefore, if blood pressure had been normalized by other means, endothelial function would have improved even in DOCA–salt hypertensive rats.
The results of immunohistochemical examination suggest that most of the NO in the perfusate may have derived from the constitutive NOS, ie, brain NOS or EC NOS. Although the immunoreactivity to brain NOS in the macula densa was more intense than that in the endothelium, the total NOS content in the endothelial cells may have exceeded that in the macula densa, judging from the large area of endothelial distribution. Furthermore, ACh, which caused rapid NO release, must have first acted on the vascular endothelial cells. Thus, most of the NO detected in the perfusate seems to have been derived from EC NOS. There were no differences in the intensity of immunoreactivity for constitutive NOS between WKY and SHRSP or between SHRSP treated with vehicle and those treated with imidapril. However, NO released in the perfusate substantially decreased in SHRSP. This suggests that mechanisms for production or release of NO rather than NOS protein synthesis may be altered in SHRSP. On the other hand, attenuated NO release in DOCA–salt hypertensive rats may be a consequence of decreases in NOS, most likely due to marked vascular damage.
Both ACh-induced renal vasodilation and NO release were attenuated in SHRSP kidneys. We have already reported that the NO release rate from the kidneys of SHR is similar to that from WKY. These differences may be due to differences in the degree of hypertensive organ damage between the two strains. SHRSP showed decreased NO-releasing activity despite normal immunoreactivity of EC NOS. This mechanism could not be clarified in the present study. However, several mechanisms may have been involved: availability of the NOS substrate, particularly L-arginine, was limited; the enzyme was catalytically inactive; and/or NO reacted with something other than guanylate cyclase, for instance, with superoxide. Furthermore, intracellular signal transduction in vessels has been suggested to be altered in the early stages of atherosclerosis because only receptor-mediated NO release is attenuated.37 Imidapril seems to have improved some of these alterations. Since imidapril did not directly increase the response of the kidneys to ACh or bradykinin, it is possible that by means of its depressor action, imidapril may have reduced mechanical insults on the endothelium, as suggested by the histological analysis, and restored agonist-induced NO release.
Chen and Sander38 showed that L-arginine prevented blood pressure elevation in Dahl salt–sensitive rats. They speculated that this phenomenon may be accountable for increased NO derived from inducible NOS because treatment with dexamethasone abolished the effects of L-arginine and decreased urinary excretion of NO metabolites. Furthermore, Xiao and Pang39 showed that vascular smooth muscle cells and macrophages from SHR suppressed the proliferation of lymphocytes. This antiproliferative effect was inhibited by L-NMMA. These findings suggest the involvement of increased inducible NOS in the regulation of blood pressure and immune function in experimental hypertension; however, our results from immunohistochemical examination did not support these results. On the other hand, it was reported that interleukin-1ß–evoked NO release in smooth muscle cells from SHRSP was also less than that in cells from WKY.18 It is also unlikely that in vivo intrarenal induction of macrophage-type inducible NOS was genetically reduced in SHRSP because WKY kidneys were also devoid of inducible NOS staining.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported in part by a grant-in-aid for scientific research on priority areas ("Vascular Endothelium–Smooth Muscle Coupling"); by grant-in-aid Nos. 06274209 and 06671132 from the Japanese Ministry of Education, Culture and Science, Japan; and by a grant from the Japan Foundation for Aging and Health. The authors wish to thank Tanabe Pharmaceutical Co for supplying imidapril.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
-
Konishi M, Su C. Role of
endothelium in dilator responses of spontaneously
hypertensive rat arteries. Hypertension.. 1983;5:881-886.
[Abstract/Free Full Text] -
Vanhoutte PM. Endothelium and
control of vascular function: state of the art lecture.
Hypertension.. 1989;13:658-667.
[Abstract/Free Full Text] - Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med.. 1990;323:22-27. [Abstract]
- Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature.. 1980;288:373-376. [Medline] [Order article via Infotrieve]
- Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev.. 1991;43:109-142. [Medline] [Order article via Infotrieve]
-
Dananberg J, Sider RS, Grekin RJ. Sustained
hypertension induced by orally administered nitro-L-arginine.
Hypertension.. 1993;21:359-363.
[Abstract/Free Full Text] - Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest.. 1992;90:278-281.
- Lüscher TF, Romero JC, Vanhoutte PM. Bioassay of endothelium-derived vasoactive substances in the aorta of normotensive and spontaneously hypertensive rats. J Hypertens. 1986;4(suppl 6):S81-S83.
-
Yamazaki J, Fujita N, Nagao T.
NG-monomethyl
L-arginine-induced pressor response at developmental
and established stages in spontaneously hypertensive rats.
J Pharmacol Exp Ther.. 1991;259:52-57.
[Abstract/Free Full Text] -
Mourlon-Le Grand MC, Benessiano J, Levy BI. cGMP
pathway and mechanical properties of carotid artery wall in WKY rats
and SHR: role of endothelium. Am J
Physiol.. 1992;263:H61-H67.
[Abstract/Free Full Text] -
Papapetropoulos A, Marczin N, Snead MD, Cheng C, Milici
A, Catravas JD. Smooth muscle cell responsiveness to
nitrovasodilators in hypertensive and normotensive rats.
Hypertension.. 1994;23:476-484.
[Abstract/Free Full Text] -
Hayakawa H, Hirata Y, Suzuki E, Sugimoto T, Matsuoka H,
Kikuchi K, Nagano T, Hirobe M, Sugimoto T. Mechanisms for
altered endothelium-dependent vasorelaxation in
isolated kidneys from experimental hypertensive rats. Am
J Physiol.. 1993;264:H1535-H1541.
[Abstract/Free Full Text] - Hayakawa H, Hirata Y, Suzuki E, Kakoki M, Kikuchi K, Nagano T, Hirobe M, Omata M. Endothelium-derived relaxing factors in the kidney of spontaneously hypertensive rats. Life Sci.. 1995;56:PL401-PL408. [Medline] [Order article via Infotrieve]
- Okamoto K, Yamori Y, Nagaoka A. Establishment of the stroke-prone spontaneously hypertensive rat (SHR). Circ Res. 1974;34(suppl I):I-143-I-153.
-
Yamori Y, Horie R, Sato M, Handa H. Pathogenetic
similarity of stroke-prone SHR and humans.
Stroke.. 1976;7:46-53.
[Abstract/Free Full Text] -
Mayhan WG, Faraci FM, Heistad DD. Impairment of
endothelium-dependent responses of cerebral
arterioles in chronic hypertension. Am J Physiol.. 1987;253:H1435-H1440.
[Abstract/Free Full Text] -
Tesfamariam B, Halpern W.
Endothelium-dependent and
endothelium-independent vasodilation in resistance
arteries from hypertensive rats. Hypertension.. 1988;11:440-444.
[Abstract/Free Full Text] - Malinski T, Kapturczak M, Dayharsh J, Bohr D. Nitric oxide synthase activity in genetic hypertension. Biochem Biophys Res Commun.. 1993;194:654-658. [Medline] [Order article via Infotrieve]
- Malinski T, Taha Z. Nitric oxide release from a single cell measured in situ by a porphyrinic-based microsensor. Nature.. 1992;358:676-678. [Medline] [Order article via Infotrieve]
- Kubo M, Fujitsuka T, Ishida R. Effects of the new angiotensin-I-converting enzyme inhibitor imidapril on the responses of isolated vascular preparations to various agonists. Arzneimittelforschung.. 1992;42:446-451. [Medline] [Order article via Infotrieve]
-
Hirata Y, Matsuoka H, Hayakawa H, Sugimoto T, Suzuki E,
Sugimoto T, Kangawa K, Matsuo H. Role of endogenous
atrial natriuretic peptide in regulating sodium excretion
in spontaneously hypertensive rats: effects of neutral
endopeptidase inhibition.
Hypertension.. 1991;17:1025-1032.
[Abstract/Free Full Text] - Kikuchi K, Nagano T, Hayakawa H, Hirata Y, Hirobe M. Detection of nitric oxide production from a perfused organ by a luminol-H2O2 system. Anal Chem.. 1993;65:1794-1799. [Medline] [Order article via Infotrieve]
-
Kikuchi K, Nagano T, Hayakawa H, Hirata Y, Hirobe
M. Real-time measurement of nitric oxide produced ex vivo by
luminol-H2O2 chemiluminescence method.
J Biol Chem.. 1993;268:23106-23110.
[Abstract/Free Full Text] -
Hirata Y, Hayakawa H, Suzuki E, Kimura K, Kikuchi K,
Nagano T, Hirobe M, Omata M. Direct measurements of
endothelium-derived nitric oxide release by
stimulation of endothelin receptors in rat kidney and its alteration in
salt-induced hypertension.
Circulation. 1995;91:1229-1235.
[Abstract/Free Full Text] - Tojo A, Gross SS, Zhang L, Tisher CC, Schmidt HHHW, Wilcox CS, Madsen KM. Immunocytochemical localization of distinct isoforms of nitric oxide synthase in the juxtaglomerular apparatus of normal rat kidney. J Am Soc Nephrol.. 1994;4:1438-1447. [Abstract]
-
Wilcox CS, Welch WJ, Murad F, Gross SS, Taylor G, Levi
R, Schmidt HHHW. Nitric oxide synthase in macula densa regulates
glomerular capillary pressure. Proc Natl Acad
Sci U S A.. 1992;89:11993-11997.
[Abstract/Free Full Text] - Panza JA, Quyyumi AA, Callahan TS, Epstein SE. Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol.. 1993;21:1145-1151. [Abstract]
-
Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S,
Momohara M, Takeshita A. Captopril improves impaired
endothelium-dependent vasodilation in hypertensive
patients. Hypertension.. 1992;20:175-180.
[Abstract/Free Full Text] -
Clozel M, Kuhn H, Hefti F. Effects of
angiotensin converting enzyme inhibitors and of
hydralazine on endothelial function in
hypertensive rats. Hypertension.. 1990;16:532-540.
[Abstract/Free Full Text] -
Kiowski W, Linder L, Kleinbloesem C, van Brummelen P,
Buhler FR. Blood pressure control by the
renin-angiotensin system in normotensive subjects:
assessment by angiotensin-converting enzyme and renin
inhibition. Circulation. 1992;85:1-8.
[Abstract/Free Full Text] -
Yang ST, Faraci FM, Heistad DD. Effects of
cilazapril on cerebral vasodilation in hypertensive rats.
Hypertension.. 1993;22:150-155.
[Abstract/Free Full Text] -
Creager MA, Robby MA. Effect of captopril and
enalapril on endothelial function in hypertensive
patients. Hypertension.. 1994;24:499-505.
[Abstract/Free Full Text] -
Tschudi MR, Criscione L, Novosel D, Pfeiffer K,
Lüscher TF. Antihypertensive therapy augments
endothelium-dependent relaxations in
coronary arteries of spontaneously hypertensive rats.
Circulation. 1994;89:2212-2218.
[Abstract/Free Full Text] - Shültz PJ, Raij L. Effects of antihypertensive agents on endothelium-dependent and endothelium-independent relaxations. Br J Clin Pharmacol. 1989;28(suppl 2):151S-157S.
-
Goldschmidt JE, Tallarida RJ. Pharmacological
evidence that captopril possesses an
endothelium-mediated component of vasodilation:
effect of sulfhydryl groups on endothelium-derived
relaxing factor. J Pharmacol Exp Ther.. 1991;257:1136-1145.
[Abstract/Free Full Text] -
Hayakawa H, Hirata Y, Suzuki E, Kimura K, Kikuchi K,
Nagano T, Hirobe M, Omata M. Long-term administration of
L-arginine improves nitric oxide release from kidney in
DOCA–salt hypertensive rats. Hypertension.. 1994;23:752-756.
[Abstract/Free Full Text] -
Vanhoutte PM, Shimokawa H.
Endothelium-derived relaxing factor and
coronary vasospasm. Circulation. 1989;80:1-9.
[Abstract/Free Full Text] -
Chen PY, Sander PW. Role of nitric oxide
synthesis in salt-sensitive hypertension in Dahl/Rapp rats.
Hypertension.. 1993;22:812-818.
[Abstract/Free Full Text] -
Xiao J, Pang PK. Does a general alteration in
nitric oxide synthesis system occur in spontaneously hypertensive
rats? Am J Physiol.. 1994;266:H272-H278.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  Q. Shao, B. Ren, V. Elimban, P. S. Tappia, N. Takeda, and N. S. Dhalla Modification of sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchanger expression in heart failure by blockade of renin-angiotensin system Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2637 - H2646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Shao, B. Ren, H. K. Saini, T. Netticadan, N. Takeda, and N. S. Dhalla Sarcoplasmic reticulum Ca2+ transport and gene expression in congestive heart failure are modified by imidapril treatment Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1674 - H1682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashi, S. Sasaki, K. Nakagawa, H. Matsuura, G. Kajiyama, and T. Oshima Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function J. Am. Coll. Cardiol., March 1, 2001; 37(3): 863 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higashi, S. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study J. Am. Coll. Cardiol., February 1, 2000; 35(2): 284 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. GROSS, W. SCHNEIDER, W.-H. SCHUNCK, E. MERVAALA, and F. C. LUFT Chronic Effects of Lovastatin and Bezafibrate on Cortical and Medullary Hemodynamics in Deoxycorticosterone Acetate-Salt Hypertensive Mice J. Am. Soc. Nephrol., July 1, 1999; 10(7): 1430 - 1439. [Abstract] [Full Text]
|
|
|
|
 |
|
 U. Onaka, K. Fujii, I. Abe, and M. Fujishima Antihypertensive Treatment Improves Endothelium-Dependent Hyperpolarization in the Mesenteric Artery of Spontaneously Hypertensive Rats Circulation, July 14, 1998; 98(2): 175 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashi, T. Oshima, S. Sasaki, Y. Nakano, M. Kambe, H. Matsuura, and G. Kajiyama Angiotensin-Converting Enzyme Inhibition, But Not Calcium Antagonism, Improves a Response of the Renal Vasculature to L-Arginine in Patients With Essential Hypertension Hypertension, July 1, 1998; 32(1): 16 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. M Pinto, M. Paul, and D. Ganten Lessons from rat models of hypertension: from Goldblatt to genetic engineering Cardiovasc Res, July 1, 1998; 39(1): 77 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hayakawa and L. Raij Nitric Oxide Synthase Activity and Renal Injury in Genetic Hypertension Hypertension, January 1, 1998; 31(1): 266 - 270. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||