(Hypertension. 1996;28:361-366.)
© 1996 American Heart Association, Inc.
Articles |
In Vitro Alteration of Aortic Vascular Reactivity in Hypertension Induced by Chronic NG-Nitro-L-Arginine Methyl Ester
Institut National de la Sante et de la Recherche Medicale (INSERM) U141, IFR Circulation–Lariboisiere, Universite Paris VII, Hopital Lariboisiere, and INSERM U367 (J.-B.M.), Paris, France.
Correspondence to D. Henrion, PhD, INSERM U141, Hopital Lariboisiere, 41 Bd de la Chapelle, 75475 Paris, Cedex 10, France.
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Abstract |
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Chronic administration of NG-nitro-L-arginine methyl ester (L-NAME) induces a rise in blood pressure that is prevented by angiotensin I–converting enzyme inhibitors or angiotensin II receptor (type 1) blockade. Alterations in vascular reactivity in this model have not been extensively studied and could potentially be involved in the pathogenesis of L-NAME–induced hypertension. In the present work, we aimed to study the vascular reactivity and cGMP content of aortic ring segments isolated from Wistar rats treated for 3 weeks with L-NAME or L-NAME plus the converting enzyme inhibitor quinapril. Quinapril prevented the rise in blood pressure in L-NAME–treated rats although acetylcholine-induced dilation in aortic rings was suppressed and sodium nitroprusside–induced dilation was increased in both L-NAME– and L-NAME plus quinapril–treated rats. In isolated aortic ring segments, chronic L-NAME decreased the contractile response to K+ (125 mmol/L), phenylephrine, angiotensin II, the G protein stimulator AlF4-, and the protein kinase C activator phorbol dibutyrate. In contrast to the upregulated sodium nitroprusside–induced dilation, the contractile capacity of the aorta in response to angiotensin II, phenylephrine, AlF4-, K+, and phorbol dibutyrate was restored by quinapril. Aortic cGMP was lowered in rats treated with L-NAME (530±120 fmol/mg protein, n=12, P<.05) and L-NAME plus quinapril (461±140 fmol/mg protein, n=12, P<.05) compared with controls (1798±522 fmol/mg protein, n=12). We hypothesize that the continuous nitric oxide blockade by L-NAME might attenuate a continuous endogenous relaxing tone and is associated with an upregulated endogenous vasoconstrictor tone in large arteries. Converting enzyme inhibition interfered more with the increased endogenous constrictor tone than with the decreased vasodilator tone in the wall of large arteries from L-NAME–treated rats.
Key Words: aorta • blood vessels • rats • nitric oxide • angiotensin II • phenylephrine • angiotensin-converting enzyme inhibitors
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Introduction |
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Nitric oxide (NO) has been extensively shown to be a potent vasodilator produced by vascular endothelial cells.1 2 3 The NO-associated intracellular pathway in smooth muscle cells involves the generation of cGMP,1 2 4 a decrease in calcium mobilization,5 6 and inhibition of phosphoinositol breakdown.7 8 NO release can also be triggered by pharmacologically vasoactive substances such as acetylcholine, ADP, bradykinin, serotonin, histamine, and phenylephrine.1 2 3 Chronic NO blockade by L-NAME in normotensive rats has been shown to induce sustained hypertension,9 10 11 suggesting continuous NO release by the endothelium and an active role for NO in the balance between the contraction and dilation of vascular smooth muscle. Chronic NO synthase blockade is associated with a decreased cGMP content in the aorta11 and with no significant change12 13 in plasma renin activity in the early stage of the model.14 Interestingly, L-NAME–induced hypertension is prevented by ACEI, Ang II receptor (type 1) antagonists,12 15 16 17 18 19 an
1-adrenoreceptor antagonist (prazosin), and calcium entry blockers.19 Our hypothesis was that the action of vasoconstrictor agents could be modified by NO blockade in order to adapt to the NO suppression. A previous study has shown that chronic NO blockade induces some changes in the in vitro reactivity of rat aortic rings.19 We designed the present study to further investigate rat aortic vascular reactivity to substances acting at the receptor level (Ang II, phenylephrine) as well as beyond receptor activation, such as the protein kinase C activator phorbol dibutyrate, the G protein stimulator AlF4-, and phenylephrine in the absence of extracellular calcium. We also tested the response of the aorta to acetylcholine and sodium nitroprusside. Aortic ring segments were isolated from rats chronically treated for 3 weeks with L-NAME or L-NAME plus the ACEI quinapril. |
Methods |
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L-NAME Treatment and Aorta Preparation
Young male Wistar rats (Iffa-Credo, Lyon, France) weighing 120 to 130 g were given L-NAME (50 mg/100 mL) in their drinking water for 3 weeks, ensuring a daily intake of L-NAME of 50 mg/kg.11 12 Other rats were given L-NAME (50 mg/100 mL) plus quinapril (10 mg/100 mL; 10 mg/kg) in their drinking water. Control rats were given tap water. After 3 weeks, rats were anesthetized (50 mg/kg pentobarbital IP), and the carotid artery was cannulated (0.6 mm ID) for blood pressure measurement. The cannula was connected to a pressure transducer (Gould P10EZ, Spectramed) and the signal displayed on a chart recorder (Gould, Recording Systems Division). Heparin (1000 IU/kg) was then injected through the cannula, and the thoracic aorta was isolated. Ring segments of aorta, cleaned of fat and connective tissues and 3 mm long, were mounted between two stainless steel wires in 3-mL organ baths containing a physiological salt solution of the following composition (mmol/L): NaCl 135.0, NaHCO3 15.0, KCl 4.6, CaCl2 1.5, MgSO4 1.2, glucose 11.0, and HEPES 5.0. The pH was adjusted to 7.4 with NaOH (1 mol/L), and the solution was bubbled with 95% O2 and 5% O2.20 A physiological salt solution containing 125 mmol/L K+ was prepared using the solution described above but with 14.4 mmol/L NaCl and 125 mmol/L KCl. One wire was attached to a fixed support, and the second wire was connected to a movable holder supporting a tension transducer (FT.03, Grass Instruments) so that isometric force measurements could be collected by a data acquisition system (MP 100, Biopac) and recorded on a computer (Macintosh Quadra 610, Apple Computers) with the Acqknowledge data acquisition and analysis software (Biopac). The artery segments were allowed to recover for 30 minutes, during which time the physiological salt solution was replaced at 15-minute intervals. After this recovery period, a 1-g preload, resulting in optimal stretch, was applied to the aortic segments, which were allowed to equilibrate for an additional 90 minutes.21 The investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Experimental Protocols
Four to eight segments of aorta were isolated per rat, and a concentration-response curve to one of the drugs described below was obtained, preceded by determination of the maximal response to K+ (125 mmol/L) and the dilation to acetylcholine (detailed below). At the end of the experimental protocol, aortic ring segments were blotted dry and weighed.
Concentration-response curves to phenylephrine or Ang II were obtained by cumulative addition of phenylephrine or Ang II to the bath solution. Data are expressed as milligram force, milligram force per milligram tissue, and percentage of K+ (125 mmol/L)–induced contraction. Concentration-response curves to sodium nitroprusside were obtained by cumulative addition of sodium nitroprusside to the physiological salt solution after the aortic segments were preconstricted with a phenylephrine concentration (30 to 300 nmol/L) sufficient to reach approximately 50% of the tissue maximum as determined with K+ (125 mmol/L). Data are expressed as percentage dilation of phenylephrine-induced preconstriction.
In some experiments, phenylephrine (1 µmol/L) was added to the bath solution containing a Ca2+-free physiological salt solution. In such conditions, only calcium released by the sarcoplasmic reticulum on stimulation by inositol triphosphate is involved in the transient contraction observed.8 In other aortic segments, contraction was elicited with either the protein kinase C activator phorbol dibutyrate (1 µmol/L) or the nonspecific G protein stimulator AlF4-. Stimulation with AlF4- was obtained by addition of NaF (5 mmol/L) and AlCl3 (10 µmol/L) to the medium.22
The response to acetylcholine (0.01 to 10 µmol/L) was tested after precontraction of the aorta with a phenylephrine concentration (30 to 300 nmol/L) sufficient to reach approximately 50% of the tissue maximum as determined with K+ (125 mmol/L). Data are expressed as percentage dilation of phenylephrine-induced preconstriction.
Determination of cGMP Concentration
cGMP content of thoracic aortic segments was determined as previously described.11 The thoracic aorta was homogenized in 10 vol HCl (0.1 mol/L) at 4°C. Homogenates were centrifuged at 15 000g for 30 minutes, and aliquots of the supernatants were stored at -20°C until assayed. One aliquot was used for determination of the protein concentration by the Coomassie brilliant blue G-250 method (Bio-Rad Laboratories). cGMP was determined by 125I radioimmunoassay.12
Statistical Analysis
Results are expressed as mean±SE. EC50 (for phenylephrine and Ang II) values were automatically calculated for each individual concentration-response curve with a computer program and the equation E=(EmaxxCn)/(ECn+Cn),23 where E is contraction, Emax is maximal contraction, C is concentration, EC is EC50, and n is Hill's coefficient. IC50 values for sodium nitroprusside and acetylcholine were automatically calculated with a similar equation:23 I=(ImaxxCn)/(ICn+Cn), where I is dilation, Imax is maximal dilation, C is concentration, IC is IC50, and n is Hill's coefficient.
Comparisons between groups were made with a one-factor ANOVA followed by Dunnett's t test when significant or by two-factor ANOVA for repeated measures to compare the concentration-response curves of Ang II, norepinephrine, and sodium nitroprusside. A probability level of less than .05 was considered significant.
Drugs
Quinapril was supplied by Parke Davis–France. All other drugs were purchased from Sigma Chemical Co.
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Results |
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L-NAME treatment induced a significant decrease in rat body weight that was only partly restored by quinapril (Table 1
). Mean arterial pressure measured in the carotid artery was significantly increased by L-NAME. L-NAME–induced hypertension was prevented by quinapril (Table 1).
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Aortic cGMP content was significantly lowered in the L-NAME group (530±120 fmol/mg protein, n=12, P<.05) and the L-NAME plus quinapril group (461±140 fmol/mg protein, n=12, P<.05) compared with controls (1798±522 fmol/mg protein, n=12).
In aortic ring segments, the contractile response to K+ (125 mmol/L) was significantly decreased by L-NAME, whereas it was not significantly different from control in the group treated with L-NAME plus quinapril (Table 1
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Phenylephrine induced a concentration-dependent contraction in aortic ring segments (Fig 1). L-NAME treatment significantly reduced the contractile response of the aorta to phenylephrine as the EC50 increased and the maximal response decreased (Table 2). Nevertheless, when expressed as percentage of K+ (125 mmol/L)–induced maximal contraction, the decrease in maximal contraction due to L-NAME was no longer significant (Fig 1). When quinapril was given to the rats together with L-NAME, no difference in the response to phenylephrine was observed compared with controls (Fig 1, Table 2).
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Ang II produced a concentration-dependent increase of wall tension in aortic ring segments (Fig 2). L-NAME treatment reduced significantly the contractile response to Ang II as shown by the increase in EC50 and decrease in maximal response (Table 2). This decreased contraction to Ang II was significant even when data were expressed as percentage of K+ (125 mmol/L)–induced contraction (Fig 2). In the L-NAME plus quinapril–treated rats, the contraction of the aorta to Ang II was restored to the control level and was even increased above the control level when expressed as percentage of K+ (125 mmol/L)–induced contraction (Fig 2).
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The G protein activator AlF4- induced a contraction (189±23 mg/mg tissue, n=7) in control aortic rings that was equivalent to 37±5% (n=7) of K+ (125 mmol/L)–induced contraction. AlF4--induced contraction was significantly attenuated by L-NAME treatment. In the L-NAME plus quinapril group, contraction of the aorta in response to AlF4- was restored to the control level. The difference between the control and L-NAME groups was not significant when data were expressed as percentage of K+ (125 mmol/L)–induced contraction (Fig 3).
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Phenylephrine (1 µmol/L)–induced contraction in a Ca2+-free medium (154±29 mg/mg tissue, n=7) represented 24±3% (n=7) of K+ (125 mmol/L)–induced contraction. This contraction was significantly lowered by L-NAME. In the L-NAME plus quinapril group, contraction of the aorta to phenylephrine in a Ca2+-free medium was identical to control levels. The difference between control and L-NAME groups was not significant when data were expressed as percentage of K+ (125 mmol/L)–induced contraction (Fig 3).
Phorbol dibutyrate (1 µmol/L) contracted aortic rings (483±53 mg/mg tissue, n=10) to 93±3% (n=10) of K+ (125 mmol/L)–induced contraction. Phorbol dibutyrate (1 µmol/L)–induced contraction was significantly decreased by L-NAME when data were expressed as milligrams per milligram tissue but not when data were expressed as percentage of K+ (125 mmol/L)–induced contraction. In the L-NAME plus quinapril group, contraction of the aorta to phorbol dibutyrate in a Ca2+-free medium was not significantly different from control levels (Fig 3).
The data from contractile experiments with K+ (125 mmol/L), phenylephrine, Ang II, AlF4-, phorbol dibutyrate, and phenylephrine in a Ca2+-free medium were not significantly affected when expressed as milligrams of force per milligram tissue or as milligrams of force.
In the control group, acetylcholine (0.01 to 100 µmol/L) induced a concentration-dependent dilation of aortic rings precontracted with phenylephrine (IC50 and maximal dilation in Table 2). Acetylcholine (0.01 to 100 µmol/L) failed to dilate aortic rings preconstricted with phenylephrine in both L-NAME– and L-NAME plus quinapril–treated rats (Table 2).
Sodium nitroprusside induced a concentration-dependent dilation of aortic rings precontracted with phenylephrine (Fig 4). Preconstriction levels did not differ significantly among the three groups (50±6%, n=16; 59±5%, n=14; and 60±8%, n=9; as percentage of K+ [125 mmol/L]–induced contraction in control, L-NAME, and L-NAME plus quinapril groups, respectively). L-NAME, both with and without quinapril, increased the sensitivity of the aorta to sodium nitroprusside, as the IC50 was significantly decreased, with no change in maximal dilation (Table 2). Sodium nitroprusside had no effect on aortic segments from all groups in the absence of preconstriction.
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Discussion |
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The present study provides evidence that chronic L-NAME administration in rat aorta in vitro is linked to a change in the vascular reactivity of the aorta to constrictor agents, an increase in reactivity to the vasodilator sodium nitroprusside, a suppression of acetylcholine-induced dilation, and a decrease in cGMP content. ACEI treatment prevented both hypertension and in vitro hyporeactivity to exogenous vasoconstrictors but not the decrease in cGMP and the upregulated sodium nitroprusside–induced dilation in vitro.
L-NAME administered chronically to rats induces a sustained hypertension that is entirely or partly prevented by ACEI (present study and Reference 15) or the Ang II receptor blocker losartan.12 14 15 16 18 19 This systemic hypertension has been suggested to be due to a decrease in the continuous NO production by the vascular endothelium.1 2 3 In the present study, we found in aortic rings isolated from L-NAME–treated rats that acetylcholine-induced dilation was suppressed and cGMP content decreased. This is consistent with previous observations that acute1 and chronic19 L-NAME treatment attenuates vasodilations because of blockade of NO production and that chronic L-NAME decreases aortic cGMP content without affecting the ability of the vessel to produce cGMP on stimulation by an NO donor.11 The concurrent increase in sensitivity to sodium nitroprusside might be regarded as a consequence of the hypostimulated state of the guanylate cyclase.2 Thus, less endogenous vasodilator tone, caused by the absence of endogenous NO production, induced an increase in the response of the aorta to pharmacologically active NO donors. The chronic L-NAME–induced decrease in endothelium-dependent vasodilation was not prevented by ACEI. This contrasts with the observation by Kung et al19 that acetylcholine-induced dilation in rat aorta, which was attenuated by treatment with L-NAME for 6 weeks, was restored totally by a calcium entry blocker and partially by an ACEI. One main difference with our study is that we used a 3-week treatment, and L-NAME–induced hypertension is not associated with a change in plasma renin activity at this early stage, whereas after 6 weeks, plasma renin activity might be increased.12 13 Another major difference is that Kung et al stopped the treatments 2 to 3 days before the experiments.
Chronic L-NAME treatment was associated with a decreased vascular reactivity of the aorta in vitro to exogenously added phenylephrine, Ang II, and drugs acting beyond receptor activation. We have recently shown that acute NO blockade differed from chronic NO blockade with L-NAME. Acute L-NAME administration was associated with an increased vascular reactivity in vitro, whereas chronic L-NAME treatment induced a hyporeactivity to the same stimulus in the same vessel in vitro.24 Responses to the nonspecific G protein stimulator AlF4-,22 to the protein kinase C activator phorbol dibutyrate,25 and to phenylephrine in the absence of extracellular calcium were decreased. In the absence of extracellular calcium, phenylephrine induces a transient contraction caused by calcium release from the sarcoplasmic reticulum.26 Moreover, the contraction caused by KCl, which activates directly the contractile apparatus by allowing massive calcium entry on depolarization of the plasma membrane,27 was attenuated. Thus, the smooth muscle contractile response seems globally attenuated in response to exogenous agents.
These observations contrast with the acute effect of L-NAME, which leads to an increase in vascular reactivity in response to vasoconstrictor agents.24 28 29 30 Thus, chronic NO blockade might induce a downregulation by chronic hyperstimulation of the contractile signaling pathways in aortic smooth muscle cells. This would be a response to an increased endogenous tonic contractile state in response to a normal level of contractile agonists, as previously shown.18 31 32 This is supported by the observations that either ACEI or angiotensin receptor blockers can prevent L-NAME–induced hypertension (References 12, 14, 17 through 19, and the present study) and that plasma renin activity is not changed or is slightly decreased in the early stages of this model.3 13 In the presence of L-NAME plus a vasodilator agent (ACEI, Ang II blocker, prazosin, or calcium entry blocker),12 14 17 18 19 both the dilator and constrictor stimuli are attenuated by L-NAME and ACEI, respectively. Therefore, if the endogenous vascular tone may be regarded as a balance between an endogenous constrictor tone and an endogenous dilator tone, NO blockade would decrease the endogenous dilator tone, thus leading to hypertension, and the ACEI would decrease the endogenous constrictor tone, thus restoring the balance. This is in agreement with previous observations showing that Ang II contributes to an endogenous continuous vasoconstrictor tone, probably by potentiating sympathetically mediated vasoconstriction.33 34 35 36 Moreover, Ang II–induced tone is associated with an endothelium- and NO-dependent increase in vascular cGMP production.37 The lack of such a compensatory endogenous dilator tone might lead to an increased response to a normal level of Ang II. We have also found that chronic infusion of a low concentration of Ang II to rats leads to downregulation of the contractile response of the aorta to KCl, phenylephrine, and Ang II38 and to an increased endogenous potentiating effect of Ang II in resistance arteries.38 39
These results obtained at a tissue level in a chronic stage agree with results obtained at the cellular level showing that in smooth muscle cell, in the presence of G kinase, cGMP decreases the vasoconstrictor pathway stimulated by agonists.7 8 At variance with our work is the result of Kung et al,19 who have shown that chronic L-NAME induced no change in the response of the aorta to KCl, norepinephrine, and Ang II, even though the response to endothelin-1 was decreased. As the species studied and duration of the treatment were different, a comparison is difficult (as discussed above). Nevertheless, compared with other models of hypertension, the two studies do not show an increased vascular reactivity to exogenous contractile agonists. In other models of hypertension, such as spontaneous hypertension or hypertension of renal origin, vascular reactivity is most commonly increased.40 Hypertension induced by deoxycorticosterone acetate–salt has been compared with L-NAME–induced hypertension, as both models are related to renal angiopathy.14 Nevertheless, the comparison does not apply to vascular reactivity, at least in the aorta. In deoxycorticosterone acetate–salt hypertension, vascular reactivity to vasoconstrictor agents40 41 and especially to Ang II39 40 is also increased. Another pathway by which NO synthase inhibition could be counterbalanced is by an overproduction of cyclooxygenase products, as suggested by a previous study.19 Thus, multiple pathways might be triggered in response to chronic NO synthase inhibition. Further investigations are certainly needed to elucidate the mechanism or mechanisms involved in L-NAME–induced hypertension, and more studies in resistance arteries would be particularly helpful.
We observed an increased maximal response to Ang II in aortic segments from rats treated with L-NAME and quinapril. This could reflect at least in part an increase in Ang II receptor density caused by the decrease in Ang II production during ACEI treatment.
In conclusion, our in vitro data provide a pharmacological profile of the in vitro vascular reactivity of aortic rings isolated from rats treated chronically with the NO synthase blocker L-NAME. They suggest that chronic L-NAME administration might be associated with a chronic decrease in endogenous vasodilator tone and with a chronic increase in endogenous vasoconstrictor tone in the aorta, leading to a certain degree of downregulation of the responsiveness of the contractile apparatus as observed in vitro. Therefore, ACEI could block the upregulated vasoconstrictor tone, even though the vasodilator tone remained low because of NO blockade, and thus reequilibrate the balance between endogenous vasodilator tone and endogenous vasoconstrictor tone.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by a grant from Parke Davis–France. Fiona J. Dowell is a Wellcome Travelling Research Fellow.
Received October 17, 1995; first decision November 24, 1995; accepted May 13, 1996.
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 G. Rossoni, B. Manfredi, P. Del Soldato, and F. Berti The Nitric Oxide-Releasing Naproxen Derivative Displays Cardioprotection in Perfused Rabbit Heart Submitted to Ischemia-Reperfusion J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 555 - 562. [Abstract] [Full Text] [PDF]
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 M.-C. Bouton, B. Richard, P. Rossignol, M. Philippe, M.-C. Guillin, J.-B. Michel, and M. Jandrot-Perrus The Serpin Protease-Nexin 1 Is Present in Rat Aortic Smooth Muscle Cells and Is Upregulated in L-NAME Hypertensive Rats Arterioscler. Thromb. Vasc. Biol., January 13, 2003; 23(1): 142 - 147. [Abstract] [Full Text] [PDF]
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P. Jolma, J. Kalliovalkama, J.-P. Tolvanen, P. Koobi, M. Kahonen, N. Hutri-Kahonen, X. Wu, and I. Porsti High-calcium diet enhances vasorelaxation in nitric oxide-deficient hypertension Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1036 - H1043. [Abstract] [Full Text] [PDF]
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M. N. Muscara, W. McKnight, F. Lovren, C. R. Triggle, G. Cirino, and J. L. Wallace Antihypertensive properties of a nitric oxide-releasing naproxen derivative in two-kidney, one-clip rats Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H528 - H535. [Abstract] [Full Text] [PDF]
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 W. Gonzalez, V. Fontaine, M. E. Pueyo, N. Laquay, D. Messika-Zeitoun, M. Philippe, J.-F. Arnal, M.-P. Jacob, and J.-B. Michel Molecular Plasticity of Vascular Wall During NG-Nitro-L-Arginine Methyl Ester-Induced Hypertension : Modulation of Proinflammatory Signals Hypertension, July 1, 2000; 36(1): 103 - 109. [Abstract] [Full Text] [PDF]
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 A. B. Driss, C. Devaux, D. Henrion, M. Duriez, C. Thuillez, B. I. Levy, and J.-B. Michel Hemodynamic Stresses Induce Endothelial Dysfunction and Remodeling of Pulmonary Artery in Experimental Compensated Heart Failure Circulation, June 13, 2000; 101(23): 2764 - 2770. [Abstract] [Full Text] [PDF]
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 J. Kalliovalkama, P. Jolma, J.-P. Tolvanen, M. Kahonen, N. Hutri-Kahonen, X. Wu, P. Holm, and I. Porsti Arterial function in nitric oxide-deficient hypertension: influence of long-term angiotensin II receptor antagonism Cardiovasc Res, June 1, 1999; 42(3): 773 - 782. [Abstract] [Full Text] [PDF]
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G. Luvara, M. E. Pueyo, M. Philippe, C. Mandet, F. Savoie, D. Henrion, and J.-B. Michel Chronic Blockade of NO Synthase Activity Induces a Proinflammatory Phenotype in the Arterial Wall : Prevention by Angiotensin II Antagonism Arterioscler. Thromb. Vasc. Biol., September 1, 1998; 18(9): 1408 - 1416. [Abstract] [Full Text] [PDF]
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N. L. Kanagy Increased vascular responsiveness to alpha 2-adrenergic stimulation during NOS inhibition-induced hypertension Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2756 - H2764. [Abstract] [Full Text] [PDF]
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A. Montanari, E. Tateo, E. Fasoli, D. Giberti, P. Perinotto, A. Novarini, and P. Dall'Aglio Angiotensin II Blockade Does Not Prevent Renal Effects of L-NAME in Sodium-Repleted Humans Hypertension, September 1, 1997; 30(3): 557 - 562. [Abstract] [Full Text]
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