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Am J Physiol Heart Circ Physiol 290: H684-H691, 2006; doi:10.1152/ajpheart.00632.2005
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Angiotensin-(1–7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME

Ibrahim F. Benter,1 Mariam H. M. Yousif,1 J. T. Anim,2 C. Cojocel,1 and D. I. Diz3

Departments of 1Pharmacology and Toxicology and 2Pathology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait; and 3The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 13 June 2005 ; accepted in final form 5 August 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We examined the influence of chronic treatment with ANG-(1–7) on development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with the nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). L-NAME administered orally (80 mg/l) for 4 wk significantly elevated mean arterial pressure (MAP) compared with SHR controls drinking regular water (269 ± 10 vs. 196 ± 6 mmHg). ANG-(1–7) (24 µg·kg–1·h–1) or captopril (300 mg/l) significantly attenuated the elevation in MAP due to L-NAME (213 ± 7 and 228 ± 8 mmHg, respectively), and ANG-(1–7) + captopril completely reversed the L-NAME-dependent increase in MAP (193 ± 5 mmHg). L-NAME-induced increases in urinary protein were significantly lower in ANG-(1–7)-treated animals (226 ± 6 vs. 145 ± 12 mg/day). Captopril was more effective (96 ± 12 mg/day), and there was no additional effect of captopril + ANG-(1–7) (87 ± 5 mg/day). The abnormal vascular responsiveness to endothelin-1, carbachol, and sodium nitroprusside in perfused mesenteric vascular bed of SHR-L-NAME was improved by ANG-(1–7) or captopril, with no additive effect of ANG-(1–7) + captopril. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1–7)- or captopril-treated SHR-L-NAME, with additive effects of combined treatment. The beneficial effects of ANG-(1–7) on MAP and cardiac function were inhibited when indomethacin was administered with ANG-(1–7), but indomethacin did not reverse the protective effects on proteinuria or vascular reactivity. The protective effects of the ANG-(1–7) analog AVE-0991 were qualitatively comparable to those of ANG-(1–7) but were not improved over those of captopril alone. Thus, during reduced nitric oxide availability, ANG-(1–7) attenuates development of severe hypertension and end-organ damage; prostaglandins participate in the MAP-lowering and cardioprotective effects of ANG-(1–7); and additive effects of captopril + ANG-(1–7) on MAP, but not proteinuria or endothelial function, suggest common, as well as different, mechanisms of action for the two treatments. Together, the results provide further evidence of a role for ANG-(1–7) in protective effects of angiotensin-converting enzyme inhibition and suggest dissociation of factors influencing MAP and those influencing end-organ damage.

angiotensin II; captopril; indomethacin; heart; AVE-0991

NORMAL CARDIOVASCULAR AGING is associated with decreased endothelium-mediated vasodilation and development and progression of vascular disease. Cardiovascular risk factors, such as hypertension, hyperlipidemia, and insulin resistance/diabetes, are associated with endothelial dysfunction (6, 45). Reduced bioavailability of nitric oxide (NO) in the setting of increased NADPH oxidase activity is a common underlying abnormality in these conditions. In hypertension, the delicate balance between the vasodilators and the vasoconstrictors is upset, with disturbance in the NO pathways that leads to a predominance of the vasoconstrictors. This may lead to a vicious cycle that maintains the high blood pressure and produces end-organ damage (30, 42). An animal model representative of clinical hypertension has been developed by chronic inhibition of NO synthase in spontaneously hypertensive rats (SHR) with nitro-L-arginine methyl ester (SHR-L-NAME). In this model of endothelial dysfunction and severe hypertension, prolonged inhibition of NO synthase produces oxidative stress and inflammatory changes accompanied by morphological and functional changes, such as marked proteinuria and severe hypertensive nephrosclerosis, as well as myocardial fibrosis and infarction, all pathological conditions that are consistent with clinical hypertensive disease (9, 14–16, 34, 35, 44). The myriad of changes in SHR-L-NAME are prevented by treatment with an angiotensin-converting enzyme (ACE) inhibitor, indicating that ANG II-induced intracellular signaling is likely a major influence in this model (9, 42–44).

ANG-(1–7), a biologically active peptide of the renin-angiotensin system (RAS), is formed from ANG I and ANG II by several endopeptidases and carboxypeptidases, including ACE-2 (1, 2, 7, 10, 24). ANG-(1–7), a vasodilator peptide, has been shown to have antithrombotic and antiproliferative properties (22, 23, 41). The effects of ANG-(1–7) are mediated by a non-ANG II type 1 or type 2 (AT1/AT2) receptor, which stimulates release of vasodilatory prostaglandins and NO (1, 7, 10, 21, 41). During ACE inhibition or AT1 blockade, ANG-(1–7) plasma levels are elevated; therefore, it has been suggested that part of the effects of ACE inhibitors and AT1 blockers may be mediated through ANG-(1–7) (10, 18–21). Neutralization of endogenous ANG-(1–7) reverses the antihypertensive effects of RAS blockade, and blockade of ANG-(1–7) stimulates a vasoconstrictor response in dietary salt-restricted SHR and [mRen-2]27 transgenic hypertensive rats (18–21). Furthermore, blockade of AT1–7 receptors reversed as much as 32% of the blood pressure-lowering effect of losartan (31). A recent study showed that blockade of AT1 receptors in SHR results in increased expression of ACE-2 and ANG-(1–7) and pressure-independent prevention of vascular remodeling of vasculature (17). Thus the present study was designed to determine whether chronic treatment with ANG-(1–7) can attenuate development of high blood pressure and end-organ damage in SHR-L-NAME. We also studied the effects of treatment with the ANG-(1–7) analog AVE-0991 (36, 46).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental procedures. Male 17-wk-old Wistar-Kyoto (WKY) rats and SHR were assigned to 10 groups: WKY and SHR controls with regular drinking water (groups 1 and 2, respectively), SHR with L-NAME in the drinking water (80 mg/l for 4 wk, SHR-L-NAME, group 3), SHR-L-NAME treated daily with ANG II (24 µg·kg–1·h–1 ip, group 4), SHR-L-NAME treated with ANG-(1–7) (24 µg·kg–1·h–1 ip) for 4 wk (group 5), SHR-L-NAME treated with ANG-(1–7) (24 µg·/kg·/h ip) + indomethacin (1.0 mg·kg–1·day–1 ip) for 4 wk (group 6), SHR-L-NAME treated with captopril in the drinking water (300 mg/l) for 4 wk (group 7), SHR-L-NAME treated with captopril + ANG-(1–7) (24 µg·kg–1·h–1 ip, group 8), and rats treated with AVE-0991 (24 µg·kg–1·h–1 ip) daily alone and with captopril in the drinking water (300 mg/l) for 4 wk (groups 9 and 10, respectively). Analyses were performed by investigators who were blinded to the treatment groups. The investigation conforms to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985) and was approved by Kuwait University Research Administration as the use of animals was in accordance with Institute for Laboratory Animal Research Guide for Care and Use of Laboratory Animals.

Blood pressure measurement. Animals were anesthetized with pentobarbital sodium (60 mg/kg), and the left femoral artery was exposed surgically. A small incision was made in the femoral artery, and a catheter was inserted and connected to a pressure transducer for blood pressure measurement. Mean arterial pressure (MAP, mmHg) was recorded on a polygraph.

Urine volume and protein determination. At the end of the 4-wk treatment period, the animals were placed in metabolic cages, and food and water were provided ad libitum. Metabolic cages provided an effective separation of feces and urine into tubes outside the cage. Urine was collected for 24 h. During this period, tubes used for urine collection were immersed in an ice-cold water bath to avoid loss of enzyme activity. Total protein concentration in the urine was determined using the method of Schacterle and Pollack (38). Lysozyme activity in the urine was determined as described previously (8).

Vascular reactivity experiments. Vascular reactivity in response to endothelin-1 (ET-1), carbachol, and sodium nitroprusside (SNP) was determined as described previously (3).

Isolation of the mesenteric vascular bed. The mesenteric beds were isolated carefully and transferred to a petri dish containing oxygenated Krebs-Henseleit (KH) solution. The mesenteric artery was cannulated using a polyethylene cannula, and the mesenteric bed was placed in a warm water-jacketed chamber at 37°C. The preparation was perfused with KH solution (at 37°C), oxygenated with 95% O2-5% CO2, and delivered at a constant flow rate of 6 ml/min via a multichannel Masterflex peristaltic pump. The composition of KH solution was as follows (mM): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 25 NaHCO3, 1.2 KH2PO4, and 11.2 glucose. Changes in perfusion pressure that reflect peripheral resistance were measured. Perfusion pressure was recorded via a pressure transducer connected to a Lectromed chart recorder. The preparation was always allowed to equilibrate for ≥30 min. A bolus injection of norepinephrine (NE, 100 nmol) was usually given at the beginning of the experiment as a test for tissue responsiveness.

Vasoconstriction studies. The vasoconstrictor response to ET-1 (0.01, 0.1, and 1.0 nmol) was investigated in the perfused mesenteric vascular bed. After the period of equilibration, successive doses of ET-1 were given at regular intervals to establish the vasoconstrictor responses (mmHg).

Vasodilation studies. The vasodilator responses to carbachol and SNP were investigated in the perfused mesenteric vascular bed. After the period of equilibration, the perfused mesenteric bed was constricted by perfusion with KH solution containing 10–5 M NE. After a steady level of precontraction was established, successive doses of carbachol (1 and 10 nmol) or SNP (0.1, 1.0, and 10 nmol) were given at regular intervals. The vasodilator response is expressed as percentage of the precontraction induced by 10–5 M NE.

Histological examination. Pieces of kidney, heart, and mesentery were fixed in 10% buffered formalin and processed routinely into paraffin sections (5 µm) that were stained with hematoxylin and eosin. Changes in the glomeruli, arterioles, and arteries of the kidney tissue were graded semiquantitatively on a scale of 0–5 (see Table 2). Changes in arterial and arteriolar walls in the mesentery were similarly graded. Presence of myocardial changes was also graded on a scale of 0–5 (see Table 2). All grading was done by a investigator blinded to the treatment groups.


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  		Table 2. Effect of ANG-(1–7) and AVE-0991 on L-NAME-induced pathology

 
Heart perfusion studies. Rats were lightly anesthetized with thiopental sodium (Intraval Sodium, 40 mg/kg body wt), and hearts were rapidly removed after administration of heparin (1,000 U/kg body wt iv). The excised hearts were immediately mounted on a Langendorff perfusion assembly (model ML870B2, ADI Instruments) and perfused initially with a constant pressure perfusion of 50 mmHg with oxygenated (95% O2-5% CO2) KH buffer (37°C). A water-filled balloon was introduced into the left ventricle and connected to a Statham pressure transducer (model P23Db), and balloon volume was adjusted to give the baseline end-diastolic pressure of 5 mmHg. Left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP) were continuously monitored. Coronary flow (CF) was measured via an electromagnetic flow probe positioned in the inflow tubing immediately above the aortic perfusion cannula. Perfusion pressure was measured immediately downstream from the flow probe in a branch of the aortic cannula via a Statham pressure transducer and was electronically maintained constant at 50 mmHg via a perfusion pressure control module. This system permits accurate adjustment of perfusion pressure between 5 and 300 mmHg to an accuracy of ±1 mmHg. Hearts were perfused for 30 min and then subjected to 40 min of ischemia followed by 30 min of reperfusion (I/R). Post-I/R left ventricular contractility and hemodynamics were recorded and compared.

Statistical analysis. MAP, urine volume and protein, and vascular reactivity were analyzed using GraphPad Prism software. Values are means ± SE. Mean values were compared using analysis of variance followed by Bonferroni’s post hoc test. The difference was considered to be significant at P < 0.05. Heart perfusion results are expressed as means ± SE. Reperfusion values were compared with their respective baseline controls using a two-tailed paired t-test. Different experimental groups were compared by a general factorial analysis of variance. Computerized statistical analysis was accomplished with SPSS for Windows (version 6.0.1, SPSS, Evanston, IL). Further comparisons were made by obtaining univariate Scheffé’s confidence intervals for the parametric estimates.

Drugs. dl-Norepinephrine bitartrate, L-NAME, ANG-(1–7), captopril, SNP, ET-1, ANG II, indomethacin, and carbachol were obtained from Sigma. AVE-0991 was a gift from Aventis.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
MAP. Administration of L-NAME in drinking water for 4 wk significantly elevated MAP compared with that of SHR controls drinking regular water (269 ± 10 vs. 196 ± 6 mmHg, P < 0.05; Table 1). MAP was significantly reduced in SHR-L-NAME treated with ANG-(1–7), captopril, or captopril + ANG-(1–7), and there was an additive effect of the combined treatment. In the ANG-(1–7)-infused animals treated with indomethacin, the reduction in MAP with ANG-(1–7) alone was prevented. SHR-L-NAME + ANG II resulted in a significant increase in MAP compared with SHR-L-NAME (Table 1). AVE-0991 alone or AVE-0991 + captopril (231 ± 8 and 217 ± 8 mmHg, respectively) caused comparable prevention of elevation in MAP similar to that of treatment with ANG-(1–7) alone or with captopril (Table 1). Consistent with the extreme hypertension in the SHR-L-NAME and SHR-L-NAME + ANG II groups, deaths occurred (4 and 1, respectively); there were no deaths in the other groups.


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  		Table 1. Effect of ANG-(1–7) and AVE-0991 on MAP and kidney function

 
Urine volume and protein. L-NAME resulted in a significant increase in urine volume (22 ± 4 ml/24 h) and urine protein (226 ± 6 mg/24 h) compared with vehicle-treated SHR (Table 1). Urine volume was lower in groups 6–8, whereas ANG-(1–7) alone did not affect urine volume. SHR-L-NAME + ANG-(1–7), SHR-L-NAME + captopril, SHR-L-NAME + ANG-(1–7) + indomethacin, and SHR-L-NAME + ANG-(1–7) + captopril significantly reduced urine protein compared with SHR-L-NAME (Table 1). There was no additive effect of the combined treatments, and indomethacin did not reverse the beneficial effects of ANG-(1–7). Similar effects were observed when urine volume and protein were expressed per gram body weight (data not shown). The L-NAME-induced increase in urinary protein was significantly lower in ANG-(1–7)- than in AVE-0991-treated animals (145 ± 12 vs. 188 ± 8 mg/24 h, P < 0.05), and urinary protein in animals treated with captopril + AVE-0991 was not different from that in animals treated with captopril alone (72 ± 12 and 96 ± 12 mg/24 h, respectively).

Vascular reactivity studies. ET-1-induced vasoconstriction was significantly augmented (P < 0.05) in the perfused mesenteric beds from the SHR-L-NAME group compared with the WKY or SHR group (Fig. 1). SHR-L-NAME + ANG-(1–7), SHR-L-NAME + captopril, or SHR-L-NAME + AVE-0991 significantly attenuated the vasoconstrictor response to ET-1 (1.0 nmol) in the perfused mesenteric vascular bed (P < 0.05; Fig. 1). There was no additive effect of treatment with ANG-(1–7) + captopril or AVE-0991 + captopril. Indomethacin tended to reverse the protective effects of ANG-(1–7).



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  		Fig. 1. Vasoconstriction induced by 1.0 nmol endothelin-1 in perfused mesenteric vascular bed of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) treated with nitro-L-arginine methyl ester (L-NAME), ANG-(1–7), indomethacin, captopril, and/or AVE-0991. Values are means ± SE (n = 6). *Significantly different from WKY. **Significantly different from SHR. #Significantly different from SHR-L-NAME.

 
The vasodilator response to carbachol or SNP was significantly reduced in the perfused mesenteric vascular bed of the SHR-L-NAME group compared with the WKY or SHR group (P < 0.05; Fig. 2). SHR-L-NAME with ANG-(1–7), captopril, ANG-(1–7) + indomethacin, or AVE-0991 fully restored the impaired carbachol- and SNP-induced vasodilation (P < 0.05; Figs. 2 and 3). There was no additive effect of combination treatment with ANG-(1–7) + captopril or AVE-0991 + captopril, and indomethacin did not reverse the effects of ANG-(1–7).



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  		Fig. 2. Vasodilation induced by 10.0 nmol carbachol in perfused mesenteric vascular bed of WKY and SHR treated with L-NAME, ANG-(1–7), indomethacin, captopril, and/or AVE-0991. Values are means ± SE (n = 6). **Significantly different from SHR. #Significantly different from SHR-L-NAME.

 


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  		Fig. 3. Vasodilation induced by 10.0 nmol sodium nitroprusside in perfused mesenteric vascular bed of WKY and SHR treated with L-NAME, ANG-(1–7), indomethacin, captopril, and/or AVE-0991. Values are means ± SE (n = 6). **Significantly different from SHR. #Significantly different from SHR-L-NAME.

 
Histological examination. Our results showed lower grades of hypertensive changes in the kidneys of animals treated with ANG-(1–7), captopril, or AVE-0991 than in the SHR-L-NAME group. Corresponding changes were also noted in the mesenteric vessels and the myocardium. Table 2 summarizes the semiquantitative analysis of morphological changes among the groups. Figure 4 illustrates the attenuation of damage in the ANG-(1–7)-treated SHR-L-NAME group relative to the vehicle-treated SHR-L-NAME group.



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  		Fig. 4. Top: representative photomicrographs showing normal myocardium (grade 0) of normal WKY rat (A), small areas of myocardial fibrosis (grade 1) of SHR (B), extensive myocardial fibrosis (grade 4) with only a few surviving hypertrophic fibers (arrows) of SHR-L-NAME (C), and myocardium of SHR-L-NAME + ANG-(1–7) with a focus (grade 2) of fibrosis (asterisk, D). Middle: representative photomicrographs showing a normal (grade 0) small intrarenal arteriole (arrow) of normal WKY rat (A), medial thickening (grade 1) of a small intrarenal artery of SHR (B), fibrinoid necrosis of intrarenal arteriole (arrow) with "onion skin" change and hemorrhage (grade 5) of SHR-L-NAME (C), and medial thickening (grade 1) of a small intrarenal artery (arrow) of SHR-L-NAME + ANG-(1–7) (D). Bottom: representative photomicrographs showing normal small mesenteric artery (grade 0) of normal WKY rat (A), moderate thickening of media (grade 1) of small mesenteric artery of SHR (B), moderate thickening of media (grade 2) of small mesenteric arteries of SHR-L-NAME (C), and mild thickening (grade 1) of small mesenteric arteries of SHR-L-NAME + ANG-(1–7) (D). Hematoxylin and eosin stain; magnification x250.

 
Cardiac recovery from I/R. Pmax, LVEDP, and CF values are shown in Tables 3 and 4. The hearts of the SHR-L-NAME group did not recover after 40 min of global ischemia. Left ventricular contractility and CF of ANG-(1–7)- or AVE-0991-treated SHR-L-NAME were similar to those of SHR. Indomethacin attenuated the beneficial effects of ANG-(1–7) on contractility and flow. Captopril treatment resulted in a trend of improvement similar to that produced by ANG-(1–7). ANG-(1–7)-treated SHR-L-NAME hearts appeared to have better left ventricular recovery values (Pmax) than captopril-treated SHR-L-NAME hearts, but the differences between these two groups were not statistically significant. ANG-(1–7) + captopril produced significantly better results than captopril alone. AVE-0991 + captopril did not result in additive protection of cardiac parameters. There tended to be slightly less correction of CF with AVE-0991 than with ANG-(1–7) (12 ± 2 and 18 ± 4% recovery, respectively); overall, however, the values were similar to those with ANG-(1–7) or captopril with no additive effects.


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  		Table 3. Effect of ANG-(1–7) and AVE-0991 on postischemic recovery in global contractility

 

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  		Table 4. Effect of ANG-(1–7) and AVE-0991 on postischemic recovery in coronary flow

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The results of the present study show that ANG-(1–7) can attenuate development of high blood pressure and end-organ damage in SHR with significant endothelial dysfunction produced by chronic inhibition of NO synthesis. The beneficial effects of chronic ANG-(1–7) treatment included a modest, but significant, decrease in MAP, improvement in proteinuria and other indexes of reduced renal damage, restoration of normal vascular reactivity to constrictor and dilator stimuli, and protection of the heart in response to global ischemia. Interestingly, the effects were comparable to those of an ACE inhibitor, as previously reported in SHR (2). Indomethacin in combination with ANG-(1–7) prevented the ANG-(1–7)-mediated decrease in MAP and cardioprotection, indicating that prostaglandins are involved. This observation is in agreement with previous studies where ANG-(1–7) has been shown to produce relaxation in several vascular preparations and intact rats by stimulating release of prostaglandins (1, 2, 10, 21, 41). Finally, combination of ANG-(1–7) with captopril further lowered MAP and provided more cardiac protection than each agent alone, suggesting additive actions with respect to the components mediated by prostanoids.

Although the present experiments did not attempt to investigate the precise mechanisms involved in the overall effects of ANG-(1–7), it is well known that actions of the peptide include release of prostaglandins [primarily prostacyclin (PGI2)] and NO and potentiation of the actions of and release or protection of kinins (1, 2, 5, 25). In addition, during ACE inhibition, levels of the peptide increase almost threefold, which is similar to the level achieved with the dose of ANG-(1–7) used in the present studies (7, 10). Evidence exists that the blood pressure-lowering effects of ACE inhibition are due in part (~30%) to the actions of the elevated ANG-(1–7) and that this component involves prostaglandins (18–21). Thus it is to be expected that some overlap may occur in the beneficial effects of the two treatments used in our study. However, it is important to emphasize that, through these interrelated mechanisms, we may also gain insight into the two major characteristics of the responses observed in the present studies. As indicated above, MAP and cardiac responses of ANG-(1–7) were mediated by prostanoids, and the actions were additive with ACE inhibition. Because ANG-(1–7) levels increase threefold with an ACE inhibitor, the additive effects may be due to an additional increase in plasma ANG-(1–7) as a result of the infusion due to decreased metabolism of the peptide (10). The increase in ANG-(1–7) would contribute to increases in prostanoids and potentiate responses to kinins, thus providing physiological antagonism of the actions of ANG II, which is incompletely lowered during chronic ACE inhibition. On the other hand, the effects of ANG-(1–7) on proteinuria were not mediated by prostaglandins and were not additive with ACE inhibition. ANG II effects in the kidney microvasculature are predominantly reduced by NO, and proteinuria is a result of unchecked actions of ANG II on the glomerular circulation in the absence of this key modulator (29, 33, 35). NO also plays a significant role in the response to ANG-(1–7) and kinins in the vasculature (5, 25). Thus this mechanism of protection by ANG-(1–7) or the ACE inhibitor and their effects on kinins would be absent in L-NAME-treated animals, and the loss of this component would prevent additive effects on renal injury, but not blood pressure or cardiac effects, which involved prostanoids to a greater degree. The dissociation of effects on MAP and proteinuria would also be consistent with the differences in mechanisms of protection provided by the two treatments individually and in combination and is consistent with previous reports in this model of severe hypertension (33). A comparison of the combined effects of the two treatments in SHR vs. SHR-L-NAME would be required to confirm the above possibilities.

L-NAME significantly increased proteinuria, a marker of renal injury. This finding is consistent with histological evidence of increased renal damage in the NO-deficient animals. ANG II treatment further damaged the kidneys, as indicated by a substantial increase in proteinuria, whereas ANG-(1–7) significantly attenuated proteinuria and improved the histological indexes of renal damage. On the other hand, captopril treatment was more effective than ANG-(1–7) in protecting the kidneys, and urinary protein in captopril-treated SHR-L-NAME was not significantly different from that in SHR. Because ANG II directly contributes to the renal impairment in these animals, the effects of captopril may be explained largely on the basis of reduced formation of ANG II (42). ANG-(1–7) + captopril did not produce any additive effect on proteinuria, suggesting a greater role for the decrease in ANG II, rather than the increase in ANG-(1–7), in this effect, as discussed above.

The primary characteristic of human essential hypertension is increased total peripheral resistance, and increased vascular reactivity is one of the factors that contribute to elevated vascular tone. Administration of ANG II at subpressor doses potentiates the vascular response of arteries to NE, thrombin, and potassium, whereas ACE inhibitors can normalize the hyperreactivity of blood vessels to pressor agents in hypertensive animals and in patients with essential hypertension (27, 28, 32). Results of the present study show that treatment with ANG-(1–7) or captopril attenuated L-NAME-induced alterations in vascular reactivity to ET-1, carbachol, and SNP in a similar manner. Indomethacin inhibited ANG-(1–7)-mediated correction of vascular reactivity to ET-1, but not to carbachol or SNP, suggesting possible differences in the contribution of prostanoids, kinins, and NO to the effects of these agents.

ANG II infusion into rats markedly stimulates DNA synthesis in neointimal and medial smooth muscle cells, an effect that is independent of the ANG II-mediated increase in blood pressure (40, 42, 45). Furthermore, neointimal formation after vascular injury is attenuated by reduction of ANG II formation by ACE inhibitors or inhibition of ANG II activity by AT1 receptor antagonists (40, 42, 45). ANG-(1–7) releases PGI2, which has autocrine and paracrine effects on vascular PGI2 receptors to increase cAMP, activate the cAMP-dependent protein kinase, and reduce mitogen-activated protein kinase activities to inhibit vascular growth (41). Exogenous ANG-(1–7) inhibited vascular smooth muscle cell proliferation associated with balloon-catheter injury (39). It has been suggested that ANG-(1–7) treatment also plays a role in attenuation of neointimal formation by structural recovery of the endothelium (41). In the present study, L-NAME treatment produced fibrinoid necrosis of the arteriolar wall with glomerular sclerosis in the kidneys, whereas only mild-to-moderate thickening of arterial and arteriolar media was observed in ANG-(1–7)- or captopril-treated animals. In mesenteric vessels, the ANG-(1–7)-mediated decrease in moderate thickening of arterial and arteriolar media was better than that mediated by captopril. In the heart, however, captopril was more potent than ANG-(1–7) in preventing the confluent interstitial fibrosis that was observed in SHR-L-NAME. This suggests that different mechanisms participate in the cardioprotection: perhaps the reduction of ANG II as well as the increase in ANG-(1–7).

In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly impaired in SHR compared with WKY rats, and the hearts from SHR-L-NAME did not recover after ischemia. Hearts from ANG-(1–7)- or captopril-treated SHR-L-NAME recovered from ischemia, with Pmax, LVEDP, and CF values similar to those of SHR. However, the most significant recovery was in hearts from SHR-L-NAME treated with ANG-(1–7) + captopril. Indomethacin was able to inhibit the improvement in recovery due to ANG-(1–7). It has been recently shown that prostaglandins mediate the cardioprotective effects of atrovastatin against I/R injury (4). Myocardial infarction results in increased expression of ACE-2 in rat and humans, and intravenous infusion of ANG-(1–7) for 8 wk and commencing 2 wk after induction of myocardial infarction in rats induced a marked regression of left ventricular failure (11, 26). One possible mechanism for the beneficial effects of ANG-(1–7) on cardiac function after myocardial infarction derives from experiments showing that ANG-(1–7) attenuates reperfusion arrhythmias in the isolated rat heart (12, 26).

We also compared the effects of AVE-0991, a stable agonist analog of ANG-(1–7) (36, 46), with those of ANG-(1–7). In all respects, the beneficial effects of AVE-0991 were qualitatively comparable to those of ANG-(1–7). This is not surprising, because others have reported that the compound mimics the actions of ANG-(1–7), including release of prostaglandins and NO and potentiation and release of kinins (36, 46); however, in most cases, the effects of AVE-0991 were smaller in magnitude. There were no additive effects on MAP and cardiac function with AVE-0991 + captopril. Although we used a dose equivalent to the dose of ANG-(1–7), we did not administer multiple doses to thoroughly investigate this issue. As discussed above, the nonadditive effects of ANG-(1–7) may imply common mechanisms of action for the two treatments, and it is possible that a component of the mechanism of action of AVE-0991 involves inhibition of converting enzyme. It has been suggested that the effects of ANG-(1–7) and AVE-0991 are mediated through activation of the Mas receptor (36). However, whether the Mas receptor is regulated by L-NAME treatment in SHR is unknown. Further studies are needed to elucidate the role of Mas receptor activation in ANG-(1–7)-mediated prevention of end-organ damage in SHR-L-NAME.

In conclusion, NO appears to be the major endogenous physiological antagonist of the cardiovascular actions of vasopressor agents such as ANG II; therefore, a balance between hypertension-promoting agents and NO appears pivotal for the maintenance of cardiovascular homeostasis. The present data suggest that impaired NO synthesis results in elevation of arterial blood pressure accompanied by severe end-organ damage due to reduced antagonism of vasopressor hormones and that ANG-(1–7) can counteract the effects of pressor systems. Our results are in agreement with a recent study in SHR-L-NAME, where it was shown that inhibition of the RAS by an ACE inhibitor and/or an AT1 blocker improved endothelial dysfunction and histopathology and increased coronary reserve, even though high blood pressure was not normalized (9). ANG-(1–7) is elevated in ACE inhibition and AT1 blockade (17–21) and can contribute to the actions of these agents through a variety of mechanisms, including prostaglandins, NO, and kinins. We conclude that ANG-(1–7) can lower MAP and improve renal, cardiac, and vascular function similar to many of the beneficial effects of RAS blockade in a model of reduced NO. Although there may be some overlap in the mechanisms of the two types of treatment, different mechanisms, including those involving prostaglandins, may be involved in the MAP and cardioprotective vs. renoprotective effects.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This work was supported by Kuwait University Research Administration Project No. RM02/03.


   FOOTNOTES
 

Address for reprint requests and other correspondence: I. F. Benter, Dept. of Pharmacology and Toxicology, Faculty of Medicine, Kuwait Univ., PO Box 24923, Safat 13110, Kuwait (E-mail: ibenter{at}hsc.edu.kw)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 

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