Nitric Oxide and Prostaglandins in the Prolonged Effects of Losartan and Ramipril in Hypertension
Abstract We investigated the role of endogenous nitric oxide, kinins, and prostaglandins in the vasodepressor and renal excretory effects of the angiotensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor ramipril administered for 1 week to spontaneously hypertensive rats. To this end, either losartan (10 mg/kg per day) or ramipril (2.5 mg/kg per day) was administered in drinking water with or without simultaneous administration of (1) the nitric oxide synthesis inhibitor NG-nitro-l-arginine methyl ester (L-NAME, 6 mg/kg per day), (2) the cyclooxygenase inhibitor indomethacin (5 mg/kg per day), (3) the bradykinin B2 receptor antagonist Hoe 140 (0.5 mg/kg per day SC), or (4) L-NAME plus indomethacin. Both losartan and ramipril significantly reduced blood pressure as measured by the tail-cuff method. L-NAME increased blood pressure when administered solely or in combination with losartan. However, L-NAME attenuated the hypotensive effect of ramipril. Indomethacin did not affect blood pressure but it reduced the antihypertensive action of losartan and ramipril. Indomethacin administration did not potentiate the increase in blood pressure induced by L-NAME. However, the concurrent administration of both inhibitors almost totally blunted the vasodepressor action of ramipril. By contrast, losartan administration in the presence of L-NAME and indomethacin increased blood pressure to a level similar to that after losartan plus L-NAME. Hoe 140 did not modify either blood pressure or the hypotensive effects of losartan or ramipril. Increases in diuresis and water intake were observed during ramipril administration. Both effects were blunted only with the concurrent administration of L-NAME and indomethacin. None of the cotreatments were able to modify renal excretory function by themselves. These data suggest a contribution of endogenous nitric oxide and prostaglandins but not of kinins in the prolonged antihypertensive effect of both losartan and ramipril in the spontaneously hypertensive rat.
- nitric oxide
- angiotensin receptors
- angiotensin-converting enzyme inhibitors
- blood pressure
- kidney function
The octapeptide Ang II, the active component of the renin-angiotensin system, plays an important role in blood pressure regulation not only by producing a potent vasoconstriction but also by inducing salt and water reabsorption.1 Because of these effects, Ang II has been reported to participate in the pathogenesis of certain forms of hypertension.2 3 Consequently, intensive research has been focused over the years on developing drugs, such as ACE inhibitors, renin inhibitors, and Ang II receptor antagonists, that interfere with the renin-angiotensin system at different levels.4
ACE inhibitors are effective antihypertensive drugs because they reduce blood pressure not only in renin-dependent models of hypertension but also in forms of hypertension that are less clearly related to the renin-angiotensin system, such as the SHR and essential hypertension in humans.3 The antihypertensive effect of ACE inhibitors has been mainly attributed to diminished formation of Ang II in both plasma and tissues5 and an accumulation of endogenous vasodilator kinins,6 as ACE catalyzes both the conversion of Ang I to Ang II and the degradation of bradykinin and related kinins.7 However, additional mechanisms appear to be involved in the hypotensive action of ACE inhibitors because we previously found that pretreatment with an NO synthase inhibitor attenuated the acute blood pressure–lowering effect induced by both captopril and ramiprilat in SHR.8
Nonpeptide Ang II receptor antagonists are a new type of antihypertensive drug that, like ACE inhibitors, reduce blood pressure in both renin-dependent and renin-independent models of hypertension.8 9 Losartan, the first of this new class of drug, is a selective and competitive AT1 receptor antagonist.9 AT1 receptors have been associated with all the known biological effects of Ang II.10 Therefore, the antihypertensive action of losartan is attributed to the blocking of any interaction between Ang II and its AT1 receptors. However, Ohlstein et al11 have recently observed that losartan can induce a prolonged antihypertensive effect in rats despite intact pressor responses to Ang I or Ang II. This suggests that losartan might lower blood pressure through additional mechanisms distinct from Ang II receptor antagonism. In this context, we have previously reported that the administration of an NO synthase inhibitor reduced the acute blood pressure–lowering effect of losartan in SHR.8 This indicates that NO could at least partially mediate the short-term hypotensive effect of losartan. However, whether NO might be involved in the hypotensive effect of ramipril or losartan in longer treatments is not yet established. In addition, several studies have implicated NO in both vascular and renal responses to kinin administration.12 13 14 Moreover, numerous interactions among Ang II, NO, kinins, and prostaglandins have been reported in the regulation of blood pressure and renal function.15 16 However, the participation of these factors in the long-term actions of ACE inhibitors and AT1 receptor antagonists is not yet well defined.
Therefore, we designed this study to investigate the role of endogenous NO, kinins, and prostaglandins in the antihypertensive and renal excretory effects of both ramipril and losartan administered for 1 week in SHR. Toward this end, the effects of these antihypertensive drugs on blood pressure and renal function were contrasted in SHR with and without concurrent administration of an NO synthase inhibitor, a B2 bradykinin antagonist, or an inhibitor of prostaglandin synthesis.
Experiments were conducted in 112 male SHR (Charles River, Barcelona, Spain), 18 to 21 weeks old, maintained under controlled light and temperature conditions. The rats were fed a normal rat chow (A.04, Panlab) and had free access to tap water. All experimental procedures were approved by the Institutional Animal Care and Use Committee according to the guidelines for ethical care of experimental animals of the European Community.
Rats were randomly divided into two groups that received concentrations of either losartan (125 μg/mL) or ramipril (20 μg/mL) for 1 week in drinking water with or without simultaneous administration of the following drugs: (1) the NO synthesis inhibitor L-NAME (75 μg/mL PO), (2) the cyclooxygenase inhibitor indomethacin (65 μg/mL PO), or (3) the specific bradykinin B2 receptor antagonist Hoe 140 (0.5 mg/kg per day, administered subcutaneously via a miniosmotic pump [Alzet]). The concentrations of losartan, ramipril, L-NAME, and indomethacin yielded approximate doses of 10, 2.5, 6, and 5 mg/kg per day, respectively.
To investigate the interaction between NO and prostaglandins in the antihypertensive and renal effects of both losartan and ramipril, we treated two rat groups with either ramipril or losartan with and without concurrent oral administration of L-NAME plus indomethacin. In additional studies, the effects induced by the separate administration of L-NAME, indomethacin, Hoe 140, or L-NAME plus indomethacin on blood pressure and renal function were also examined.
SBP and plasma and urinary creatinine levels were measured basally and at the end of the experiment as detailed below. During the last 2 days of each period, rats were housed in metabolic cages for urine collection and control of food and water intakes.
Blood Pressure Measurement
Ten days before the beginning of the experiment, rats were trained daily for measurement of SBP by the tail-cuff method (Narco Biosystems). Each day (9 am), rats in their maintenance cages were placed in a room at 28°C for 2 hours. Once the rats were considered trained and not susceptible to stress by the tail-cuff method procedure, SBP measurements were performed. SBP was measured for 2 consecutive days at the same time (11 am) within each studied period. Eight SBP measurements were carried out each day in each rat, the maximum and minimum values being rejected. Under these conditions, we had previously reported a close correlation between these values and measurements obtained by a direct method.17 In the present study, to validate the tail-cuff method for blood pressure measurements, we implanted a catheter in the femoral artery of eight rats treated for 1 week with 10 mg/kg per day losartan. Two days later, catheters were connected to a pressure transducer (model P23XL, Spectromed), and SBP was recorded on a polygraph (model 7E, Grass Instruments) for 60 minutes. The mean value of direct SBP (150±4 mm Hg) compared with the mean value of indirect measurements (156±4 mm Hg) showed a correlation of 96%.
Sodium and potassium concentrations in plasma and urine were measured by flame photometry (NAK-I, Pacisa). Creatinine levels in plasma and urine were evaluated by a colorimetric reaction (Medical Analysis, Inc).
Ramipril and Hoe 140 (d-Arg,[Hyp3,Thi5,d-Tic7,Oic8]-bradykinin) were obtained from Hoescht AG. The AT1 receptor antagonist losartan (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4 yl)methyl]imidazole, potassium salt) was provided by DuPont Merck Pharmaceutical Co. Indomethacin and L-NAME were purchased from Sigma Chemical Co.
Results are expressed as mean±SEM of eight rats per group. Comparisons among the different groups were performed by ANOVA for multiple comparisons, followed by a Newman-Keuls test, with the use of the Complete Statistical System (CSS) program (Statsoft Inc). A value of P<.05 was considered significant.
Study 1: Role of Endogenous NO, Kinins, and Prostaglandins in the Antihypertensive and Renal Effects of Losartan
Losartan induced a significant decrease of SBP in SHR (−36±3 mm Hg, Fig 1⇓, Table 1⇓). Oral administration of L-NAME increased SBP (+25±4 mm Hg, Fig 2⇓, Table 1⇓). Similarly, an increase in SBP was also observed during the concurrent administration of losartan and the NO synthesis inhibitor L-NAME (+15±2 mm Hg, Fig 1⇓, Table 1⇓).
Administration of the kinin antagonist Hoe 140 did not modify blood pressure (Fig 2⇑, Table 1⇑) or the hypotensive effect of losartan (−34±3 versus −36±3 mm Hg, Fig 1⇑, Table 1⇑). The inhibition of prostaglandin synthesis by indomethacin administration was not able to change SBP (Fig 2⇑, Table 1⇑). However, indomethacin significantly attenuated the hypotensive effect of losartan (−12±2 versus −36±3 mm Hg, Fig 1⇑, Table 1⇑) when they were administered together.
Indomethacin administration in SHR treated with L-NAME did not potentiate the hypertensive effect induced by this NO synthesis inhibitor, because the increase in SBP observed in this rat group was similar to that in rats which received only L-NAME (+25±1 versus +25±4 mm Hg, Fig 2⇑, Table 1⇑). An increase (P<.05) in SBP during losartan administration in the presence of L-NAME and indomethacin was observed and was comparable to that observed during the coadministration of losartan and L-NAME (+14±4 mm Hg, Fig 1⇑, Table 1⇑).
Oral administration of losartan alone or in combination with any of the cotreatments did not significantly modify water intake, urine volume, sodium excretion, or potassium excretion (Table 2⇓). Furthermore, none of the cotreatments by themselves modified urine volume, sodium excretion, or potassium excretion (Table 3⇓). Creatine clearance values (ranging from 1.3 to 2.0 mL/min) were not significantly modified by any treatment. Increases in body weight (P<.05) were similar among the groups (Table 1⇑).
Study 2: Role of Endogenous NO, Kinins, and Prostaglandins in the Antihypertensive and Renal Effects of Ramipril
Ramipril induced a sustained decrease (P<.05) in SBP (−51±4 mm Hg, Fig 3⇓, Table 1⇑). The coadministration of ramipril and the NO synthesis inhibitor L-NAME reduced SBP to a much lower extent than when ramipril was administered alone (−8±2 mm Hg, Fig 3⇓, Table 1⇑).
Administration of the kinin antagonist Hoe 140 did not modify the hypotensive effect of ramipril (−49±1 versus −51±4 mm Hg, Fig 3⇑, Table 1⇑). By contrast, the inhibition of prostaglandin synthesis significantly attenuated the hypotensive effect of ramipril (−31±3 versus −51±4 mm Hg) when they were administered together (Fig 3⇑, Table 1⇑). The decrease in SBP induced by ramipril was significantly lower (P<.05) in rats treated with both indomethacin and L-NAME than in those treated with ramipril coadministered with either indomethacin or L-NAME alone (1±1 versus −9±2 or −31±3 mm Hg, Fig 3⇑, Table 1⇑).
Ramipril administration induced a significant diuretic effect (Fig 4⇓) that was not associated with an increase in either sodium excretion (689±95 versus 620±34 μmol/d) or potassium excretion (1380±71 versus 1327±97 μmol/d). The diuretic effect was accompanied by a significant increase in water intake (P<.05) from 23±1 to 44±4 mL/24 h. In contrast to what we observed with SBP, the diuretic response of ramipril was not modified by either NO or prostaglandin synthesis inhibition (Fig 4⇓, left). Likewise, the administration of the bradykinin B2 receptor antagonist did not alter the increase in urine volume induced by ramipril (Fig 4⇓, top right). In all these situations, water intake was augmented in a fashion similar to that when ramipril was administered alone (ramipril plus L-NAME: from 25±2 to 46±4 mL/24 h; ramipril plus Hoe 140: from 25±2 to 52±4; ramipril plus indomethacin: from 24±1 to 43±6). On the other hand, ramipril administration during the simultaneous inhibition of NO and prostaglandin synthesis was not able to increase urine volume (Fig 4⇓, bottom right). Under these conditions, water intake remained unchanged (26±1 versus 30±1 mL/24 h). None of the treatments significantly modified creatinine clearance values (ranging from 1.1 to 1.9 mL/min). Body weight increased in a significant (P<.05) and similar manner in every group (Table 1⇑).
Study 1: Role of Endogenous NO, Kinins, and Prostaglandins in the Antihypertensive and Renal Effects of Losartan
The present study shows that losartan administered for 1 week decreased SBP in SHR. This effect was reduced during the concurrent administration of indomethacin but was not affected by the bradykinin B2 receptor antagonist Hoe 140. However, coadministration of losartan and the NO synthesis inhibitor L-NAME increased SBP. This elevation was comparable to elevations observed during the administration of L-NAME alone and of losartan in the presence of L-NAME and indomethacin. These data suggest a mediatory role of prostaglandins and NO but not of kinins in the depressor effect of losartan in SHR.
The results also show that the separate administration of Hoe 140 or indomethacin did not modify SBP. These data suggest that prostaglandins and kinins do not play a key role in the basal control of blood pressure in SHR. However, L-NAME administration elevated SBP levels. This increase was comparable to that observed in rats treated with indomethacin plus L-NAME, thus suggesting a predominant role of NO in the regulation of basal blood pressure in SHR. This has also been demonstrated in normotensive rats, as the administration of NO synthesis inhibitors increases blood pressure levels in a dose-dependent manner.17 18
The mechanism underlying the participation of prostaglandins in the vasodepressor effect of losartan could be an increase in prostaglandin synthesis. Supporting this concept has been the recent reporting of losartan as a potent stimulus for both prostaglandins E2 and I2 in cultured endothelial cells.19 Moreover, prostaglandins can be stimulated by components of the renin-angiotensin system other than Ang II, such as Ang-(1-7).20 This peptide is generated endogenously from Ang II, which has been reported to accumulate after treatment with losartan.21
Although the participation of NO in the vasodepressor action of AT1 receptor antagonists is not entirely defined yet, numerous interactions between the renin-angiotensin system and NO have been documented. It has been demonstrated that NO is the physiological antagonist of the actions of Ang II at both renal and vascular levels.22 23 24 In addition, it has been reported that Ang II is able to stimulate NO synthesis via AT2 receptors in cultured bovine endothelial cells.25 This notion is supported by Scheuer and Perrone,26 who reported that AT2 receptors mediate a depressor response of Ang II in rats. Consequently, it could be proposed that during AT1 receptor antagonism with losartan, Ang II would bind to unblocked AT2 receptors, thus leading to the stimulation of NO synthesis. This increased NO production might mediate the hypotensive effect of losartan in the present study. Thus, the increase in SBP observed during the concomitant administration of losartan and L-NAME could be due to the inhibition of a losartan-stimulated NO production. In addition, it is worth noting that the increases in SBP during losartan administration in the presence of L-NAME and in the presence of L-NAME plus indomethacin were comparable. This would indicate that the participation of NO in the depressor effect of losartan appears to be more important than that of prostaglandins. Consequently, the presence of NO appears to be necessary for the full expression of the blood pressure–lowering effect of losartan.
It has been proposed that NO and prostaglandins could be mediators of the biological actions of kinins.12 13 14 27 Therefore, it could be thought that the participation of NO and prostaglandins in the mechanism of the action of losartan might be kinin mediated. However, the present results do not support this notion because Hoe 140 administration did not modify the hypotensive effect of losartan. Similarly, in a previous study we observed that the short-term vasodepressor action of losartan was impaired by pretreatment with another NO synthesis inhibitor, NG-monomethyl-l-arginine, but not with a kinin antagonist.8
In the present study losartan administration did not modify urine volume or electrolyte excretion, nor did any of the cotreatments. Studies on the effect of losartan on renal excretory function have yielded conflicting results. In hypertensive dogs losartan acutely reduced blood pressure and the fractional tubular reabsorption of water and sodium.28 By contrast, Fenoy et al29 found in SHR that short-term losartan, at a dose that did not modify blood pressure, reduced diuresis but did not modify natriuresis, whereas a hypotensive dose of losartan only slightly decreased both parameters. Nevertheless, in the present study losartan did not modify either diuresis or electrolyte excretion in SHR when administered for 1 week. An explanation for these opposite results could reside in the different effects on blood pressure exerted by the doses of losartan used in the studies as well as in the different time periods of administration.
Study 2: Role of Endogenous NO, Kinins, and Prostaglandins in the Antihypertensive and Renal Effects of Ramipril
The present study demonstrates that the hypotensive effect induced by ramipril orally administered for 1 week in SHR was reduced by cotreatment with an NO synthesis inhibitor as well as with indomethacin. Furthermore, the depressor effect of ramipril was abolished when L-NAME and indomethacin were administered together. Therefore, these data indicate an additive role of endogenous NO and prostaglandins in the mechanisms of action of ACE inhibitors in long-term treatments. This mediatory role of NO and prostaglandins appears not to be dependent on kinins, because cotreatment with Hoe 140 did not modify the antihypertensive effect induced by ramipril.
ACE catalyzes not only the conversion of Ang I to Ang II but also the degradation of kinins.30 Thus, the participation of kinins in the antihypertensive effect of ACE inhibitors has been hypothesized. However, our results in SHR do not support this notion. Similarly, Bao et al31 also reported that long-term administration of Hoe 140 did not modify the long-term hypotensive action of ramipril in adult SHR. The participation of kinins in the mechanism of action of ACE inhibitors appears to depend on the model of hypertension, because the long-term administration of Hoe 140 attenuated the hypotensive effect of ramiprilat in renovascular hypertension. Moreover, it has been reported that the administration of a kinin antagonist increases blood pressure in two-kidney, one clip hypertensive rats.31 The disparity of these results appears to reside in the different characteristics of both experimental models of hypertension.
A contribution of prostaglandins to the blood pressure–lowering effect of ACE inhibitors has been documented by different investigators. Moore et al32 demonstrated that the short-term antihypertensive effect of captopril was reduced by concomitant treatment with aspirin or indomethacin in hypertensive patients. Furthermore, ACE inhibitors have been shown to promote prostaglandin synthesis.33 34 Consequently, the observed mediatory role of prostaglandins on the hypotensive effect of ramipril might be in part due to activation of prostaglandin synthesis. It should be mentioned that in our previous study indomethacin did not alter the short-term hypotensive effect of ramiprilat in SHR.8 Therefore, it might be proposed that longer administration of either ramipril or indomethacin should be necessary for a reduction in the hypotensive effect of ramipril to be observed.
The present results further support the notion of NO as a mediator of the antihypertensive effect of ACE inhibitors. This concept was previously suggested during the short-term administration of ramiprilat and captopril in SHR.8 However, the way in which NO could participate in the mechanism of action of ACE inhibitors is not yet clear. The fact that under the present experimental conditions kinin antagonism did not affect the antihypertensive action of ramipril rules out the possibility that these drugs would stimulate NO synthesis via kinins. However, a direct stimulation of NO by ramipril might be hypothesized. Consequently, the reduced hypotensive effect of ramipril observed during the concomitant administration of L-NAME could be due to the inhibition of a ramipril-stimulated NO production. An alternative mechanism to explain the reduced antihypertensive effect of ramipril during L-NAME administration would involve the equilibrium existing between the actions exerted by NO and Ang II.22 23 24 Consequently, when Ang II synthesis is inhibited, the actions of NO could be overexpressed. Then, when Ang II and NO are simultaneously blocked, the consequences of Ang II inhibition would be reduced.
Finally, it should be mentioned that the mechanisms underlying the hypotensive effect of ramipril seem to depend on the duration of treatment. In our previous study evaluating the factors involved in the short-term vasodepressor action of ACE inhibitors, we observed that both a kinin antagonist and an NO synthase inhibitor blunted this effect.8 On the other hand, concomitant administration of indomethacin did not modify the vasodepressor action of these drugs. Consequently, it could be postulated that kinins participate in the blood pressure–lowering effect of ACE inhibitors under short-term circumstances in adult SHR. By contrast, prostaglandins appear to mediate this effect during longer treatments and NO during both short- and long-term administration.
It is well established that ACE inhibitors have diuretic and natriuretic properties as a consequence of their actions on glomerular and tubular functions.35 Our results confirm those data because ramipril increased urine volume, although it was not associated with any modification in electrolyte excretion. These data are in agreement with a previous study in normotensive rats in which ramipril administered for 1 week induced a diuresis that was not accompanied by an increase in sodium excretion.36 By contrast, the administration of captopril through a renal medullary interstitial infusion37 or systemic intravenous infusion38 produced an increase in diuresis and natriuresis in SHR and Wistar Munich rats, respectively. This discrepancy could be due to the different experimental conditions and/or the behavior of these drugs during short-term or longer treatments. During ramipril administration an increase in water intake was also observed; therefore, an alternative explanation could be that the diuretic effect observed during ramipril administration might be a consequence of an increase in water intake. However, as Ang II has a dipsogenic effect, it is difficult to justify the possibility that the administration of an ACE inhibitor such as ramipril could stimulate water intake. In fact, previous studies have shown that quinapril did not modify water intake in rats with reduced renal mass.39 Consequently, we prefer the interpretation that ramipril induced an increase in urine volume, which is followed by an increase in water intake.
The present results also show that the diuresis induced by ramipril was not affected by the administration of L-NAME, indomethacin, or Hoe 140. However, the concurrent inhibition of NO and prostaglandins blocked the increases in diuresis and water intake observed during ramipril administration. Consequently, it could be suggested that NO and prostaglandins are involved in these effects and that both systems might play a compensatory role. In contrast to these results, we previously had found that ramipril administration to normotensive rats was accompanied by an increase in urinary kinins, which suggested a possible role of this system in the diuretic effect of ACE inhibitors.36 Furthermore, in the same study, prostaglandin inhibition blocked the diuresis induced by ramipril. These opposite results indicate that different factors appear to be involved in the diuresis induced by ACE inhibitors under normotensive and hypertensive conditions.
In summary, the present data indicate that both NO and prostaglandins participate in the long-term antihypertensive effect of losartan and ramipril in SHR. In addition and in view of these results, the existence of an equilibrium between vasoconstrictor Ang II and vasodilator NO and prostaglandins could be proposed. This balance could play an important role in the mechanisms of action of AT1 receptor antagonists or ACE inhibitors. Consequently, when Ang II action is eliminated by any of these drugs, the actions of NO and prostaglandins should be overexpressed, even in the presence of normal levels of these systems. Furthermore, when Ang II and either NO or prostaglandins are simultaneously blocked, the consequences of Ang II inhibition should be reduced. Therefore, intact NO and prostaglandin systems are necessary for the full antihypertensive efficacy of AT1 receptor antagonists and ACE inhibitors.
Selected Abbreviations and Acronyms
|AT1||=||angiotensin type 1|
|AT2||=||angiotensin type 2|
|L-NAME||=||NG-nitro-l-arginine methyl ester|
|SBP||=||systolic blood pressure|
|SHR||=||spontaneously hypertensive rat(s)|
This work was supported by a grant from Fondo de Investigaciones Sanitarias (FIS), Spain, 94/00 36-02, and a Medical School grant from The DuPont Merck Pharmaceutical Co, Wilmington, Del. The authors thank Lucila Krauss for her excellent technical assistance, Dr Bernward A. Schölkens (Hoechst AG, Frankfurt, Germany) for kindly supplying ramipril and Hoe 140, Merck Pharmaceutical Co for kindly providing losartan, and Anthony DeMarco for his editorial assistance.
- Received October 21, 1994.
- Revision received November 29, 1994.
- Accepted May 2, 1995.
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