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(Hypertension. 1996;28:738-742.)
© 1996 American Heart Association, Inc.

Articles

Pressure-Dependent Renin Release During Chronic Blockade of Nitric Oxide Synthase

Penny R. Knoblich; Ronald H. Freeman; Daniel Villarreal

Department of Physiology, University of Missouri School of Medicine, Columbia.

Correspondence to Ronald H. Freeman, Department of Physiology, Medical Science Building, MA415, University of Missouri School of Medicine, Columbia, MO 65212.

	Abstract

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We evaluated pressure-dependent stimulation of renin release in rats with sustained hypertension induced by chronic blockade of nitric oxide synthase with N-nitro-L-arginine methyl ester (L-NAME) for 5 to 7 days. Rats were anesthetized and catheters were inserted into the carotid artery and abdominal aorta for measurement of arterial pressures. An adjustable snare was placed around the suprarenal aorta, and this snare was tightened to reduce renal perfusion pressure. Pressure-dependent renin release was evaluated in hypertensive rats by reducing renal perfusion pressure to 125, 85, and 65 mm Hg. Renin release was also evaluated in normotensive control rats at these same pressures. Basal systemic arterial pressures averaged 159±3 and 124±4 mm Hg (P<.001), respectively, in the L-NAME–treated (n=22) and normotensive control (n=18) rats. Basal plasma renin activity was lower in L-NAME than control rats (5.0±0.3 versus 9.5±1.3 U, P<.01), and plasma renin activity was markedly attenuated at all comparable levels of renal perfusion pressure. Maximal plasma renin activity levels were achieved at perfusion pressures reduced to 65 mm Hg, and plasma renin activity averaged 14±2 and 34±7 U (P<.01) in L-NAME hypertensive and control rats, respectively. However, infusion of the nitric oxide donor sodium nitroprusside similarly stimulated plasma renin activity levels to 39±3 and 45±3 U (P>.05), in the hypertensive and normal control groups, respectively. Overall, these findings are consistent with the hypothesis that prolonged L-NAME administration attenuates pressure-dependent renin release by inhibiting nitric oxide formation, which may function as a paracrine mechanism inversely linking renal perfusion pressure with the stimulation of renin release.

Key Words: perfusion • renin • nitric oxide • nitroprusside

	Introduction

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The renin-angiotensin-aldosterone hormonal system is a major determinant of long-term regulation of blood pressure and body fluid–volume homeostasis. Activity of this hormonal system is determined primarily by the rate of renin secretion, which is controlled by intrarenal and extrarenal inputs converging on the juxtaglomerular cells located within the wall of the afferent arteriole. Early studies of pressure-dependent renin release indicated that changes in renal perfusion pressure are sensed and transduced by the vascular wall itself, but the nature of the mechanism by which intrarenal hemodynamic forces are translated into a cellular signal for renin release remains unclear.^{1 2 3} Vanhoutte⁴ recently postulated that the renal vascular endothelium, via the release of endothelium-derived nitric oxide (NO), may link renal perfusion pressure and/or blood flow with the regulation of renin release. Several isoforms of the enzyme NO synthase are present in both vascular and tubular elements of the kidney.^{5 6 7} Moreover, a variety of studies have provided evidence that substituted analogues of L-arginine, which inhibit NO synthesis, also function as powerful inhibitors of basal renin release in the anesthetized rat,^{8 9 10} the conscious rabbit,¹¹ and the isolated perfused rat kidney.^{12 13} When acutely administered, L-arginine analogues also markedly attenuate the stimulation of renin release in the isolated perfused rat kidney preparation¹⁴ and in conscious dogs¹⁵ during graded reductions in renal perfusion pressure. Although the response is attenuated, pressure-dependent stimulation of renin release remains functional during acute blockade of NO formation,^{9 14 15} thus suggesting an additional non-NO signal that is engaged during reductions in renal perfusion pressure. It is unclear whether this non-NO signal for renin release becomes enhanced as a compensatory mechanism under conditions of chronic blockade of the NO pathway.¹⁶ Indeed, currently it is not known whether the effect of NO synthesis blockade on pressure-dependent renin release is merely transient or is sustained under conditions of chronic blockade. We designed the present study to determine whether pressure-dependent stimulation of renin release remains attenuated or becomes reset in rats chronically administered the NO synthase inhibitor L-NAME for 5 to 7 days. To our knowledge, pressure-dependent renin release under conditions of chronic blockade of NO synthase has not been systematically evaluated. In addition, we evaluated renin release in chronic L-NAME–treated rats during infusion of SNP to assess the tissue capacity for renin release in this experimental model.

	Methods

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All experiments were performed on male Sprague-Dawley rats weighing 275 to 400 g. Rats were maintained on a 12-hour light/dark cycle and provided with normal rat chow (Ralston Purina) and tap water ad libitum for at least 1 week before assignment to a specific experimental protocol. Sustained hypertension in rats was induced by chronic blockade of NO synthase with L-NAME at a dose of 185 µmol/kg body wt IP every 12 hours for 5 to 7 days as described previously.¹⁶ Both hypertensive and normotensive control rats were fasted overnight before the acute experiment on the following day. Rats were anesthetized with 5-sec-butyl-5-ethyl-2-thiobarbituric acid (Inactin, 100 mg/kg IP) and intubated with polyethylene tubing to facilitate respiration. Body temperature was monitored and maintained at 37°C throughout surgery and subsequent experimentation. Cannulas were placed in a carotid artery for the continuous recording of mean arterial pressure and heart rate and in a jugular vein for infusions. Also, a femoral artery was cannulated and the tip of the catheter was advanced into the abdominal aorta for recording of renal perfusion pressure. In selected groups of rats, an adjustable snare was introduced through a flank incision and loosely placed around the suprarenal aorta, or alternatively, the infrarenal aorta in one group. This snare could be tightened to control renal perfusion pressure independently of systemic arterial pressure. After the completion of surgery, a continuous saline infusion of 50 µL/min was initiated and maintained throughout the experiment. Arterial pressure and heart rate were allowed to stabilize under these conditions for 20 to 30 minutes in all experimental protocols. Two series of experiments were performed.

Series 1: PRA in Chronic L-NAME–Treated Rats With Renal Perfusion Pressure Set to Different Levels
Four groups each of normotensive control and chronic L-NAME–treated hypertensive rats were studied in this experimental series. After completion of surgery and initiation of saline infusion, arterial pressure and heart rate were allowed to stabilize for 20 to 30 minutes. The chronic L-NAME–treated hypertensive rats were subdivided randomly into four groups (groups 1 through 4). In group 1 (n=22), the suprarenal aortic snare was not tightened, and renal perfusion pressure remained unaltered. In group 2 (n=10), the snare was tightened to reduce renal perfusion pressure to 125 mm Hg for the 30-minute duration of the experiment. In groups 3 and 4 (both n=11), the snare was tightened to reduce renal perfusion pressure to 85 and 65 mm Hg, respectively, for the duration of the experiment. The normotensive control rats also were subdivided randomly into four groups (groups 5 through 8). In group 5 (n=18), the suprarenal aortic snare was not tightened to alter renal perfusion pressure. In group 6 (n=10), the superior mesenteric artery was occluded, and an infrarenal aortic snare was tightened to increase renal perfusion pressure above baseline for the 30-minute duration of the experiment. In group 7 (n=11) and group 8 (n=12), the suprarenal aortic snare was tightened to reduce renal perfusion pressure to 85 and 65 mm Hg, respectively, for the duration of the experiment. At the end of the 30-minute period, an arterial blood sample (3.0 mL) for PRA was obtained and placed in a polystyrene tube containing disodium EDTA (Sigma Chemical Co) (1 mg/mL blood). The blood sample was centrifuged immediately, and the plasma was frozen at -20°C until assayed for PRA.

Series 2: Effects of SNP Infusion on PRA in Chronic L-NAME–Treated Rats
Two groups of rats (groups 9 and 10) were studied in this experimental series. Group 9 (n=12) consisted of chronic L-NAME–treated hypertensive rats, and group 10 (n=12) consisted of normotensive control rats. After the stabilization period of 20 to 30 minutes, an intravenous infusion of the nitrovasodilator SNP was begun and continued for 30 minutes to provide an exogenous source of NO.^{9 11 14} The SNP infusion dose was adjusted to maintain renal perfusion pressure at 65 mm Hg in both the hypertensive and normotensive groups. This infusion dose of SNP averaged 26±5 µg/kg per minute in the L-NAME–treated hypertensive rats and 37±7 µg/kg per minute in the normotensive control rats (P>.18). An arterial blood sample for PRA was obtained at the end of the 30-minute SNP infusion period as described for series 1.

Analytic Methods and Materials
Inactin was obtained from Research Biochemicals International. SNP and L-NAME were obtained from Sigma. PRA was measured by radioimmunoassay of angiotensin I (Ang I) generated during a 1-hour incubation period at pH 5.4 and 37°C, as previously described.¹⁷ Previously,⁹ we documented that PRA measured in plasma samples after the direct addition of L-NAME was not different from PRA measured in paired, untreated samples; ie, L-NAME does not exert a direct action on the in vitro assay.

Results are expressed as mean±SE. One-way ANOVA followed by Tukey's post hoc test for multiple comparisons was used for analysis of data obtained from control groups and from the chronic L-NAME–treated groups in series 1. Student's t test for unpaired observations was used for the statistical evaluation of data between control and chronic L-NAME groups of series 1 and series 2. Differences at the 5% level of significance were considered to be statistically significant.

	Results

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Series 1: PRA in Chronic L-NAME–Treated Rats With Renal Perfusion Pressure Set to Different Levels
Body weight, heart rate, and systemic arterial pressure values are presented in the Table for the four groups of L-NAME–treated rats and the four groups of untreated control rats. Body weights and heart rates were similar among all eight rat groups. Compared with the control rats of group 5, the chronic L-NAME–treated rats of group 1 exhibited a significantly higher (P<.05) basal mean arterial pressure. Constriction of the abdominal aorta to produce reductions (groups 2, 3, 4, 7, and 8) or elevations (group 6) in renal perfusion pressure increased upper body mean arterial pressures in all experimental groups, but this maneuver did not reduce heart rates (P>.05) (Table).

View this table: [in this window] [in a new window]   Table 1. Body Weight, Heart Rate, and Mean Arterial Pressure for Chronic L-NAME–Treated Hypertensive and Control Rats With and Without Aortic Constriction

Basal PRA was significantly lower in the L-NAME–treated rats of group 1 compared with basal PRA levels in the control rats of group 5 (5.0±0.3 vs 9.5±1.3 ng Ang I/mL per hour, P<.05). As illustrated in the Figure, PRA was a nonlinear function of renal perfusion pressure in both the control and chronic L-NAME–treated rats. PRA was attenuated in the chronic L-NAME–treated compared with the control rats at all comparable levels of perfusion pressure, ie, at 65, 85, and 120 to 125 mm Hg. The attenuation of PRA in the L-NAME–treated rats was especially pronounced in the low-pressure range, ie, at 65 and 85 mm Hg. Within both the control and L-NAME–treated groups, PRA was significantly elevated at 65 and 85 mm Hg compared with PRA at higher perfusion pressures (Figure). However, PRA was not significantly reduced (P>.05) in control rats in which renal perfusion pressure was elevated above baseline to 139±2 mm Hg by constriction of the abdominal aorta below the kidneys.

View larger version (15K): [in this window] [in a new window]   Figure 1. PRA as a function of renal perfusion pressure in control () and L-NAME–treated () rats. Values are mean±SE. L-NAME dose was 50 mg/kg body wt, twice daily for 5 to 7 days. *P<.05 between groups; P<.05 within groups. Ang I indicates angiotensin I.

Series 2: Effects of SNP Infusion on PRA in Chronic L-NAME–Treated Rats
The infusion dose of SNP averaged 26±5 µg/kg per minute in the L-NAME rats and 37±7 µg/kg per minute in the control rats (P>.18). Arterial pressure decreased from 163±5 to 65±1 mm Hg in the L-NAME rats during SNP infusion and from 127±4 to 65±1 mm Hg in the control rats during SNP infusion. Basal heart rates between groups were not different (data not shown), but heart rate was significantly higher in the L-NAME group during SNP infusion (460±16 versus 409±16 beats per minute, P<.05). PRA, however, did not differ significantly between these two experimental groups infused with SNP (39±3 versus 45±3 ng Ang I/mL per hour, P>.05). Thus, tissue responsiveness for renin release during SNP infusion appears intact in the chronic L-NAME–treated rats compared with the normal control rats. It is noteworthy that the PRA of 39±3 ng Ang I/mL per hour in the SNP-infused chronic L-NAME–treated rats was significantly elevated (P<.05) compared with the PRA of 13.8±2.0 ng Ang I/mL per hour obtained in the chronic L-NAME–treated rats of group 4 in which renal perfusion pressure was mechanically reduced to the identical level of 65±1 mm Hg.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We designed the present study specifically to determine whether pressure-dependent stimulation of renin release remains attenuated or becomes reset in rats with hypertension induced by prolonged blockade of NO production. The results clearly demonstrate that pressure-dependent renin release remains markedly attenuated in rats with sustained hypertension induced by chronic L-NAME administration compared with pressure-dependent renin release in normal control rats. Thus, the inhibitory effect of L-NAME on pressure-dependent renin release is not transient but is sustained under chronic administration. However, mechanical reductions in renal perfusion pressure to the range of 65 to 85 mm Hg did significantly increase PRA approximately twofold to threefold over baseline values in the L-NAME–treated hypertensive rats. Thus, the intrarenal pressure-sensing mechanism for the control of renin release is partially but not completely deactivated during chronic blockade of NO synthase. Overall, the experimental data from this study suggest strongly that prolonged blockade of NO formation not only produces sustained hypertension but also attenuates pressure-dependent renin release with little or no resetting of this intrarenal pressure-sensitive mechanism.

Because both baseline and pressure-dependent renin release were attenuated in these rats with chronic blockade of NO synthase for 5 to 7 days, the capacity of the juxtaglomerular apparatus for renin release was evaluated in this experimental model during infusion of the NO donor SNP.¹⁸ Comparable infusion doses of SNP, which reduced arterial pressure to 65 mm Hg in both control and L-NAME hypertensive groups, resulted in similarly elevated plasma renin levels for both rat groups. Thus, the responsiveness of the juxtaglomerular apparatus for stimulation of renin release during SNP infusion appeared intact in the chronic L-NAME–treated rats compared with the normal control rats. This hypotensive dose of SNP presumably stimulated renin release via several pathways, including reflex activation of the renal sympathetic nerves, reduction of renal perfusion pressure, and a direct stimulatory signal of NO for renin release from the juxtaglomerular cells.^{9 11 14} Under the experimental conditions of the present study, the attenuated pressure-dependent stimulation of renin release in the L-NAME–induced hypertensive rat model appears unrelated to a nonspecific reduction in the capacity of the juxtaglomerular apparatus to release renin. However, there is evidence to suggest that prolonged blockade of NO synthase with L-NAME also can attenuate renal renin gene expression in response to unilateral renal arterial stenosis of 2 days' duration in rats.^{19 20}

The mechanism by which NO-stimulated renin release varies inversely with renal perfusion pressure is unclear. Pressure-induced alterations in the responsiveness of the juxtaglomerular cells to the renin stimulatory actions of NO may occur. Scholtz and Kurtz¹⁴ described an increased responsiveness to the renin-stimulating actions of the NO donor SNP when perfusion pressure was decreased in the isolated perfused rat kidney. They postulated that the sensitivity of the juxtaglomerular cells to the renin-stimulating actions of NO may change inversely with renal perfusion pressure and thus be responsible for the inverse relationship between renal perfusion pressure and renin release. Increased formation of NO also may be involved in this relationship between perfusion pressure and renin release. One well-defined hemodynamic stimulus for NO formation is shear stress acting on the endothelium.^{21 22} However, shear stress increases in proportion to arterial pressure, and thus this mechanism is unlikely to be responsible for the observed inverse relationship between renal perfusion pressure and renin release. Other potential components of a hemodynamic signal that are sensed and transduced by the vascular endothelium to stimulate NO formation are poorly understood. With regard to pressure-dependent renin release, however, it is well appreciated that vascular wall tension and transmural pressure may be important components of the hemodynamic signal sensed and transduced by the juxtaglomerular apparatus.^{1 3} Interestingly, an inverse relationship between static changes in transmural pressure and NO release from cultured human endothelial cells has been described.^{23 24} The rate of NO release was highest in the low transmural pressure range and lowest in the high transmural pressure range.^{23 24} Thus, NO formation over a wide range of perfusion pressures may represent a balance between shear stress and transmural pressure forces acting on the endothelial cells. Clearly, the role of NO in pressure-dependent renin release is not a simple one but may include pressure-induced adjustments in endothelial cell NO production and enhanced responsiveness of the juxtaglomerular cells to the renin-stimulating effects of NO. Finally, it is possible that pressure-induced changes in chloride delivery to the macula densa also may influence NO production to alter renin release.^{5 6 8 9}

The findings of the present study demonstrate that blockade of NO synthase for 5 to 7 days with L-NAME produced arterial hypertension associated with the suppression of basal PRA in rats. These findings are similar to those reported in several earlier studies,^{25 26 27} but other studies have reported an increase in basal PRA after chronic blockade of NO synthesis.^{28 29 30 31} The reasons for this discrepancy are unclear but may be related to differences in dose and the time that L-arginine analogues were administered. It has been reported previously that prolonged administration of L-NAME for weeks produced severe hypertension in rats in association with structural damage to the vasculature, including the renal arterioles, and activation of the renin-angiotensin system.^{29 30 31} Xu and colleagues³¹ concluded that structural renal ischemia secondary to renal arteriolar angiopathy may have caused stimulation of renin release in this rat model of hypertension induced by weeks of L-NAME administration. Fujihara et al³⁰ reached similar conclusions, suggesting that increased renin release in L-NAME–induced hypertensive rats may have been secondary to renal arteriolar narrowing and glomerular ischemia. Thus, it is possible that chronically reduced renal perfusion pressure secondary to renal arteriolar vascular damage may have enhanced the non-NO component of the intrarenal baroreceptor mechanism for stimulating renin release in these studies.^{30 31} The observed suppression of basal PRA in the present study suggests that no secondary stimulation of renin release occurred for the 5- to 7-day duration of L-NAME administration.

In summary, the results of the present study demonstrate that prolonged blockade of NO formation for 5 to 7 days with L-NAME caused sustained arterial hypertension, reduced basal PRA, and markedly attenuated pressure-dependent stimulation of renin release in this hypertensive rat model. These results suggest that there is little, if any, compensatory resetting of the intrarenal baroreceptor mechanism for the control of renin release in this experimental model. Infusions of the NO donor SNP to circumvent the blockade of the L-arginine–NO pathway stimulated renin release similarly in these hypertensive rats and in normal control rats. Overall, these findings are consistent with the hypothesis that prolonged L-NAME administration attenuates pressure-dependent renin release by inhibiting NO formation, which may function as a paracrine mechanism inversely linking renal perfusion pressure with the stimulation of renin release.

	Selected Abbreviations and Acronyms

 

L-NAME = N-nitro-L-arginine methyl ester NO = nitric oxide PRA = plasma renin activity SNP = sodium nitroprusside

	Acknowledgments

 
This study was supported by a grant from the National Institutes of Health (HL-10612), Bethesda, Md. The authors wish to thank their technician for her assistance.

Received January 11, 1996; first decision February 1, 1996; accepted May 24, 1996.

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