Nitric oxide modulates the development and surgical reversal of renovascular hypertension in rats

OBJECTIVE: To evaluate the role of nitric oxide (NO) in the development and unclipping-induced reversal of blood pressure and bilateral renal function in two-kidney, one clip (2K1C) Goldblatt hypertensive rats. METHODS: Goldblatt hypertensive rats were prepared by clipping the left renal artery 4 weeks before unclipping experiments. NG-nitro-L-arginine methyl ester (L-NAME) was administered after clipping and during unclipping to inhibit nitric oxide (NO) synthesis. Blood pressure and bilateral renal responses were measured. RESULTS: Chronic L-NAME treatment accelerated and aggravated blood pressure elevations and increased plasma nitrite and nitrate levels in 2K1C rats. Surgical removal of the renal artery clip induced profound reductions in blood pressure in rats with and without L-NAME treatment. However, the magnitude of the unclipping-induced depressor response at the first post-unclipping hour was significantly smaller in L-NAME-treated rats compared to those without L-NAME administration (15 +/- 1 versus 22 +/- 1%, P < 0.05). Two hours after unclipping, blood pressure of both groups fell to a comparable, normal level. Acute intravenous infusion of L-NAME in established 2K1C hypertensive rats further increased blood pressure. Subsequent unclipping caused a depressor response similar to that observed in hypertensive rats treated chronically with L-NAME. Despite the marked decreases in blood pressure, unclipping induced striking increases in glomerular filtration rate (GFR), urine flow and sodium and potassium excretion rates in the ipsilateral kidney. However, the magnitudes of increases in GFR and the diuretic and natriuretic responses in rats without L-NAME treatment were significantly greater than in rats with L-NAME administration. In contrast, unclipping reduced these function indices in the contralateral kidney to a similar level in rats with and without L-NAME treatment. CONCLUSIONS: NO exerts vasodilator action and thereby lessens renal artery clipping-induced blood pressure elevation. Furthermore, unclipping-induced release of NO partially contributes to the early reduction in blood pressure and changes in bilateral renal function but does not directly mediate the normalization of blood pressure after unclipping in this hypertension model.     

Functional Evidence of Inhibitory Reno-renal Reflexes in Spontaneously Hypertensive Rats

The experiments were performed to study the role of the renal nerves and the reno-renal reflexes in the control of water and sodium excretion in spontaneously hypertensive rats (SHR) compared to their normotensive controls, Wistar Kyoto (WKY) rats. Unilateral renal denervation in anaesthetized animals produced a slight, progressive decrease in arterial pressure in both WKY and SHR rats. The glomerular filtration rate temporarily increased in the kidney that underwent the denervation in the SHR group only. After unilateral renal denervation a sharp increase in water and sodium excretion from the ipsilateral kidney was observed in both WKY and SHR. One hour after the denervation, the percent changes in water and sodium excretion were smaller in WKY (+32 ± 19% and +24 ± 17%) than in SHR rats (+84 ± 15% and +93 ± 20%). In the kidney contralateral to the denervation a reduction in water and sodium excretion was observed and this reduction was prompter in SHR than in WKY rats. One hour after the denervation, the percent changes in water and sodium excretion were similar in WKY (-21 ± 8% and -18 ± 7%) and SHR (-19 ± 6% and -19 ± 7%). In control groups, sham denervation did not cause significant changes in glomerular filtration rate, and urinary water and sodium excretion. Arterial pressure slightly and progressively decreased in both control groups. Electrical stimulation of the efferent renal nerves performed in WKY and SHR produced similar decreases in renal blood flow, glomerular filtration rate, and water and sodium excretion in the two groups for the same frequencies of stimulation. As this finding indicates that renal targets in hypertensive rats are normally responsive to the neural drive, our data demonstrate that renal responses to unilateral renal denervation in hypertensive rats are equal to the responses observed in normotensive rats. Our results indicate that tonically active inhibitory reno-renal reflexes normally operate in spontaneously hypertensive rats.     

Arterial pressure and renal function in two-kidney, one clip Goldblatt hypertensive rats maintained on a high-salt intake

Arterial blood pressure and renal function of both clipped and non-clipped kidneys of benign two-kidney, one clip (2K1C) Goldblatt hypertension were evaluated in order to determine whether high-salt intake alters the course of the development and magnitude of hypertension or influences renal function. The administration of 0.9% sodium chloride as a drinking solution for 3 weeks suppressed plasma renin activity (PRA) and kidney renin content of the clipped kidney to normal values. Despite suppression of PRA and kidney renin content, the saline-drinking clipped rats still developed hypertension of the same magnitude as the water-drinking clipped rats. However, the onset of hypertension was delayed by 4 days. Urine flow, glomerular filtration rate (GFR) and sodium excretion rate from the clipped kidneys of the saline-drinking clipped rats were higher than the corresponding values in the water-drinking rats, and approached those observed in control animals. Thus, the high-salt intake which was associated with suppression of the activity of the renin-angiotensin system delayed the onset of, but not the final magnitude of, the hypertension. In addition, kidney function in the clipped kidneys of saline-drinking clipped rats was enhanced compared with that observed in the water-drinking clipped rats.     

Determination of role of sympathetic and renin-angiotensin systems in Goldblatt hypertension with urapidil and captopril

The objective of this study was to determine the sympathetic and renin-angiotensin contributions to the control of blood pressure and renal blood flow (RBF) in conscious normotensive and Goldblatt hypertensive dogs. Urapidil (2 mg/kg), an alpha-adrenoceptor antagonist, and then captopril (0.2 mg/kg) were administered acutely intravenously (i.v.) to instrumented normotensive and two-kidney, one clip Goldblatt hypertensive dogs. Urapidil decreased mean arterial blood pressure (MAP) in the hypertensive (n = 11) and normotensive dogs (n = 9). Contralateral RBF was unchanged in the hypertensive, but was increased in the normotensive dogs. Captopril caused a further fall in MAP of the hypertensives and increased RBF. MAP of the normotensives was further decreased and RBF increased by captopril. Urapidil increased plasma renin activity in the normotensives, but not in the hypertensives, whereas heart rate was increased and renal vascular resistance was decreased in both groups. In nine hypertensive dogs, captopril alone (0.2 mg/kg i.v.) had a smaller effect on MAP and RBF than after alpha blockade. These results indicate that the combined influence of the sympathetic and renin-angiotensin systems accounts for a major portion of the MAP increase in two-kidney, one clip Goldblatt hypertension, and elimination of their influence causes profound hypotension and renal vasodilatation.     

Systemic and renal effect of chronic omapatrilat in sodium-restricted, one-kidney, one-clip hypertensive rats

OBJECTIVE: The systemic and renal effect of omapatrilat was evaluated and compared with that of enalapril (30 and 10 mg/kg per day) in sodium-depleted, one-kidney, one-clip hypertensive rats. Participation of kinins was assessed by concomitant infusion of Hoe140 (300 microg/kg per day). DESIGN: Four weeks after clipping and uninephrectomy, dietary sodium was withdrawn for 2 weeks and rats were treated during the last 6 days of the study. METHODS: Tail-cuff pressure and sodium excretion were determined in conscious rats. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined in anesthetized rats using clearance methods. The heart weight index was calculated. RESULTS: Omapatrilat was as effective as enalapril in reducing arterial pressure, and Hoe140 had no influence. Natriuresis increased to a similar extent with omapatrilat and enalapril. Hoe140 prevented the sodium loss only in enalapril-treated rats. Compared with untreated rats, GFR was reduced to a lesser extent by omapatrilat than enalapril (694 +/- 93 and 364 +/- 40 versus 848 +/- 43 microl/min per g kidney weight). Hoe140 had no influence on GFR in omapatrilat-treated animals but attenuated the reduction of GFR in enalapril-treated rats (662 +/- 22 and 543 +/- 62 microl/min per g kidney weight). Since RPF was not significantly affected, reduction of the filtration fraction was more marked in enalapril- than omapatrilat-treated rats (60 and 28%, respectively). Heart weight index was lower in omapatrilat-treated rats than in untreated or enalapril-treated rats. Hoe140 failed to significantly obliterate the antihypertrophic effect of omapatrilat. CONCLUSION: These results suggest that accumulation of natriuretic peptides due to neutral endopeptidase inhibition participated in the antihypertrophic effect of omapatrilat and tended to counteract the deleterious effect of ACE inhibition on renal function.     

Chronic cyclooxygenase-2 inhibition does not alter blood pressure and kidney function in renovascular hypertensive rats

BACKGROUND: It has been shown that the macula densa participates in the regulation of increased renin expression in two-kidney one-clip (2K1C) renovascular hypertension. Prostaglandins might be one of the mediators of macula densa function, because the cyclooxygenase-2 (COX-2), one of the rate-limiting enzymes of the prostaglandin pathway, is upregulated in 2K1C renovascular hypertensive rats. We tested the effect of chronic COX-2 inhibition on blood pressure, urinary aldosterone excretion and kidney morphology, as well as kidney function. METHODS: Four groups were established: two groups of 2K1C renovascular hypertensive rats treated with the specific COX-2 inhibitor Celecoxib (cele) (15 mg/kg per day) or placebo immediately after operation, and two sham-operated control groups fed with Celecoxib or placebo. RESULTS: Long-term COX-2 inhibition in 2K1C renovascular hypertensive rats did not alter blood pressure at any point of time. Urinary aldosterone excretion was elevated by clipping the renal artery (2K1C, 8.1 +/- 1.9, versus controls, 3.6 +/- 0.5 ng/24 h; P = 0.05) but was not influenced by treatment with Celecoxib. Also, Celecoxib treatment did not alter glomerular filtration rate (GFR), serum sodium, serum creatinine, serum urea or proteinuria in 2K1C renovascular hypertensive rats. Interstitial fibrosis of the left clipped kidney was markedly reduced (2K1C, 6.19 +/- 0.83% versus 2K1C + cele 3.00 +/- 0.68% of total area; P = 0.012), whereas the interstitial fibrosis of the non-clipped kidney or the glomerulosclerosis of both kidneys were not affected by Celecoxib treatment. CONCLUSIONS: Celecoxib reduces the interstitial fibrosis of the clipped kidney. Blood pressure, urinary aldosterone excretion or whole kidney function were not affected in renal hypertensive rats.     

Angiotensin II is a necessary component for the development of hypertension in the two kidney, one clip rat

The current study was undertaken to define the role of the renin-angiotensin system in the development of hypertension in the two kidney, one clip Goldblatt rat. Captopril was administered orally (100 mg/kg/day) to two groups of rats (n = 8 each) 24 hours before and each day after unilateral renal artery clipping (0.2 mm internal diameter): the drug was given for either 16 weeks (group I) or 24 weeks (group II). Sham-operated (n = 5) and Goldblatt (n = 8) rats not receiving captopril were prepared for comparisons of plasma renin activity and systolic blood pressure. Indomethacin (20 mg/kg/day subcutaneously) was administered for 48 hours concomitantly with captopril to the rats in group I. In group II, systolic blood pressure was monitored for 7 weeks after cessation of captopril. Continual captopril administration to Goldblatt rats completely prevented the rise in systolic blood pressure, a rise that was observed in Goldblatt rats not receiving captopril. Whereas systolic blood pressure of captopril-treated rats approximated 100 mm Hg throughout the study, that of Goldblatt rats not receiving the drug increased to nearly 180 mm Hg within 6 weeks after clipping. Systolic blood pressure of sham-operated rats remained normal. Indomethacin did not change systolic blood pressure in the drug-treated rats in group I. On cessation of captopril therapy in group II, systolic blood pressure increased gradually in a manner that paralleled the development of the disease in the Goldblatt rats that did not receive captopril. Plasma renin activity was determined in Goldblatt and sham-operated rats at either 16 weeks (group I) or 24 weeks (group II) after clipping; the rats from either group with mild hypertension (systolic blood pressure less than 180 mm Hg) had normal plasma renin activity whereas those with severe hypertension (systolic blood pressure greater than 180 mm Hg) had greatly elevated plasma renin activity. In summary, captopril can completely prevent the increase in systolic blood pressure for up to 24 weeks in Goldblatt rats, and this hypotensive effect is not mediated by the prostaglandins. It is concluded that the renin-angiotensin system is a necessary component of the hypertensive process in this experimental model.     

Lithium infusion to study sodium handling in unanesthetized hypertensive rats

To investigate renal tubular handling of sodium in various types of experimental hypertension, sodium, lithium, and inulin clearances were measured simultaneously in unanesthetized rats. Fractional excretion of lithium was used as an index of proximal sodium reabsorption. Eight groups of animals, all of the Wistar-Kyoto strain, were studied. Three were hypertensive: spontaneously hypertensive rats (SHR), rats with two-kidney, one clip renal hypertension, and uninephrectomized rats with deoxycorticosterone-salt hypertension. The five normotensive control groups included animals given normal, low, or high dietary sodium loads and rats with reduced renal mass. Fractional excretion of lithium was not influenced by moderate changes of glomerular filtration rate, but was sharply enhanced by sodium loading. Increased blood pressure was associated with enhanced urinary sodium excretion in uninephrectomized deoxycorticosterone-salt hypertensive and two-kidney, one clip hypertensive rats, as a result of decreased distal tubular reabsorption ("pressure natriuresis"). In contrast, SHR showed reduced sodium excretion and decreased fractional excretion of lithium, which suggests that increased sodium reabsorption in the proximal tubule may contribute significantly to the maintenance of hypertension.     

Effect of nitric oxide inhibition on kidney function in experimental renovascular hypertension

We examined the effect of acute systemic blockade of nitric oxide (NO) synthesis on blood pressure and renal function in rats with angiotensin II dependent two-kidney, one-clip Goldblatt hypertension. Hypertensive animals had significantly higher blood pressures, plasma NO metabolite concentrations and urinary NO metabolite excretion rates than control rats. Intravenous administration of N(G)-nitro-L-arginine methylester (L-NAME) (10 mg/kg) increased mean arterial pressure in both hypertensive and control animals with the magnitude of increase being greater in hypertensive than control rats (32 +/- 3 vs. 20 +/- 2 mmHg, p < 0.05). L-NAME did not affect glomerular filtration rates of normal and clipped kidneys but significantly decreased non-clipped kidney glomerular filtration rate (1.1 +/- 0.1 vs. 0.7 +/- 0.1 ml/min per g kidney wt, p < 0.05). Blood flow to normal and non-clipped kidneys fell in response to L-NAME. Percent reduction in renal blood flow produced by L-NAME was significantly greater in non-clipped than normal kidneys (38 +/- 3 vs. 24 +/- 2%, p < 0.05). In contrast, clipped kidney blood flow increased after L-NAME (3.3 +/- 0.2 vs. 4.0 +/- 0.2 ml/min per g kidney wt, p < 0.05). An identical improvement in clipped kidney blood flow occurred when arterial pressure was raised with aortic constriction indicating that the systemic pressor effect of L-NAME was responsible for this finding. These results indicate that NO plays an important role in systemic and non-clipped kidney hemodynamics in renovascular hypertension. Because NO has little influence on stenotic kidney function, the stimulus for increased NO system activity in this disease appears to be vascular shear stress rather than elevated circulating or intrarenal angiotensin II concentrations.     

Effects of angiotensin inhibition and renal denervation in two-kidney, one clip hypertensive rats

Neural and angiotensin-mediated influences that alter hemodynamic and excretory behavior of the nonclipped kidney of two-kidney, one clip hypertensive rats were assessed by sequential acute surgical denervation of the nonclipped kidney and intravenous infusion of converting enzyme inhibitor (SQ 20881), 3 mg/kg X hr. Normal and two-kidney, one clip hypertensive rats (0.2-mm silver clip on the right renal artery 3-4 weeks before study) were prepared to allow study of each kidney. Mean arterial blood pressure of two-kidney, one clip hypertensive rats fell significantly from control values of 149 +/- 6 to 135 +/- 6 mm Hg after denervation of the nonclipped kidney. Despite this decrease in arterial pressure, the nonclipped kidney exhibited significant increases in glomerular filtration rate (from 1.00 +/- 0.08 to 1.24 +/- 0.08 ml/min), sodium excretion (from 88 +/- 39 to 777 +/- 207 nEq/min), fractional sodium excretion (from 0.06 +/- 0.02 to 0.54 +/- 0.14%), and urine flow rate (from 3.7 +/- 0.5 to 8.2 +/- 1.1 microliter/min). A significant decrease in glomerular filtration rate (from 1.12 +/- 0.07 to 0.85 +/- 0.08 ml/min) with no change in excretory function was observed for the clipped kidney following denervation of the nonclipped kidney. Intravenous addition of converting enzyme inhibitor significantly increased renal blood flow (from 7.0 +/- 1.3 to 10.6 +/- 1.5 ml/min) and sodium excretion (from 777 +/- 207 to 1384 +/- 425 nEq/min) for the nonclipped kidney; blood pressure decreased from 135 +/- 6 to 123 +/- 4 mm Hg, and renal vascular resistance decreased significantly (from 22 +/- 3 to 13 +/- 2 mm Hg X min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of atrial natriuretic factor on blood pressure, heart rate, and renal functions in conscious, spontaneously hypertensive rats

Atrial natriuretic factors, polypeptides released by atrial myocytes, may play a role in the control of blood pressure and the regulation of renal salt and water excretion. Our studies were designed to assess the role of a synthetic peptide, atriopeptin II, on blood pressure and heart rate, renal hemodynamics, and salt and water excretion in conscious, spontaneously hypertensive rats and in normotensive Wistar-Kyoto rats. Changes in mean arterial pressure and heart rate were recorded following intravenous bolus injections (0.1, 1.0, 10, 100 micrograms/kg) of atriopeptin II in 5 spontaneously hypertensive and 5 Wistar-Kyoto rats. In a second group of rats the peptide was infused for 90 minutes in two different doses: low dose, 1 microgram/kg + 2 micrograms/kg/hr; and high dose, 10 micrograms/kg + 20 micrograms/kg/hr. Bolus injections of atriopeptin II resulted in dose-dependent decreases in mean arterial pressure in the hypertensive, but not in the normotensive, rats; heart rates remained unchanged. Blood pressure decreased gradually during the sustained infusion of both doses of atriopeptin II, with the spontaneously hypertensive strain showing increased sensitivity compared to the Wistar-Kyoto strain. Heart rate decreased in both strains during infusion of the high dose; the decrease was significant only in the hypertensive rats. The low dose of atriopeptin II increased the clearance of free water in both strains of rats; sodium excretion was increased only in the hypertensive rats. The high-dose atriopeptin II was associated with transient natriuresis, unaltered glomerular filtration rate, and decreased effective renal blood flow in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dietary L-Arginine Attenuates Blood Pressure in Mineralocorticoid-Salt Hypertensive Rats

The present study was designed to investigate the influence of dietary L-arginine supplementation on blood pressure and on ex vivo vascular reactivity in mineralocorticoid-salt (DOCA-salt) hypertensive rats. Systolic blood pressure and heart rate were determined throughout the experimental period in unanaesthetized rats. Plasma and urine electrolyte levels were measured. Vasoconstrictor response to noradrenaline and vasodilator responses to acetylcholine and sodium nitroprusside were evaluated in the isolated perfused mesenteric vascular bed. DOCA-salt hypertensive rats were divided into 2 groups: a control group and a treated group receiving 0.8% L-arginine supplementation in drinking water. Dietary L-arginine supplementation attenuated systolic blood pressure in conscious DOCA-salt hypertensive rats, but did not modify heart rate. Plasma calcium and sodium concentrations and urinary magnesium excretion were decreased by L-arginine supplementation. Noradrenaline-induced vasoconstriction decreased and acetylcholine-induced vasodilatation increased, whereas sodium nitroprusside-induced vasodilatation was not modified, in the L-arginine-supplemented rats. It is concluded that dietary L-arginine supplementation in the diet lowers systolic blood pressure in DOCA-salt hypertensive rats, probably through vascular action.     

EFFECT OF NITRIC OXIDE INHIBITION ON KIDNEY FUNCTION IN EXPERIMENTAL RENOVASCULAR HYPERTENSION

We examined the effect of acute systemic blockade of nitric oxide (N0) synthesis on blood pressure and renal function in rats with angiotensin II dependent two-kidney, one-clip Goldblatt hypertension. Hypertensive animals had significantly higher blood pressures, plasma NO metabolite concentrations and urinary NO metabolite excretion rates than control rats. Intravenous administration of N^G-nitro-L-arginine methylester (L-NAME) (10 mg/kg) increased mean arterial pressure in both hypertensive and control animals with the magnitude of increase being greater in hypertensive than control rats (32±3 vs. 20±2 mmHg,p< 0.05). L-NAME did not affect glomerular filtration rates of normal and clipped kidneys but significantly decreased non-clipped kidney glomerular filtration rate (1.1±0.1 vs. 0.7±0.1 ml/min per g kidney wt, p< 0.05). Blood flow to normal and non-clipped kidneys fell in response to L-NAME. Percent reduction in renal blood flow produced by L-NAME was significantly greater in non-clipped than normal kidneys (38±3 vs. 24±2%,p< 0.05). In contrast, clipped kidney blood flow increased after L-NAME (3.3±0.2 vs. 4.0±0.2 ml/min per g kidney wt,p< 0.05). An identical improvement in clipped kidney blood flow occurred when arterial pressure was raised with aortic constriction indicating that the systemic pressor effect of L-NAME was responsible for this finding. These results indicate that NO plays an important role in systemic and non-clipped kidney hemodynamics in renovascular hypertension. Because NO has little influence on stenotic kidney function, the stimulus for increased NO system activity in this disease appears to be vascular shear stress rather than elevated circulating or intrarenal angiotensin II concentrations.     

Salt sensitivity in Goldblatt hypertensive rats--role of extracellular fluid volume and renin-angiotensin system

Effects of a high-salt diet on blood pressure, extracellular fluid volume, and the renin-angiotensin system in rats with the two types of Goldblatt hypertension were examined. Both in one-kidney, one clip (1K1C) rats and in one-kidney, sham-clipped (1K) rats, systolic blood pressures of rats which received a high-salt diet for 4 weeks were higher than those of rats of respective groups on a normal-salt diet, suggesting an increased sensitivity of blood pressure to changes in salt intake. Whereas sodium space was increased in 1K rats on the high-salt 1K1C rats receiving the high-salt did not have significantly increased sodium space. These results suggest that acceleration of 1K1C hypertension with salt load could not be explained only by changes in extracellular fluid volume. In contrast, both in two-kidney, one clip (2K1C) rats and in two-kidney, sham-clipped (2K) rats, the high-salt diet produced no change in blood pressure despite the increase in sodium space, suggesting a decreased salt sensitivity. Although on the normal-salt diet the blood pressure of 2K1C rats tended to correlate with plasma renin activity, on the high-salt diet plasma renin activity was markedly decreased, and then blood pressure highly correlated with sodium space. Accordingly, the lesser salt sensitivity in 2K1C rats is probably attributable to the counterbalance of the suppressed renin-angiotensin system against volume expansion. Evidence presented suggests, therefore, that 1K1C rats have greater salt sensitivity of blood pressure than 2K1C rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular permeability defect in hypertension is dependent on renin angiotensin system activation

BACKGROUND: The aim of the present study was to compare glomerular permeability alterations associated with experimental hypertension models known to have different effects on the circulating renin-angiotensin system (RAS). METHODS: Five groups, 10 animals each, were studied. One group served as a nonhypertensive control. The other four groups of hypertensive animals were composed of spontaneously hypertensive rats, deoxycorticosterone acetate hypertensive rats, Goldblatt two-kidney, one-clip rats, and a group of Wistar rats infused with angiotensin II (200 ng/kg/min). Tail-cuff sphygmomanometric systolic blood pressure (BP), albumin permeability determined in isolated glomeruli exposed to oncotic gradients (P(alb)), glomerular filtration rate (GFR, iopamidol method), plasma renin activity (PRA), and albuminuria were evaluated. RESULTS: Alterations in P(alb) and albumin excretion rate were more evident in the experimental models with an activation of the RAS despite similar levels of systolic BP and GFR. A positive correlation was found between P(alb) and albuminuria (r = 0.51; P < .001) and between systolic BP and albuminuria (r = 0.37; P < .01). No relation was found between systolic BP and P(alb). CONCLUSIONS: The present study indicates that the activation of the RAS plays a significant role in the development of glomerular albumin permeability defects in hypertensive models and may contribute to the mechanisms that lead to target organ damage in hypertension.     

Dietary sodium restriction and the renin-angiotensin system in young spontaneously hypertensive rats

Severe dietary sodium restriction initiated early in life is required to prevent development of hypertension in spontaneously hypertensive rats (SHR). Moderate sodium restriction does not affect hypertension development. This relative insensitivity to sodium restriction may be related to compensatory increases in other pressor mechanisms, specifically the renin-angiotensin system. We evaluated this possibility by measuring plasma renin activity, the blood pressure response to the angiotensin converting enzyme inhibitor captopril as well as blood pressure responsiveness to exogenous angiotensin II in SHR and Wistar-Kyoto rats (WKY) raised from birth until 6 or 16 weeks on control (101 mumol Na+/g food), moderate (26 mumol/g) or two severe (17 or 9 mumol/g) sodium-restricted diets. Moderate sodium restriction did not affect development of hypertension, but also did not cause significant increases in PRA or the blood pressure response to captopril in SHR or WKY. In contrast, severe sodium restriction blunted or prevented the development of hypertension in SHR and was associated with (1) marked increases in plasma renin activity (2) increased maintenance of blood pressure by the renin-angiotensin system (as assessed by captopril), and (3) a marked decrease in the blood pressure response to angiotensin II. We conclude that the relative insensitivity of hypertension development in SHR to dietary sodium restriction does not relate to a compensatory increase in the activity of the renin-angiotensin system. The moderate sodium restriction employed (26 mumol/g) may rather represent the lower end of the normal range.     

Different Mechanisms Maintaining High Blood Pressure in Chronic One-Kidney,One-Clip,and Two-Kidney,One-Clip Hypertensive Rats

To evaluate the difference of the blood pressure regulating mechanisms of chronic(12–14 weeks) one-kidney, one-clip(1K-1C) and chronic two-kidney, one-clip(2K-1C) hypertensive rats, we administered captopril, captopril plus indomethacin, and indomethacin to the rats. Pretreatment values of plasma renin concentration, plasma aldosterone concentration and urinary kallikrein excretion were significantly higher in 2K-1C than in 1K-1C hypertensive rats. Captopril-induced blood pressure reduction was greater in 2K-1C than in 1K-1C hypertensive rats. When captopril was administered to the rats treated with indomethacin, captopril-induced blood pressure reduction was attenuated only in 2K-1C hypertensive rats. Indomethacin produced renal impairment and further raised the blood pressure in 1K-1C hypertensive rats, but did not in 2K-1C hypertensive rats. These results suggest that the renin-angiotensin system functions to maintain high blood pressure more predominantly in chronic 2K-1C than in 1K-1C hypertensive rats. The renal kallikrein-kinin system is suppressed in chronic 1K-1C hypertensive rats but not in 2K-1C hypertensive rats. The renal prostaglandin system is more important for regulating the renal circulation in chronic 1K-1C than in 2K-1C hypertensive rats.     

Angiotensin II modulates calponin gene expression in rat vascular smooth muscle cells in vivo.

OBJECTIVES: It has been shown that angiotensin II (Ang II) induces the expression of calponin, a 34 kD actin-binding protein, in vascular smooth muscle cells in vitro. The aim of this study was to investigate whether Ang II can modulate calponin gene expression in rat aorta in vivo. DESIGN: Aortic calponin gene expression was studied after chronic exogenous Ang II administration and in Goldblatt hypertension. METHODS: To investigate the effect of Ang II administration, Sprague Dawley rats were treated for 6 days with a continuous infusion of Ang II (200 ng/kg per min) or saline by osmotic minipumps. The effect of endogenous Ang II on aortic calponin mRNA expression was studied in Goldblatt hypertensive rats with (2K1C model), or without (1K1C model) activation of the renin-angiotensin system. In particular, calponin gene expression in 2K1C rats was studied both at 1 week (2K1C-HR, high renin) and 4 weeks after the onset of hypertension, when plasma renin activity (PRA) was returned to normal values (2K1C-NR, normal renin). Systolic blood pressure (SBP) was measured twice a week. At the end of the experimental period, PRA was measured by radioimmunoassay, and aortic calponin gene expression was measured by Northern hybridization. RESULTS: SBP was significantly higher (P < 0.01), whereas PRA was suppressed (P < 0.01), in Ang II versus saline-treated rats. Northern hybridization showed that the aortic calponin gene expression significantly increased (2.5-fold) in Ang II-treated rats (P = 0.01). In Goldblatt hypertensive rats, SBP was significantly higher in 2K1C-HR (P < 0.01), 2K1C-NR (P < 0.01) and 1K1C (P < 0.01) rats compared with the corresponding sham-treated rats. Activation of the renin-angiotensin system was present only in 2K1C-HR rats (P < 0.01), and Northern analysis showed that aortic calponin mRNA expression was significantly increased (2.2-fold) in this group of rats only (P < 0.01). CONCLUSIONS: Our data demonstrate that both exogenous and endogenous Ang II increase calponin gene expression in aortic smooth muscle cells, independently of the hemodynamic effect of Ang II.     

Effects of angiotensin converting enzyme inhibitors and calcium antagonists on atrial natriuretic peptide release and action and on albumin excretion rate in hypertensive insulin-dependent diabetic patients.

Abnormalities in sodium homeostasis and in atrial natriuretic peptide (ANP) behavior could play a role in determining and accelerating the development of glomerular hypertension, hypertension, and microalbuminuria in insulin-dependent diabetes. The aim of the present study was to investigate in 32 hypertensive insulin-dependent diabetic patients (HD) with an altered albumin excretion rate the natriuretic response and ANP release to saline load (2 mmol/kg 90 min, and the effects angiotensin converting enzyme inhibitor therapy 2.5 to 5.0 mg cilazapril, once daily), and calcium antagonists (sustained release verapamil: 120 to 240 mg Isoptin Press, once daily, and long acting nifedipine: 20 to 40 mg Adalat AR, twice daily) on sodium homeostasis and albumin excretion rate. Eight normal subjects matched for sex, age, and weight served as controls. The 32 HD patients showed a blunted response in ANP release and sodium excretion during saline infusion in comparison with controls. The cilazapril and verapamil treatments were tested in 16 of the 32 HD patients and were both effective in ameliorating natriuretic and ANP response to saline load and in decreasing albumin excretion rate. The combined cilazapril and verapamil treatment further improved both these parameters in these patients, although blood pressure levels were comparable. The other 16 HD patients underwent sequential verapamil and nifedipine treatment. Verapamil was more effective than nifedipine in improving natriuresis and ANP release to saline load and in lowering the albumin excretion rate. The results of the present study demonstrate that sodium homeostasis and ANP release are altered in hypertensive nephropathic patients, and both cilazapril and verapamil are more effective than nifedipine in ameliorating natriuresis, ANP release, and albumin excretion rate.     

Superoxide dismustase mimetic tempol decreases blood pressure by increasing renal medullary blood flow in hyperinsulinemic-hypertensive rats

Insulin resistance and compensatory hyperinsulinemia often coexist in hypertensive patients, which may play a role in the development of hypertension. Because medullary blood flow (MBF), which is strongly influenced by the nitric oxide (NO) system, is thought to be an important component of blood pressure and sodium balance, we focused particularly on MBF in fructose-induced hypertensive rats. Moreover, it has been reported that the increased reactive oxygen species (ROS) in the kidney may contribute to the development of hypertension. Our study was thus designed to test the hypotheses that MBF is diminished in fructose-hypertensive rats (FFR) and that administration of tempol, a membrane-permeable mimetic of superoxide dismutase (SOD), decreases mean arterial pressure (MAP) by increasing MBF. Male Sprague-Dawley rats (180 to 200 g) were divided into 6 groups: control untreated (C, n = 5), control tempol-treated (in drinking water) (CT, n = 4), control L-arginine-treated (in drinking water) (CA, n = 6), fructose-fed untreated (F, n = 7), fructose-fed tempol-treated (FT, n = 7), and fructose-fed L-arginine-treated rats (in drinking water) (FA, n = 6). MAP and 24-hour urine samples were measured weekly over a 4-week test period. Changes in MBF, cortical blood flow (CBF), and renal blood flow (RBF) were determined by implanted optical fiber-, laser- and pulse-Doppler flow measurement techniques 4 weeks after starting the diet. Fructose feeding resulted in hyperinsulinemia, significantly elevated MAP, decreased MBF without changes in RBF or CBF, and decreased sodium excretion in the F group compared to the C group. Administration of tempol significantly decreased MAP and plasma insulin in contrast to increased MBF and sodium excretion in the FT group compared to those in the F group. Results indicated that MBF played an important role in the development of hypertension in the F group. Impairment of renal medullary NO systems may induce sustained elevation of blood pressure and retention of sodium in fructose-fed rats. The decrease in MAP with an increase of MBF in the FT group is consistent with the hypothesis that tempol increases the level of NO available to influence mechanisms involved in the control of MBF.