[Sodium restriction prevents cardiovascular remodeling associated with insulin-resistance in the rat]. / La restriction sodée prévient le remodelage cardiovasculaire dans l'insulinorésistance chez le rat.

AIM OF THE STUDY: In the present work, the objective was to evaluate the influence of a dietary sodium restriction on cardiovascular morphology changes associated with insulin-resistance. ANIMALS AND PROTOCOL: At 8 weeks of age, rats were fed for 12 weeks a 60%-fructose diet containing a regular sodium content (0.64%) or totally lacking in sodium chloride (<0.01%). A group of rats fed a wheat starch-based diet with regular sodium content served as control group. RESULTS: Elevated HOMA index and plasma insulin confirm the presence of insulin-resistance in fructose-fed rats. Concomitantly, an increase in cardiac mass and in cardiac collagen (Sirius red staining) was detected without obvious change in arterial pressure or cardiac aldosterone synthase mRNA expression. In addition, cross-sectional area of the carotid artery was higher in fructose-fed rats. Production of superoxide anion, equated with dihydroethidium (DHE) staining, was enhanced in cardiac tissue of rats with insulin-resistance. Withdrawal of sodium from the fructose diet prevented all the cardiovascular effects of fructose consumption, including DHE staining. CONCLUSION: These results are in favor of the participation of oxidative stress normalization in the beneficial influence of dietary sodium deprivation on cardiovascular remodeling in this model of insulin-resistance in rats.

[Oxydative stress and beneficial effect of sodium restriction on kidney damage associated with insulin resistance in rats]. / Stress oxydant et effets bénéfiques rénaux de la restriction sodée dans l'insulinorésistance chez le rat.

The aim of this work was to evaluate the influence of dietary sodium restriction on metabolic and renal changes associated with insulin resistance. At 8 weeks of age, rats received either a diet containing 60% fructose with or without sodium or a standard diet for 12 weeks. The insulin resistance and albuminuria induced by the high fructose diet were associated with a fibrosis and increase in oxidative stress in the kidney. The low salt diet prevented insulin resistance, renal fibrosis and albuminuria induced by the fructose diet. These beneficial effects on the kidney were associated with a decrease in kidney NADPH oxidase activity. Oxidative status is probably one of the major targets of the favourable effect of salt restriction on renal changes associated with insulin resistance, without excluding the involvement of other mechanisms.

Carbon monoxide pollution impairs myocardial perfusion reserve: implication of coronary endothelial dysfunction.

Chronic exposure to simulated urban CO pollution is reported to be associated with cardiac dysfunction. Despite the potential implication of myocardial perfusion alteration in the pathophysiology of CO pollution, the underlying mechanisms remain today still unknown. Therefore, the aim of this work was to evaluate the effects of prolonged exposure to simulated urban CO pollution on the regulation of myocardial perfusion. Cardiac hemodynamics and myocardial perfusion were assessed under basal conditions and during the infusion of a ß-Adrenergic agonist. The effects of CO exposure on capillary density, coronary endothelium-dependent vasodilatation, eNOS expression and eNOS uncoupling were also evaluated. Our main results were that prolonged CO exposure was associated with a blunted myocardial perfusion response to a physiological stress responsible for an altered contractile reserve. The impairment of myocardial perfusion reserve was not accounted for a reduced capillary density but rather by an alteration in coronary endothelium-dependent vasorelaxation (-45% of maximal relaxation to ACh). In addition, though chronic CO exposure did not change eNOS expression, it significantly increased eNOS uncoupling. Therefore, the present work underlines the fact that chronic CO exposure, at levels found in urban air pollution, is associated with reduced myocardial perfusion reserve. This phenomenon is explained at the coronary-vessel level by deleterious effects of CO exposure on the endothelium NO-dependent vasorelaxation via eNOS uncoupling.

High plasmatic angiotensin-converting enzyme (ACE) activity is not correlated with training-induced left ventricular growth in ACE congenic rats.

AIM: The aim of this study was to determine the influence of angiotensin-converting enzyme (ACE) genotype on left ventricular growth after endurance training, in ACE congenic rats with plasma ACE activity twice as high as the donor strain (LOU), thus mimicking the ACE I/D polymorphism observed in humans. METHODS: LOU and congenic rats (n = 12) were submitted to an endurance training on a treadmill for 7 weeks, while similar LOU and congenic rats (n = 10) constituted the control groups. Blood pressure, skeletal muscle citrate synthase activity, plasma and left ventricular ACE activity were assessed, and echocardiography was performed before and after the training. RESULTS: Angiotensin-converting enzyme plasmatic activity of congenic rats (188.2 +/- 26.6 in controls and 187.1 +/- 22.6 IU in trained rats respectively) was twofold that of the LOU strain (91.9 +/- 23.3 in controls, and 88.3 +/- 18.1 IU in trained rats respectively). After training, congenic and LOU rats showed a similar significant increase in citrate synthase activity (P < 0.05), and in the left ventricular mass/body mass ratio x 10(3): 3.7 +/- 0.3 and 3.6 +/- 0.6 in the trained congenic and LOU groups, respectively, vs. 3.0 +/- 0.1 and 2.9 +/- 0.2 in the control congenic and LOU groups respectively (P < 0.05). There was no significant correlation between ACE plasma activity and left ventricular mass in trained or untrained congenic rats. CONCLUSION: We conclude that training-induced left ventricular growth is not associated with plasma ACE activity in congenic rats.

[Renin-angiotensin system inhibition and cardiac and renal alteration induced by a high sodium diet in rat]. / Inhibition du système rénine-angiotensine et altérations cardiaque et rénale induites par une consommation excessive de sodium chez le rat.

BACKGROUND: The present study was designed to assess the influence of losartan on cardiac hypertrophy and albuminuria associated with early high sodium feeding in rats and to compare it to an angiotensin-converting enzyme inhibitor, enalapril, effect. METHODS: Male Sprague-Dawley rats received a regular diet (0.8% NaCl, NS, n=7), or high sodium diet (8% NaCl, HS, n=21) from weaning for 8 weeks. After 4 weeks of diet, two HS groups were treated or not for 4 weeks with losartan or enalapril (30 and 10 mg/kg(-1) x day(-1) respectively, n=7 in each). Food and water consumption, body weight, urinary volume and urinary excretion of sodium, potassium and albumin were measured at the end of treatment as well as arterial pressure (anesthetized rats), heart and kidney weight. RESULTS: Eight weeks after weaning, heart weight index and albuminuria were significantly higher in HS control group when compared to the control NS group without change of arterial pressure. Treatment with losartan or enalapril had no effect either on arterial pressure or cardio-renal alterations.

[Sodium ion inhibits angiogenesis of cultured rat aortic and coronary rings]. / L'ion sodium inhibe les capacités angiogéniques in vitro d'explants d'aorte et d'artère coronaire de rat.

High sodium intake is associated with the development of cardiac hypertrophy in man and rats independently of the rise of blood pressure. In addition, the reduced capillary density observed in striated muscle of rats fed a high salt diet suggests that angiogenesis is altered. The aim of the present experiments was to investigate the angiogenic capacities of vascular rings isolated from the aorta and the coronary artery of rats. Vascular rings (external diameter of 1 669 +/- 9 and 323 +/- 26 microm for aorta and coronary artery. respectively) are cultured in a three-dimensional collagen type I lattice and a standard medium (DMEM+HAMF12) containing 152 mM of sodium. Sodium ion associated with chloride or citrate is added to the standard medium to achieve a final concentration of sodium of 160 and 176 mM. The role of sodium-proton exchanger is evaluated through the addition of amiloride to the culture medium. Sprouts formed from vascular explants are counted every second day until days 8 to 10. Kinetics of new vessels formation and the number of sprouts were similar in aortic and coronary rings (83 +/- 5 and 95 +/- 5 sprouts, respectively). Elevation of sodium chloride concentration inhibits by 50 to 80% the neo-vessels formation in both the aorta and the coronary artery. Anti-angiogenic effect of the high sodium medium was not affected when citrate was substituted to chloride. Amiloride (3.10(-5) M) reduced the number of sprouts formed in the standard medium; however, it counteracted the anti-angiogenic effect of elevated sodium concentration. These results indicate that high extracellular concentration of sodium and not chloride anion is accompanied by a deleterious effect on angiogenic capacities of cultured aortic and coronary artery rings through modifications of trans-membrane sodium exchanges.

[Influence of angiotensin I on angiogenesis in vitro in the rat]. / Influence de l'angiotensine II sur les capacités angiogéniques d'explants vasculaires de rat.

The regulation of angiogenesis involves complex interactions. The aim of our study was to assess the influence of angiotensin II (ANG II) on different vascular beds in rat. Aortic, renal and mesenteric rings from 10 male Sprague-Dawley rats were cultured using a three-dimensional culture system consisting of rat type I collagen lattice. We assessed the influence of different ANG II concentrations (10(-7) et 10(-9) mol/L) on these rings as well as the effect of AT1 blockade by losartan (10(-7 mol/L). ANG II inhibited angiogenesis at 10(-7) mol/L on renal artery. However, these was a angiogenic effect at 10(-9) mol/L on the mesenteric artery. Every time losartan prevented the effect of ANG II in any kind of vessel rings. No significant effect on ANG II was found on aortic rings but coadministration of losartan induced a dramatic decrease in the number of capillary sprouts. In conclusion, ANG II seems to be deeply involved in angiogenesis. However, its effect depends on the concentration of ANG II and the type of vessel. ANG II appears to be angiogenic on mesenteric arteries via an AT1 receptor effect and mostly anti-angiogenic on the renal arteries with possible involvement of AT2 receptors.

Effects of spironolactone and fosinopril on the spontaneous and chronic ventricular arrhythmias in a rat model of myocardial infarction.

We documented chronic ventricular arrhythmias in a first group of 58 rats after myocardial infarction (MI), then assessed the effects of spironolactone and fosinopril on morphological indexes and arrhythmias in a second group (n = 33). Rats underwent Holter monitoring at 2 months after MI. Treatment was randomly given from 1 until 4 months after MI: placebo in 12 rats (P), fosinopril in 9 (F) and spironolactone + fosinopril in 12 (SF). The score of ventricular premature beats (VPBs) was related to the MI size and the delay from MI (p < 0.01). VPB's reduction/increase required to demonstrate anti/pro-arrhythmic effects were 55 and 59%. Mass indexes were lower in F and SF (p = 0.01). VPB's difference (4 months vs. 1) was positive in P, significantly lower in F and negative in SF (p = 0.04). In this relevant model of spontaneous and chronic ventricular arrhythmias, SF association did not increase mortality but lowered the arrhythmic score.

Influence of irbesartan and enalapril on changes of renal function associated with the established phase of l-NAME hypertension.

OBJECTIVE: Reversibility of the systemic and renal alterations induced by N(omega)-nitro-L-arginine-methyl ester(L-NAME) was assessed by treatment with irbesartan and enalapril (30 and 10 mg/kg per 24 h, respectively) alone or in combination. DESIGN: L-NAME (20 mg/kg per 24 h) was given to rats for 6 weeks and treatments were administered during the last 2 weeks. Glomerular filtration rate and renal plasma flow [GFR and RPF per g of kidney weight (KW)] were determined using the clearance technique. RESULTS: Arterial pressure was similarly reduced by treatments. GFR was lower in L-NAME-treated rats than in controls (552 +/- 52 versus 1106 +/- 78 microl/min per g KW), whereas RPF was reduced to a larger extent, thus resulting in an increase in filtration fraction. GFR was normalized by irbesartan but not enalapril or the combination (1042 +/- 50, 790 +/- 79 and 725 +/- 38 microl/min per g KW, respectively). RPF returned to normal and filtration fraction fell markedly with the combination. All treatments reduced the lesions of preglomerular vessels and reversed L-NAME-induced albuminuria and cardiovascular hypertrophy. At a dose of 3 mg/kg per 24 h, irbesartan only reduced the lesions of the afferent arteriole. CONCLUSIONS: Through its effects on AT1 receptors, angiotensin II may play an important role in the maintenance of L-NAME hypertension and associated alterations. The lower GFR and filtration fraction observed with enalapril in the presence of irbesartan suggests the intervention of non-angiotensin II-mediated mechanism, and at the postglomerular level, in the effect of angiotensin-converting enzyme (ACE) inhibitors.

Endothelin blockade in angiotensin II hypertension: prevention and treatment studies in the rat.

1. The participation of endothelin (ET) in the development and maintenance of hypertension induced by angiotensin (Ang) II was assessed using the non-specific ET receptor antagonist bosentan (30 mg/kg per day). 2. In the prevention study, bosentan was given 24 h prior to and during the 17 day period of AngII infusion (200 ng/kg per min, s.c., osmotic pump), whereas in the treatment study, bosentan was administered from day 10 to day 17. Tail-cuff pressure (TCP) was measured before and on days 10 and 17 of AngII infusion. At the end of studies, heart weight index was calculated as the ratio of heart to bodyweight (HWI) and the wall thickness of the carotid artery (perfusion/fixation at 120 mmHg) was measured. Tail-cuff pressure increased from 129 +/- 3 to 179 +/- 7 and 189 +/- 9 mmHg on days 10 and 17 of AngII infusion, respectively. 3. Final TCP was markedly lowered in rats pretreated with bosentan, whereas TCP remained comparable with untreated hypertensive rats when bosentan was given from day 10 of AngII infusion (177 +/- 9 mmHg). 4. The increase in cardiac mass associated with AngII hypertension was similarly attenuated in the two groups receiving bosentan. 5. The HWI was 3.49 +/- 0.12 mg/g in untreated hypertensive rats and 3.18 +/- 0.08 and 3.11 +/- 0.09 mg/g in rats pretreated with bosentan and those receiving the antagonist from day 10. 6. The increase in carotid wall thickness induced by AngII was prevented, but not reversed, by bosentan. 7. These results support the hypothesis that endogenous ET participates only in the initial phase of AngII hypertension. In addition, the beneficial effect of bosentan of cardiac mass but not on arterial wall thickness is in favour of a role of ET as a local mediator of the cardiac hypertrophic effect of AngII, independently of the level of blood pressure and duration of hypertension.

Nitric oxide inhibition and renal alterations.

Acute and chronic administrations of L-arginine analogues are associated with renal functional and structural alterations that can be prevented or reversed by pharmacological blockade of other vasoactive systems. When given acutely, L-arginine derivatives have an antinatriuretic effect that is overridden by elevation of perfusion pressure and both endothelin and angiotensin II play an important role in the systemic and renal haemodynamic alterations associated with impaired nitric oxide availability. Long-term administration of L-arginine derivatives, mainly NG-nitro-L-arginine methylester (L-NAME), resulted in hypertension, intrarenal vascular, tubular and glomerular lesions and reduction in renal function. In prevention studies, blockade of the renin-angiotensin system markedly reduced hypertension and the renal morphological alterations associated with L-NAME administration. Although improvement in renal function may be achieved when arterial pressure is fully controlled, several reports indicate that the L-NAME-induced renal structural changes were independent of blood pressure and at least partly mediated by endothelin. In intervention studies, blockers of the renin-angiotensin system decreased but did not completely normalize arterial pressure, improved renal function and normalized albuminuria. Both the renin-angiotensin and the sympathetic nervous systems contribute to the sustained phase of chronic nitric oxide synthase inhibition, the adrenergic component being prominent with time. L-NAME hypertension can also be reversed by calcium antagonists, possibly via inhibition of angiotensin II-induced vasoconstriction, and the T-type antagonist had a greater effect than the L-type antagonist in reducing pre-glomerular resistance. The rat model of hypertension induced by chronic inhibition of nitric oxide generation has provided a useful tool to study both the development and the treatment of renal lesions resembling those found in human hypertension, a disease associated with early generalized impairment of endothelial function.

[Simvastatin attenuates cardiovascular effects and oxidative stress induced by angiotensin II]. / La simvastatine atténue les atteintes cardiovasculaires et le stress oxydant induits par l'angiotensine II.

The effects of an HMG-CoA reductase inhibitor, simvastatin (statin, 60 mg/Kg/24 h by forced feeding), were studied on the development of hypertension, cardiac hypertrophy and oxidating stress induced by chronic perfusion of angiotensin II (ANG II, 200 ng/Kg/min s.c., for 10 days) in the rat. The statin was giver 24 hours before, and during the 10 days of ANG II. At the end of the study, mean blood pressure was measured and blood sampling performed under anaesthesia (sodium pentobarbital). The cardiac mass index was measured (cardiac mass/body weight, mg/Kg). TBARS (thiobarbituric acid reactive substances), representing the index of lipid peroxidation, was assessed by fluorimetry. The statin attenuated the development of hypertension (131 +/- 9 vs 164 +/- 4 mmHg) and the increase in cardiac mass (3.13 +/- 0.09 vs 3.46 +/- 0.09 mg/g) associated with ANG II. The overproduction of TBARS induced by ANG II was partially prevented by simvastatin (598 +/- 40 vs 794 +/- 79 pmol/mL). These results indicate that simvastatin attenuates the cardiovascular effects and lipid peroxidation induced by chronic administration of angiotensin II.

[Cardiac and vascular hypertrophy in hypertension due to angiotensin II. Effect of losartan and bosentan]. / Hypertrophie cardiaque et vasculaire dans l'hypertension à l'angiotensine II. Influence du losartan et du bosentan.

We assessed the role of angiotensin (Ang) II type 1 receptor (AT1) and endothelin type A and B (ETA & ETB) receptor in cardiovascular hypertrophy associated with angiotensin II-induced hypertension (200 ng/kg.min s.c. for 10 or 17 days). Antagonism of AT1 receptors was obtained by oral administration of losartan (10 or 30 mg/kg.day) and blockade of ETA and ETB receptors was obtained by oral administration of bosentan (30 mg/kg.day). Losartan and bosentan were administered 24 h before and during the 10 days of angiotensin II (prevention) or they were given after the development of hypertension i.e. from day 10 to 17 of angiotensin II (treatment). Tail-cuff pressure (TCP) was measured before and at the end of the period of administration of antagonists. At the end of experiments, cross sectional area (CSA, mm2) of the carotid was measured after perfusion and fixation at 100 mmHg and heart weight index (HWI, mg/g body weight) was determined. Results are mean +/- SEM. [table: see text] In addition to its blood pressure lowering effect, both doses of losartan prevented and reversed the cardiovascular hypertrophy induced by angiotensin II. Similarly, bosentan prevented and reversed the effect of angiotensin II on cardiovascular structure independently of arterial pressure. These results indicate that the effect of angiotensin II on blood pressure, heart and carotid structure is exclusively mediated by AT1 receptors. The influence of bosentan suggests that endothelin plays an important role in local action of angiotensin II independently of blood pressure level.

Angiotensin II type 1 receptor antagonist versus angiotensin I-converting enzyme inhibitor in experimental renal diseases.

Angiotensin II has an important role in the structural and functional regulation of the cardiovascular and renal systems. Blockade of the renin-angiotensin system can be achieved with angiotensin-converting enzyme (ACE) inhibitors and non-peptidic, orally active, angiotensin II type I receptor (AT1) antagonists. However, the question that has yet to be answered is whether ACE inhibitors and AT1 receptor antagonists have similar renoprotective effects in various experimental diseases. Although many studies have assessed the role of either ACE inhibitors or AT1 receptor antagonists, we have reviewed the literature comparing both types of blocker in the same experiment. In most models of hypertension or renal failure, both classes of blocker appear to have similar antihypertensive and renal profiles. In a few models, the influence of the ACE inhibitor on arterial pressure and/or renal function is more marked than that of the AT1 receptor antagonist. Even though the maximum dose-effect curve for each compound was not often carried out for the systemic haemodynamics and renal alterations, the difference between both classes of blocker, when observed, appeared to favour the participation of non-angiotensin II or non-AT1-mediated mechanisms. Among them are the stimulation of prostaglandin production, kinin accumulation, nitric oxide generation and modulation of endothelin or TGFbeta1 expression via direct or indirect pathways. Future experimental and probably human studies aimed at comparing angiotensin II receptor antagonists and ACE inhibitors, with respect to blood pressure and renal damage, should be designed with all these concerns in mind.

Blood pressure variability in established L-NAME hypertension in rats.

METHODS: Blood pressure variability was evaluated in conscious Wistar control rats and rats with established L-NAME hypertension (20 mg/kg per 24 h, 4 weeks). RESULTS: Final systolic arterial pressure was 185+/-5 and 132+/-4 mm Hg in the Nomega-nitro-L-arginine methyl ester (L-NAME)-treated and control rats, respectively. The standard deviation of systolic arterial pressure in the L-NAME group was 70% greater than in the control rats, indicating a significant increase in the overall variability. Arterial pressure in the L-NAME rats exhibited aperiodical, abrupt rises and falls and data was grossly non-stationary. Blood pressure variability was therefore evaluated using Poincaré plot analysis. The variance of the difference (delta) between two successive values of systolic arterial pressure, determined for time intervals of 0.2 to 5 s (0.2 s increment), was always significantly higher in the L-NAME group compared with untreated animals. The variance of delta systolic arterial pressure increased with the time interval and plateaued for time intervals of 2.4 and 1.4 s in hypertensive and normotensive rats, respectively. These differences vanished when the sudden events oberved in L-NAME rats were omitted in the construction of Poincaré plots. Acute administration of prazosin (1 mg/kg), but not losartan (10 mg/kg) markedly reduced the variance of delta systolic arterial pressure in hypertensive rats. CONCLUSIONS: Nitric oxide participates in the control of arterial pressure variability. The sympathetic nervous system seems to be a major determinant of the increased short-term variability of arterial pressure in this model.

Chronic bradykinin infusion and receptor blockade in angiotensin II hypertension in rats.

The influence of endogenous bradykinin(BK) on the control of arterial pressure and the development of cardiac hypertrophy was assessed in chronically angiotensin II(Ang II)-infused rats (200 ng. kg-1. min-1) through the effects of concomitant infusion of 3 doses of BK (15 ng. kg-1. d-1, 100 ng. kg-1. d-1 and 100 ng. kg-1. min-1 ie, 144 000 ng. kg-1. d-1) or BK-blockade by Hoe140 (300 microg. kg-1. d-1) for 10 days. In Ang II-infused rats, tail-cuff pressure increased from 124+/-3 to 174+/-6 mm Hg (P<0.001). The pressor effect of Ang II was not affected by simultaneous infusion of BK or Hoe140. At the end of the experiments, cardiac mass was higher in rats infused with Ang II alone (3.56+/-0.10 versus 2.89+/-0.05 mg/g in untreated controls, P<0.01) and the development of cardiac hypertrophy was not modified by administration of the 3 doses of BK or Hoe140. In addition, the fall in cardiac output associated with Ang II was prevented only by the moderate and high doses of BK, mainly through an increase in stroke volume and a decrease in total peripheral resistance. In the same way, the renal vasoconstrictor effect of Ang II was abolished by the medium and high dose of BK. Hoe140 did not affect cardiac output or renal blood flow in this model. No influence of BK or Hoe140 on the increase in albuminuria induced by Ang II was detected. In conclusion, exogenous BK may oppose the effect of Ang II on vascular tone, but it cannot prevent hypertension and target-organ damage associated with this experimental model of hypertension, even at a very high dose.

Nitric oxide participates in the renal vasodilatory effect of candesartan in anesthetized rats.

Inhibition of nitric oxide synthase by L-arginine analogues was shown to attenuate the antihypertensive effect of angiotensin II (AngII) type-1 receptor blockade, thus suggesting that nitric oxide might partly mediate the systemic effect of these agents. In the present experiment, the effects of an acute administration of candesartan on arterial pressure, renal blood flow (transit time method), and resistance were assessed in anesthetized normotensive rats infused or not with NG-nitro-L-arginine methyl ester (L-NAME) (20 microg/kg per min for 60 min). Candesartan was given at a dose of 0.5 mg/kg intravenous bolus in normotensive rats. Candesartan reduced arterial pressure by 15+/-2% and renal vascular resistance by 31+/-2% in nonpretreated rats. Pretreatment by L-NAME did not affect the BP lowering effect of candesartan but blunted by 60 to 100% the renal response to candesartan. Concomitant administration of L-arginine restored the renal vasodilatory action of candesartan. Plasma renin concentration was reduced by L-NAME from 122+/-23 to 69+/-14 ng AngI/ml per h and not further modified by L-arginine (71+/-16 ng AngI/ml per h). Neither the systemic and renal hemodynamic responses to AngII nor its blockade by candesartan were affected by L-NAME. The loss of renal vasodilatory effect of candesartan during L-NAME infusion suggests that AT1 receptor blockade is associated with an increase in nitric oxide-dependent tone, which participates in the full expression of the renal vasodilatory action of AngII type-1 receptor blockade in anesthetized normotensive rats.

Candesartan and progression of preglomerular lesions in N(G)-nitro-L-arginine methyl ester hypertensive rats.

Chronic administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces systemic hypertension and progressive development of preglomerular sudanophilic (SB+) lesions. This study investigates whether progression of SB+ lesion formation froin 4 to 6 wk of L-NAME treatment (20 mg/kg per d, orally) would be affected by 2 wk administration of either the angiotensin II type 1 receptor antagonist candesartan cilexetil (3 and 10 mg/kg per d) or the vasodilator hydralazine (15 mg/kg per d). Frequencies of arcuate arterial branches (ArcB), interlobular arteries (ILA), and afferent arterioles (AA) endowed with SB+ lesions were assessed on preglomerular vasculatures isolated after HCl maceration. Systolic BP (SBP, tail-cuff manometry) increased from a baseline of 125+/-2 to 185+/-4, and to 193+/-4 mmHg after 4 and 6 wk of L-NAME treatment, respectively. During the fourth- to sixth-week period, albumin excretion increased significantly from 3.7+/-1.1 to 52.5+/-22.4 mg/24 h. At that time, SB+ lesions affected 62+/-8, 61+/-8, and 13+/-4% of ArcB, ILA, and AA, respectively. Candesartan cilexetil dose dependently reduced SBP, albumin excretion, and lesion development. At the highest dose, SB+ lesions only affected 12+/-6, 15+/-7, and 1+/-1% of ArcB, ILA, and AA, respectively. Hydralazine similarly reduced SBP and albumin excretion, although frequencies of SB+ lesions appeared less affected along ArcB and ILA. In conclusion, progression of preglomerular SB+ lesion formation during L-NAME hypertension can be prevented by angiotensin II type 1 receptor blockade, partly through pressure-lowering effects.

Contrasting renal effects of chronic administrations of enalapril and losartan on one-kidney, one clip hypertensive rats.

OBJECTIVE: To compare the effects of chronic administrations of the angiotensin II antagonist losartan and of the angiotensin I converting enzyme inhibitor enalapril on renal function in sodium-depleted rats with one-kidney, one clip hypertension, and to examine the contribution of endogenous kinins to the effect of enalapril. METHODS: We administered enalapril and losartan (10 and 30 mg/kg per day, respectively) for 6 days to hypertensive rats that had been subjected to dietary sodium-intake restriction for 6 days prior to treatment and continued to be subjected to this restriction during treatment. In an additional group, administration of enalapril was combined with infusion of the bradykinin B2-receptor antagonist Hoe 140 (300 microg/kg per day subcutaneously via an osmotic pump). Renal function of anesthetized rats was assessed by using a clearance technique. RESULTS: Despite there being similar falls in arterial pressure, glomerular filtration rate (867 +/- 40 microl/min per g kidney weight in untreated rats) was decreased to a larger extent in enalapril-treated than it was in losartan-treated rats (284 +/- 29 versus 438 +/- 36 microl/min per g kidney weight, P < 0.01). Although infusion of Hoe 140 had no influence on the effect of enalapril on arterial pressure, the level of glomerular filtration achieved in rats of this group (545 +/- 55 microl/min per g kidney weight) was similar to that found in losartan-treated rats. No effect of either treatment on renal plasma flow was detected; as a consequence, the excessive decrease in filtration fraction observed for rats in the enalapril-treated group was corrected by concomitant administration of Hoe 140. Interestingly, administration of enalapril resulted in a greater loss of sodium than did administration of losartan (723 +/- 147 versus 308 +/- 57 micromol during 6 days), and this effect was abolished by infusion of Hoe 140 (353 +/- 42 micromol during 6 days). CONCLUSION: Administration of enalapril to sodium-depleted rats with one-kidney, one clip hypertension reduces their glomerular filtration rate to a greater extent than does administration of losartan despite these agents having similar effects on systemic blood pressure. Combined administration of enalapril and Hoe 140 has a less marked effect on glomerular filtration rate than does that of enalapril alone. This suggests that kinins play a role in the regulation of efferent arteriolar tone in this rat model.

[Effect of chronic bradykinin infusion on angiotensin II hypertension in rats]. / Effet de l'administration chronique de bradykinine dans l'hypertension induite par l'angiotensine II chez le rat.

In previous studies, we demonstrated that in ANG II-treated rats, prevention of cardiac hypertrophy (CH) by enalapril was blunted by bradykinin (BK) blockade by Hoe140. The putative role of BK was assessed by chronic exogenous BK infusion and in 46 male Sprague-Dawley rats infused with ANG II. ANG II (200 ng/kg/min) alone and associated with BK at low (BKlow, 15 ng/kg/day), mid (BKmid, 100 ng/kg/day) and high doses (BKhigh, 100 ng/kg/min) were delivered by Alzet osmotic pumps for 10 days and compared to control animals (Veh). Values of systolic arterial pressure (SAP, mmHg) in conscious rats and heart weight (HW, mg/g bw) at the end of the study are reported below. Results were submitted to ANOVA and are expressed as mean +/- SEM.