Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism

OBJECTIVE: A reduction in glomerular number and/or size has been implicated in the development of hypertension. This study investigated whether differences in glomerular number and/or size occur during the development of hypertension in the spontaneously hypertensive rat (SHR) and whether angiotensin II is responsible for any glomerular differences. METHODS: SHR (n=6) and Wistar-Kyoto (WKY) rats (n=6) were administered the angiotensin II type I receptor antagonist TCV-116 from 4 to 10 weeks of age. At 10 weeks of age, the kidneys from these rats and those from untreated SHR (n=6) and WKY rats (n=6) controls were perfusion fixed at physiological pressures and analysed using unbiased stereological techniques. RESULTS: There were no significant differences in glomerular number, glomerular volume or total glomerular volume between SHR and WKY rats. Treatment of SHR with TCV-116 significantly lowered systolic blood pressure but had no significant effect on glomerular number or volume or total glomerular volume. Treatment of WKY rats with TCV-116 reduced systolic blood pressure, body weight, glomerular volume and total glomerular volume; however, total glomerular volume per body weight of treated WKY rats was not significantly different from that of untreated WKY rats. CONCLUSION: There were no differences in glomerular number or volume in SHR compared with WKY rats at 10 weeks of age. We therefore conclude that glomerular changes are not responsible for the development of hypertension in SHR. Angiotensin II, via the type 1 receptor, does not contribute to glomerular growth during the development of hypertension in the SHR.     

Angiotensin II type 1A receptors in vascular smooth muscle cells do not influence aortic remodeling in hypertension

Vascular injury and remodeling are common pathological sequelae of hypertension. Previous studies have suggested that the renin-angiotensin system acting through the type 1 angiotensin II (AT(1)) receptor promotes vascular pathology in hypertension. To study the role of AT(1) receptors in this process, we generated mice with cell-specific deletion of AT(1) receptors in vascular smooth muscle cells using Cre/Loxp technology. We crossed the SM22α-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Agtr1a gene (Agtr1a (flox)), encoding the major murine AT(1) receptor isoform (AT(1A)). In SM22α-Cre(+)Agtr1a (flox/flox) (SMKO) mice, AT(1A) receptors were efficiently deleted from vascular smooth muscle cells in larger vessels but not from resistance vessels such as preglomerular arterioles. Thus, vasoconstrictor responses to angiotensin II were preserved in SMKO mice. To induce hypertensive vascular remodeling, mice were continuously infused with angiotensin II for 4 weeks. During infusion of angiotensin II, blood pressures increased significantly and to a similar extent in SMKO and control mice. In control mice, there was evidence of vascular oxidative stress indicated by enhanced nitrated tyrosine residues in segments of aorta; this was significantly attenuated in SMKO mice. Despite these differences in oxidative stress, the extent of aortic medial expansion induced by angiotensin II infusion was virtually identical in both groups. Thus, vascular AT(1A) receptors promote oxidative stress in the aortic wall but are not required for remodeling in angiotensin II-dependent hypertension.     

Effects of candesartan on the proteinuria of chronic glomerulonephritis

Angiotensin I-converting enzyme (ACE) inhibitors are commonly used for the treatment of hypertension, progressive chronic renal disease, diabetic nephropathy, and congestive heart failure. Because angiotensin II acts through membrane bound type 1 (AT1) and type 2 (AT2) receptors, ACE inhibitors and angiotensin II-receptor antagonists have distinct effects. ACE inhibitors inhibit production of angiotensin II thus suppressing the action of angiotensin II on both AT1 and AT2. In contrast, the effect of AT1-receptor antagonists is to selectively block the activation of the AT1 receptor. This AT1-receptor blockade leaves the AT2 receptors unopposed to elevated levels of endogenous angiotensin II. Thus, there may be an advantage of AT1-receptor blockade over ACE inhibition in the management of a variety of chronic vascular diseases, including chronic glomerulonephritis and other glomerular diseases. In a clinical trial candesartan, an AT1-receptor antagonist, effectively lowered urinary protein excretion in patients with chronic glomerular nephritis. Evidence indicates that functionally active AT1 receptors, as well as AT2 receptors, are present in both afferent and efferent arteriole of the glomerulus, and that angiotensin II induces afferent and efferent arteriolar dilatation via AT2 receptors.     

Angiotensin II type 2 receptor blockade partially negates antihypertrophic effects of type 1 receptor blockade on pressure-overload rat cardiac hypertrophy.

We investigated the effects of angiotensin II type 2 (AT2) receptor blockade on the antihypertrophic effects of type 1 receptor (AT1) blockade in pressure-overload cardiac hypertrophy in adult rats. Cardiac hypertrophy was induced by banding the abdominal aorta above the renal arteries. The rats were treated with either an AT1 receptor antagonist TCV-116 (TCV, 10 mg/kg/day), an AT2 receptor antagonist PD123319 (PD, 20 mg/kg/day), or both for 4 weeks after the aortic banding. We measured systolic and diastolic blood pressure (BP), body weight (BW), left ventricular weight (LVW), and serum and cardiac angiotensin converting enzyme (ACE) activities. Aortic banding increased BP and LVW/BW, and TCV reversed both these increases. PD affected neither BP nor LVW/BW. TCV+PD reversed the increase in BP but not LVW/BW. Thus, PD was considered to counteract the antihypertrophic effect of TCV without affecting BP. All three treatments reduced cardiac ACE activity without affecting serum ACE activity. Our data demonstrated that AT2 receptor blockade negates the antihypertrophic effects of AT1 receptor blockade in an adult rat model of pressure-overload cardiac hypertrophy. AT2 receptors may mediate the signaling pathways involved in growth inhibition, which could counteract mediation of the cellular growth signaling pathways by AT1 receptors.     

Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.

OBJECTIVE: To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. RESULTS: Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.     

Angiotensin AT2 receptors: control of renal sodium excretion and blood pressure.

The renin-angiotensin system is a coordinated hormonal cascade of crucial importance in cardiovascular and renal function. The primary effector peptide angiotensin II functions at two major receptors, the AT1 and AT2 receptors. AT2 receptors mediate vasodilation and natriuresis. Regarding vasodilator actions, AT2 receptors oppose the AT1 receptor-mediated vasoconstrictor action of angiotensin II. Regarding the natriuretic actions of AT2 receptors, des-aspartyl 1-angiotensin II, rather than angiotensin II, is the preferred agonist. Regarding both the vasodilator and natriuretic properties of AT2 receptors, the beneficial blood pressure reduction and natriuretic responses to AT1 receptor blockade are mediated, at least in part, by AT2 receptor activation. In addition, AT2 receptor activation suppresses renin biosynthesis and release at renal juxtaglomerular cells. Therefore, AT2 receptors are potential therapeutic targets in hypertension.     

Chronic angiotensin II antagonism with losartan in one-kidney,one clip hypertensive rats: effect on cardiac hypertrophy,urinary sodium and water excretion and the natriuretic system

OBJECTIVE: To evaluate the effect of 7-day angiotensin II antagonism with losartan, an AT1-receptor antagonist, on systolic blood pressure, renal sodium and water excretion and on the atrial natriuretic factor system in one-kidney, one clip hypertensive rats. METHODS: The one-kidney, one clip hypertensive rats were separated into four groups: untreated (group 1), low-sodium diet (group 2), losartan (20 mg/kg orally, group 3) and low-sodium diet with losartan (group 4). All of the rats were kept in metabolic cages with urinary volume, urinary sodium level and water intake being evaluated daily. Body weight and blood pressure were assessed before treatment and at the end of the observation period. Renal glomerular and papillary atrial natriuretic factor receptors were assessed by radioligand binding experiments. RESULTS: No differences were observed either in body weight or in blood pressure between groups at the outset After 1 week, blood pressure was 184+/-4, 184+/-7, 170+/-5 and 78+/-8 mmHg, in groups 1, 2, 3 and 4, respectively. Group 3 rats failed to gain weight and had high urinary volume. In contrast, group 4 rats lost 15% of their original body weight. Both of the losartan-treated groups presented an apparently reduced cardiac hypertrophy but it was only clear in the low-sodium diet group. Both of the losartan-treated groups had high plasma renin activity. All of the three treated groups showed upregulation of glomerular and no changes in papillary atrial natriuretic factor receptors. Overall, mortality was 18, 27, 0 and 36% in groups 1, 2, 3 and 4, respectively. CONCLUSION: Losartan administration reduces blood pressure in one-kidney, one clip rats only when combined with a low-sodium diet. Both low-sodium diet and angiotensin II antagonism upregulate renal glomerular but not papillary atrial natriuretic factor receptors, suggesting a divergent regulatory mechanism.     

Angiotensin II Antagonism and Pre-Glomerular Arterial Wall Dimensions in the Kidney of the Spontaneously Hypertensive Rat

The effects of the angiotensin II type 1 receptor antagonist TCV-116 on the wall dimensions of the interlobular and arcuate arteries have been studied. SHR rats were treated with TCV-116 between 4 and 10 weeks, at which time their kidneys were perfusion-fixed and examined using stereological techniques. TCV-116 reduced arterial pressure and left ventricle/body weight ratio, but did not reduce renal arterial wall dimensions. For both arcuate and interlobular arteries, wall density/kidney ratio was significantly greater in the TCV-116 treated SHR than in untreated SHR and wall:lumen ratio was also significantly greater for the interlobular arteries in the TCV-116 treated rats. These findings are similar to those obtained previously using enalapril, and indicate that hypertrophy of the walls of these intra-renal arteries is not secondary to the elevated arterial pressure, unlike in other vascular beds.     

Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade

Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT(1)) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT(1) receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT(1) receptor blockade that is induced. Dahl S rats received a high-salt (1370 micromol Na(+)/g) or regular (101 micromol Na(+)/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 microg. kg(-1). d(-1), oral treatment with control versus irbesartan at 125 or 500 mg. kg(-1). d(-1) once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg. kg(-1). d(-1) by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to approximately 160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT(1) receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT(1) receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT(1) receptor blockade.     

Role of Angiotensin II in Reflex Tachycardia During Hypotension Caused by a Calcium Channel Blocker

Blood pressure and heart rate were measured by telemetry in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to investigate the contribution of angiotensin II to the reflex tachycardia resulting from exaggerated hypotension caused by a high dose of a calcium channel blocker. Pre-treatment with TCV-116, an angiotensin II AT1 receptor antagonist, or enalapril partially attenuated the reflex tachycardia induced by manidipine, but TCV-116 had almost no effect on the sinus tachycardia induced by isoproterenol. The suppressive effects of TCV-116 against the reflex tachycardia tended to be more obvious in WKY than in SHR, though the difference was not statistically significant. Concurrent administration of propranolol almost completely inhibited both the reflex tachycardia and the sinus tachycardia in SHR and WKY, indicating that the sympathetic nervous system contributes to both types of tachycardia. We demonstrated that angiotensin II may be involved in the reflex tachycardia induced by calcium channel blockers probably via activation of some component of the sympathetic nervous system other than postsynaptic factors at the sinus node.     

Local angiotensin formation in hindlimbs of uremic hypertensive and renovascular hypertensive rats.

To examine and characterize the vascular renin--angiotensin system in low-renin models of renal hypertension with and without the presence of overt renal insufficiency, we studied the formation and metabolism of angiotensin in isolated perfused rat hindquarter preparations. Rats with 5/6 nephrectomy (5/6NX) and rats with one-kidney, one clip (1K1C) hypertension were compared to sham operated (sham) animals. Angiotensin peptides in plasma or perfusate were characterized by high-performance liquid chromatography and radioimmunoassay (RIA). Plasma angiotensin II was lower, and blood pressure was higher in both experimental groups, compared to sham animals. Plasma angiotensinogen, measured by both direct and indirect RIA, was increased in both experimental groups. The spontaneous release of angiotensin I and angiotensin II from perfused hindquarters did not differ between the groups. Angiotensin I conversion was not different in 5/6NX or 1K1C groups compared with controls. Furthermore, angiotensin conversion was completely inhibited by captopril (1 mumol/l) in all groups. Renin-induced angiotensin release was significantly increased in 5/6NX as compared with sham rats, whereas there was no difference in renin-induced angiotensin release between 1K1C and sham animals. Angiotensin II degradation was significantly attenuated in 5/6NX rats when compared with sham rats (27.6% versus 53.9%, respectively, P less than 0.05) but was unaltered in 1K1C rats. Thus, in chronic uremic hypertension, renin-induced angiotensin formation was increased in the face of decreased angiotensin II degradation. These data suggest that vascular angiotensin may contribute to the elevated blood pressure observed in chronic renal failure. In 1K1C rats, vascular angiotensin formation and metabolism was unchanged despite suppressed plasma angiotensin II.     

Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats.

This study examines the effects of angiotensin II on hypertrophy and proliferation of aortic smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats and the receptor subtypes mediating these effects. In quiescent confluent cells, angiotensin II induced a dose-dependent increase in thymidine and leucine incorporation without stimulating cell proliferation. In nonconfluent cells, angiotensin II stimulated cell proliferation only in combination with a submaximal concentration of fetal calf serum. These effects were enhanced in cells from spontaneously hypertensive rats compared with Wistar-Kyoto rats. The effects of angiotensin II could be blocked by the AT1 receptor antagonist DuP 753 but not by the AT2 receptor ligand PD 123177. In receptor binding studies with cells derived from both rat strains, AT1-typical binding was observed. These data show that the angiotensin II receptors present in vascular smooth muscle cells in culture from both rat strains are of the AT1 receptor subtype. This receptor subtype appears to mediate vascular smooth muscle cell hypertrophy and proliferation as well as vasoconstriction. Although no difference in the receptor profile was detectable between the two rat strains, the affinity for the ligands to the receptor and the receptor density tended to be greater in cells from spontaneously hypertensive rats than in cells from Wistar-Kyoto rats. These results may partly explain the greater hypotensive response to angiotensin II receptor blockade in spontaneously hypertensive rats than in Wistar-Kyoto rats, although both rat strains have the same plasma concentrations of angiotensin II.     

AT(1)-receptor blockade and the kidney: importance of non-ACE pathways in health and disease

Large-scale trials with angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT(1))-receptor blockers have clearly shown that blockade of the renin-angiotensin system reduces the deterioration in renal function associated with diabetes. AT(1)-receptor blockers represent a more rational approach to blockade of this system than ACE inhibitors, due to the presence of non-ACE pathways of angiotensin II formation. Studies in healthy volunteers maintained on a low-salt diet indicate that such pathways account for approximately 30-40% of total angiotensin II formation, and this figure increases to 60-70% in individuals maintained on a high-salt diet (resembling the situation in most human populations). Activation of the renin-angiotensin system is increased in diabetic patients, and comparison of the renal vascular responses to captopril and candesartan shows a strong correlation between the effects of ACE inhibition and AT(1)-receptor blockade, indicating that the deleterious effects of renin-angiotensin system activation in diabetes are mediated largely through angiotensin II. The presence of multiple risk factors, such as genetic predisposition, hyperglycaemia, obesity and tissue damage, places diabetic patients at high risk of disease related to activation of the renin-angiotensin system. Effective and early blockade of this system is therefore an important aspect of management.     

The angiotensin II receptor antagonist candesartan cilexetil (TCV-116) ameliorates retinal disorders in rats

Aims/hypothesis. The results of the EUCLID trial (EURODIAB Controlled Trial of Lisinopril in Insulin-dependent Diabetes Mellitus) highlighted the importance of the renin-angiotensin system in the pathogenesis of diabetic retinopathy. Candesartan cilexetil (TCV-116), a potent angiotensin II (AII) receptor antagonist, has beneficial effects on hypertension as well as on heart, renal and cerebrovascular disease. We aimed to evaluate the effectiveness of candesarten cilexetil in ameliorating retinal disorders induced by hyperglycaemia. Methods. We compared retinal vascular endothelial growth factor (VEGF) mRNA expression and the latencies of retinal oscillatory potentials in TCV-116-treated and control groups of stroke-prone spontaneously hypertensive rats with streptozocin (STZ)-induced diabetes. Results. Retinal VEGF mRNA expression was significantly higher and the latencies of oscillatory potentials were significantly elongated in STZ-treated spontaneously hypertensive rats compared with a non-treated spontaneously hypertensive rat group matched for age. These changes were dependent on hyperglycaemia but independent of hypertension. Treatment with TCV-116 (3 mg/kg) significantly diminished retinal VEGF mRNA expression and the latencies of oscillatory potential peaks, but had no effect on plasma glucose concentrations. Conclusion/interpretation. These results suggest that TCV-116 is effective in preventing the development of diabetic retinopathy already in the early stages. [Diabetologia (2001) 44: 883–888] Received: 23 December 2000 and in revised form: 2 March 2001     

Endogenous angiotensin and pressure modulate brain angiotensinogen and AT1A mRNA expression

In the coarctation hypertension model, we showed both dissociation of plasma renin activity from cardiovascular-induced effects and the reversal of hypertension-induced responses by losartan. In this study, we investigated the effects of hypertension on the expression of brain renin-angiotensin system components and the simultaneous functional responses and effects of long-term angiotensin II (AT) receptor blockade on these responses. Rats were given vehicle or losartan for 9 days and subjected to subdiaphragmatic aortic constriction or sham surgery after 4 days of treatment. On the fifth postsurgical day, pressure and heart rate were measured in the conscious state; the brain was perfused and removed afterward. Sequential slices of brainstem were hybridized with 35S-oligodeoxynucleotide probes for angiotensinogen, AT1A, and AT1B receptors and processed for autoradiography and densitometry. In vehicle-treated rats, hypertension was accompanied by tachycardia and marked increments in angiotensinogen and AT1A mRNA expression in the cardiovascular system-controlling brainstem areas. In the nucleus tractus solitarii, AT1A density was correlated with both pressure and heart rate values (P<0.01), whereas angiotensinogen levels were correlated with pressure only (P<0.05). Losartan did not change the pressure of hypertensive rats (142+/-4 versus 146+/-2 mm Hg, losartan versus vehicle) and the hypertension-induced angiotensinogen mRNA expression but did block both tachycardic response and hypertension-induced AT1A mRNA expression. Hypertension and losartan did not change AT1B mRNA expression. The hypertension-induced positive feedback on angiotensinogen and AT1A mRNA expression supports the concept of a permissive role for brain angiotensin II in orchestrating circulatory responses during the development of hypertension. These data also explain the efficacy of long-term AT1 receptor blockade to reverse hypertension-induced effects.     

Renin, angiotensin, sodium and organ damage.

Angiotensin II and sodium balance affect the status of each other and both--either separately or together--can lead to an increase in blood pressure. They also can cause vascular and cardiac damage due to direct effects and effects mediated by the blood pressure increase. This paper reviews the important interactions among these three variables. Acute blood pressure elevation during sleeping but not during waking hours causes cardiac hypertrophy in rats. Similarly, lowering of blood pressure with an angiotension converting enzyme (ACE) inhibitor during sleep but not when awake causes regression of cardiac hypertrophy in rats with 2kidney (K)-1clip (C) Goldblatt hypertension. If angiotensin is given to rats on a low (0.4%) NaCl diet, blood pressure rises but there is less cardiac hypertrophy. Cardiac hypertrophy is greatest after angiotensin administration in rats on a high (4%) NaCl diet. In both the 2K-1C and 1K-1C Goldblatt models, a high salt intake reduces the blood pressure lowering effect of captopril and losartan and prevents regression of cardiac hypertrophy. Combined administration of an ACE inhibitor and an angiotensin type 1 (AT1) receptor blocker to rats on a low (0.2%) NaCl diet produces a syndrome that leads to death with cardiac involution. All features of the syndrome are reversed or prevented by 4% NaCl intake. It is hypothesised that the interaction between angiotensin II and sodium intake can be explained by differences in the way protons produced by contracting cells are neutralized. The sodium hydrogen exchanger and the sodium 2 bicarbonate cotransporter are stimulated by the AT1 and angiotensin type 2 (AT2) receptor, respectively. If the ratio of receptors is altered in favour of the AT2 receptor, then less cardiac hypertrophy will result from the same workload. Review of the clinical literature reveals that many of these results in rats have correlations in clinical medicine. Thus high night time blood pressure is associated with a greater morbidity and high salt intake causes cardiac hypertrophy and vascular stiffness independent of blood pressure levels. When deciding on treatment in human hypertension these results have important clinical implications.     

Vascular renin-angiotensin system in two-kidney, one clip hypertensive rats

The possible role of the renin-angiotensin system in the maintenance of hypertension in two-kidney, one clip hypertensive rats was studied. Plasma renin activity rose rapidly and markedly in association with the elevation of blood pressure and then decreased gradually, although blood pressure remained high. Renin activity in the lung, aorta, and mesenteric artery also increased with the development of hypertension and then decreased in a way similar to that of plasma renin activity at the chronic stage of hypertension. Plasma angiotensin converting enzyme activity did not change significantly until 16 weeks after unilateral renal artery clipping, whereas vascular angiotensin converting enzyme activity significantly increased at the chronic, but not the acute, stage of hypertension. In chronically renal hypertensive rats, 1-sarcosine, 8-isoleucine angiotensin II or enalapril, an angiotensin converting enzyme inhibitor, lowered the blood pressure and enalapril also lowered the angiotensin converting enzyme activity of vascular tissues. The constrictor effect of angiotensin I was greater in isolated arteries from chronically hypertensive rats than in those from age-matched normotensive rats. These results suggest that the vascular renin-angiotensin system plays an important role in the maintenance of two-kidney, one clip hypertension. Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle.     

Altered AT1 receptor regulation of ETB receptors in renal proximal tubule cells of spontaneously hypertensive rats

The renin-angiotensin and endothelin systems regulate blood pressure, in part, by affecting renal tubular sodium transport. In rodents, ETB receptors decrease proximal tubular reabsorption, whereas AT1 receptors produce the opposite effect. We hypothesize that ETB and AT1 receptors interact at the receptor level, and that the interaction is altered in spontaneously hypertensive rats (SHRs). In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto (WKY) rats, angiotensin II, via AT1 receptors, increased ETB receptor protein in a time- and concentration-dependent manner. In contrast, in SHR RPT cells, angiotensin II (10(-8) M/24 hours) had no effect on ETB receptor protein. AT1/ETB receptors colocalized and co-immunoprecipitated in both rat strains but long-term angiotensin II (10(-8) M/24 hours) treatment increased AT1/ETB co-immunoprecipitation in WKY but not in SHR cells. Short-term angiotensin II (10(-8) M/15 minutes) treatment decreased ETB receptor phosphorylation in both WKY and SHR cells, and increased ETB receptors in RPT cell surface membranes of RPT cells in WKY but not SHRs. Basal cell surface membrane ETB receptor expression was also higher in WKY than in SHRs. We conclude that AT1 receptors regulate ETB receptors by receptor interaction and modulation of receptor expression. The altered AT1 receptor regulation of ETB receptors in SHRs may play a role in the pathogenesis of hypertension.     

Bradykinin May Not Be Involved in Improvement of Insulin Resistance by Angiotensin Converting Enzyme Inhibitor

We have previously demonstrated that captopril ameliorates glucose intolerance by partially preventing the reduction in postprandial skeletal muscle blood flow. The present study was designed to clarify the mechanism by which ACE inhibitors affect glucose metabolism in fructose (FRU)-fed Wistar rats with hypertension, glucose intolerance and hyperinsulinermia. Eight-week-old male rats (n=51) were divided into six groups. Controls were given a normal chow, while fructose-rich (55%) chow was administered to the remainder for eight weeks. The different groups were administered alacepril (ALA, 30 mg/kg/day) with or without a continuous infusion of Hoe 140, a kinin B₂ receptor antagonist (150 μ/kg/day), Hoe 140 alone or TCV-116 (1 mg/kg/day), an angiotensin II receptor antagonist, alone. After measuring the body weight and systolic bolld pressure (BP), steady-state plasma glucose (SSPG) levels were determined. FRU significantly increased BP from 141 mmHg in controls to 156 mmHg. ALA with or without Hoe 140 decreased BP to 124 mmHg or 117 mmHg, respectively, but Hoe 140 alone did not affect BP. TCV-116 also decreased BP to 11 6 mmHg. The SSPG levels increased from 7.58 mM in controls to 8.98 mM in FRU-fed rats. This was lowered with both ALA and TCV-116. Hoe 140 alone, however, did not affect SSPG levels. Hoe 140 did not show any effects on ALA-induced improvement of SSPG. These results suggest that the improvement in glucose tolerance observed with ACE inhibitors is not due to the kinins, and angiotensin II receptor antagonists also improve insulin sensitivity.