Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring

Our previous studies have demonstrated that the introduction of angiotensin II type I receptor antisense (AT(1)R-AS) cDNA by a retrovirally mediated delivery system prevents the development of hypertension in the spontaneously hypertensive rat (SHR), an animal model for primary hypertension in humans. These results have led us to propose the hypothesis that an interruption of the renin-angiotensin system (RAS) activity at a genetic level would prevent hypertension on a permanent basis. F(1) and F(2) generations of offspring from a retroviral vector, LNSV- and LNSV-AT(1)R-AS-treated SHR, were generated, and various physiological parameters indicative of hypertension were studied and compared with those of their parents to investigate this hypothesis. Both F(1) and F(2) generations of LNSV-AT(1)R-AS-treated SHR expressed a persistently lower blood pressure, decreased cardiac hypertrophy and fibrosis, decreased medial thickness, and normalization of renal artery excitation-contraction coupling, Ca(2+) current, and [Ca(2+)](i) when compared with offspring derived from the LNSV-treated SHR. In fact, the magnitude of the prevention of these pathophysiological alterations was similar to that observed in the LNSV-AT(1)R-AS-treated SHR parent. The prevention of cardiovascular pathophysiology and expression of normotensive phenotypes are, at least in part, a result of integration and subsequent transmission of AT(1)R-AS from the SHR parents to offspring. These data demonstrate that a single intracardiac injection of LNSV-AT(1)R-AS causes a permanent cardiovascular protection against hypertension as a result of a genomic integration and germ line transmission of the AT(1)R-AS in the SHR offspring.     

Delivery of angiotensin II type 1 receptor antisense inhibits angiotensin action in neurons from hypertensive rat brain.

Increased brain angiotensin II (AII) type 1 receptor (AT1R) expression has been implicated in the hyperactive brain angiotensin system and the development and maintenance of hypertension in the genetically spontaneously hypertensive (SH) rat. Neuronal cells in primary culture from the cardioregulatory-relevant brain areas (hypothalamus/brainstem) mimic increased brain AT1R gene expression and AT1R function of the adult SH rat. They have been utilized in the present study to determine whether cellular actions of AII could be regulated by the transfer of AT1R antisense (AT1R-AS) with the use of a retroviral-mediated gene delivery system developed for the central nervous system cultures. AII stimulates norepinephrine (NE) uptake in neuronal cultures of both normotensive (Wistar Kyoto) and SH rat brains. This neuromodulatory action is mediated by the AT1R subtype, is significantly higher in SH neurons, and is associated with a parallel stimulation of mRNAs for c-fos and NE transporter. Infection of neuronal cultures with a retrovirus vector that contains AT1R-AS (LNSV-AT1R-AS) results in an inhibition of AT1R-mediated stimulation of both c-fos and NE transporter mRNA, as well as NE uptake in both strains of rats; however, the inhibition is more pronounced in SH neurons compared with Wistar Kyoto rat brain neurons. The higher sensitivity of the SH rat brain neurons is further supported by our observation that a certain dose of LNSV-AT1R-AS that fails to induce inhibition of cellular actions of AII in WKY neurons causes a significant inhibition of AII actions in SH neurons. These observations show that retrovirally mediated delivery of AT1R-AS could be used to selectively control the actions of AII in primary neuronal cultures from SH rat brain.     

Inability to induce hypertension in normotensive rat expressing AT(1) receptor antisense

Our previous studies have shown that neonatal delivery of angiotensin type 1 receptor antisense (AT(1)R-AS) in a retroviral vector prevents spontaneously hypertensive rats from developing hypertension for life but has no effect on blood pressure (BP) in normotensive animals. Based on these results, we hypothesized that AT(1)R-AS transduction in normotensive rats would protect them from developing experimental hypertension. The present study was designed to evaluate this hypothesis. A single intracardiac administration of AT(1)R-AS by a retroviral-mediated delivery system (LNSV-AT(1)R-AS) in 5-day-old normotensive Sprague-Dawley rats resulted in long-term expression of the AT(1)R-AS without an effect on basal BP. However, angiotensin II (Ang II)-induced BP, dipsogenic responses, and renovascular contractility were significantly attenuated in the LNSV-AT(1)R-AS-treated rats. Chronic infusion of low-dose Ang II (55 ng. kg(-)(1). min(-)(1)) in LNSV-alone-treated rats caused a modest increase in BP, profound increase in cardiac hypertrophy, and increased vascular contractility. In contrast, the LNSV-AT(1)R-AS-treated rats were protected from developing these changes after Ang II infusion. These data establish that LNSV-AT(1)R-AS pretreatment protects healthy rats from developing Ang II-dependent hypertension.     

Influence of autoantibodies against AT1 receptor and AGTR1 polymorphisms on candesartan-based antihypertensive regimen: Results from the Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies trial

The autoantibodies against angiotensin AT₁ receptors (AT₁-AAs) in patients with essential hypertension exhibited an agonistic action like angiotensin II and maintained high blood pressure (BP). Angiotensin II receptor gene (AGTR1) polymorphisms were associated with BP response to RAS inhibition in the hypertensive population. Furthermore, the BP response to AT₁ receptor blockers varied significantly among individuals with hypertension. We hypothesized that the polymorphisms of the AGTR1 and AT₁-AAs might affect antihypertensive response to AT₁ receptor blockers based in patients with primary hypertension. Patients who received a candesartan-based regimen came from the SOT-AT₁ study (Study of Optimal Treatment in Hypertensive Patients with Anti-AT₁-Receptor Autoantibodies). The established enzyme-labeled immunosorbent assay was used to detect AT₁-AAs in the sera of the patients. Genotype 3 single nucleotide polymorphisms in AGTR1 gene was used by DNA sequencing. The correlations among AT₁-AAs, AGTR1 gene polymorphisms or haplotypes, and the antihypertensive effect candesartan-based were analyzed using SPSS. The percentage of systolic BP reduction that was candesartan-based was greater in AT₁-AA positive groups than in AT₁-AA negative ones (21 ± 8 vs. 18 ± 9; P = .001). Meanwhile, systolic BP reduction that was candesartan-based was more significant in the group of rs5186 AC genotypes than AA homozygotes after adjusting for other confounding factors (37.55 ± 13.7 vs. 32.47 ± 17.27 mm Hg; adjusted P = .028). Furthermore, haplotypes (GCC) and (AAC) had impacts on the antihypertensive effect of candesartan therapy. The AT₁-AAs, AGTR1 gene polymorphisms and haplotypes solely or jointly have influences on candesartan-based antihypertensive response in patients with primary hypertension.     

Gene therapy attenuates the elevated blood pressure and glucose intolerance in an insulin-resistant model of hypertension

OBJECTIVE : Fructose feeding in male Sprague-Dawley (SD) rats results in a mild hypertension and glucose intolerance. Although the mechanism of this glucose intolerance and hypertension is not completely understood, a role for the renin-angiotensin system (RAS) has been proposed. In the current study our aim was to test the hypothesis that intervention of the RAS with a gene therapy approach would be effective in preventing the development of hypertension and glucose intolerance in this animal model. DESIGN AND METHODS : Five-day-old SD rats were administered either an empty retroviral vector (LNSV) or retroviral vector containing AT1 receptor antisense DNA (AT1R-AS). The virus (25 microl, 8 x 10(9) CFU/ml) was injected into the heart and the animals were returned to their mothers. After weaning, half the animals from each group were placed on breeder's chow or a 60% fructose diet. Indirect blood pressures (BP) were determined and an oral glucose tolerance test (OGTT) was performed when the animals had been on the respective diets for 2 months. RESULTS : Fructose-fed animals developed mild hypertension (145 +/- 3 versus 132 +/- 4 mmHg) by 6 weeks of dietary intervention. This increase in BP was prevented by AT1R-AS treatment (125 +/- 3 mmHg). At 2 months of age, fasting blood glucose was comparable among the four groups; however, the glucose excursion during the OGTT was significantly greater and more prolonged in the LNSV-treated, fructose-fed group than the other three groups. AT1R-AS treatment significantly prevented glucose intolerance in the fructose rat to levels observed in the controls. CONCLUSIONS : Early fructose dietary treatment results in moderate hypertension and glucose intolerance, which is prevented by a single neonatal treatment with AT1R-AS. These results suggest that the RAS is involved in the glucose intolerance associated with fructose feeding and that genetic intervention is effective in this rat model.     

Losartan prevents the imbalance between renal dopaminergic and renin angiotensin systems induced by fructose overload. l-Dopa/dopamine index as new potential biomarker of renal dysfunction

BackgroundThe renin angiotensin system (RAS) and the renal dopaminergic system (RDS) act as autocrine and paracrine systems to regulate renal sodium management and inflammation and their alterations have been associated to hypertension and renal damage. Nearly 30–50% of hypertensive patients have insulin resistance (IR), with a strong correlation between hyperinsulinemia and microalbuminuria.ObjectiveThe aim of this study was to demonstrate the existence of an imbalance between RAS and RDS associated to IR, hypertension and kidney damage induced by fructose overload (FO), as well as to establish their prevention, by pharmacological inhibition of RAS with losartan.Materials/MethodsNinety-six male Sprague-Dawley rats were randomly divided into four groups and studied at 4, 8 and 12 weeks: control group (C4, C8 and C12; tap water to drink); fructose-overloaded group (F4, F8 and F12; 10% w/v fructose solution to drink); losartan-treated control (L) group (L4, L8 and L12; losartan 30 mg/kg/day, in drinking water); and fructose-overloaded plus losartan group (F + L4, F + L8 and F + L12, in fructose solution).ResultsFO induced metabolic and hemodynamic alterations as well as an imbalance between RAS and RDS, characterized by increased renal angiotensin II levels and AT₁R overexpression, reduced urinary excretion of dopamine, increased excretion of l-dopa (increased l-dopa/dopamine index) and down-regulation of D₁R and tubular dopamine transporters OCT-2, OCT-N1 and total OCTNs. This imbalance was accompanied by an overexpression of renal tubular Na⁺, K⁺-ATPase, pro-inflammatory (NF-kB, TNF-α, IL-6) and pro-fibrotic (TGF-β1 and collagen) markers and by renal damage (microalbuminuria and reduced nephrin expression). Losartan prevented the metabolic and hemodynamic alterations induced by FO from week 4. Increased urinary l-dopa/dopamine index and decreased D₁R renal expression associated to FO were also prevented by losartan since week 4. The same pattern was observed for renal expression of OCTs/OCTNs, Na⁺, K⁺-ATPase, pro-inflammatory and pro-fibrotic markers from week 8. The appearance of microalbuminuria and reduced nephrin expression was prevented by losartan at week 12.ConclusionThe results of this study provide new insight regarding the mechanisms by which a pro-hypertensive and pro-inflammatory system, such as RAS, downregulates another anti-hypertensive and anti-inflammatory system such as RDS. Additionally, we propose the use of l-dopa/dopamine index as a biochemical marker of renal dysfunction in conditions characterized by sodium retention, IR and/or hypertension, and as a predictor of response to treatment and follow-up of these processes.     

Angiotensin II Type 1 Receptor Gene Polymorphism Is Associated With Increase of Left Ventricular Mass But Not With Hypertension

A genetic epidemiologic approach is useful to elucidate the genes responsible for hypertension. Genetic analyses of the components of the renin-angiotensin system have succeeded in showing an association between their polymorphism and hypertension. Recently, two types of angiotensin II receptor were cloned and characterized. To examine the genetic contribution of angiotensin II type 1 receptor (AT₁) and type 2 receptor (AT₂) genes in human essential hypertension, a case-control study was performed in Japanese subjects. The study comprised 321 subjects with hypertension who satisfied the criteria for essential hypertension, together with 215 age and sex matched controls. The significance of the differences in genotype distribution between hypertensive and normotensive subjects was examined by χ² analysis. Neither AT₁ nor AT₂ gene variants were associated with human essential hypertension in the Japanese subjects. However, the AT₁ receptor gene polymorphism was associated with left ventricular mass index in normotensive subjects. The study results suggest that gene polymorphisms of both angiotensin II receptors are not directly involved in the increase of genetic risk for hypertension, but that the AT₁ receptor gene might contribute genetically to the increase of left ventricular mass.     

Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT₁ and AT₂ receptors. For that reason, the aim of this work was to study the gene and protein expression of AT₁ and AT₂ receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60?mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT₁ receptors than normotensive rats while the AT₂ expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT₁ and AT₂ receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT₁ and AT₂ receptors. However, the overexpression of AT₂ could be associated with the reduction in the response to Ang II in the early stage of diabetes.     

Clinical profile of eprosartan

Angiotensin II (AII) receptor blockers offer an alternative means of blocking the renin-angiotensin-aldosterone system (RAAS) to angiotensin converting enzyme (ACE) inhibitors. Being highly selective for the AII receptor subtype AT₁, AII receptor blockers may avoid side-effects associated with ACE inhibitor treatment, such as cough. Eprosartan is a non-biphenyl, non-tetrazole competitive blocker that is chemically distinct from other AII receptor blockers, which may account for differences in its pharmacological properties. It induces dual blockade of AT₁ receptors both presynaptically and postsynaptically, reducing sympathetic nerve activity to a significantly greater degree than other AT₁ receptor blockers.At the recommended dose of 600 mg once daily, eprosartan effectively lowers blood pressure (BP) in hypertensive patients to a similar degree as seen with other AII receptor blockers and ACE inhibitors. However, a greater proportion of patients achieved adequate BP control compared with enalapril. When eprosartan is given in combination with hydrochlorothiazide (HCTZ), it provides a significantly greater BP reduction compared with eprosartan alone.Eprosartan has a side-effect profile that is similar to placebo and to other AII receptor blockers, but is better than that of enalapril because it lacks the propensity to cause dry cough. Eprosartan is not metabolized by the cytochrome P450 enzyme system, and so has no interaction with drugs that affect this system. Eprosartan completely reverses renal vasoconstriction induced by AII and may, therefore, have further applications in situations where stimulation of the RAAS is a problem. In summary, eprosartan, alone or in combination with HCTZ, provides an effective and well-tolerated approach to lowering BP in patients with all grades of hypertension. Further development of eprosartan may offer therapeutic opportunities that go far beyond the current recommendations.     

Update: Role of the angiotensin type-2 (AT2) receptor in blood pressure regulation

In the past, virtually all of the physiologic actions of angiotensin II (ANG II) were thought to be mediated by the type-1 ANG II receptor. However, there is now a compelling body of evidence suggesting that the type-2 (AT₂) receptor is an important regulator of renal function and blood pressure (BP). The AT₂ receptor stimulates a bradykinin (BK)-nitric oxide (NO)-cyclic GMP vasodilator cascade in blood vessels and in the kidney. Recent studies have shown that absence of the AT₂ receptor lends to pressor and natriuretic hypersensitivity to ANG II. Furthermore, there is now excellent evidence that the AT2 receptor mediates pressure natriuresis. The AT₂ receptor also stimulates the conversion of prostaglandin E2 (PGE₂) to PGF₂. In addition, it is now apparent that the therapeutic reduction in BP with AT₁ receptor blockade (eg, losartan, valsartan, candesartan) is mediated by ANG II stimulation of the AT₂ receptor, leading to increased levels of BK, NO, and cGMP. Current evidence predicts that AT₂ receptor agonists would be beneficial in the treatment of hypertension.     

Renal sympathetic denervation lowers arterial pressure in canines with obesity-induced hypertension by regulating GAD65 and AT1R expression in rostral ventrolateral medulla

To explore the roles of glutamate acid decarboxylase 65 (GAD65) and angiotensin II type 1 receptor (AT₁R) in the action of renal sympathetic denervation (RSD) on obesity-induced hypertension in canines. Thirty-two beagles were randomly divided into a hypertensive model (n = 22) and control (n = 10) groups. A hypertensive canine model was established by feeding a high-fat diet. Twenty hypertensive beagles were randomized equally to a sham-surgery and RSD-treated group receiving catheter-based radiofrequency RSD. Compared with the control group, the sham-surgery group exhibited significant increases in blood pressure, serum angiotensin II level, rostral ventrolateral medulla (RVLM) glutamate level, and AT₁R mRNA and protein expression and decreases in γ-amino acid butyric acid (γ-GABA) level and GAD65 mRNA and protein expression in the RVLM (all P < 0.05). Treatment with RSD significantly attenuated the above abnormal alterations (all P < 0.05). Linear correlation analysis revealed that angiotensin II level was positively correlated with glutamate level (r = 0.804) and inversely correlated with γ-GABA level (r = ?0.765). GAD65 protein expression was positively correlated with γ-GABA level (r = 0.782). Catheter-based radiofrequency RSD can decrease blood pressure in obesity-induced hypertensive canines. The antihypertensive mechanism might be linked to upregulation of GAD65 and downregulation of AT₁R in the RVLM.     

Vaccination: A novel strategy for inhibiting the renin-angiotensin-aldosterone system

Immunologic approaches to renin-angiotensin-aldosterone system (RAAS) inhibition have been studied for more than 50 years. In animal models, vaccination against renin was effective but resulted in fatal autoimmune renal disease; vaccines directed at small peptides including angiotensin I and II and a segment of the AT₁ receptor reduced blood pressure (BP) without causing autoimmune disease. In humans, angiotensin I vaccination did not reduce BP. More promising is the AngQb vaccine, which uses an immunization technology involving conjugation of angiotensin II to virus-like particles. In a phase 2 trial, hypertensive patients vaccinated with 300 μg showed a difference of 9.0/4.0 mm Hg from baseline in mean daytime ambulatory BP after 14 weeks (P = 0.015 for systolic BP, P = 0.064 for diastolic BP), and a marked reduction in early morning BP. No serious adverse events were attributed to vaccine administration. Although questions remain regarding efficacy and safety, RAAS immunization represents an innovative and promising approach to hypertension treatment.     

The Renin-Angiotensin System in Hypertension,a Constantly Renewing Classic: Focus on the Angiotensin AT2-Receptor

It is common knowledge that the renin-angiotensin system (RAS), in particular angiotensin II acting through the angiotensin AT₁-receptor (AT₁R), is pivotal for the regulation of blood pressure (BP) and extracellular volume. More recent findings have revealed that the RAS is far more complex than initially thought and that it harbours additional mediators and receptors, which are able to counteract and thereby fine-tune AT₁R-mediated actions. This review will focus on the angiotensin AT₂-receptor (AT₂R), which is one of the “counter-regulatory” receptors within the RAS. It will review and discuss data related to the role of the AT₂R in regulation of BP and focus on the following 3 questions: Do peripheral AT₂R have an impact on BP regulation, and, if so, does this effect become apparent only under certain conditions? Are central nervous system AT₂R involved in regulation of BP, and, if so, which brain areas are involved and what are the mechanisms? Does dysfunction of AT₂R contribute to the pathogenesis of hypertension in preeclampsia?     

Renal Angiotensin II Receptors,Hyperinsulinemia, and Obesity

Angiotensin II, via activation of AT₁ receptors in the kidney regulates sodium/fluid homeostasis and blood pressure. An exaggerated action of angiotensin II mediated via activation of AT₁ receptors has been implicated in the increased renal sodium retention and the resetting of the pressure natriuresis in obesity related hypertension. Treatment of obese Zucker rats with AT₁ receptor blockers reduces blood pressure to a greater extent and produces greater natriuresis. Also, there is an increased membranal AT₁ receptor numbers and angiotensin II produces greater activation of sodium transporters in the isolated tubules from obese Zucker rats. Interestingly, AT₂ receptors, which are believed to be beneficial to the renal and cardiovascular function in terms of their action on kidney and blood vessels, are greatly increased in proximal tubular membranes of obese Zucker rats. Whole animal and in vitro studies indicate that higher plasma insulin level, generally associated with obesity, is responsible for the up‐regulation of both AT₁ and AT₂ receptors in the kidney. Determining the consequence of selective blocking of AT₁ receptors and/or activation of the AT₂ receptors on renal and cardiovascular function, and the effect of lowering insulin on these receptors present an important area of further investigation in obesity.     

Regression of left ventricular hypertrophy by at1 receptor blockade in renal transplant recipients

AT₁ receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT₁ receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four–hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 ± 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 ± 1.8 mm Hg (P < .01 and P < .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 ± 0.2 mm, 0.91 ± 0.2 mm and 0.04 ± 0.01 mm, respectively (all P < .001). Left ventricular mass index decreased by 18.1 ± 4.7 g/m² (P < .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 ± 0.3 g/dL and 3.6% ± 0.9%, respectively (P < .002 and P < .001) without a change in serum erythropoetin level. In renal transplant recipients the AT₁ receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.     

The renin-angiotensin and adrenergic nervous system in cardiac hypertrophy in fructose-fed rats

BackgroundHyperinsulinemia and insulin resistance are associated with left ventricular hypertrophy (LVH) and cardiovascular complications in hypertensive subjects. The aim of this study was to explore the mechanisms for LVH including activation of the renin-angiotensin system system (RAS) and the sympathetic nervous system and their activation by insulin using a rat model of hyperinsulinemia and insulin resistance.Methods:Male Sprague-Dawley rats were fed a high-fructose or control diet. The fructose-fed rats (FFR) were divided into four subgroups that were administrated either vehicle or the following antihypertensive drugs (n = 6–8) for 4 weeks: 1) olmesartan, an angiotensin II type 1 (AT₁) receptor antagonist; 2) bunazosin, an α₁-receptor blocker; and 3) hydralazine, a direct vasodilator.Results:Fructose feeding induced significant increases in mean systolic blood pressure (BP) levels at 4 weeks (control, 117 v fructose, 131 mm Hg), left ventricular weight, and the sum of the insulin level in response to a glucose tolerance test (2 g/kg). Fructose feeding also increased urinary excretion of epinephrine and norepinephrine, the density of cardiac α₁-adrenergic receptors, and the content of angiotensin II in the left ventricle. All antihypertensive drugs decreased systolic BP, but only the AT₁ receptor antagonist attenuated the development of LVH in FFR. The AT₁ receptor antagonist did not affect glucose-mediated insulin responses, but did suppress urinary catecholamine excretion and cardiac α₁-adrenergic receptor density.ConclusionsLeft ventricular hypertrophy in FFR may be less dependent on systemic elevations of BP and more dependent on the RAS and the sympathetic nervous system. Use of an AT₁ receptor antagonist might be the most beneficial way to prevent progression of LVH through direct effects on tissue RAS and the sympathetic nervous system in FFR. As these changes occur in a rat model with hyperinsulinemia, insulin may have a role in promoting LVH by activating the local RAS and sympathetic nervous system activity.     

At1 Receptor Density Changes During Development of Hypertension in Hyperinsulinemic Rats

In a previous study we showed that the renin-angiotensin system (RAS) plays a role in the etiology of fructose-induced hypertension. To our knowledge, no previous study has evaluated changes in angiotensin II (Ang II) type I receptor (AT₁) density in fructose-fed rats that are insulin resistant and hypertensive. The purpose of this study was to determine the changes in plasma Ang II and AT₁ density associated with the elevation of blood pressure in fructose-treated rats. Male Sprague-Dawley rats were divided into two groups and were fed either normal rat chow or a 60% fructose-enriched diet for four weeks. Plasma Ang II and serum insulin levels of the fructose-treated rats were significantly elevated (p<0.01) by the end of the second week of fructose treatment. Plasma Ang II levels of the fructose-fed rats returned to basal levels by the end of the fourth week of dietary treatment, whereas the serum insulin levels consistently remained elevated. Blood pressure was significantly elevated in the fructose-fed rats within two weeks of fructose treatment. Elevation of blood pressure was associated with left ventricular hypertrophy. Furthermore, there was a significant increase in AT₁ receptor density in the ventricles and a significant decrease in AT₁ receptor density in the aortas of fructose-fed rats at the end of fourth week. There were no significant changes in receptor density in the hypothalami or adrenal glands of fructose-treated rats. These results suggest that chronic fructose treatment activates the renin-angiotensin system, which is manifested by an increase in plasma Ang II, elevation of blood pressure, cardiac hypertrophy, and changes in AT₁ receptor density.     

Angiotensin Receptor Blockers and the Kidney: Possible Advantages over ACE Inhibition?

This review deals with similarities and differences between the effects of ACE inhibitors and AT₁‐receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT₁ blockers arise from two mechanisms: the reduction of the AT₁ receptor mediated response and the increase in plasma levels of Ang II through the AT₁‐receptor blockade, which leads to increased stimulation of the AT₂ receptor (the so‐called yin‐yang effect). Both ACE inhibition and AT₁‐receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT₁ receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT₁‐receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long‐term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.