angiotensin-i and candesartan

This is the second part in a series of papers dealing with various aspects of clinical pharmacology of the first AT1-receptor antagonist losartan and its therapeutic use in hypertension, diabetic nephropathy, chronic heart failure, and acute phase of myocardial infarction. This part contains review of literature data concerning the use of losartan for the treatment of hypertension and diabetic nephropathy including results of two major randomized trials which for the first time demonstrated ability of losartan to improve long term prognosis in patients with hypertension and diabetic nephropathy.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diastole; Diuretics; Drug Therapy, Combination; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Losartan; Meta-Analysis as Topic; Placebos; Prognosis; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; Systole; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan

The intrarenal renin-angiotensin system plays a critical role in the paracrine regulation of renal function and the pathophysiology of hypertension. Angiotensin II (AngII) is formed intrarenally from systemically delivered angiotensin I (AngI) and intrarenally formed AngI. Intrarenal AngII content, which is greater than can be explained by the circulating AngII concentrations, is compartmentalized such that proximal tubule concentrations of AngI and AngII greatly exceed plasma concentrations. Proximal tubule cells are thought to secrete AngII or precursors of AngII into the tubular fluid to activate luminal AngII receptors. Recent immunohistochemical studies have demonstrated an abundance of AT1 receptors on the luminal surface of proximal and distal tubule cells and on afferent and efferent arteriolar vascular smooth muscle cells and mesangial cells of glomeruli. Activation of luminal AT1 receptors stimulates tubular sodium reabsorption rate. To evaluate the direct effects of AT1 receptor blockade on renal function in AngII-dependent hypertension, experiments were performed on two-kidney, one-clip (2K1C) Goldblatt hypertensive rats. Although the nonclipped kidney is renin-depleted, the intrarenal AngII levels are not suppressed, and AngII concentrations in proximal tubular fluid remain high (10(-8) M). Candesartan was administered into the renal artery of nonclipped kidneys to avoid the confounding consequences of decreases in arterial pressure. Blockade of intrarenal AT1 receptors elicited significant increases in GFR, renal blood flow, sodium excretion, and fractional sodium excretion, suggesting synergistic actions on tubular transport and vascular smooth muscle cells.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney; Natriuresis; Rats; Receptors, Angiotensin; Renal Circulation; Renin-Angiotensin System; Tetrazoles

Topics: Age Factors; Aged; Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Captopril; Clinical Trials as Topic; Death, Sudden, Cardiac; Enalapril; Heart Failure; Humans; Losartan; Prodrugs; Prognosis; Randomized Controlled Trials as Topic; Risk Factors; Tetrazoles; Time Factors

Not all hypertensive patients respond well to ACE inhibition. Here we determined whether renin-angiotensin system (RAS) phenotyping, i.e., the measurement of renin or ACE, can predict the individual response to RAS blockade, either chronically (enalapril vs. enalapril + candesartan) or acutely (enalapril ± hydrochlorothiazide, HCT).. Chronic enalapril + candesartan induced larger renin rises, but did not lower blood pressure (BP) more than enalapril. Similar observations were made for enalapril + HCT vs. enalapril when given acutely. Baseline renin predicted the peak changes in BP chronically, but not acutely. Baseline ACE levels had no predictive value. Yet, after acute drug intake, the degree of ACE inhibition, like Δrenin, did correlate with ΔBP. Only the relationship with Δrenin remained significant after chronic RAS blockade. Thus, a high degree of ACE inhibition and a steep renin rise associate with larger acute responses to enalapril. However, variation was large, ranging >50 mm Hg for a given degree of ACE inhibition or Δrenin. The same was true for the relationships between Δrenin and ΔBP, and between baseline renin and the maximum reduction in BP in the chronic study.. Our data do not support that RAS phenotyping will help to predict the individual BP response to RAS blockade. Notably, these conclusions were reached in a carefully characterized, homogenous population, and when taking into account the known fluctuations in renin that relate to gender, age, ethnicity, salt intake and diuretic treatment, it seems unlikely that a cut-off renin level can be defined that has predictive value.

Topics: Aged; Aldosterone; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cross-Over Studies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Phenotype; Precision Medicine; Renin; Renin-Angiotensin System; Tetrazoles

We investigated the role of angiotensin (Ang) II in maintaining blood pressure (BP) by administering a small dose of candesartan, an Ang II type 1 receptor antagonist, in postmenopausal women receiving long-term hormone replacement therapy (HRT).. A single dose of 2 mg of candesartan was administered orally to 13 normotensive postmenopausal women receiving HRT (continuous combined conjugated estrogen and medroxyprogesterone acetate orally; HRT group) and 13 normotensive postmenopausal women not receiving HRT (control group). Both BP and heart rate (HR) were measured at baseline and at 1, 2, 3, 4, 5, and 6 h after administration. Plasma renin activity (PRA) and Ang I, Ang II, and bradykinin concentrations were measured at baseline and 4 h after the administration of candesartan.. Candesartan lowered the BP and raised the HR in both groups. However, the decrease in BP was significantly greater in the HRT group than in the control group (P < .05), whereas no significant difference in the change in HR was observed between the two groups. In the HRT group, significant increases were found in PRA, Ang I, and Ang II (all P < .05) and a significant decrease in bradykinin (P < .01) with candesartan treatment. In the control group, candesartan as associated with an increase in PRA (P < .05) but not in Ang I, Ang II, or bradykinin.. Based on our study results, Ang II plays an important role in maintaining BP in normotensive postmenopausal women receiving HRT. Maintenance of BP may be dependent on the balance between the hypertensive effect of Ang II and the hypotensive effect of bradykinin.

Topics: Administration, Oral; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; Bradykinin; Drug Therapy, Combination; Epinephrine; Estrogens; Female; Heart Rate; Hormone Replacement Therapy; Humans; Middle Aged; Norepinephrine; Peptidyl-Dipeptidase A; Postmenopause; Renin; Tetrazoles; Treatment Outcome

Hypertensive transgenic (mRen2)27 rats exhibit impaired baroreflex sensitivity (BRS) for control of heart rate (HR). Intracerebroventricular infusion of Ang-(1-7) improves indices of vagal BRS independent of lowering mean arterial pressure (MAP), whereas AT1 receptor blockade normalizes MAP and indices of sympathetic tone without correcting the vagal BRS. Scavenging cellular reactive oxygen species (ROS) with tempol in brain fails to correct either hypertension or sympathovagal balance in these animals, despite reports that mitochondrial ROS contributes to Ang II-infusion hypertension. To examine effects of a putative preferential mitochondrial ROS scavenger in the brain of (mRen2)27 rats, ICV infusions of Mito-TEMPO (3.2 μg/2.5 μL/h) were compared with artificial cerebrospinal fluid (aCSF; 2.5 μL/h) and combination AT1 receptor antagonist candesartan (CAN: 4 μg/2.5 μL/h) plus Ang-(1-7) (0.1 μg/2.5 μL/h) treatment. MAP was lower after CAN + Ang-(1-7) treatment, and both vagal and sympathetic components of BRS and sympathovagal balance were improved. By contrast, Mito-TEMPO improved sympathetic components of BRS and tended to improve overall sympathovagal balance but failed to alter MAP in this model of hypertension. Although further studies are required to determine whether Mito-TEMPO or CAN + Ang-(1-7) treatment at the doses used altered mitochondrial ROS, optimal therapeutic benefits are achieved by shifting the balance from Ang II toward Ang-(1-7) in this model of chronic RAS-dependent hypertension.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Arterial Pressure; Baroreflex; Benzimidazoles; Biphenyl Compounds; Brain; Disease Models, Animal; Drug Combinations; Free Radical Scavengers; Heart; Heart Rate; Hypertension; Male; Mitochondria; Organophosphorus Compounds; Peptide Fragments; Piperidines; Rats, Transgenic; Reactive Oxygen Species; Renin; Sympathetic Nervous System; Tetrazoles; Vagus Nerve

AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Benzimidazoles; Biphenyl Compounds; Cardiotonic Agents; Cholesterol; Cytokines; Male; Mice, Inbred C57BL; Mice, Knockout; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Tetrazoles; Triglycerides; Vascular Cell Adhesion Molecule-1

ANG (1-7) contributes to the blood pressure (BP)-lowering effect of angiotensin receptor blockers (ARBs) in male experimental animals. Females have greater ANG (1-7) concentrations than males; however, the contribution of ANG (1-7) to ARB-mediated decreases in BP in females is unknown. The current study tested the hypothesis that female spontaneously hypertensive rats (SHR) have a larger ANG (1-7) contribution to the BP-lowering effects of the ARB candesartan than male SHR. Twelve-week-old male and female SHR were randomized to receive candesartan (0.5 mg·kg(-1)·day(-1); 7 days), candesartan plus ANG II (200 ng·kg(-1)·min(-1); 7 days), the ANG (1-7) antagonist A-779 (48 μg·kg(-1)·h(-1)) plus candesartan and ANG II. Candesartan decreased basal BP in males and females (baseline vs. candesartan: 142 ± 2 vs. 122 ± 3 and 129 ± 1 vs. 115 ± 1 mmHg, respectively; P < 0.05); however, the decrease was greater in males. ANG II increased BP in males in the presence of candesartan (149 ± 2 mmHg; P < 0.05); candesartan blocked ANG II-induced increases in BP in females (116 ± 1 mmHg). Pretreatment with A-779 abolished candesartan-mediated decreases in BP in females, but not males. A-779 also exacerbated ANG II-induced proteinuria (26 ± 6 vs. 77 ± 11 μg·kg(-1)·day(-1), respectively; P < 0.05) and nephrinuria (20 ± 5 vs. 202 ± 58 μg·kg(-1)·day(-1), respectively; P < 0.05) in candesartan-treated female SHR, with no effect in males. In conclusion, females are more sensitive to the BP-lowering effect of ARBs during ANG II infusion, whereas males are more sensitive under basal conditions. In addition, ANG (1-7) has a greater contribution to ARB-mediated decreases in BP, protein, and nephrin excretion in females relative to males.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cell Adhesion Molecules; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hypertension; Male; Membrane Proteins; Peptide Fragments; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Sex Factors; Tetrazoles

Betamethasone is administered to accelerate lung development and improve survival of premature infants but may be associated with hypertension later in life. In a sheep model of fetal programming resulting from exposure at day 80 of gestation to Betamethasone (Beta-exposed), adult sheep at 6 to 9 months or 1.8 years of age have elevated mean arterial pressure (MAP) and attenuated spontaneous baroreflex sensitivity (sBRS) for control of heart rate compared to age-matched controls associated with imbalances in angiotensin (Ang) II vs Ang-(1-7) tone. At 6 weeks of age, evoked BRS is already low in the Beta-exposed animals. In this study, we assessed the potential contribution of the renin-angiotensin system to the impaired sBRS. Female lambs (6 weeks old) with Beta exposure in utero had similar MAP to control lambs (78±2 vs 77±2 mm Hg, n=4-5 per group), but lower sBRS (8±1 vs 16±3 ms/mm Hg; P<0.05) and impaired heart rate variability. Peripheral AT1 receptor blockade using candesartan lowered MAP in both groups (≈10 mm Hg) and improved sBRS and heart rate variability in Beta-exposed lambs to a level similar to control. AT7 receptor blockade by infusion of D-ala Ang-(1-7) (700 ng/kg/min for 45 minutes) reduced sBRS 46%±10% in Beta-exposed vs in control lambs (P<0.15) and increased MAP in both groups (≈6±2 mm Hg). Our data reveal that Beta exposure impairs sBRS and heart rate variability at a time point preceding the elevation in MAP via mechanisms involving an imbalance in the Ang II/Ang-(1-7) ratio consistent with a progressive loss in Ang-(1-7) function.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Animals, Newborn; Baroreflex; Benzimidazoles; Betamethasone; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Female; Glucocorticoids; Heart Rate; Hypertension; Peptide Fragments; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Sheep; Tetrazoles

In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion. RI coinfusion of specific angiotensin type 2 receptor antagonist PD-123319 abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI angiotensin (1-7) alone or together with angiotensin-converting enzyme inhibition. Similarly, neither RI angiotensin II alone or in the presence of aminopeptidase A inhibitor increased urine sodium excretion. In the absence of systemic angiotensin type 1 receptor blockade, Ang III alone did not increase urine sodium excretion, but natriuresis was enabled by the coinfusion of aminopeptidase N inhibitor and subsequently blocked by PD-123319. In angiotensin type 1 receptor-blocked rats, RI administration of aminopeptidase N inhibitor alone also induced natriuresis that was abolished by PD-123319. Ang III-induced natriuresis was accompanied by increased RI cGMP levels and was abolished by inhibition of soluble guanylyl cyclase. RI and renal tissue Ang III levels increased in response to Ang III infusion and were augmented by aminopeptidase N inhibition. These data demonstrate that endogenous intrarenal Ang III but not angiotensin II or angiotensin (1-7) induces natriuresis via activation of angiotensin type 2 receptors in the proximal tubule via a cGMP-dependent mechanism and suggest aminopeptidase N inhibition as a potential therapeutic target in hypertension.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin III; Animals; Benzimidazoles; Biphenyl Compounds; Female; Imidazoles; Kidney Tubules, Proximal; Models, Animal; Natriuresis; Peptide Fragments; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Tetrazoles

Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity for heart rate control and high nicotinamide adenine dinucleotide phosphate oxidase and kinase-to-phosphatase signaling activity in medullary tissue compared with normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin II actions, supplementing angiotensin-(1-7), or scavenging reactive oxygen species in brain differentially alters mean arterial pressure, baroreflex sensitivity, or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular infusions of the angiotensin II type 1 receptor antagonist candesartan (4 μg/5 μL/h), angiotensin-(1-7) (0.1 μg/5 μL/h), a reactive oxygen species scavenger tempol (25 μg/5 μL/h), or artificial cerebrospinal fluid (5 μL/h) for 2 weeks. Mean arterial pressure was reduced in candesartan-treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, angiotensin-(1-7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower mean arterial pressure. Tempol significantly reduced nicotinamide adenine dinucleotide phosphate oxidase activity in brain dorsal medullary tissue but had no effect on mean arterial pressure or autonomic function. Candesartan tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase signaling pathways in dorsal medulla. Although additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary nicotinamide adenine dinucleotide phosphate oxidase or mitogen-activated protein kinase in hypertensive (mRen2)27 rats.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Antioxidants; Baroreflex; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blotting, Western; Cerebrospinal Fluid; Cyclic N-Oxides; Heart Rate; Hypertension; Infusions, Intraventricular; Medulla Oblongata; Mice; Mitogen-Activated Protein Kinases; NADPH Oxidases; Peptide Fragments; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reactive Oxygen Species; Renin; Spin Labels; Tetrazoles; Vagus Nerve

Transgenic hypertensive (mRen2)27 rats overexpress the murine Ren2 gene and have impaired baroreflex sensitivity (BRS) for control of the heart rate. Removal of endogenous angiotensin (Ang)-(1-7) tone using a receptor blocker does not further lower BRS. Therefore, we assessed whether blockade of Ang II with a receptor antagonist or combined reduction in Ang II and restoration of endogenous Ang-(1-7) levels with Ang-converting enzyme (ACE) inhibition will improve BRS in these animals. Bilateral solitary tract nucleus (nTS) microinjections of the AT(1) receptor blocker, candesartan (CAN, 24 pmol in 120 nl, n=9), or a peptidic ACE inhibitor, bradykinin (BK) potentiating nonapeptide (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro; BPP9α, 9 nmol in 60 nl, n=12), in anesthetized male (mRen2)27 rats (15-25 weeks of age) show that AT(1) receptor blockade had no significant effect on BRS, whereas microinjection of BPP9α improved BRS over 60-120 min. To determine whether Ang-(1-7) or BK contribute to the increase in BRS, separate experiments using the Ang-(1-7) receptor antagonist D-Ala(7)-Ang-(1-7) or the BK antagonist HOE-140 showed that only the Ang-(1-7) receptor blocker completely reversed the BRS improvement. Thus, acute AT(1) blockade is unable to reverse the effects of long-term Ang II overexpression on BRS, whereas ACE inhibition restores BRS over this same time frame. As the BPP9α potentiation of BK actions is a rapid phenomenon, the likely mechanism for the observed delayed increase in BRS is through ACE inhibition and elevation of endogenous Ang-(1-7).

Topics: Anesthesia; Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Heart Rate; Hypertension; Male; Microinjections; Oligopeptides; Peptide Fragments; Rats; Rats, Transgenic; Solitary Nucleus; Tetrazoles

Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers (ARBs) slow the progression of various chronic kidney diseases and chronic allograft dysfunction. RAS inhibition can be achieved also by directly blocking renin upstream from ACE. However, direct renin inhibition can have additional effects since formation of renoprotective Ang II breakdown products such as angiotensin (Ang) (1-7) that are produced by ACE2 are also inhibited.. Using a Fischer-to-Lewis renal transplantation model, the effect of the renin inhibitor aliskiren (10 mg/kg/day) was assessed on the development of chronic allograft dysfunction compared with vehicle treatment and Ang II receptor blockers candesartan.. Aliskiren had no effect on renal function (proteinuria, creatinine clearance) or on renal morphological changes (glomerulosclerosis collagen deposition, myofibroblast accumulation and macrophage infiltration) compared with the vehicle- and candesartan-treated animals determined 24 weeks after transplantation. On the other hand, atrophy of tubular cells was significantly attenuated. Candesartan reduced both proteinuria and structural injury of the kidney. In aliskiren-treated animals reduced serum Ang II and Ang (1-7) levels were detected, whereas the level of urine angiotensinogen was unchanged.. The renin inhibitor aliskiren does not slow the progression of chronic allograft dysfunction. We suggest that the lack of protection might be due to reduced formation of the protective Ang II breakdown products such as Ang (1-7) or due to unchanged intrarenal RAS activity demonstrated by urinary angiotensinogen levels.

Topics: Amides; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Fumarates; Kidney; Kidney Transplantation; Male; Models, Animal; Peptide Fragments; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Tetrazoles; Transplantation, Homologous

Angiotensin-(1-9) is present in human and rat plasma and its circulating levels increased early after myocardial infarction or in animals treated with angiotensin-converting enzyme inhibitor. However, the cardiovascular effects of this peptide are unknown.. To determine whether angiotensin-(1-9) is a novel anti-cardiac hypertrophy factor in vitro and in vivo and whether this peptide is involved in the pharmacological effects of cardiovascular drugs acting on the renin-angiotensin system.. The administration of angiotensin-(1-9) to myocardial infarcted rats by osmotic minipumps (450 ng/kg per min, n = 6) vs. vehicle (n = 8) for 2 weeks decreased plasma angiotensin II levels, inhibited angiotensin-converting enzyme activity and also prevented cardiac myocyte hypertrophy. However, cardiac myocyte hypertrophy attenuation triggered by angiotensin-(1-9) was not modified with the simultaneous administration of the angiotensin-(1-7) receptor antagonist A779 (100 ng/kg per min, n = 6). In experiments in vitro with cultured cardiac myocytes incubated with norepinephrine (10 micromol/l) or with insulin-like growth factor-1 (10 nmol/l), angiotensin-(1-9) also prevented hypertrophy. In other experimental setting, myocardial infarcted rats (n = 37) were randomized to receive either vehicle (n = 12), enalapril (10 mg/kg per day, n = 12) or angiotensin II receptor blocker candesartan (10 mg/kg per day, n = 13) for 8 weeks. Both drugs prevented left ventricle hypertrophy and increased plasma angiotensin-(1-9) levels by several folds. Angiotensin-(1-9) levels correlated negatively with different left ventricular hypertrophy markers even after adjustment for blood pressure reduction.. Angiotensin-(1-9) is an effective and a novel anti-cardiac hypertrophy agent not acting via the Mas receptor.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Cardiomegaly; Cell Enlargement; Cells, Cultured; Enalapril; Humans; Hypertrophy, Left Ventricular; In Vitro Techniques; Insulin-Like Growth Factor I; Male; Myocardial Infarction; Myocytes, Cardiac; Norepinephrine; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Ventricular Function, Left

An understanding of aminopeptidase A in hypertension is important, given its ability to cleave the N-terminal aspartic acid of potent vasoconstrictor angiotensin II. However, the role of aminopeptidase A in hypertension has received limited attention. Because we have succeeded in producing recombinant human aminopeptidase A, the effect of aminopeptidase A on systolic blood pressure in the spontaneously hypertensive rat was examined. Aminopeptidase A of 0.016 mg/kg was administrated intravenously to spontaneously hypertensive rats and blood pressure was monitored for 72 h. For repeated administration, aminopeptidase A doses of 0.016 mg/kg and 0.1-mg/kg doses of candesartan (an angiotensin II receptor 1 subtype blocker) were administrated daily in spontaneously hypertensive rats and blood pressure was monitored for 5 d. Bolus intravenous injection of aminopeptidase A at a dose of 0.016 mg/kg significantly decreased systolic blood pressure for 36 h in spontaneously hypertensive rats. A comparison of the antihypertensive effects of aminopeptidase A versus candesartan in spontaneously hypertensive rats showed that the effective dose of aminopeptidase A was about one-tenth that of candesartan. These results suggest the novel approach of utilizing aminopeptidase A to treat hypertension by degrading circulating angiotensin II before it binds to the receptor 1 subtype.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Baculoviridae; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Genetic Vectors; Glutamyl Aminopeptidase; Humans; Hypertension; Male; Mutation; Nitroprusside; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins; Tetrazoles

Age-related impairments in baroreflex sensitivity in Sprague-Dawley rats are associated with low solitary tract nucleus content of angiotensin-(1-7). However, transgenic rats with low-brain angiotensinogen resulting from glial overexpression of an antisense oligonucleotide to angiotensinogen (ASrAOGEN) are spared age-related declines in cardiovascular function characteristic of Sprague-Dawley rats. We examine whether cardiovascular and reflex actions of angiotensin-(1-7) persist in the solitary tract nucleus of older (16 to 22 months) ASrAOGEN rats. Baroreflex sensitivity for control of heart rate and chemosensitive vagal afferent activation in response to phenylbiguanide were measured before and after bilateral microinjection of the angiotensin II type 1 receptor antagonist candesartan and angiotensin-(1-7) receptor antagonist (D-Ala(7))-angiotensin-(1-7) in urethane/chloralose-anesthetized rats. In older anesthetized ASrAOGEN rats, candesartan had no effect, whereas (D-Ala(7))-angiotensin-(1-7) significantly reduced baroreflex sensitivity (1.80+/-0.43 versus 0.50+/-0.17 ms/mm Hg). Phenylbiguanide responses were attenuated by injection of candesartan (-79+/-6 versus -55+/-12 mm Hg and -277+/-12 versus -156+/-27 bpm; P<0.05). In addition, resting blood pressure was reduced by injection of candesartan or (D-Ala(7))-angiotensin-(1-7). Within the solitary tract nucleus of older ASrAOGEN rats, it appears that glial angiotensinogen is the main source of angiotensin II attenuation of baroreflex sensitivity; endogenous angiotensin-(1-7) from nonglial sources enhances baroreflex sensitivity; nonglial sources of angiotensin II contribute to chemosensitive vagal afferent activation; and receptors for both peptides modulate resting arterial pressure under anesthesia. These results suggest a novel mechanism for the preservation of baroreflex sensitivity during aging.

Topics: Aging; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Angiotensins; Animals; Animals, Genetically Modified; Baroreflex; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Heart Rate; Male; Neuroglia; Peptide Fragments; Rats; Renin-Angiotensin System; Solitary Nucleus; Tetrazoles

Pancreatic stellate cells (PSCs) are involved in pancreatic inflammation and fibrosis. Recent studies have shown that blocking the renin-angiotensin system (RAS) attenuates pancreatic inflammation and fibrosis. However, there are few data about the direct effects of high glucose on extracellular matrix (ECM) protein synthesis and angiotensin II (Ang II) induction in PSCs. PSCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5.5 mM (LG group) or 27 mM D-glucose (HG group). Levels of Ang II and transforming growth factor-beta (TGF-beta) in culture media were measured and Ang II-positive cells were counted. We used real-time polymerase chain reaction (PCR) to detect Ang II receptor expression and Western blot analysis for the expression of ECM proteins such as connective-tissue growth factor (CTGF) and collagen type IV. Cells were also treated with an Ang II-receptor antagonist (candesartan, 10 microM) or angiotensin-converting enzyme (ACE) inhibitor (ramiprilat, 100 nM). Thymidine uptake by PSCs increased fourfold with high glucose treatment. Ang II levels and the proportion of Ang II-positive PSCs were significantly increased after 6 h under high-glucose conditions. TGF-beta concentrations also increased significantly with high glucose. After 72 h, the expression of CTGF and collagen type IV proteins in high-glucose cultures increased significantly and this increase was effectively attenuated by the candesartan or the ramiprilat. All together, high glucose induced PSCs proliferation and ECM protein synthesis, and these effects were attenuated by an Ang II-receptor antagonist. The data suggest that pancreatic inflammation and fibrosis aggravated by hyperglycemia, and Ang II play an important role in this pathogenesis.

Topics: Angiotensin I; Angiotensin II; Animals; Benzimidazoles; Biphenyl Compounds; Collagen; Connective Tissue Growth Factor; Dose-Response Relationship, Drug; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Fibrosis; Glucose; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Male; Pancreas; Pancreatitis; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta

Given that angiotensin-(1-7) (Ang-[1-7]) has been frequently reported to exert direct in vitro vascular effects but less often in vivo, we investigated whether a vasodepressor effect of Ang-(1-7) could be unmasked acutely in conscious spontaneously hypertensive rats (SHR) against a background of angiotensin II type 1 (AT1) receptor blockade. Mean arterial pressure (MAP) and heart rate were measured over a 5-day protocol in various groups of rats randomized to receive the following drug combinations: saline, AT1 receptor (AT1R) antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, Ang-(1-7) (5 pmol/min) alone, candesartan plus Ang-(1-7), and candesartan plus Ang-(1-7) and angiotensin II type 2 (AT2) receptor (AT2R) antagonist PD123319 (50 microg/kg per minute). In Wistar-Kyoto (WKY) rats, saline, Ang-(1-7), or candesartan alone caused no significant alteration in MAP, whereas Ang-(1-7) coadministered with candesartan caused a marked, sustained reduction in MAP. A similar unmasking of a vasodepressor response to Ang-(1-7) during AT1R blockade was observed in SHR. Moreover, the AT(2)R antagonist PD123319 markedly attenuated the enhanced depressor response evoked by the Ang-(1-7)/candesartan combination in SHR and WKY rats, whereas in other experiments, the putative Ang-(1-7) antagonist A-779 (5 and 50 pmol/min) did not attenuate this vasodepressor effect. In separate experiments, the bradykinin type 2 receptor antagonist HOE 140 (100 microg/kg IV) or the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (1 mg/kg IV) abolished the depressor effect of Ang-(1-7) in the presence of candesartan. Collectively, these results suggest that Ang-(1-7) evoked a depressor response during AT1R blockade via activation of AT2R, which involves the bradykinin-NO cascade.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Drug Combinations; Imidazoles; Male; Peptide Fragments; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 2; Tetrazoles; Vasoconstrictor Agents

Age-related baroreflex reductions in function may originate from central neural dysregulation as well as vascular structural/functional changes. We determined the role of 2 angiotensin (Ang) peptides at the nucleus tractus solitarii in age-related baroreflex impairment. Baroreflex sensitivity control of heart rate in response to increases in blood pressure was tested in younger (3 to 5 months) and older (16 to 20 months) anesthetized male Sprague-Dawley rats before and after bilateral solitary tract injections of the Ang II type 1 (AT1) receptor antagonist candesartan (24 pmol) or the Ang-(1-7) antagonist (D-Ala7)-Ang-(1-7) (144 fmol or 24 pmol). Basal reflex sensitivity of older rats was significantly lower than younger rats. In younger rats, the reflex was facilitated by bilateral candesartan injections and attenuated by bilateral (D-Ala7)-Ang-(1-7) injections. In older rats, the reflex was facilitated by AT1 blockade; however, (D-Ala7)-Ang-(1-7) injected into the solitary tract nucleus had no effect. Neprilysin mRNA in the medulla was lower in older rats compared with younger rats, whereas angiotensin-converting enzyme (ACE), ACE2, and mas receptor mRNA levels of older rats did not differ from values of younger rats. Thus, opposing actions of endogenous Ang II and Ang-(1-7) in the solitary tract nucleus contribute to baroreflex function in response to increases in mean arterial pressure of younger rats. The attenuated counterbalancing effect of Ang-(1-7) on baroreflex function is lost in older rats, which may be attributable to diminished production of the peptide from neprilysin.

Topics: Aging; Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Baroreflex; Benzimidazoles; Biphenyl Compounds; Heart Rate; Injections; Male; Neprilysin; Peptide Fragments; Rats; Rats, Sprague-Dawley; RNA, Messenger; Solitary Nucleus; Tetrazoles

The effect of angiotensin (Ang)-1-7 on dopamine, gamma-aminobutyric acid (GABA) and glutamate release in the striatum of the rat was examined using in vivo microdialysis. Ang-(1-7) was administered locally in the striatum through the microdialysis probe. At a concentration of 100 microm, Ang-(1-7) caused a significant increase in extracellular dopamine and GABA but had no effect on glutamate release. The Ang-(1-7)-induced dopamine release was blocked by EC33, an inhibitor of aminopeptidase A, an enzyme which converts Ang-(1-7) into Ang-(3-7), suggesting that this effect occurs after metabolism into Ang-(3-7). Indeed, administration of Ang-(3-7) (10-100 microm) into the striatum caused a more potent increase in the striatal dopamine release than Ang-(1-7). Because Ang-(3-7) is an inhibitor of insulin-regulated aminopeptidase (IRAP) and because Ang IV, another IRAP inhibitor, also causes a concentration-dependent increase in dopamine in the rat striatum, IRAP may be involved in this effect. In contrast, EC33 had no effect on the Ang-(1-7)-induced GABA increase but the GABA release was blocked by the putative AT(1-7) receptor antagonist A779 (0.1 microm) and by the nitric oxide synthase inhibitor L-NAME (1 mm). These drugs could not block the effect of Ang-(1-7) on the striatal dopamine release suggesting that only the observed effects on GABA release are mediated by the AT(1-7) receptor and/or are associated with a release of nitric oxide.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Chromatography; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; gamma-Aminobutyric Acid; Imidazoles; Male; Microdialysis; NG-Nitroarginine Methyl Ester; Peptide Fragments; Pyridines; Rats; Rats, Wistar; Sulfonic Acids; Tetrazoles; Time Factors

Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure, but their inhibitory actions on angiotensin I-induced increases in blood pressure in heart failure are not clear. Angiotensin I blocking and cardioprotective properties of the angiotensin II receptor blocker candesartan and the angiotensin-converting enzyme inhibitor quinapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Low-dose candesartan (0.5 mg/kg) showed the same angiotensin I blocking action as high-dose quinapril (20 mg/kg) in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (43/58, 74%) were divided into three groups and given quinapril at 20 mg/kg per day (group Q, n = 14), candesartan at 0.5 mg/kg per day (group C, n = 14) or vehicle alone (group V, n = 15). After oral administration for 1 month, four of 15 (27%) rats in group V and two of 14 (14%) in group C died. None of the animals in group Q died. Although angiotensin II levels of the blood and the left ventricle in group V [367 +/- 26 and 437 +/- 18% versus normal rats (group N)] were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). The left ventricular end-diastolic pressure and the area of myocardial fibrosis were lower, and the first derivative +/-dP/dt was higher in group Q (7.0 +/- 1.7 mmHg, 9 +/- 3% and +3451+/- 170/-3182 +/- 186 mmHg/s, respectively) than in group V (16.7 +/- 1.3 mmHg, 36 +/- 6% and +2601 +/- 235/-2156 +/- 257 mmHg/s, respectively) and in group C (11.2 +/- 2.0 mmHg, 26 +/- 4% and +3063 +/- 164/-2734 +/- 174 mmHg/s, respectively). Although levels of expression of transforming growth factor beta1 and collagen III mRNA in groupV (367 +/- 26 and 437 +/- 18% versus group N) were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). These results suggested that although low-dose candesartan can block increases in blood pressure with circulating angiotensin I to the same extent as high-dose quinapril, it does not confer sufficient protection against injury from the renin-angiotensin system in heart failure.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Cardiomyopathy, Dilated; Isoquinolines; Male; Quinapril; Rats; Rats, Inbred Lew; Receptors, Angiotensin; Tetrahydroisoquinolines; Tetrazoles

Angiotensin II (Ang II)-dependent hypertension is associated with augmented intrarenal concentrations of Ang II; however, the distribution of the increased intrarenal Ang II has not been fully established.. To determine the changes in renal interstitial fluid Ang II concentrations in Ang II-induced hypertension and the consequences of treatment with an angiotensin II type 1 (AT1) receptor blocker.. Rats were selected to receive vehicle (5% acetic acid subcutaneously; n = 6), Ang II (80 ng/min subcutaneously, via osmotic minipump; n = 7) or Ang II plus an AT1 receptor antagonist, candesartan cilexetil (10 mg/kg per day, in drinking water; n = 6) for 13-14 days, at which time, experiments were performed on anesthetized rats. Microdialysis probes were implanted in the renal cortex and were perfused at 2 microl/min. The effluent dialysate concentrations of Ang I and Ang II were measured by radioimmunoassay and reported values were corrected for the equilibrium rates at this perfusion rate.. Ang II-infused rats developed greater mean arterial pressures (155 +/- 7 mmHg) than vehicle-infused rats (108 +/- 3 mmHg). Ang II-infused rats showed greater plasma (181 +/- 30 fmol/ml) and kidney (330 +/- 38 fmol/g) Ang II concentrations than vehicle-infused rats (98 +/- 14 fmol/ml and 157 +/- 22 fmol/g, respectively). Renal interstitial fluid Ang II concentrations were much greater than plasma concentrations, averaging 5.74 +/- 0.26 pmol/ml in Ang II-infused rats - significantly greater than those in vehicle-infused rats (2.86 +/- 0.23 pmol/ml). Candesartan treatment prevented the hypertension (87 +/- 3 mmHg) and led to increased plasma Ang II concentrations (441 +/- 27 fmol/ml), but prevented increases in kidney (120 +/- 15 fmol/g) and renal interstitial fluid (2.15 +/- 0.12 pmol/ml) Ang II concentrations.. These data indicate that Ang II-infused rats develop increased renal interstitial fluid concentrations of Ang II, which may contribute to the increased vascular resistance and reduced sodium excretion. Furthermore, the augmentation of renal interstitial fluid Ang II is the result of an AT1 receptor-mediated process and can be dissociated from the plasma concentrations.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Body Weight; Extracellular Fluid; Hypertension, Renal; Kidney; Male; Microdialysis; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles; Vasoconstrictor Agents

Topics: Acrylates; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Clinical Trials as Topic; Germany; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Olmesartan Medoxomil; Placebos; Telmisartan; Tetrazoles; Therapeutic Equivalency; Thiophenes; Time Factors; Valine; Valsartan

Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT(1) receptor-dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT(1) receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114+/-2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185+/-4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348+/-58 versus 119+/-16 fmol/mL) and 2-fold (399+/-39 versus 186+/-26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100+/-283 versus 71+/-12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88+/-22 versus 37+/-7 fmol/mg protein). Flow cytometric analysis detected significant increases in AT(1A) receptor antibody binding in endosomal and intermicrovillar clefts of Ang II-infused rats. The hypertension induced by Ang II was prevented in rats treated concurrently with candesartan (2 mg/kg/d, 119+/-3 mm Hg). Candesartan treatment (n=8) also prevented increases in kidney (215+/-19 fmol/g), endosomal (96+/-29 fmol/mg protein), and intermicrovillar cleft Ang II levels (11+/-2 fmol/mg protein). These results indicate that there is substantial intracellular accumulation of angiotensin peptides in renal cortical endosomes during Ang II-dependent hypertension via an AT(1) receptor-mediated process.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antibodies; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dextrans; Endosomes; Flow Cytometry; Fluoresceins; Hypertension; Kidney; Male; Microvilli; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin; Systole; Tetrazoles

This study analyzed the influence of two main metabolites of angiotensin II, angiotensin IV and angiotensin-(1-7), on basal and angiotensin II-dependent [Ca2+](i) in rat mesangial cells. Angiotensin IV behaved as a weak agonist. Its effects were abolished by angiotensin AT(1) receptor antagonists. Treatment with angiotensin II abolished the effect of a subsequent treatment with angiotensin IV whereas two successive angiotensin IV-dependent [Ca2+](i) peaks were obtained. Angiotensin II increased [Ca2+](i) in a Ca2+-free medium whereas angiotensin IV was inactive. Leucine-valine-valine-hemorphin 7, a hemorphin specific for the angiotensin AT(4) receptor, was devoid of any agonistic or antagonistic effect. In contrast, angiotensin-(1-7), if without influence on basal [Ca2+](i), inhibited angiotensin II- and angiotensin IV-dependent [Ca2+](i) increases. Total inhibition of the angiotensin IV effect was obtained whereas association of angiotensin-(1-7) to 8-(NN-diethylamino)-octyl-3,4,5-trimethoxybenzoate, an inhibitor of inositol phosphate-mediated Ca2+ release, was necessary to suppress the effect of angiotensin II. These results provide evidence that angiotensin II metabolites may participate in the control of [Ca2+](i) in mesangial cells at the initial stage of binding to the angiotensin AT(1) receptors.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Calcium; Cell Culture Techniques; Cytosol; Dose-Response Relationship, Drug; Glomerular Mesangium; Inositol Phosphates; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Vasoconstrictor Agents

To determine the effects of physiological alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity (RSNA) and its arterial baroreflex regulation, angiotensin II type 1 receptor antagonists were microinjected into the rostral ventrolateral medulla of anesthetized rats consuming a low, normal, or high sodium diet that were instrumented for simultaneous measurement of arterial pressure and RSNA. Plasma renin activity was increased in rats fed a low sodium diet and decreased in those fed a high sodium diet. Losartan (50, 100, and 200 pmol) decreased heart rate and RSNA (but not mean arterial pressure) dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a high sodium diet. Candesartan (1, 2, and 10 pmol) decreased mean arterial pressure, heart rate, and RSNA dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a normal or high sodium diet. [D-Ala(7)]Angiotensin-(1-7) (100, 200, and 1000 pmol) did not affect mean arterial pressure, heart rate, or RSNA in rats fed either a low or a high sodium diet. In rats fed a low sodium diet, candesartan reset the arterial baroreflex control of RSNA to a lower level of arterial pressure, and in rats with congestive heart failure, candesartan increased the arterial baroreflex gain of RSNA. Physiological alterations in the endogenous activity of the renin-angiotensin system influence the bradycardic, vasodepressor, and renal sympathoinhibitory responses to rostral ventrolateral medulla injection of antagonists to angiotensin II type 1 receptors but not to angiotensin-(1-7) receptors.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Baroreflex; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Heart Failure; Heart Rate; Hemodynamics; Kidney; Losartan; Male; Medulla Oblongata; Microinjections; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Sodium, Dietary; Sympathetic Nervous System; Tetrazoles

We have previously demonstrated that microinjections of the selective angiotensin-(1-7) [ANG-(1-7)] antagonist, A-779, into the rostral ventrolateral medulla (RVLM) produces a significant fall in mean arterial pressure (MAP) and heart rate (HR) in both anesthetized and conscious rats. In contrast, microinjection of angiotensin II (ANG II) AT(1) receptor antagonists did not change MAP in anesthetized rats and produced dose-dependent increases in MAP when microinjected into the RVLM of conscious rats. In the present study, we evaluated whether endogenous ANG-(1-7) and ANG II acting at the RVLM contribute to the hypertension of transgenic rats harboring the mouse renin Ren-2 gene, TGR(mREN2)27. Unilateral microinjection of A-779 (0.1 nmol) produced a significant fall in MAP (-25 +/- 5 mmHg) and HR (-57 +/- 20 beats/min) of awake TGR rats. The hypotensive effect was greater than that observed in Sprague-Dawley (SD) rats (-9 +/- 2 mmHg). Microinjection of the AT(1) antagonist CV-11974 (0.2 nmol) produced a fall in MAP in TGR rats (-14 +/- 4 mmHg), contrasting with the pressor effect observed in SD rats (33 +/- 9 mmHg). These results indicate that endogenous ANG-(1-7) exerts a significant pressor action in the RVLM, contributing to the hypertension of TGR(mREN2)27 transgenic rats. The role of ANG II at the RVLM seems to be dependent on its endogenous level in this area.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Heart Rate; Hypertension; Male; Medulla Oblongata; Microinjections; Peptide Fragments; Rats; Rats, Sprague-Dawley; Renin; Tetrazoles

This study was designed to explore the mechanisms mediating the expression of the type 1 angiotensin II (AngII) receptor (AT1) in neuronal and renal tissues. Four groups of rats were given 1% NaCl in water and subjected to the renal reduced mass protocol (RRM), RRM + ramipril (Ram, 10 mg/kg per d), RRM + candesartan (Can, 10 mg/kg per d), or sham surgery. After 12 d, mean arterial pressure (MAP) was significantly higher in RRM rats than in RRM + Ram, RRM + Can, and sham-operated rats. Northern blot analysis showed that renal AT1 receptor mRNA levels (AT1 mRNA/18 rRNA) were significantly decreased in RRM (1.08+/-0.05) and RRM + Ram (0.82+/-0.02) compared with sham-operated rats (1.38+/-0.06) and that candesartan treatment caused a further decrease in renal AT1 mRNA content (0.73+/-0.07) compared with RRM. In contrast, dorsal root ganglia AT1 receptor mRNA content was significantly decreased in RRM (0.52+/-0.06) compared with sham-operated rats (1.18+/-0.07), and this decrease was abolished by ramipril (1.40+/-0.13) and candesartan treatment (1.56+/-0.11). RIA showed that levels (ng/mg protein) of calcitonin gene-related peptide (CGRP) in the dorsal root ganglia were significantly increased in RRM (1.60+/-0.11) but not in RRM + Ram (1.14+/-0.20) and RRM + Can (1.18+/-0.09), compared with sham-operated rats (0.94+/-0.05). Thus, RRM-induced downregulation of neuronal AT1 mRNA expression is mediated by AngII activation of the AT1 receptor, whereas an AT1-independent mechanism is operant in mediating renal AT1 gene expression. Furthermore, the inverse relationship between neuronal AT1 expression and CGRP content indicates that activation of the neuronal AT1 receptor inhibits CGRP synthesis in the dorsal root ganglia. The functional implications of these findings are discussed.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Calcitonin Gene-Related Peptide; Hypertension; Kidney; Male; Neurons, Afferent; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Tetrazoles

-Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19+/-1.06 pmol/mL, whereas plasma Ang II levels averaged 483+/-55 fmol/mL and kidney Ang II content averaged 650+/-66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 microg) did not significantly decrease MAP in 2K1C rats (152+/-3 versus 148+/-3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65+/-0. 06 to 0.83+/-0.11 mL. min-1. g-1) and renal blood flow (6.3+/-0.7 to 7.3+/-0.9 mL. min-1. g-1), and proportionately greater increases in absolute sodium excretion (0.23+/-0.07 to 1.13+/-0.34 micromol. min-1. g-1) and fractional sodium excretion (0.38+/-0.1% to 1.22+/-0. 35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Data Interpretation, Statistical; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney; Kidney Tubules, Proximal; Male; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renal Circulation; Renin-Angiotensin System; Tetrazoles

Contrary to previous reports, recent enzymatic assays showed the predominance of chymase-like activity in rat arteries. We determined the existence and significance of such alternative pathways in rat carotid arteries by measuring contraction of arterial rings in organ baths and blood pressure in conscious rats. Hamster aorta served as a positive control for chymase. Temocapril (30 micromol/L) inhibited the contractions to angiotensin (Ang) I (10(-9) to 10(-5) mol/L) except at high concentrations of Ang I (>10(-7) mol/L). Addition of chymostatin (100 micromol/L) to temocapril exerted a synergistic inhibitory effect. Hamster aorta gave similar results, except that temocapril was 30-fold less effective than in rat arteries. [Pro(11), D-Ala(12)]Ang I (10(-8) to 10(-5) mol/L), a chymase-specific substrate, provoked similar responses in rat and hamster arteries; chymostatin, but not temocapril, attenuated the responses. CV 11974 (30 micromol/L), an Ang II type 1 receptor antagonist, abolished the responses to both peptides. In conscious rats, Ang I (0.03 to 30 microg/kg) and [Pro(11),D-Ala(12)]Ang I (7 to 700 microg/kg) produced similar pressor responses. Not only CV 11974 (1 mg/kg) but also temocapril (2 mg/kg) abolished Ang I-induced responses in vivo. CV 11974, but not temocapril, inhibited responses to [Pro(11), D-Ala(12)]Ang I. Our results showed the presence of the alternative pathway in rat arteries, but it did not play a major role. Arteries with the opposing characteristics of chymase responded equally to [Pro(11),D-Ala(12)]Ang I. These findings suggest that biochemical and [Pro(11),D-Ala(12)]Ang I-derived results may not reflect the functional significance of chymase.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Arteries; Benzimidazoles; Biphenyl Compounds; Carotid Arteries; Cricetinae; Male; Mesocricetus; Pressoreceptors; Rats; Rats, Inbred WKY; Serine Proteinase Inhibitors; Tetrazoles; Time Factors; Vasoconstriction

Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of beta-adrenergic receptors (beta-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes.. The density of beta-ARs on the myocyte surface was determined with a binding assay with [3H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 micromol/L) increased beta-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT1) receptor antagonist, CV-11974, nor angiotensin-I affected beta-AR density. However, the bradykinin B2 receptor antagonist Hoe 140 abolished the effect of captopril on beta-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of beta-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours.. The results suggest that captopril enhances beta-AR responsiveness by inducing beta-AR upregulation and that the latter effect is mediated by activation of bradykinin B2 receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT1 receptor antagonists in the treatment of heart failure.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Benzimidazoles; Biphenyl Compounds; Bradykinin; Captopril; Cells, Cultured; Female; In Vitro Techniques; Isoproterenol; Male; Myocardium; Protein Kinase C; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Bradykinin; Tetrazoles; Up-Regulation

Like human chymase, hamster chymase is an ANG II-forming enzyme, but pathophysiological roles of chymase are still unknown. We determined the functional conversion of ANG I and [Pro11, D-Ala12]ANG I, a chymase-selective substrate, to ANG II in the hamster cardiovascular system. ANG I and [Pro11, D-Ala12]ANG I produced similar dose-dependent pressor responses in conscious hamsters. Captopril and CV-11974, an ANG II type 1 (AT1)-receptor antagonist, inhibited the responses to ANG I; in contrast, the pressor responses to [Pro11, D-Ala12]ANG I were suppressed only by CV-11974. In the isolated aorta, captopril suppressed ANG I-induced contraction by 84%; administration of captopril with either chymostatin or aprotinin eliminated the contraction. [Pro11, D-Ala12]ANG I-induced contraction was not affected by captopril but was attenuated by chymostatin (71%) and aprotinin (57%). CV-11974 abolished the responses to both substrates, whereas PD-123319, an AT2-receptor antagonist, had no effect. In homogenates of the aorta and heart, soybean trypsin inhibitor-inhibitable ANG II formation predominated over captopril- or aprotinin-inhibitable ANG II formation. These data suggest that [Pro11,D-Ala12]ANG I and part of ANG I were functionally converted to ANG II by chymase and other serine protease(s) in hamster vessels, inducing AT1-receptor-mediated vasoconstriction. Biochemical data supported a role for chymase in the alternative pathway.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Aorta, Thoracic; Aprotinin; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Captopril; Chymases; Cricetinae; Heart Ventricles; Humans; In Vitro Techniques; Male; Mesocricetus; Muscle Contraction; Muscle, Smooth, Vascular; Myocardium; Oligopeptides; Serine Endopeptidases; Substrate Specificity; Tetrazoles; Vasoconstriction

1. Angiotensin II is known to enhance sympathetic neurotransmission in the vasculature by increasing the release of noradrenaline, but little is known about the effect on the co-released transmitter, adenosine 5'-triphosphate (ATP). In the present study we have examined the effect of angiotensin II on the excitatory junction potential (e.j.p.) elicited by repetitive field stimulation in the guinea-pig isolated mesenteric artery, to establish the angiotensin II receptor subtype involved in modulating the release of ATP and the role of the endothelium in converting angiotensin I to angiotensin II. 2. Suramin (300 microM), a P2 purinoceptor antagonist, abolished both the e.j.p.s and depolarizing response to alpha,beta-methylene-ATP, a stable analogue of ATP, without affecting the resting membrane potential and noradrenaline-induced depolarization. 3. Angiotensin II (0.1 microM) affected neither the resting membrane potential nor the amplitude of the first e.j.p., but increased the amplitudes of the subsequent e.j.p.s. This enhancing effect of angiotensin II was abolished by CV-11974 (0.1 microM), an angiotensin II type 1 (AT1) receptor antagonist, but unaffected by PD 123319 (1 microM), an angiotensin II type 2 (AT2) receptor antagonist, or CGP 42112A (1 microM), AT2 receptor ligand. 4. Angiotensin I (0.1 microM) exerted a similar effect on e.j.p.s to that of angiotensin II. CV-11974 (0.1 microM) or temocaprilat (10 microM), an angiotensin converting enzyme (ACE) inhibitor, abolished the effect of angiotensin I. Removal of the endothelium did not alter the action of angiotensin I. 5. The results of the present study indicate that the release of ATP from sympathetic nerves innervating the guinea-pig isolated mesenteric artery, as determined from the magnitude of the e.j.p., can be enhanced by angiotensin II via activation of prejunctional AT1 receptors. Qualitatively similar effects were observed with angiotensin I, which appears to be converted into angiotensin II by a subendothelial process.

Topics: Adenosine Triphosphate; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Electric Stimulation; Evoked Potentials; Female; Guinea Pigs; Imidazoles; In Vitro Techniques; Membrane Potentials; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Oligopeptides; Purinergic P2 Receptor Antagonists; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Suramin; Synaptic Transmission; Tetrazoles; Vasoconstrictor Agents

The pharmacological properties of 2-butyl-4-(methylthio)-1-[[2'-[[[(propylamino)carbonyl] amino]sulfonyl](1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), a novel non-peptide angiotensin (Ang) II type I (AT1) receptor antagonist, were characterized in both in vitro and in vivo systems. In vitro autoradiography using 125I-[Sar1,Ile8]Ang II as a ligand revealed that HR720 competitively inhibited the specific binding of the ligand to the adrenal cortex. The IC50 value for the adrenal cortex was 1.5 x 10(-8) M, and the IC50 for medulla was 1.4 x 10(-6) M. Similar results were obtained in the adrenal cortex with CV-11974, a known potent AT1-receptor antagonist. Since AT1 receptors are known to predominate in the adrenal cortex and AT2-receptors in the adrenal medulla, it is considered that HR720 is highly selective for AT1 receptors. HR720 inhibited the Ang II-induced contraction of isolated rabbit aortic strips and human gastroepiploic arteries in a noncompetitive manner, pD'2=9.40 and 9.62 for rabbit aorta and human artery, respectively. With CV-11974, pD'2 values of 9.84 in isolated rabbit aorta and 10.00 in human artery were obtained. HR720 did not affect the norepinephrine-, serotonin- or KCl-induced contraction even at a concentration of 1 x 10(-5) M. In anesthetized hamsters, HR720 induced a dose-dependent inhibition of the pressure response to Ang II. The potency of HR720 to antagonize the Ang II-induced pressure response was similar to that of CV-11974. These results demonstrate that HR720 is a potent and selective AT1-receptor antagonist.

Topics: Adrenal Glands; Adult; Aged; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cricetinae; Humans; Imidazoles; In Vitro Techniques; Losartan; Male; Mesocricetus; Middle Aged; Muscle, Smooth, Vascular; Rabbits; Rats; Tetrazoles; Thermodynamics

1. Spontaneously hypertensive rats and Wistar-Kyoto rats underwent a two-stage operation for the implantation of Doppler flow probes and intravascular catheters to determine the regional haemodynamic profiles of the angiotensin type 1 receptor antagonists, CV-11974 and EXP 3174. 2. Angiotensin II was given before and up to 24 h after the intravenous administration of CV-11974 (0.1 and 1.0 mg/kg) and EXP 3174 (1.0 mg/kg) to separate groups of conscious rats. 3. The dose of angiotensin II causing an equieffective pressor response (20-25 mmHg) was smaller in spontaneously hypertensive rats (6 ng) than in Wistar-Kyoto rats (25 ng) and was associated with marked renal and mesenteric vasoconstriction in both groups. CV-11974 (0.1 mg/kg) markedly attenuated the cardiovascular effects of angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats over the subsequent 6 h. In spontaneously hypertensive rats only, CV-11974 by itself caused a progressive fall in mean arterial pressure over 6 h together with a transient increase in renal flow (1 h) and a sustained increase in renal conductance over 6 h. Minimal changes occurred in the mesenteric and hindquarters circulations. All haemodynamic variables had returned to predrug levels by 24 h. A 10-fold higher dose of CV-11974 essentially evoked a similar haemodynamic profile. In Wistar-Kyoto rats, CV-11974 did not alter regional haemodynamics except for causing a small decrease in mean arterial pressure after 4-6 h. 4. In a separate group of spontaneously hypertensive rats, EXP 3174 caused haemodynamic changes similar to those obtained using CV-11974, i.e. there was a progressive reduction in mean arterial pressure together with a transient increase in renal flow only (90 min), whereas renal conductance was elevated over 6 h. 5. The angiotensin type 1 receptor antagonists CV-11974 and EXP 3174 blocked the regional haemodynamic effects of angiotensin II and caused relatively selective renal vasodilatation in conscious spontaneously hypertensive rats only. This action is likely to contribute to the hypotensive action of angiotensin type 1 receptor antagonists in conscious spontaneously hypertensive rats.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Imidazoles; Losartan; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Tetrazoles; Vasodilation

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.

Topics: Administration, Oral; Angiotensin I; Angiotensin II; Angiotensin III; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Enalapril; Enzyme Activation; Hypertension, Renal; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Artery; Surgical Instruments; Tetrazoles; Vasoconstrictor Agents

1. The regulation of angiotensin II (AII) receptor subtypes was studied in peripheral tissues of 20 week old male spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats. 2. AII receptor binding was determined by a quantitative in vitro autoradiography using [125I]-[Sar1,Ile8]AII as a ligand on the kidney, adrenal gland, thoracic aorta and heart. CV-11974, a specific AT1 receptor antagonist, and CGP42112B, a specific AT2 antagonist, were used in competition with [125I]-[Sar1,Ile8]AII to differentiate AT1 and AT2 receptor binding. 3. The relative abundance of each subtype was very similar between SHR and WKY rats. In both strains of rats, the adrenal cortex contained predominantly AT1 receptors, while AT2 receptors predominated in the adrenal medulla. The kidney contained exclusively AT1 receptors over glomeruli, proximal tubules and outer medulla. AT1 receptors were predominant in the thoracic aorta and heart. 4. As for relative receptor density, important differences were observed between SHR and WKY rats. In SHR, the adrenal cortex, outer medulla of the kidney, and heart displayed higher AT1 receptor density than WKY rats. 5. These results indicate that the expression of AT1 receptors is differently regulated in some important targets of AII in SHR, and suggest that the altered regulation of AT1 receptor presented in this study should be relevant to the pathophysiological features of SHR.

Topics: Adrenal Glands; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Autoradiography; Benzimidazoles; Biphenyl Compounds; Heart; Hypertension; Kidney; Male; Muscle, Smooth, Vascular; Myocardium; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Tetrazoles