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1.
Neuroscience ; 314: 90-105, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26656220

ABSTRACT

Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1 µg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. Other sets of rats received chronic intra-cerebroventricular (icv) infusion of aldo synthase (AS) inhibitor FAD286, MR blocker eplerenone or vehicle, electrolytic or sham lesions of the SFO, or intra-PVN infusion of AAV-MR-siRNA or AAV-AT1aR-siRNA. Infusion of aldo had no effect on 11ßHSD2, MR and AT1R mRNA in different nuclei but increased CYP11B2 mRNA in the SFO, and serum and glucocorticoid-kinase 1 (Sgk1) and epithelial sodium channel (ENaC) γ subunit mRNA in the SFO and supraoptic nucleus (SON). MR-siRNA decreased both MR and AT1R mRNA in the PVN by ∼ 60%, but AT1aR-siRNA only decreased AT1R mRNA. SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼ 50% and hypertension by ∼ 70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.


Subject(s)
Aldosterone/metabolism , Drinking Behavior , Hypertension/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Receptors, Mineralocorticoid/metabolism , Subfornical Organ/metabolism , Supraoptic Nucleus/metabolism , Aldosterone/administration & dosage , Animals , Arterial Pressure/drug effects , Corticosterone/metabolism , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Drinking Behavior/drug effects , Eplerenone , Fadrozole/administration & dosage , Hypertension/chemically induced , Hypertension/physiopathology , Male , Mineralocorticoid Receptor Antagonists/administration & dosage , Neurons/drug effects , Neurons/metabolism , Paraventricular Hypothalamic Nucleus/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , Sodium Chloride/administration & dosage , Spironolactone/administration & dosage , Spironolactone/analogs & derivatives , Subfornical Organ/drug effects , Supraoptic Nucleus/drug effects
2.
Pediatr Obes ; 9(1): 63-70, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23504985

ABSTRACT

What is already known about this subject The prevalence of childhood obesity has increased markedly in the past 2 decades. Abdominal fat is a better predictor of risk than body mass index. Waist circumference (WC) as a measure of abdominal fat has limited sensitivity and specificity. What this study adds Epicardial adipose tissue (EAT) as measured by echocardiography represents a simple and reliable marker of visceral adiposity. In children, both body mass index and EAT show a similar or better correlation with markers of cardiometabolic risk than does waist circumference. BACKGROUND: Epicardial adipose tissue (EAT) is the visceral fat deposit around the heart and is commonly increased in obese subjects. EAT is related to cardiometabolic risk factors and non-alcoholic fatty liver disease (NAFLD) in adults, but this relationship is not well known in children. OBJECTIVES: Echocardiographic assessment of EAT and its association with cardiometabolic risk factors in overweight and obese children. STUDY GROUPS AND METHODS: In 25 (mean age 13.0 ± 2.3) overweight and obese subjects and 24 lean controls, blood pressure (BP), WC, fasting plasma glucose and insulin, lipids, uric acid and hepatic enzymes were measured. EAT thickness was measured by transthoracic echocardiography. RESULTS: In overweight and obese subjects, EAT was significantly higher compared to normal weight children. Overweight and obese children had significantly higher body mass index (BMI), WC, BP, triglycerides (TAG), low-density lipoprotein and total cholesterol, hepatic enzymes alanine aminotransferase (ALT) and γ-glutamyl transferase, and lower high-density lipoprotein cholesterol (HDL-C). EAT correlated significantly with BP, TAG, uric acid, HDL-C, apoprotein B and ALT. Correlation coefficients were similar or better than for WC, but similar or lower than for BMI. CONCLUSION: EAT thickness in children is associated with an unfavourable cardiometabolic risk profile including biochemical signs of NAFLD and hyperuricaemia, but is not a stronger indicator than BMI.


Subject(s)
Blood Glucose/metabolism , Body Mass Index , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Fatty Liver/epidemiology , Intra-Abdominal Fat/diagnostic imaging , Pediatric Obesity/pathology , Waist Circumference , Adipose Tissue , Adiposity , Adolescent , Blood Pressure , Body Composition , Cardiovascular Diseases/diagnostic imaging , Cardiovascular Diseases/prevention & control , Child , Fatty Liver/diagnostic imaging , Fatty Liver/prevention & control , Female , Humans , Hyperuricemia/epidemiology , Hyperuricemia/prevention & control , Insulin Resistance , Male , Non-alcoholic Fatty Liver Disease , Pediatric Obesity/complications , Pediatric Obesity/diagnostic imaging , Pediatric Obesity/epidemiology , Risk Factors , Ultrasonography
3.
Br J Pharmacol ; 152(6): 903-14, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17906684

ABSTRACT

BACKGROUND AND PURPOSE: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. EXPERIMENTAL APPROACH: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. KEY RESULTS: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. CONCLUSION AND IMPLICATION: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/prevention & control , Hypertension/chemically induced , Hypertension/prevention & control , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/chemistry , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Cardiovascular Diseases/pathology , Drinking/drug effects , Echocardiography , Fibrosis , Heart Rate/drug effects , Hypertrophy , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Injections, Subcutaneous , Kidney/pathology , Kidney Diseases/pathology , Lisinopril/chemistry , Lisinopril/metabolism , Lisinopril/pharmacology , Male , Organ Size/drug effects , Peptidyl-Dipeptidase A/metabolism , Rats , Rats, Inbred Dahl , Receptor, Angiotensin, Type 1/metabolism , Sodium, Dietary/toxicity , Telemetry
4.
J Hum Hypertens ; 21(1): 86-93, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17066085

ABSTRACT

To evaluate the persistence of the antihypertensive effect of perindopril 4 mg+indapamide 1.25 mg once daily for up to 72 h using the 'missed-dose' technique. Hypertensive patients were initially treated with perindopril 2 mg+indapamide 0.625 mg once daily. After 4 weeks, the 135 of 216 patients who still had a diastolic BP> or =85 mm Hg went on to receive perindopril 4 mg+indapamide 1.25 mg daily for a further 8 weeks. During either week 9 or 11, placebo was substituted for perindopril 4 mg+indapamide 1.25 mg on either one or two consecutive days to simulate BP changes, which might occur after one or two missed doses. A 24-h ambulatory BP recording was performed at baseline, after 9 or 11 weeks of perindopril+indapamide therapy and during the simulated missed doses, 24- 48 and 48-72 h after the administration of perindopril 4 mg+indapamide 1.25 mg. Significant (P<0.001) reductions in mean (+/-s.d.) 24-h ambulatory BP (mm Hg) during the first 24 h after perindopril 4 mg+indapamide 1.25 mg therapy versus baseline were noted for patients later randomized to the one missed dose (-15.9+/-10.5/-9.4+/-7.6) or two missed dose (-17.4+/-8.7/-10.3+/-5.1) sub-groups. A significant reduction in BP (P<0.001 versus baseline) was still present on the days when placebo was substituted for perindopril 4 mg+indapamide 1.25 mg with decreases in mean 24-h ambulatory BP from 24 to 48 h and 48 to 72 h after dosing being -11.9+/-10.1/-6.9+/-6.2 and -10.6+/-9.9/-5.8+/-5.7, respectively. Use of the 'missed-dose' technique has demonstrated a prolonged antihypertensive effect for perindopril 4 mg+indapamide 1.25 mg for up to 72 h, supporting the use of this combination as therapy for hypertension.


Subject(s)
Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacokinetics , Hypertension/drug therapy , Indapamide/administration & dosage , Indapamide/pharmacokinetics , Perindopril/administration & dosage , Perindopril/pharmacokinetics , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Time Factors
5.
Control Clin Trials ; 22(6): 659-73, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11738122

ABSTRACT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trial's recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypolipidemic Agents/therapeutic use , Myocardial Infarction/prevention & control , Personnel Selection/methods , Randomized Controlled Trials as Topic , Black People , Female , Humans , Male , Middle Aged , Multicenter Studies as Topic , United States
6.
Am J Physiol Heart Circ Physiol ; 281(6): H2410-6, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11709406

ABSTRACT

To assess the possible contribution of the circulatory and cardiac renin-angiotensin system (RAS) to the cardiac hypertrophy induced by a beta-agonist, the present study evaluated the effects of isoproterenol, alone or combined with an angiotensin I-converting enzyme inhibitor or AT(1) receptor blocker, on plasma and LV renin activity, ANG I, and ANG II, as well as left ventricular (LV) and right ventricular (RV) weight. Male Wistar rats received isoproterenol by osmotic minipump subcutaneously and quinapril or losartan once daily by gavage. Plasma and LV ANGs were measured by radioimmunoassay after separation by HPLC. Isoproterenol alone decreased blood pressure, more markedly when combined with losartan or quinapril. Isoproterenol significantly increased LV and RV weight and total collagen. Neither losartan nor quinapril inhibited the increases in LV or RV weight. Losartan prevented the increase in RV collagen but enhanced the increase in LV collagen. Isoproterenol increased plasma renin, ANG I, and ANG II three- to fourfold. Isoproterenol combined with losartan or quinapril, caused marked further increases except for a significant decrease in plasma ANG II with quinapril. Isoproterenol alone did not increase LV ANG II and, combined with losartan or quinapril, actually decreased LV ANG II. These results indicate that isoproterenol-induced cardiac hypertrophy is associated with clear increases in plasma ANG II, but not in LV ANG II. Both losartan and quinapril lower LV ANG II below control levels, but do not prevent the isoproterenol-induced cardiac hypertrophy. These findings do not support a role for the circulatory or cardiac RAS in the cardiac trophic responses to beta-receptor stimulation.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Cardiomegaly/physiopathology , Coronary Circulation/physiology , Isoproterenol/pharmacology , Renin-Angiotensin System/physiology , Tetrahydroisoquinolines , Angiotensin I/blood , Angiotensin II/blood , Animals , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Cardiomegaly/chemically induced , Cardiomegaly/metabolism , Collagen/metabolism , Coronary Circulation/drug effects , Heart Rate/drug effects , Isoquinolines/pharmacology , Losartan/pharmacology , Male , Myocardium/metabolism , Myocardium/pathology , Organ Size , Peptidyl-Dipeptidase A/metabolism , Quinapril , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1 , Receptors, Angiotensin/metabolism , Renin/blood , Renin-Angiotensin System/drug effects
7.
Can J Physiol Pharmacol ; 79(10): 861-7, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11697745

ABSTRACT

Central administration of AT1 receptor blockers prevents salt-sensitive hypertension and inhibits progression of CHF. We investigated in Wistar rats the effectiveness of peripheral administration of two AT1 receptor blockers, losartan and embusartan, in exerting central AT1 receptor blockade. Losartan or embusartan at doses of 30 and 100 mg/kg were administered subcutaneously (s.c.) as a single dose, or one dose daily for 6 days. The BP responses to intracerebroventricular (i.c.v.) injection of Ang II, i.c.v. infusion of Na+-rich aCSF (0.3 M NaCl), and intravenous (i.v.) injection of Ang II were then measured. Losartan or embusartan at 30 and 100 mg/kg both inhibited the BP increases induced by i.c.v. Ang II and, to a lesser extent, by Na+-rich aCSF. After a single dose, this inhibition was more pronounced for losartan. However, after 6 days of treatment, there were no significant differences between the effects of losartan and embusartan. Losartan and embusartan blocked responses to Ang II i.v. to a similar extent. These results indicate that results from single-dose studies may not reflect the chronic steady-state, and that during chronic treatment both AT1 receptor blockers are similarly effective in inhibiting AT1 receptors in the central nervous system, when assessed by pressor responses to acute increases in CSF Na+ or CSF Ang II.


Subject(s)
Angiotensin II/pharmacology , Angiotensin Receptor Antagonists , Blood Pressure/drug effects , Peripheral Nervous System/drug effects , Sodium/pharmacology , Animals , Dihydropyridines/pharmacology , Dose-Response Relationship, Drug , Heart Rate/drug effects , Injections, Intravenous , Injections, Intraventricular , Losartan/pharmacology , Male , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1 , Tetrazoles/pharmacology
8.
J Korean Med Sci ; 16(5): 553-7, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11641522

ABSTRACT

To investigate whether brain AT1 receptor stimulation contributes as a hypertensive mechanism to deoxycorticosterone acetate (DOCA)-salt hypertension, losartan (1 mg/4 microL) or artificial cerebrospinal fluid (aCSF) was injected into the lateral cerebral ventricle in conscious control uninephrectomized Wistar rats or rats with DOCA-salt for 2 or 4 weeks, and mean arterial pressure (MAP) and heart rates (HR) were recorded. In rats with DOCA-salt treatment, resting MAP increased to 144+/-6 mmHg after 2 weeks and to 170+/-5 mmHg after 4 weeks versus 115- 120 mmHg in controls. In rats with 2 week DOCA-salt treatment, MAP started declining at 4 hr after intracerebroventricular (icv) injection of losartan, and significant decreases in MAP were found at 18 and 24 hr. In rats with 4 week DOCA-salt treatment, MAP was significantly decreased at 4, 18 and 24 hr. In both groups MAP decreased to that of control rats. In control rats, icv losartan had no effect on MAP and HR. Icv aCSF did not significantly change MAP and HR in either DOCA-salt hypertensive rats or control rats. Normalization of MAP after icv administration of the AT1 receptor antagonist suggests a significant role for brain AT1 receptor stimulation in the development and maintenance of hypertension in the DOCA-salt hypertensive rat model.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Losartan/therapeutic use , Animals , Blood Pressure/drug effects , Desoxycorticosterone , Heart Rate/drug effects , Hypertension/physiopathology , Injections, Intraventricular , Losartan/administration & dosage , Male , Rats , Rats, Wistar , Renin-Angiotensin System/physiology , Sodium Chloride
9.
Am J Physiol Heart Circ Physiol ; 281(5): H1881-9, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11668047

ABSTRACT

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+ were evaluated. In conscious young (5-6 wk old) and adult (10-11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2-0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 microl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular alpha2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus "ouabain" significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain "ouabain" is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.


Subject(s)
Blood Pressure/physiology , Sympathetic Nervous System/physiology , Adrenergic alpha-Agonists/pharmacology , Age Factors , Animals , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/drug effects , Brain/metabolism , Guanabenz/pharmacology , Heart Rate/drug effects , Heart Rate/physiology , Hypertension/physiopathology , Injections, Intraventricular , Kidney/innervation , Male , Ouabain/metabolism , Potassium/cerebrospinal fluid , Rats , Rats, Inbred Dahl , Rats, Wistar , Sodium/cerebrospinal fluid , Sodium, Dietary/pharmacology
10.
Am J Physiol Heart Circ Physiol ; 281(3): H1210-6, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11514289

ABSTRACT

Pressor responses to increases in cerebrospinal fluid (CSF) sodium in Wistar rats and to high salt intake in spontaneously hypertensive rats (SHR) involve both brain ouabainlike activity ("ouabain") and the brain renin-angiotensin system (RAS). Because some of the effects of "ouabain" are mediated by the median preoptic nucleus (MnPO) and this nucleus contains all elements of the RAS, the present study assessed possible interactions of "ouabain" and ANG II in this nucleus. In conscious Wistar rats, injection of ANG II into the MnPO significantly increased mean arterial pressure (MAP) and heart rate (HR). This response was not affected by pretreatment with a subpressor dose of ouabain. MAP and HR increases by ouabain in the MnPO were significantly attenuated by MnPO pretreatment with losartan. In Wistar rats, losartan in the MnPO also abolished pressor and HR responses to intracerebroventricular 0.3 M NaCl and attenuated MAP and HR responses to intracerebroventricular ouabain. Five weeks of a high-salt diet in SHRs resulted in exacerbation of hypertension and increased responses to air-jet stress and intracerebroventricular guanabenz. Losartan injected into the MnPO reversed the salt-sensitive component of the hypertension and normalized the depressor response to guanabenz but did not change responses to air-jet stress. We conclude that in the MnPO, ANG II via AT(1) receptors mediates cardiovascular responses to an acute increase in CSF sodium as well as the chronic pressor responses to high sodium intake in SHR.


Subject(s)
Angiotensin II/metabolism , Preoptic Area/metabolism , Sodium, Dietary/metabolism , Sodium/cerebrospinal fluid , Angiotensin II/pharmacology , Angiotensin Receptor Antagonists , Animals , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Drug Interactions , Enzyme Inhibitors/pharmacology , Heart Rate/drug effects , Injections, Intraventricular , Losartan/pharmacology , Male , Microinjections , Ouabain/antagonists & inhibitors , Ouabain/pharmacology , Preoptic Area/drug effects , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Saline Solution, Hypertonic/pharmacology , Sodium, Dietary/pharmacology
11.
Drugs ; 61(7): 943-54, 2001.
Article in English | MEDLINE | ID: mdl-11434450

ABSTRACT

Mild to moderate hypertension still remains poorly controlled. This relates to multiple factors including low antihypertensive efficacy of single drug therapies reluctance of primary care physicians to modify/titrate initially chosen therapy to obtain target blood pressure, and poor compliance with medication. Several guidelines for the treatment of high blood pressure now include combination therapy with low doses of 2 drugs as one of the strategies for the initial management of mild/moderate arterial hypertension. Evidence discussed in this article points to superior control of blood pressure by combinations of low doses of 2 drugs as compared with monotherapy in regular doses. This superior effectiveness of combined therapy relates to a better antihypertensive efficacy and higher response rates in the low range of doses as the result of complementary mechanisms of antihypertensive effects, better tolerance as a result of a lower rate of adverse effects in the low dose range, improved compliance from better tolerance and simple drug regimen, and lower cost. Whether increased use of fixed low dose combination therapies would translate to better control of arterial hypertension in the population and thereby further reduction of cardiovascular/cerebrovascular morbidity and mortality caused by hypertension remains to be assessed.


Subject(s)
Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Drug Therapy, Combination , Hypertension/drug therapy , Patient Compliance , Humans , Randomized Controlled Trials as Topic
12.
Curr Hypertens Rep ; 3(4): 314-21, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11470014

ABSTRACT

It is generally assumed that the arterial vasodilation induced by inhibition of Ca(2+) influx into vascular smooth muscle cells represents the main mechanism for the hypotensive effect of dihydropyridine calcium channel blockers. Increases in sympathetic tone have been related to activation of the arterial baroreflex by rapid lowering of blood pressure. This review highlights new findings in two areas. First, in animal studies, direct central administration of dihydropyridines such as nifedipine or amlodipine lowers sympathetic nerve activity and thereby blood pressure. Peripheral administration of nifedipine or amlodipine at low rates appears to result in gradual accumulation of drug in the central nervous system, and also causes lowering of sympathetic nerve activity and thereby lowering of blood pressure (rather than by arterial vasodilation). Second, in hypertensive humans treated with long-acting dihydropyridines and presumably little activation of the arterial baroreflex, some studies have demonstrated lowering of sympathetic activity (as assessed by plasma norepinephrine), but others reported increases (as assessed by plasma norepinephrine or microneurography). This sympathoexcitatory response may be due to activation of the renin-angiotensin system, particularly at higher doses.


Subject(s)
Calcium Channel Blockers/pharmacology , Hypertension/physiopathology , Neural Inhibition/drug effects , Neural Inhibition/physiology , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiopathology , Animals , Blood Pressure/physiology , Calcium Channel Blockers/therapeutic use , Humans , Hypertension/drug therapy , Rats
13.
Hypertension ; 37(2): 209-15, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11230273

ABSTRACT

Chronic treatment with minoxidil induces cardiac trophic and sympathetic responses, which may increase the propensity for lethal arrhythmias. To test this hypothesis, acute coronary artery occlusion was performed in conscious normotensive rats treated for 2 or 5 weeks with minoxidil with the use of a 2-stage approach to cause a myocardial infarction. For comparison, rats with aortocaval (A-V) shunts and spontaneously hypertensive rats (SHR) were studied. Minoxidil increased left ventricular and right ventricular weights by 15% to 20%, and the A-V shunt increased these weights by 30% to 40%. In SHR, left ventricular weight was increased by 50%, and right ventricular weight was increased by 25%. In rats treated with minoxidil for 5 weeks, coronary artery occlusion caused a rapid and marked mortality, and 4 hours after myocardial infarction, only 18% of these rats were alive versus 61% of the control rats. In rats with the A-V shunt, coronary artery occlusion was also associated with increased mortality, and after 6 hours, 33% were still alive compared with 59% of the control rats. In contrast, SHR with marked hypertension and cardiac hypertrophy showed only a minor increase in mortality (survival rates were 53% versus 60% in SHR versus Wistar-Kyoto rats, respectively). Mortality was preceded by high arrhythmia scores, and ventricular fibrillation was the cause of death. Discontinuation of minoxidil for 1 week, sympathetic blockade with nadolol or clonidine, or blockade of the renin-angiotensin system with enalapril or losartan did not improve minoxidil-induced excess mortality. We conclude that ventricular stretch and other mechanisms (eg, cardiac vagal activity) in rats appear to be more potent than hypertension-induced left ventricular hypertrophy in predisposing for lethal arrhythmias in the setting of acute ischemia.


Subject(s)
Cardiomegaly/physiopathology , Coronary Disease/mortality , Animals , Arteriovenous Shunt, Surgical , Blood Pressure/physiology , Cardiomegaly/etiology , Coronary Disease/physiopathology , Coronary Vessels/physiopathology , Coronary Vessels/surgery , Disease Models, Animal , Electrocardiography , Heart Rate/physiology , Hypertension/physiopathology , Ligation , Male , Minoxidil/administration & dosage , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Survival Rate
14.
Hypertension ; 37(2 Pt 2): 683-6, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11230356

ABSTRACT

Studies with angiotensin (Ang) II type 1 receptor blockers suggest that the brain renin-angiotensin system contributes to sodium-induced sympathoexcitation and hypertension. To provide more specific evidence for the involvement of Ang II, locally produced in the brain, transgenic rats were used, which express an antisense RNA against angiotensinogen mRNA specifically in the brain, reducing angiotensinogen levels in the brain by >90%. In freely moving transgenic rats and Sprague-Dawley rats as control animals, blood pressure and heart rate responses to intracerebroventricular infusion (3.8 microL/min for 10 minutes) of artificial cerebrospinal fluid and Na(+)-rich artificial cerebrospinal fluid (containing 0.2, 0.3, and 0.45 mol/L Na(+)) as well as intracerebroventricular injection of ouabain (0.3 and 0.6 microgram/2 microL) were assessed. Central infusion of Na(+)-rich artificial cerebrospinal fluid increased blood pressure and heart rate in a dose-related manner. However, the peak increases by each dose of Na(+) were attenuated by 50% to 70% in the transgenic versus Sprague-Dawley rats. Increases in blood pressure and heart rate in response to ouabain at both doses were attenuated by 55% to 70% in the transgenic versus Sprague-Dawley rats. In the hypothalamus, Ang I level was markedly lower (31+/-9 versus 76+/-13 pg/g, P<0.05) and Ang II level tended to be lower in the transgenic versus Sprague-Dawley rats. These results indicate that the production of angiotensins in the brain is decreased in transgenic rats. The attenuated sympathoexcitatory and pressor responses to ouabain and Na(+)-rich artificial cerebrospinal fluid in transgenic rats support the concept that the local brain renin-angiotensin system, that is, locally produced Ang II, plays an important role in the sympathoexcitatory effects of ouabain and sodium.


Subject(s)
Angiotensinogen/deficiency , Brain/metabolism , Ouabain/pharmacology , Sodium/pharmacology , Angiotensin I/metabolism , Angiotensin II/metabolism , Animals , Animals, Genetically Modified , Blood Pressure/drug effects , Cerebrospinal Fluid/chemistry , Heart Rate/drug effects , Injections, Intraventricular , Male , Rats , Rats, Sprague-Dawley , Renin-Angiotensin System
15.
Hypertension ; 37(3): 981-4, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11244027

ABSTRACT

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


Subject(s)
Angiotensin Receptor Antagonists , Antihypertensive Agents/pharmacology , Biphenyl Compounds/pharmacology , Hypertension/prevention & control , Tetrazoles/pharmacology , Administration, Oral , Angiotensin II/administration & dosage , Angiotensin II/pharmacology , Animals , Antihypertensive Agents/administration & dosage , Biphenyl Compounds/administration & dosage , Blood Pressure/drug effects , Brain/drug effects , Brain/physiology , Dose-Response Relationship, Drug , Heart Rate/drug effects , Injections, Intraventricular , Injections, Subcutaneous , Irbesartan , Male , Rats , Rats, Inbred Dahl , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Renin-Angiotensin System/drug effects , Sodium Chloride, Dietary , Tetrazoles/administration & dosage
16.
Am J Physiol Heart Circ Physiol ; 280(3): H1318-23, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11179079

ABSTRACT

Sympathetic hyperactivity and hypertension caused by chronic treatment with ouabain or sodium-rich artificial cerebrospinal fluid (aCSF) can be prevented by central administration of an angiotensin type 1 (AT(1)) receptor blocker. In the present study, we assessed whether, in Wistar rats, chronic peripheral treatment with the AT(1) receptor blockers losartan and embusartan can exert sufficient central effects to prevent these central effects of ouabain and sodium. Losartan or embusartan (both at 100 mg x kg(-1) x day(-1)) were given subcutaneously once daily. Ouabain (50 microg/day) was infused subcutaneously, and sodium-rich aCSF (1.2 M Na(+), 5 microl/h) was infused intracerebroventricularly, both by osmotic minipump for 13-14 days. The mean arterial pressure (MAP) at rest and in response to air stress and intracerebroventricularly injection of guanabenz (75 microg/7.5 microl), ANG II (30 ng/3 microl), and ouabain (0.5 microg/2 microl) were then measured. In control rats, chronic treatment with ouabain subcutaneously and hypertonic saline intracerebroventricularly both increased baseline MAP by 20-25 mmHg and enhanced twofold the pressor responses to air stress and depressor responses to the alpha(2)-adrenoceptor agonist guanabenz. Simultaneous treatment with losartan or embusartan fully prevented hypertension, maintained normal responses to air stress and guanabenz, and attenuated pressor responses to acute intracerebroventricular injection of ANG II and ouabain. We concluded that peripheral administration of losartan as well as embusartan can cause sufficient central effects to prevent the sympathetic hyperactivity and hypertension induced by chronic peripheral ouabain and central sodium.


Subject(s)
Angiotensin Receptor Antagonists , Cardiotonic Agents/pharmacology , Hypertension/physiopathology , Ouabain/pharmacology , Sympathetic Nervous System/physiopathology , Air Movements , Angiotensin II/pharmacology , Animals , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Chronic Disease , Guanabenz/pharmacology , Heart Rate/drug effects , Hypertension/chemically induced , Hypertension/drug therapy , Injections, Intraventricular , Losartan/pharmacology , Male , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Saline Solution, Hypertonic/pharmacology , Stress, Physiological/physiopathology , Sympathetic Nervous System/drug effects , Vasoconstrictor Agents/pharmacology
17.
J Hypertens ; 19(1): 89-98, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11204309

ABSTRACT

OBJECTIVES: To assess changes in the activity of the brain renin-angiotensin system during (i) the development of salt-sensitive hypertension; and (ii) the prevention of salt-sensitive hypertension by blocking brain 'ouabain'. METHODS: In protocol I, angiotensin converting enzyme (ACE) mRNA and activity and angiotensin I and II levels were assessed in the hypothalamus and pons of Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on regular (120 micromol Na+ per g) or high (1370 micromol Na+ per g) salt diet from 4-6 weeks or 4-9 weeks of age. In protocol II, ACE mRNA and activity were assessed in the hypothalamus and pons in Dahl S on regular or high salt treated with intracerebroventricular (i.c.v.) Fab fragments blocking brain 'ouabain' or gamma-globulins, and in Dahl R on high or regular salt ACE mRNA was assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay and angiotensin I and II by radioimmunoassay after high-performance liquid chromatography. In protocol III, effects of i.c.v. angiotensin I and i.c.v. bradykinin on renal sympathetic nerve activity (RSNA), heart rate and blood pressure before and after i.c.v. captopril were assessed in Dahl S and R rats on regular or high salt intake from 4-8 weeks of age. RESULTS: High salt diet caused a gradual, but marked increase in blood pressure in Dahl S but not Dahl R rats. Dahl S rats showed small but significant increases in ACE mRNA in the hypothalamus on regular salt diet. In Dahl S rats on high salt diet for 2 or 5 weeks ACE mRNA levels significantly increased in both hypothalamus and pons, compared with Dahl R rats on either diet or Dahl S rats on regular diet. After 5 weeks of high salt diet, ACE mRNA levels in the hypothalamus in Dahl S rats were almost three-fold higher and in the pons two-fold higher than in Dahl R rats on either diet or Dahl S on regular salt diet. High salt diet also increased ACE activity of the hypothalamus and pons in Dahl S but not Dahl R. Consistent with this increased ACE activity, central responses to angiotensin I were clearly enhanced and to bradykinin markedly diminished in Dahl S on high salt intake. Chronic blockade of brain 'ouabain' by i.c.v. Fab fragments prevented the increases in blood pressure, ACE mRNA and activity in the hypothalamus and pons by high salt intake in Dahl S rats. Angiotensin I levels in the hypothalamus and pons were similar in both groups of rats and there were no significant changes caused by high salt diet in Dahl S and R rats. On regular salt intake angiotensin II levels in the hypothalamus of Dahl S rats showed a significant decrease as compared with Dahl R rats on regular salt diet, and were similar in the pons of the two strains. High salt intake did not affect angiotensin II levels in either hypothalamus or pons in Dahl S and R rats. CONCLUSIONS: These results indicate that high salt intake increases blood pressure, ACE expression and activity in the hypothalamus and pons of Dahl S rats without a parallel increase in angiotensin II levels. Effects of high salt intake on ACE mRNA and activity appear to be secondary to activation of brain 'ouabain'.


Subject(s)
Angiotensin II/metabolism , Angiotensin I/metabolism , Brain/metabolism , Hypertension/metabolism , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , Sodium, Dietary/toxicity , Angiotensin I/administration & dosage , Angiotensin I/genetics , Angiotensin II/genetics , Animals , Bradykinin/administration & dosage , Brain/drug effects , Chromatography, High Pressure Liquid , Enzyme Inhibitors/administration & dosage , Hypertension/chemically induced , Immunoglobulin Fab Fragments/administration & dosage , Injections, Intraventricular , Male , Ouabain/administration & dosage , Peptidyl-Dipeptidase A/genetics , RNA, Messenger/analysis , Radioimmunoassay , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Fluorescence
18.
J Cardiovasc Pharmacol ; 36(6): 704-10, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11117369

ABSTRACT

Short-term (by hour) intracerebroventricular (i.c.v.) or i.v. infusion of nifedipine at low rates evokes parallel decreases in renal sympathetic nerve activity (RSNA) and blood pressure (BP) in spontaneously hypertensive rats (SHR). In the present study, effects of long-term administration of nifedipine on BP and control of sympathetic tone were examined in SHR on a high-salt (8%) diet. From 6 to 8 weeks of age, for 2 weeks concomitant with taking a high-salt diet, rats were also treated with subcutaneous infusion of nifedipine at 10, 50, or 100 microg/kg/h or vehicle solvent as control using osmotic minipumps. At the end of the 2-week treatment period, mean arterial pressure (MAP), heart rate (HR), and RSNA at rest and in response to air-jet stress, i.c.v. injection of the alpha-adrenoceptor agonist guanabenz (25 microg), and i.v. injection of the ganglionic blocker hexamethonium were recorded in conscious rats. In rats on nifedipine 50 or 100 microg/kg/h, resting MAP was significantly lower (136+/-4 or 130+/-4 vs. 145+/-2 mm Hg in control rats, p < 0.05 for both), the sympathoinhibitory and depressor responses to i.c.v. guanabenz were significantly decreased, and the absolute decreases in MAP in response to i.v. injection of hexamethonium were significantly smaller. Sympathoexcitatory and pressor responses to air-jet stress, however, were not affected by nifedipine. Infusion of nifedipine at the three rates for 2 weeks caused concentrations of plasma nifedipine in a dose-related manner. Nifedipine was not detected in tissues of rats treated with 10 microg/kg/h nifedipine but was present in brain and other tissues of rats treated with nifedipine at the two higher rates. Thus in SHR on high-salt intake long-term treatment with nifedipine at 50 or 100 microg/kg/h decreased resting BP and the sympathetic component in BP control. In addition to possible peripheral effects, long-term administration of nifedipine may also act centrally to decrease sympathetic activity and BP, likely by increasing activity in central pathways involving sympathoinhibition, but not in pathways involving sympathoexcitation as evaluated by air-stress.


Subject(s)
Antihypertensive Agents/pharmacology , Nifedipine/pharmacology , Sodium Chloride, Dietary/pharmacology , Sympatholytics/pharmacology , Animals , Blood Pressure/drug effects , Guanabenz/pharmacology , Heart Rate/drug effects , Hexamethonium/pharmacology , Infusions, Intravenous , Injections, Intraventricular , Kidney/drug effects , Kidney/innervation , Male , Nicotinic Antagonists/pharmacology , Nifedipine/pharmacokinetics , Rats , Rats, Inbred SHR
19.
J Hypertens ; 18(9): 1319-26, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10994763

ABSTRACT

OBJECTIVE: On high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin-angiotensin system (RAS). METHODS: Cardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 micromol/g food) or regular salt (120 micromol/g food) diet for 2-5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension. RESULTS: In Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4-5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet Chronic intra-cerebroventricular treatment with Fab fragments blocking brain 'ouabain' prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II. CONCLUSIONS: These data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.


Subject(s)
Cardiomegaly/physiopathology , Myocardium/enzymology , Renin-Angiotensin System/physiology , Sodium, Dietary/pharmacology , Angiotensin I/blood , Angiotensin II/blood , Animals , Blood Pressure , Brain Chemistry/immunology , Cardiomegaly/chemically induced , Cardiomegaly/pathology , Gene Expression/physiology , Heart Ventricles/enzymology , Heart Ventricles/pathology , Immunoglobulin Fab Fragments/pharmacology , Male , Myocardium/pathology , Organ Size , Ouabain/immunology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/analysis , Rats , Rats, Inbred Dahl , Renin/blood , Sympathetic Nervous System/physiology
20.
Brain Res ; 876(1-2): 17-21, 2000 Sep 08.
Article in English | MEDLINE | ID: mdl-10973588

ABSTRACT

In normotensive Wistar rats, systemic administration of exogenous ouabain for 10 days or more induces hypertension, presumably through central mechanisms. To identify which neuronal populations may be involved, we assessed Fos-like immunoreactivity (FLI) using an antibody that recognizes the protein products of the fos family comprising Fos, Fos B, Fra 1 and Fra 2, thus enabling detection of chronic neuronal activation. Young Wistar rats received s.c. infusions of either ouabain (50 microg/day) or saline for 7 or 14 days. At the end of the experimental period, mean arterial pressure (MAP) was assessed. In a separate set of rats FLI was detected immunohistochemically and quantified in cardiovascular and osmo-regulating centers. Resting MAP in ouabain-treated rats was significantly higher than in control rats at 14 but not at 7 days (125+/-4 vs. 101+/-6, P<0.05 and 102+/-4 vs. 98+/-6 (not significant), respectively). Within the supraoptic nucleus, ouabain induced significant increases in FLI compared with control rats at 14 days (9+/-2 vs. 2+/-2, P<0.05) but not at 7 days. Within the locus ceruleus, FLI was only detectable in rats that received ouabain infusions for 14 days but not in other groups of rats. Ouabain treatment did not induce significant changes in FLI within other areas. These results demonstrate that chronic s.c. ouabain infusion only increases neuronal FLI in the supraoptic nucleus and locus ceruleus where increases in FLI parallel the increase in blood pressure.


Subject(s)
Hypertension/chemically induced , Hypertension/metabolism , Neurons/metabolism , Ouabain , Proto-Oncogene Proteins c-fos/metabolism , Animals , Blood Pressure/drug effects , Hypertension/physiopathology , Immunohistochemistry , Injections, Subcutaneous , Locus Coeruleus/metabolism , Male , Ouabain/pharmacology , Rats , Rats, Wistar , Reference Values , Supraoptic Nucleus/metabolism
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