Advance therapy in hypertension... jyoti..ppt

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Advance therapy in hypertension... jyoti..ppt

  1. 1. BY : JYOTI B. SHARMA GUIDE : Mr. IMTIYAZ ANSARI ORIENTAL COLLEGE OF PHARMACY
  2. 2. Sr. No. 1 2 3 4 5 6 7 8 9 CONTENTS Introduction Effect of hypertension on our body Mechanism of hypertension Causes of resistant hypertension Classification of Oral Anti-hypertensive Agents Investigations and New therapies in hypertension Invasion therapy Cow urine therapy Reference
  3. 3. How to remain without tension ?
  4. 4. WHAT IS HYPERTENSION ?
  5. 5. • Hypertension is generally defined as mild when the diastolic pressure is between 90 to 104 mmHg, moderate when it is 105 to 114 mmHg and severe when it is above 115 mmHg. • Hypertension can be divided into two major divisions: a) Primary or essential hypertension: where definite cause for the rise in BP is unknown but sympathetic and renin-angiotensin system may overactive and do contribute to the tone of blood vessels and cardiac output in hypertension. b) Secondary hypertension: secondary to renal (chronic diffuse glomerulonephritis, pyelonephrities, polycystic kidneys); endocrine (Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism); and vascular (renal artery disease, pulmonary artery disease, coarctation of aorta) lesion.
  6. 6. • ADOLESCENT • CHILDHOOD • INFANT 100 / 75 mmHg 85 / 55 mmHg 70 / 45 mmHg • Systolic Hypertension is marker of Macro-Vascular Disease large Arterial stiffening. (atherosclerosis ) • Diastolic Hypertension is consequence of Micro-Vascular Disease involving arterioles of < 1mm size (arteriosclerosis ) • As per Joint National Committee for Detection, Evaluation and Treatment of high BP has defined ‘Normal BP’ as that below 120/80 mmHg and following:
  7. 7. Categories of hypertension Categories Systolic Diastolic High Normal 130-139 85-89 Stage 1 140-159 90-99 Stage 2 160-179 100-109 Stage 3 > 180 >110 ISH > 140 < 90 PPH (pulse pressure > 65 mmHg) Normal ration is 3:2:1 (systolic/diastolic/pulse pressure) HYPERTENSION
  8. 8. Effect of hypertension
  9. 9. Classification of Hypertensive crises. Hypertensive Urgency Introduction: • a rapid and severe elevation in BP in the absence of organ injury • Those experiencing hypertensive urgency may or may not experience one or more of these symptoms: • Severe headache • Shortness of breath • Nosebleeds • Severe anxiety • urgencies may be treated on an outpatient basis, by gradually reducing BP using oral antihypertensives Hypertensive Emergency Introduction: •a rapid and severe elevation in BP in the presence of target organ damage •The clinical presentation will depend on the particular organ that is undergoing injury, addition to other symptoms like Swelling or edema (fluid buildup in the tissues), severe chest pain, Severe headache, accompanied by confusion and blurred vision, nausea and vomiting, severe anxiety, shortness of breath, seizures & unresponsiveness • requires more immediate treatment with IV antihypertensives in an inpatient setting
  10. 10. Mechanism of hypertension • The kidney plays a crucial role in blood pressure regulation. It controls the excretion of salt and water from the body, which affects blood volume and blood pressure. The organ also communicates with the brain, which helps regulate blood pressure by narrowing blood vessels or increasing the pumping action of the heart • There are 3 main mechanism responsible for hypertension: 1. Renal mechanism, 2. Vascular mechanism and 3. Central mechanism.
  11. 11. Prehypertension Established hypertension KIDNEY HEART BRAIN Proteinuria Nephrosclerosis Left-ventricular hypertrophy Retinopathy Binswanger lesions Chronic Renal failure End- stage renal disease Systolic/ diastolic dysfunction Myocardial infarction Atrial fibrillation Ventricular arrhythmias Congestive heart failure Ventricular tachycardiaor Ventricular fibrillation 12 Dementia Transient ischemic attack Stroke
  12. 12. Renal mechanism    The renin-angiotensin system (RAS) or the renin-angiotensinaldosterone system (RAAS) is a hormone system that regulate blood pressure and water (fluid) balance. This system is synergistic with sympathetic nervous system, for e.g. by increasing the release of noradrenalin from sympathetic nerve terminals. It stimulates aldosterone secretion and control Na+ excretion and also control vascular tone.  Renin :  It is a proteolytic enzyme that is secreted by the juxtaglomerular apparatus, which is a part of nephrone in kidneys.  The secretion of renin is controlled by three pathways 1. Macula densa pathways 2. Intrarenal baroreceptor or pathways 3. B-adrenergic receptor pathways
  13. 13. INHIBITION OF RENIN-ANGIOTENSIN SYSTEM: 1. 2. 3. 4. 5. Sympathetic blockers (B-blockers, adrenergic neuron blockers, central sympatholytics )-decrease renin release. Renin inhibitory peptides and renin specific antibodies block renin action-interfere with generation of A-1 from angiotensinogen (rate limiting step) Angiotensin converting enzyme inhibitors-prevent generation of active principle A-2. Angiotensin receptor (AT1) antagonists-block the action of A-2 on target cells. Aldosterone antagonists- block mineralocorticoid receptor.
  14. 14. Nitric oxide synthase and Nitric oxide Serotonin transporter and Serotonin uptake Dysfunctional Kv channels Environmental factor Genetic Mutation Pulmonary vascular remodeling and vasoconstriction PAH Modifier Genes Endothelin Prostacyclin synthase and Prostacyclin ACE Angiotensin 2
  15. 15. Role of cholesterol in hypertension
  16. 16. Causes of resistant hypertension 1. Improper BP Measurement 2. Volume Overload and Pseudo-tolerance • Excess sodium intake • Volume retention from kidney disease 3. Drug-Induced cause hypertension • Non-adherence • Inadequate doses • Inappropriate combinations • Non-steroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors • Cocaine, amphetamines, other illicit drugs • Sympathomimetics (decongestants, anorectics) • Oral contraceptives
  17. 17. • • • • • Adrenal steroids Cyclosporine and tacrolimus Erythropoietin Liquorice (including some chewing tobacco) Selected over-the-counter dietary supplements and medicines(e.g., ephedra, ma hang, bitter orange) 4. Associated Conditions • Obesity • Excess alcohol intake 5. Identifiable Causes of Hypertension. • Chronic kidney disease • Primary aldosteronism • Renovascular disease • Chronic steroid therapy and Cushing’s syndrome • Pheochromocytoma • Coarctation of the aorta • Thyroid or parathyroid disease
  18. 18. Classification of Oral Anti-hypertensive Agents Class Drug Some Side Effects Thiazide diuretics Chlorothiazide , chlorthalidone, hydrochlorothiazide, polythiazide, indapamide, metolazone , metolazone. Decreased levels of potassium and magnesium, increased levels of calcium and uric acid, sexual dysfunction in men, and digestive upset Loop diuretics bumetanide furosemide torsemide Potassium-sparing diuretics amiloride triamterene Decreased levels of potassium and magnesium, temporarily increased levels of blood sugar and cholesterol, an increased level of uric acid, sexual dysfunction in men, and digestive upset With all, a high potassium level and digestive upset and menstrual irregularities in women
  19. 19. Aldosterone receptor blockers eplerenone spironolactone Dizziness, an increased potassium level, angioedema (rare), and, in pregnant women, serious injury to the fetus, With spironolactone, breast enlargement in men (gynecomastia) B-blockers (BBs) Atenolol, betaxolol, bisoprolol, metoprolol , metoprolol, nadolol , propranolol , propranolol, timolol . Spasm of the airways (bronchospasm), an abnormally slow heart rate (bradycardia), heart failure, possible masking of low blood sugar levels after insulin, injections impaired peripheral circulation, insomnia, fatigue, shortness of breath, depression, Raynaud syndrome, vivid dreams, hallucinations, and sexual dysfunction With some beta-blockers, an increased triglyceride level Combined alpha- and carvedilol BBs labetalol., etc Low blood pressure when the person stands and spasm of the airways Angitensinogin Converting Enzyme Inhibitor(ACEIs) Cough (in up to 20% of people), low blood pressure, an increased potassium level, rash, angioedema (allergic swelling that affects the face, lips, and windpipe and may interfere with breathing), and, in pregnant women, serious injury to the fetus Benazepril, captopril Enalapril, fosinopril Lisinopril, moexipril perindopril., quinapril Ramipril, Trandolapril
  20. 20. Angiotensin II antagonists Candesartan, eprosartan Irbesartan, losartan Olmesartan, telmisartan Valsartan. Calcium Channel Diltiazem , diltiazem Blockers (CCBs)— Verapamil. non-Dihydropyridines Headache, dizziness, flushing, fluid retention, problems in the heart's electrical conduction system (including heart block), an abnormally slow heart rate (bradycardia), heart failure, and enlarged gums. With verapamil, constipation CCBs— Dihydropyridines Amlodipine, felodipine Isradipine, Nicardipine Dizziness, fluid retention in the ankles, flushing, headache, heartburn, enlarged gums, and an abnormally fast heart rate (tachycardia). Vasodilators Hydralazine, Minoxidil, Diazoxide, Sodium nitroprusside.
  21. 21. Investigations and New therapies in hypertension
  22. 22. Sr. no. 1. Potential classes of new medications Novel approaches for treatment of hypertension a. b. Prostacyclin receptor agonists c. Endothelin Receptor Blockers d. Rho-kinase inhibitors e. Serotonin inhibitors f. Vasoactive intestinal peptide g. Adrenomedullin h. 2. Guanylate cyclase stimulators Endothelial nitric oxide synthase couplers Agents that target proliferation and apoptosis in the treatment of hypertension a. Tyrosine kinase inhibitor b. EGF receptor blockers 3. Drugs targeting the BMP/TGFβ pathway 4. Gene therapy for hypertension 5 Stem cells therapy for hypertension
  23. 23. Guanylate cyclase stimulators: • Riociguat has a dual mechanism of action: a) To stimulate sGC in an NOdependent and-independent mode of action and thereby to enhance cGMP synthesis, producing vasodilatation. b) Riociguat improved pulmonary hemodynamics and prevented adverse structural remodeling.
  24. 24. Phosphodiesterase-5 Inhibitors: a. Sildenafil: • PDE type 5 inhibitor • Reduce metabolism of cGMP • Metabolized by CYP3A4 and 2C9 substrate • Concentration increased by concurrent bosentan b. Tadalafil: • It is a longer acting PDE-5 inhibitor which is currently undergoing clinical trials and remains investigational as a therapeutic agent for patients with PAH.
  25. 25. Prostacyclin receptor agonists: • Epoprostenol:  Administered Intravenously.  It was first prostacyclin analog approved by the US FDA to treat hypertension.  It has rapid onset of action with very short half life. • Treprostinil:  Administered Subcutaneously.  It is a prostacyclin analog with a longer half life.
  26. 26. • Iloprost:  It is a synthetic prostanoid  Administered by inhalation through an adaptive aerosol device. • Beraprost:  Orally active prostanoids, not FDA approved, but currently used in Japan.  It has been shown to improve symptoms of hypertension. • Selexipag:  It is a first-in-class orally active prodrug.  It’s metabolized to the highly selective prostacyclin receptor agonist, which has a half-life of over six hours.  Selexipag exerts vasodilatory activity on both large and small pulmonary arterial branches.  These properties show greater vasodilatory activity than with beraprost and iloprost.
  27. 27. Endothelin Receptor Blockers: • Endothelin-1 which is the most potent vasoconstrictor ever isolated. • Various endothelin receptor blockers are available for therapy. a. Bosentan:  It is a non-selective endothelin antagonist blocking both ETA and ETB and was the first oral drug which was FDA approved for the treatment of PAH b. Sitaxsentan:  It is an ETA receptor selective antagonist which is administered as a once daily oral dose.  It is not FDA approved, but is currently in use in Europe and Canada.  It is not as hepatotoxic as bosentan
  28. 28. Rho-kinase inhibitors • Rho-kinase inactivates MLC phosphatase, leading to increased levels of phosphorylated MLC which causes vascular smooth muscle contraction. • Agents that inhibits phosphorylation of the myosin light chain (MLC) • Its activity is switched on when Rho-GTP binds to the kinase coiled-coil domain • Rho-kinase inhibitor are as follow: a) Azaindole-1: • Precursor for fasudil. b) Fasudil: • Administred by inhalation, to avoid systemic vasodilation.
  29. 29. Serotonin inhibitors • Serotonin promotes PASMC proliferation, PA vasoconstriction and local microthrombosis. • Inhibition of serotonin receptors or the serotonin transporter (SERT) has been shown to inhibit PAH. • There are currently six SSRIs prescribed are: • Citalopram • Escitalopram • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline
  30. 30. Vasoactive intestinal peptide (VIP): • The lack of gene for VIP spontaneously developed features of • • • • moderately severe iPAH. Administration of VIP to these animals had a beneficial therapeutic effect in PAH. Administered by inhalation of peptide. The patients having deficiency in the production of the peptide (for a variety of reasons), in those patient substitution of the hormone results in substantial improvement of hemodynamic parameters. Systemic dosing may be limited by reduced systemic vascular resistance.
  31. 31. Adrenomedullin (ADM) • ADM is a potent vasodilator peptide. • Its effects are mediated through cAMP and nitric oxide (NO) dependent mechanisms. • ADM gene-modified endothelial progenitor cells (EPCs) have been shown to incorporate into the lung tissue and attenuate PH. • Aerosolized ADM appears not to cause systemic vasodilatation. • Administration of ADM, either by intravenous or intratracheal routes, significantly decreases PA pressure and pulmonary vascular resistance in patients with PH.
  32. 32. eNOS couplers: • Endothelial dysfunction. • impaired production/bioavailability and downstream activity of NO. • eNOS is critical to maintain normal tone in the vasculature. • Two potential eNOS couplers are: a) Pteridine cofactor tetrahydrobiopterin (BH4) b) Cicletanine hydrochloride
  33. 33. • Pteridine cofactor tetrahydrobiopterin (BH4):  Function: eNOS activity and maintain endothelial function.  The pharmaceutical formulation of BH4 is sapropterin dihydrochloride, was studied as add-on to treatment with sildenafil and/or ERAs. • Cicletanine hydrochloride:  An antihypertensive with thiazide-like diuretic properties for the treatment of systemic hypertension.  The treatment of disorders associated with endothelial dysfunction.  Co-administered with any two-drug combination to improve in exercise tolerance, symptoms, or cardiopulmonary hemodynamics .  Used to decreases the production of peroxynitrite or decreases superoxide in treated patients.
  34. 34. Tyrosine kinases (TKs) inhibitors: • Tyrosine kinase inhibitors are therapeutic effects due to inhibition of cell growth-related kinases and attenuate vascular remodeling. • Concentration-dependently and completely reversed the contraction of hypertensive pulmonary arterial due to inhibition of nitric oxide synthase. • Tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their longterm beneficial effect against pulmonary hypertension. • Inhibitors are imatinib, sorafenib, and nilotinib.
  35. 35. • Imatinib:  Imatinib reversed serotonin-induced contractions.  Imatinib inhibited activation of myosin phosphatase which is produced by phosphorylation of myosin light chain phosphatase (Ca2+ desensitization).  Acute intravenous administration of imatinib reduced high right ventricular systolic pressure, with little effect on left ventricular systolic pressure and cardiac output. • Sorafenib  Sorafenib is a multi-kinase inhibitor  It relaxed the induced contraction with a wider spectrum of TK activity than imatinib and shown to attenuate pulmonary vascular remodeling and hemodynamic changes.  Sorafenib conferred increases in ejection fraction. • Nilotinib  The second-generation RTK inhibitor.  Nilotinib showed efficacy on hemodynamics and pulmonary vascular remodeling.
  36. 36. EGF receptor blockers • Activated serine elastases within the PA wall can directly activate EGF receptors, this lead to the auto-phosphorylation of the EGF receptor. • EGF receptor blockers inhibit EGF signaling might mimic inhibition of serine elastases which was shown to both, inhibit and reverse remodeling. • This is important because at the moment elastase inhibitors, it inhibits phosphorylation and activation of the EGF receptor, results in decrease PA pressure, reverse vascular remodeling, and improve survival in PH. • Similarly, the EGF receptor antagonist’s are :  Gefitinib,  Erlotinib and  Lapatinib.
  37. 37. Drugs targeting the BMP/TGFβ pathway: • BMPR2 is a receptor for the transforming growth factor-beta • • • • • (TGF-β) superfamily Mutations have been identified beneficial in increasing BMPR2 expression (by adenovirus) Mutations in BMPR2 has been identified in activin-like receptor kinase-1 (ALK-1) in PAH patients, as well as mutations in genes encoding the canonical downstream BMP signaling intermediaries, Smad 1 and 8. The lung endothelial targeting of BMPR2 expression specific mutations in the ligand-binding domain of BMPR2 are retained within the endoplasmic reticulum due to protein misfolding. Correction of misfolding offers the opportunity for intervention in these cases.
  38. 38.  the cells in the central core of plexiform lesions lack the expression of TGF-β receptor 2, TGF-β receptor 1 and their signaling Smad(s) 2,1, 3 and 4, including the phosphorylated Smad 1/5/8 and 2.  ???????????????????????????????????????????????????????? ???????????????????????????????????????????????????????? ????????????????????????????????????????????????
  39. 39. Gene Therapy Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although the technology is still in its infancy, it has been used with some success.
  40. 40. Goal of gene therapy in hypertension • Gene therapy aimed at nullifying the renninAngiotensin system is a speculation, through not in conceivable, approach to the semi-permanent or permanent treatment of hypertension. • In this regard, two approaches have been suggested: a) A mutant angiotensinogen gene strategy and b) An antisense strategy.
  41. 41. Genetic Studies: • Establish an international blood and tissue bank for PAH that will have wide access for genomic, proteomic, biomarker and histological studies. • Support sequencing of the complete BMPR2 gene in patients without known predisposing mutations and the search for other major genes causing heritable PPH. • Screen BMPR2 mutation :- positive families for genes that modify the penetrance of disease using genome; wide searches and new techniques of statistical genetics. • Support functional studies of likely candidate modifier genes (e.g., serotonin transporter, NOS synthase, VIP, many others). • Transgenic mice and transfected cells are important models for testing biological effects of altered genes and for therapies, and need further implementation.
  42. 42. Adenovirus • A recombinant adenovirus vector has been used to incorporate the p21 gene, which regulates cell cycle progression of pulmonary hypertension. • The p21 adenovirus vector was successfully transfected into the tissue, and the overexpression of p21 inhibited the development of PAH.
  43. 43. Adeno-Associated Viral • An adeno-associated viral (AAV) vector used to transfect human PGIS to determine the effect on PAH. • The AAV-PGIS was injected and significant pulmonary hypertension was observed that a smaller increase in RV systolic pressures, upregulation of brain natriuretic peptide levels in the RV • Decrease in pulmonary arterial wall thickening and prolonged survival.
  44. 44. Nonviral Gene Therapy • Nonviral approaches have been developed for gene transfer. • Naked gene-transfer of PGIS • Polyplex nanomicelles-used to deliver a therapeutic plasmid with the gene for human adrenomedullin, a vasodilator peptide. • Biocompatible micelle nanovectorsused for gene transfer
  45. 45. Tissue-Specific Gene Therapy
  46. 46. Stem Cell Therapy • Stem Cells are cells that can divide to replace indefinite cells. They can also give rise to daughter cells, called “progenitor” cells • This cell cannot self-renew and have a limited capacity to differentiate, produce mature cells of a single type. • Stem cells come from two main sources: a) Embryonic stem cells b) Adult stem cells c) Pluripotent stem cells
  47. 47. Invasive therapy: • Renal denervation:  Renal denervation may help to reduce high blood pressure in patients with so-called treatment-resistant disease.  Nerve signals from the brain to the kidney tend to increase blood pressure, in part by stimulating production of the enzyme renin, which initiates a cascade of hormones that directly and indirectly lead to narrowing of arteries and decreases in excretion of salt and water.  When the kidney can’t ―hear‖ the brain, blood pressure seems to fall. Thus the disruption of signaling to the kidney seems not to cause other problems
  48. 48. • Pulmonary Thrombentarterctomy:  It is a highly specialized surgery.  It considered as a treatment option in patients with CTEPH if they have surgically accessible disease.  Emboli in the pulmonary arteries can cause several problems. If enough of these arteries are blocked, the amount of oxygen delivered to the blood is decreased.  These blockages in the arteries in the lungs also make it harder for the right side of the heart to pump properly.  The pressure in the blood vessels in the lungs increases, resulting in pulmonary hypertension.  The purpose of a pulmonary thromboendarterectomy is to remove blood clots that are blocking the pulmonary arteries in order to allow the right side of the heart to work properly
  49. 49. • Atrial septostomy:  Creating an interatrial communication allows right to left shunting decompressing the right ventricle.  It has been shown to be of benefit in patients with refractory right heart failure. • Lung and combined heart lung transplant:  These have been used as treatment options for 30 years with long term outcomes being comparable with patients with other primary indications for the same surgery.  Hemodynamic studies, post-surgery, have shown improvement in pulmonary hemodynamics with reduction in pulmonary vascular resistance and improvement in right ventricular function.
  50. 50. Hypertension and Cow Urine Therapy:  Pharmacological Activities:  Cardiotonic : A tonic for heart, increases the efficiency of        contractions of the heart muscle. Anti-inflammatory: Reduces inflammation. Antioxidant: Capable of slowing down or preventing the oxidation of molecules, to protect body cells from the damaging effects of oxidation. Helps reduce stress Cardioprotective: Protects heart Suppresses fast rhythms of the heart. Anti hypertensive: Helps reduce hypertension Diuretic: Helps elevate the rate of urination.
  51. 51. • Cow urine is considered to have fat-lowering qualities. Apart • • • • • from this, it is also known to bring down the quantity of glucose and blood lipids in the blood. Cow urine is also known for its clot dissolving abilities and it also helps to smoothen the muscles of the blood vessels. Cow urine also gives strength to the heart and the brain. Cow urine has high antioxidant properties besides being prominently used for building up the immunity system of the body. All these qualities of cow urine are found to be quite useful in the treatment and remedy of hypertension symptoms. Cow urine therapy is also gaining popularity because it has the ability to cure many different ailments affecting our body and that too without any side effects.
  52. 52. Conclusion: • Hypertension is one of the most common chronic diseases worldwide. However, many people have hypertension without awareness and treatment of the disease, indicating it is necessary to provide some basic knowledge and essential information of hypertension to our audience, upper primary pupils at early stage of their life's to prepare them early in prevention or management of this disorder in their future life. • Many risk factors are related with hypertension. Avoiding the factors help to prevent hypertension, reduce symptoms and prolong lives. • Complications of hypertension are major sources of mortality. Reducing blood pressure with medication or keeping it within normal range will prevent, attenuates or reduce these complications. • The content (advance therapy) created in this seminar report will be important and useful resources for future education on hypertension.
  53. 53. REFERENCE: 1. 2. 3. 4. 5. 6. K.D. Tripathi. Essentials of Medical Pharmacology; six edition; 539-554. Sathoskar, Bhandarkar. Pharmacology and pharmacotherapeutics; 20th edition; 402-404 Article on hypertension crisis, MSPC Drug Information Center’s Online Refresher Course for Registered Pharmacist. http://www.mspcindia.org/DICORC Goodmann and Gilman’s pharmacological basis of therapeutics, Edited by Laurence Brunton, Bruce Chadner and Bjorn Knollman, McGraw Hill. 894, 909. Rang and Dale’s pharmacology—Elsevier Churchill Livingston; Borkowski KR, Quinn P. Adrenaline and the development of spontaneous hypertension in rats. Journal of Autonomic Pharmacology. 1985; 5(2):89–100.
  54. 54. 7. Cabassi A, Vinci S, Calzolari M, Bruschi G, Borghetti A. Regional sympathetic activity in pre-hypertensive phase of spontaneously hypertensive rats. Life Sciences.1998; 62(12):1111–1118. 8. Huang BS, Ahmadi S, Ahmad M, White RA, Leenen FHH. Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-―ouabain‖ pathway. American Journal of Physiology. 2010; 299(2):H422–H430. 9. Xue B, Beltz TG, Yu Y, et al. Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension. American Journal of Physiology.2011; 300(2):H555– H564. 10. Minami J, Ishimitsu T, Matsuoka H. Is there overlap in blood-pressure response to the blockers of the renin-angiotensin system between lower and higher renin subjects?American Journal of Hypertension. 2008; 21(2):130–131. 12. Hirose S, Ohsawa T, Inagami T, Murakami K. Brain renin from bovine anterior pituitary: isolation and properties. The Journal of Biological Chemistry.1982; 257(11):6316–6321. 13. Tada M, Fukamizu A, Seo MS, Takahashi S, Murakami K. Renin expression in the kidney and brain is reciprocally controlled by captopril. Biochemical and Biophysical Research Communications. 1989; 159(3):1065–1071.

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