Physiology and Pharmacology of Hypertension - Essay Example

? Physiology and Pharmacology of Hypertension Cardiovascular diseases are the most important cause of morbidity and mortality in the world responsible for more than third of global causes of death and hypertension has important role in developing cardiovascular diseases, ischemic disease of the heart and heart and kidney failure. According to WHO there are at least 970 million people in the world who suffer from high blood pressure and in the same time WHO recognizes the hypertension as the most significant factor for premature death world-wide. In the same time WHO is predicting that the problem is only growing and is estimating that until year 2025 there will 1.25 billion people who will suffer from hypertension (Kearney et al. 2005) (Mackay and Mensah 2004) (WHO 2002). It is found that treating hypertension had lead to 40 percents reduction of cerebral stroke and about 15 percents reduction of acute myocardial infarction (WHO 2002) (Colins et al. 1990). What is interesting data obtained globally in the world found that about 62 percents of cerebral insults and about 50 percents of ischemic heart morbidity can be attributed to sub-optimal regulated blood pressure (systolic pressure above 115 mmHg). This only means that blood pressure should be monitored more closely by trained and experienced physicians. However World health organization found that globally the ability to treat hypertension is variable with huge difference between the countries. In this survey conducted on 167 countries by the World health organization in 67 percents of them there was no national anti-hypertension program, physicians were not trained to manage hypertension in 45 percents of the countries, antihypertensive drugs were not available in 25 percents, basic equipment was not available in 8 percents etc. (Alwan et al. 2001). Hypertension is believed to be a disease of the modern society, but the prevalence of hypertension in developing countries, especially in the urban areas is now similar to the prevalence in western countries (Vorster 2002). This can be attributed to the modern day of life that is accepted in the developing countries because it is found that primitive people around the world have no hypertension and their blood pressure doesn’t elevate with age (Carvalho et al 1989). This is important because we can see that hypertension is a modifiable factor that is dependent on the lifestyle of the person and along with other modifiable factors like obesity, stress, sedentary lifestyle, smoking, alcohol intake, vitamin D deficiency and other factors. Hypertension however is the most important modifiable factor that can significantly influence the well being of the general population worldwide (Kyrou et al. 2006) (Wofford and Hall 2004). Hypertension is defined as elevated systolic or diastolic pressure above the normal reference values. Normal blood pressure is systolic blood pressure lower that 120 mmHg and diastolic pressure lower that 80 mmHg The systolic pressure is recognized as normal in population above age 50 if it is not greater than 140 mmHg and systolic not greater than 90 mmHg. (Chobanian et al. 2003). There are two main types of hypertension primary and secondary hypertension. Secondary hypertension is responsible for only 5 percents of the incidence of hypertension worldwide (Chiong et al 2008). It is a condition where the elevated blood pressure is a result of some other morbidity within the organism that is treatable or non treatable and is the primary factor for elevated blood pressure. It is very important to distinguish between these two types because the treatment is much different. Secondary hypertension can be caused by variety of condition like disease in endocrine system like Cushing’s disease where the adrenal glands produce excess cortisol (Dodt et al. 2009). Other condition that can lead to secondary hypertension is hyperthyroidism, where in order to treat the hypertension we will also need to treat the primary disease that is causing the elevated blood pressure (Geffner and Hershman 1992). Pheochromocitoma, coarctation of the aortha, hyperaldoseronism, polycystic kidney disease, acromgaly, brain tumor, cocaine usage, hyperparathireoidism and a number of other primary conditions can cause secondary hypertension. Characteristic of secondary hypertension is that the treatment of the primary condition will result in reducing of the hypertension. This is the main difference between primary and secondary hypertension (Chiong et al. 2008). Primary or essential hypertension on the other hand is responsible for 95 percents of all cases of hypertension (Carretero and Oparil 2000). Characteristic for primary hypertension is that the incidence of primary hypertension increases with age, and younger persons with relatively for age elevated blood pressure at younger ages are at increased risk of developing essential hypertension later in life. Essential hypertension is also a risk factor for other secondary complications like cerebro-vascular disease, cardiac events, renal diseases and other conditions (Franz et al. 2007). It is characteristic that the main cause for essential hypertension is not known. There are a lot of theories that try to explain the etiology of this condition, but almost all agree that modern way of life and habits are the most important factors contributing to essential hypertension. This is supported by the fact that essential hypertension is not present in primitive societies, as shown by some studies (Carvalho et al 1989). Essential hypertension is characterized by sustained elevated systolic blood pressure above 140 mmHg and diastolic blood pressure above 90 mmHg. Other characteristics of essential hypertension are: - Normal or elevated cardiac output or after-load early in the disease; - Increased cardiac work; - Reduced renal and skin blood flow, accelerated excretion of sodium by the kidney’s and other kidney abnormalities and in the same time normal blood flow to most other organ systems; - Reduced plasma volume; - Over-reactivity of the blood pressure to stress, abnormal vascular reactions on trigger factors (cold, heat, other factors), changed circulatory homeostasis etc. (Laragh et al. 1983). There are many suggested etiological factors that are found to predispose to developing essential hypertension. First mentioned is the genetic predisposition to essential hypertension. It is well known fact that family history of hypertension leads to susceptibility to essential hypertension in one individual. Many genes are recognized that are associated with increased susceptibility to hypertension (more than 50) and new genes are identified on a daily basis (Loscalzo el al. 2008). At least 10 genes are found to have direct effect on raising or lowering the blood pressure by increasing or decreasing the salt and water ressorption or excretion in the kidney’s (Lifton 1996). Examples of Mendellian inheritance where only one gene is responsible for genetically predisposed hypertension are rare, for example in Liddle’s syndrome, due to mutation of the epithelial sodium channel (ENaC) (Rossier and Schild 2008). More commonly inherited susceptibility to essential hypertension has multifactorial inheritance, where multiple genes have influence in increased susceptibility to hypertension. Genes that can lead to fenotype that can additionally lead to increased susceptibility to hypertension, genes responsible for obesity, diabetes mellitus, renal function changes etc. and other yet not recognized genes that may lead to increased susceptibility to essential hypertension in some patients (Kotchen et al. 2000). Excess sodium intake is another suspected etiological factor that is believed that is responsible to the development of essential hypertension. Excess intake of sodium can elevate the blood pressure with multiple mechanisms once the ability of the kidney’s to eliminate excess sodium are reached. Excess dietary sodium leads to increase in fluid volume in the blood circulation and therefore increased preload of the heart, which results in increased cardiac output or afterload. Local regulatory mechanisms in peripheral blood circulation then increase the vascular resistance in order to compensate for the increased circulation due to increased blood pressure, which causes even greater rise in blood pressure. Elevated concentrations of sodium on the other hand stimulate antidiuretic hormone and activates the reniin-angiotensin system that further leads to reabsorption of water and salt (Loscalzo el al. 2008). But excess sodium intake causes hypertension by other mechanisms also like affects the reactivity of the blood vessels, affects the normal renal function etc. (Campese et al. 1996) (Barba et al. 1996). The importance of excess sodium intake can be best seen on some studies on primitive people. It is found in a number of studies that primitive societies that have small salt intake don’t have hypertension and their blood pressure remains normal with age (Carvalho et al 1989) (Page et al. 1981). Now when these primitive people adopt modern day diet and they also manifest elevated blood pressure and increase hypertension incidence with increased age (Klag et al. 1995). Also experimental studies show that hypertensive patients when conducted on salt ingestion diet tend to significantly reduce their blood pressure (Cutler et al. 1991). A term called salt sensitivity is introduced in order to recognize the increased susceptibility to hypertension in some individuals with excess salt intake. Weinberger et al. 1986 found that hypertensive people react with higher blood pressures after a 1 day 10 mmol diet of salt compared to non-hypertensive people (51 percents compared to 21 percents). There are many other suggested reasons for this salt sensitivity (genetic, environmental etc) (Weinberger et al. 1986). Increased cardiac output as a cause of essential hypertension is found as a cause especially in younger adults. This increase of cardiac output in younger people is caused by increased contractibility of the heart by increased sympathetic stimulation. However this is believed that is only the first step in the evolution of essential hypertension because it is found that in developed essential hypertension increased peripheral resistance is accompanied by normal cardiac output (Cowley 1992). However this initial elevation of the blood pressure caused by overactive sympathetic system can further induce persistent elevation on the peripheral resistance by blood vessel thickening and remmodelation (Higashi et al. 1997). Abnormal activation of the rennin-angiotensin system is another factor that is found that may have influence in developing essential hypertension. This is very important mechanism of essential hypertension and essential hypertension is divided in 2 groups: rennin elevated and non-renin elevated essential hypertension. There are several mechanisms that may induce activation of the rennin-angiotensin system. Nephron heterogenicity is one hypothesis for increased activity of the rennin-angiotensin system in essential hypertension. Base on this theory there are ischemic nephrons along with hiperfiltering nephrons within the kidney and the ischemic nephrons are responsible for the excess rennin production (Sealey et al. 1988). Obesity is another important factor that may lead to increased susceptibility to essential hypertension. It is found that more that 85 percents of the cases of essential hypertension are present in persons with body mass index above 25 (Haslam and James 2005). It is found that obesity causes elevated blood pressure by a number of mechanisms, including activation of the sympathetic nervous system and activation of the rennin-angiotensin system (Rahmouni et al. 2005). Obesity is also closely related to insulin resistance which is another factor that may predispose to essential hypertension. It is a condition of elevated levels of insulin on the blood due to reduced sensibility to insulin in the tissues that are effector-organs for insulin (like muscles, liver etc). Adipose tissues in obese people raises the level of non-saturated fatty acids in the blood, alter the metabolism of the liver, lead to increased production of inflammatory cytokines, plasminogen activator factor – 1 and other active products that lead to a condition similar to chronic inflammation that can lead to elevated blood pressure. Insulin is responsible for regulating the metabolism of glucose in the body, but also can stimulate the sympathetic nervous system that can lead to elevated blood pressure (Grundy et al 2005). There are studies also that show that increased insulin level in insulin resistance leads to salt sensitivity also (Modan et al. 1985). There are other suggested hypotheses and possible factors that can predispose to essential hypertension, but as we mentioned above the exact cause of this condition is still unknown. Newer the less essential hypertension can be categorized in several groups based on it severity. Condition called prehypertension is a condition where is estimated that the person is at risk to develop hypertension further in his life. At this stage high blood pressure can still be treated with life style modifications and medicament al treatment is still not necessary (Shaw 2009). It is declared as measurement of systolic pressure between 120-139 mmHg and diastolic pressure between 80 and 89 mmHg (Chobanian et al. 2003). At this stage the elevated blood pressure can still be modified with life style changes and no medication treatment is still necessary. Life stage changes include: - weight loss and moderate aerobic exercises- it is found that regular, moderate exercises (like walking) improve the resting heart rate and lower blood pressure (Elley and Arroll 2002) - reducing dietary salt intake and adoption of diet rich in potassium (or usage of potassium chloride as a substitute for sodium chloride) because potassium helps eliminate excess sodium through the kidney’s (Klaus et al. 2009) - cessation of tobacco and alcohol consumption which are found that induce hypertension by yet not fully understood mechanisms, however it is found that tobacco and alcohol cessation significantly reduces the complications of hypertension like cerebrovascular insults and myocardial infarction (Groppeli et al. 1992). - additional dietary changes, like acceptance of the so called DASH diet (dietary approaches to stop hypertension), which is diet rich in fruits and vegetables that is low fat or saturated fat-free diet (Appel et al. 1997) . Reducing stress with some relaxation techniques (bio-feedback or progressive muscle relaxation or other techniques) or reducing the environmental triggers of stress (like high noise pollution, bad work lighting, bad work-relations etc.) is found that can significantly reduce hypertension (Nakao et al. 2003). - Other factors are also important like reducing dietary shugar, increasing omega 3 fatty acids intake and other factors. On the other hand prehypertension may progress to other more severe stages of hypertension that are classified as stage 1 where the systolic blood pressure is between 140-159 mmHg and diastolic blood pressure is between 90 and 99 mmHg and stage 2 where systolic pressure is above 160 mmHg and diastolic above 100 mmHg. These two stage of hypertension require medicamentation in order to regulate the blood pressure and reduce the incidences of complications. There are many antihypertensive drugs that are now available in order to treat elevated blood pressure. All of them can be divided in several groups based on their mechanism of action. They are thiazide diuretics, ACE inhibitors, calcium-channel blockers, beta adrenergic blockers, angiotensin II receptor antagonists, vasodilators etc. Thiazide diuretics lower blood pressure by inhibiting the reabsorbtion of sodium and chloride in the distal tubules of the kidney’s by blocking the activity of the Na+Cl- channels (Hughes 2004). They are recommended as first line drugs of choice in treating hypertension due to their positive effect on reducing the risk of death due to heart attack and heart failure or cerebral insult (Wright and Musini 2009). They are also the first choice of treatment because they are the cheapest antihypertensive drugs with smaller economical impact on the patients and the economy (Whitworth 2003). Angiotensing converting enzyme inhibitors (ACE inhibitors) are already the first drugs of choice in treating hypertension some developed countries like Australia (Guide to management of hypertension 2008). In the normal physiology of the kidney’s, drop of blood volume in the kidney’s results in production of rennin. Rennin than stimulates production of angiotensin I, that is then converted by the angiotenzin converting enzyme to angiotenzin II. Angiotensin II causes blood vasoconstriction and additionally stimulates secretion of aldosterone. ACE inhibitors manifest their antihypertensive activity by blocking the chain of events in the rennin-angiotensin system that is causing activation of aldosterone, that causes reabsorption of water and sodium and therefore increasing the blood pressure by increasing the preload of the heart (Ajayi et al. 1985). It is found that ACE inhibitors have additional positive effect against heart muscle remmodellation in hypertension and manifest cardio-protective effects (Krum et al 2004). Additionally they have reno-protective effect in patients with diabetes mellitus (Luno et al 2005). This is why ACE inhibitors are one of the most important drugs in treating hypertension. Also ACE inhibitors have additional synergistic effect on lowering blood pressure when they are used with thiazide diuretics (British National Formulary; 54th Edition (2007). Calcium channel blockers are a group of drugs that are used for treating hypertension and their antihypertensive effect is attributed to the blockage of the calcium channels in the heart muscle cells and blood vessels. The manifest their antihypertensive effect by decreasing the force of myocardial contraction (or negative inotropic effect), also the slow the rate of myocardial contraction (or they have negative chronotropic effect), and also in the blood vessels the cause relaxation of the smooth muscles and effect of vasodilatation and therefore they decrease the afterload of the heart. Calcium channel blockers are found to be the most effective antihypertensive treatment in older patients with essential hypertension due to their vasodilatatory effect (Nelson 2010). Beta adrenergic blockers are a group of drugs that decrease the effect of the sympathetic nervous system on the heart by diminishing the effect of epinephrine and other catecholamine’s (Frishman, Cheng and Nawarskas 2005). Catecholamine’s stimulate the Beta 1 receptors in the heart that produce increased heart rate (positive chronotropic effect) and increased heart force of contraction (inotropic effect). In the kidney’s beta 1 receptor stimulation produces release of rennin and activation of the rennin-angiotensin system (Perez 2006). The antihypertensive effect of beta-blocker is due to blockage of the effects of this stimulation and therefore reduction of the cardiac output with their negative chronotropic and inotropic effect and also reduction of the rennin secretion and activation of the rennin-angiotensin system. Therefore the main mode of action of these drugs is reducing the effect of stress and sympathetic activity on the heart (Frishman, Cheng and Nawarskas 2005). This is why beta-blockers are most effective in younger individuals where the hypertension is caused by overactive sympathetic nervous system due to stress and other factors (Frishman, Cheng and Nawarskas 2005). There are other antihypertensive drugs available like aldosterone antagonists, vasodilatators, centrally active adrenergic drugs and other that have different mechanisms of action but are used in some special cases when other drugs are ineffective. Combination of antihypertensive drugs is also used if a single drug therapy remains ineffective however the above mentioned drugs are the drugs that are most commonly used in treating hypertension (Nelson 2010). References: World health organization (2002), The world heath report 2002, Risks to health 2002. Genewa: World health organization. Colins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA (1990), Blood pressure, stroke and coronary heart disease, Part 2: Short term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lncet 1990; 335:827-838 Vorster HH (2002), The emergence of cardiovascular disease durring urbanisation of Africans, Public heath Nutr 2002; 5:239-243 Alwan A, Maclean D, Mandil A (2001), Assessnebt of national capacity for noncommunicable disease prevention and control, The report of a global survey 2001, WHO/MNC/. 01.2 Genewa: WHO 2001. Carvalho JJM, Baruzzi RG, Howard PF et al. Blood pressure in four remote populations in the Intersalt study. Hypertension 1989; 14: 238-4 Page LB, Vandevert DE, Nader K et al. Blood pressure of Qush’ qui pastoral nomads in Iran in relation to culture, diet and body form. Am J Clin Nutr 1981; 34: 527-38. PM Kearney, M Whelton, K Reynolds, P Muntner, PK Whelton, J He (2005), Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365:217-223 J Mackay, G Mensah (2004), Atlas of Heart Disease and Stroke. 2004 World Health Organization. Geneva Kyrou I, Chrousos GP, Tsigos C (November 2006). "Stress, visceral obesity, and metabolic complications". Annals of the New York Academy of Sciences 1083: 77–110. doi:10.1196/annals.1367.008. PMID 17148735. Wofford MR, Hall JE (2004). "Pathophysiology and treatment of obesity hypertension". Current Pharmaceutical Design 10 (29): 3621–37. doi:10.2174/1381612043382855. PMID 15579059. Shaw, Gina (2009). "Prehypertension: Early-stage High Blood Pressure". WebMD. Retrieved 2009-07-03. Chobanian AV, Bakris GL, Black HR, et al. (2003). "Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure". Hypertension 42 (6): 1206–52. doi:10.1161/01.HYP.0000107251.49515.c2. PMID 14656957. Elley CR, Arroll B (2002). "Review: aerobic exercise reduces systolic and diastolic blood pressure in adults". ACP J. Club 137 (3): 109. PMID 12418849. Klaus D, Bohm M, Halle M, et al. (May 2009). "[Restriction of salt intake in the whole population promises great long-term benefits]" (in German). Deutsche Medizinische Wochenschrift (1946) 134 Suppl 3: S108–18. doi:10.1055/s-0029-1222573. PMID 19418415. Groppeli A, Giorgi DM, Omboni S, Parati G, Mancia G. (1992). "Persistent blood pressure increase induced by heavy smoking". Journal of Human Hypertension 10 (5). Appel LJ, Moore TJ, Obarzanek E et al. (April 1997). "A clinical trial of the effects of dietary patterns on blood pressure". New England Journal of Medicine 336 (16): 1117–24. doi:10.1056/NEJM199704173361601. PMID 9099655. Nakao M, Yano E, Nomura S, Kuboki T (January 2003). "Blood pressure-lowering effects of biofeedback treatment in hypertension: a meta-analysis of randomized controlled trials". Hypertens. Res. 26 (1): 37–46. doi:10.1291/hypres.26.37. PMID 12661911. Dodt C, Wellhoner JP, Schutt M, Sayk F (January 2009). "[Glucocorticoids and hypertension]" (in German). Der Internist 50 (1): 36–41. doi:10.1007/s00108-008-2197-6. PMID 19096817. Geffner DL, Hershman JM (July 1992). "?-Adrenergic blockade for the treatment of hyperthyroidism". The American Journal of Medicine 93 (1): 61–8. doi:10.1016/0002-9343(92)90681-Z. PMID 1352658. Chiong JR, et al. Secondary hypertension: Current diagnosis and treatment. International Journal of Cardiology. 2008;124;6. Carretero OA, Oparil S (January 2000). "Essential hypertension. Part I: definition and etiology". Circulation 101 (3): 329–35. PMID 10645931. Retrieved 2009-06-05. Franz H Messerli, Bryan Williams and Eberhard Ritz (2007), Essential hypertension, The Lancet, Volume 370, Issue 9587, Pages 591 - 603, 18 August 2007, doi:10.1016/S0140-6736(07)61299-9 Laragh JH ,Niarchos AP, Sealey JE (1983), Arterial hypertension. In Stein JA (ed): Internal Medicine. Little, Brown, Boston, 1983; 19 Loscalzo, Joseph; Fauci, Anthony S.; Braunwald, Eugene; Dennis L. Kasper; Hauser, Stephen L; Longo, Dan L. (2008). Harrison's principles of internal medicine. McGraw-Hill Medical. ISBN 0-07-147691-1. Lifton RP. Molecular genetics of human blood pressure variation. Science 1996; 276: 676-80 Rossier, B. and Schild, L. Epithelial Sodium Channel: Mendelian Versus Essential Hypertension. Hypertension 2008;52;595-600 Kotchen TA, Kotchen JM, Grim CE, et al. (July 2000). "Genetic determinants of hypertension: identification of candidate phenotypes". Hypertension 36 (1): 7–13. PMID 10904005. Campese VM, Tawadrous M, Bigazzi R et al. Salt intake and plasma arterial natriuretic peptide and nitric oxide in hypertension. Hypertension 1996; 28: 335-40. Barba G, Cappuccio FP, Russ L et al. Renal function and blood pressure response to dietary salt restriction in normotensive men. Hypertension 1996; 27: 1160-4 Chiong JR, et al. Secondary hypertension: Current diagnosis and treatment. International Journal of Cardiology. 2008;124;6. Klag MJ, He J, Corsh J et al. The contribution of urinary cautions to the blood pressure differences associated with migration. Am J Epidemiol 1995; 142: 295-303 Cutler JA, Follmann D, Elliott P, Suh I. An overview of randomized trials of sodium reduction and blood pressure. Hypertension 1991; 17 (Suppl I): 127-31 Weinberger NH, Miller JZ et al. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 1986; 8 (Suppl II): II127-II134 Sealey JE, Blumenfeld JD, Bell GM et al. On the renal basis of essential hypertension : nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasocenstriction volume relation. J Hypertens 1988; 6: 763-77 Haslam DW, James WP (2005). "Obesity". Lancet 366 (9492): 1197–209. doi:10.1016/S0140-6736(05)67483-1. PMID 16198769. Rahmouni K, Correia ML, Haynes WG, Mark AL (January 2005). "Obesity-associated hypertension: new insights into mechanisms". Hypertension 45 (1): 9–14. doi:10.1161/01.HYP.0000151325.83008.b4. PMID 15583075. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. Oct 25 2005;112(17):2735-52. [Medline]. Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, Shitrit A, Fuchs Z. Hyperinsulinemia: a link between hypertension obesity and glucose intolerance. J Clin Invest. 1985;75:809–817 Hughes AD (2004). "How do thiazide and thiazide-like diuretics lower blood pressure?". J Renin Angiotensin Aldosterone Syst 5 (4): 155–60. doi:10.3317/jraas.2004.034. PMID 15803433. Wright JM, Musini VM (July 2009). "First-line drugs for hypertension". Cochrane Database Syst Rev 8 (3): CD001841. doi:10.1002/14651858.CD001841.pub2. PMID 19588327. Whitworth JA (2003), World Health Organization, International Society of Hypertension Writing Group (November 2003). "2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension". J Hypertens 21 (11): 1983–92. doi:10.1097/00004872-200311000-00002. PMID 14597836. Guide to management of hypertension 2008. National Heart Foundation Australia. 2008. accessed online at www.heartfoundation.org Ajayi, Adesuyi A.; Campbell, Brian C.; Howie, Catherine A.; Reid, John L. (1985). "Acute and Chronic Effects of the Converting Enzyme Inhibitors Enalapril and Lisinopril on Reflex Control of Heart Rate in Normotensive Man". Journal of Hypertension 3 (1): 47. doi:10.1097/00004872-198502000-00008. PMID 2987341. Krum; Carson, P; Farsang, C; Maggioni, AP; Glazer, RD; Aknay, N; Chiang, YT; Cohn, JN (2004). "Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT.". European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology 6 (7): 937–45. doi:10.1016/j.ejheart.2004.09.005. PMID 15556056. Luno; Praga, M; De Vinuesa, SG (2005). "The reno-protective effect of the dual blockade of the renin angiotensin system (RAS).". Current pharmaceutical design 11 (10): 1291–300. doi:10.2174/1381612053507413. PMID 15853685. British National Formulary; 54th Edition (2007) British Medical Association and Royal Pharmaceutical Society of Great Britain, London. Nelson Mark (2010), "Drug treatment of elevated blood pressure". Australian Prescriber (33): 108–112. Retrieved August 11, 2010. Frishman W.H.; Cheng-Lai A, Nawarskas J (2005). Current Cardiovascular Drugs. Current Science Group. pp. 152. ISBN 9781573402217. Retrieved 2010-09-07. Perez, Dianne M.] (2006). The Adrenergic Receptors In the 21st Century. Humana Press Inc.. p. 135. ISBN 1588294234. Retrieved 2010-09-08. Cowley AW (1992), Long term control of arterial blood pressure. Physiol Rev 1992; 72: 231-30 Higashi Y, Oshima T, Sasaki N (1997), Relationship between insulin resistance and endothelium dependent vascular relaxation in patients with essential hypertension. Hypertension 1997; 29: 280-5 Read More