Pathophysiology and Treatment of Essential Hypertension

Posted on November 21, 2008
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Hypertension, usually defined as a chronic elevation of systolic and diastolic blood pressure, and is one of the most common chronic diseases that afflict humanity. Hypertension can be mild, moderate or severe (grade 1, 2, 3) or systolic hypertension, according to the figures for blood pressure determined by a mercury manometer preferably (anaeroides pressure gauges or automatic, must be controlled with a mercury manometer every six months.

CLASSIFICATION OF HYPERTENSION:
According to WHO and the International Society of Hypertension Blood pressure levels may be optimal when the systolic blood pressure (PS) is <120 mmHg and diastolic pressure <80 mmHg (Guidelines for the Diagnosis and Treatment of the British Hypertension Society , 2004). These values are based on the determination of blood pressure in clinics rather than in ambulatory conditions. For the ambulatory condition, the controlled pressure values during 24 hours is greater than 125/80 mmHg.

The pressure is normal when the PS is <130 and the PD <85 mmHg.
Hypertension:
Mild grade 1: When the values of diastolic pressure is between 90 to 99 mmHg and systolic pressure values between 140 to 159 mmHg
Grade 2 or moderately When diastolic pressure values are above 100 to 109 mmHg systolic and 160 mmHg to 169.
Grade 3 or severe when the diastolic pressure values are> / – 110 mmHg systolic and> / -180 mmHg
Isolated Systolic Hypertension
Grade 1, PS 140 to 159 mmHg and Grade 2> 160 mmHg PD usually <90 mmHg

EPIDEMIOLOGY
All statistics agree that the values of blood pressure increase with age (above 50 years) in both sexes, preferably the pressure in part by a lack of prevention, when it occurs early in an inadequate diet (increased sodium intake) or by the lack of adequate treatment of cholesterol levels that lead to an increase in the rigidity of the arteriolar tree.

HISTORICAL BACKGROUND
Never was able to demonstrate that levels of plasma renin correlated with levels of blood pressure in essential hypertension.
Describe the polypeptide angiotensin I and II occurs at plasma glomerular without notice and that is synthesized at tissue (Nature, 1969, FEBS 1970) found that after synthesis in many tissues such as brain, endocrine glands, blood vessels , primarily in the immune system and cardiac tissue, which also synthesized in a continuous in-vitro was the organ containing the largest concentration of the polypeptide.
The removal of the last amino acid of the polypeptide chain C terminal, generates angiotensin 1-7.
Finally, in an article published in PNAS in 1972 found the first peptide, angiotensin II increased in the cerebrospinal fluid of patients with essential hypertension which is correlated with systemic hypertension.

FISIOPATOLOGI
Angiotensin II increases peripheral vascular resistance as triggers in the central nervous system areas (circumventriculares organ, vascular organ of lamina terminalis, nucleus supraóptico, hypothalamus, nucleus of the solitary tract, nucleus ambiguous, amygdala) that regulate blood pressure, heart rate, blood volume and extracellular sodium.
Angiotensin II acting at AT-1 receptor causes most of the pathophysiological changes within the cardiovascular system described in hypertension, these are:
1 .- increased peripheral resistance (vasoconstriction).
2 .-. -enlarged cardiac myocytes with hypertrophy and hyperplasia of interstitial fibrous.
3 .- Excess sodium reabsorption in the renal tubular level.
4 .- nefrina increase in a pro-inflammatory protein that is expressed in glomerular podocitos.
5.-increase in the recruitment of leukocytes (leukocyte activation in the migration)
6 .- serotonin release with the consequent formation of edema.
7.-release of interferon gamma.
8.-activation of the mononuclear phagocytic system with the release of TNF-alpha and pro-inflammatory cytokines such as IL-6 and IL-1, through the translocation of the nucleus NFk-B .-
9 activation of cyclooxygenase.
10 .- Activation of oxidative stress with increase of free radicals mediated by cytokines, amines, prostaglandins and endothelins.
11.-half the production of PDGF (platelet-derived factor) fibroesclerosis accelerating processes.
12 .- increase in extracellular matrix (interstitial fibrosis with fibroblastic proliferation) and cell apoptosis.
13 .- Increase of aldosterone secretion
14 .- interacts with the insulin receptor substrate (IRS-1)
15 .- Inhibition of PPAR gamma (a subfamily of intracellular receptors) that regulate the homeostasis of glucose and lipids are closely linked to the AT-1 receptor for angiotensin II
However, in the body there is a regulatory system that is opposed to these effects, such as angiotensin II receptor subtype AT-2 and atrial natriuretic peptide system.
When the AT-1 receptor is blocked, the angiotensin II and the rise and active metabolite 1-7 AT-2 receptor plays an important role in the remodeling and the antiproliferative effect on vascular and cardiac muscle.

One question that arises from what is published, if hypertension does not more, than an epiphenomenon of a chronic inflammatory disease, cardiovascular level? If this were the case, angiotensin II play a central role, which is produced in excess or the formation of the peptide is increased expression of the synthesis of AT-1 receptor with a critical decrease of AT-2 receptor which are responsible for disease. Both phenomena could survive.

ANGIOTENSINERGICO SYSTEM IMPACT ON CELL PHYSIOLOGY
Been established for over 30 years that the angiotensinogen molecule by limiting cell in the synthesis of tissue angiotensin II. Different proteases, in addition to producing renin-angiotensin II (chimasas, dolphins etc). And on the other receptor polypeptide that is found widely distributed externally on the plasma membrane and intracellular level in the endoplasmic reticulum (ER) and the nuclear membrane.
Since the activity of angiotensinérgico causes a change in the intracellular signaling mechanisms of insulin, particularly the nuclear factors involved in gene transcription, has been shown in experimental studies both in vitro and in-vivo that thiazolidinediones ( glitazones = ligand selective PPAR-gamma, a subfamily of intracellular receptors that regulate the homeostasis of blood pressure, and metabolism of glucose and lipids) to increase the activity of insulin sensitivity, have a common path with the system angiotensinergico and also have an anti-hypertensive and antiateroesclerótico.

DIAGNOSIS AND TREATMENT

The basis of treatment of hypertension is to prevent vascular stiffness, as well as vascular thrombotic events that the disease entails. In addition to myocardial hypertrophy prevalence of interstitial fibrosis, inflammatory lesions leads to renal glomerular and small vessels, particularly in the brain and retinal level.
Treatment of hypertension alone without considering other factors of risk is unacceptable, and determination in patients with high normal blood pressure (130-139/85-89) should be monitored more frequently.
Statins should be recommended for primary prevention of all patients with high blood pressure complicated by cardiovascular disease, regardless of the concentration of cholesterol or cholesterol levels linked to low density lipoproteins (LDL cholesterol). In patients with diabetes mellitus is advisable to initiate treatment of systolic blood pressure of> / – 140 mmHg or a diastolic pressure of> / – 90 mmHg. Always remember that proper treatment and causes a permanent regression of vascular lesions in the course, improving the quality of life.

General Measures:
Following the guidelines of the 1999 WHO / International Society of Hypertension should be implemented the following criteria:
1) Restriction of sodium, because it increases the expression of messenger RNA of tissue angiotensinogen, the precursor of angiotensin II and decreases the expression of messenger RNA of the AT-2 receptor subtype receptor angiotensinaII, which is an antagonist for all purposes harmful to the activation of AT-1 receptor;
2) You must inform the patient to avoid consumption of foods preserved with sodium nitrite and increasing consumption of potassium salts (salt without sodium);
3) Identify risk factors associated with hypertension, gout (hyperuricemia), hypercholesterolemia, diabetes and obesity. It is important that hypertensive refrain from smoking, because this is another risk factor that adds to other known;
4) initially there should be a clinical assessment (family) and having in mind the differential diagnosis such as drugs (anti-inflammatory steroids and non-steroidal inflammatory drugs (NSAIDs, except that it lacks LOXITENK effects on renal sodium retention) contraceptives steroids and sympathetic mimetics as pseudo ephedrine or phenylephrine, renal diseases (polycystic kidney, hydronephrosis or glomerular nephritis or reno-vascular disease) coarctation of aorta, pheochromocytoma, Cushing’s disease and Conn’s syndrome (hypokalemia, polyuria, muscle weakness ). Other factors that are overweight and environmental stress;
5) The methods for determining the target organs that could be affected during the development of hypertension to) cardiovascular hypertrophy (concentric or eccentric) and the wall by an ultrasonographic method of very high quality level of the heart and carotid arteries assessing left ventricular mass (VI should not exceed 125 g / m in men and 110 g / m in women) and b) determining the thickness of the index at the close of the carotid arteries (IMT). In kidney, an index of glomerular inflammation is the increase in microalbuminuria of 24 hours, and observe the changes of creatininemia.

Hypertension is one of the conditions treated poorly, even in developed countries such as England only 14% of patients achieved a year of treatment an adequate control of blood pressure.
Drug normotensores: We should warn the patient starts a drug treatment that the treatment must not be abandoned and if you have adverse reactions to carry out the consultation must be remembered that the treatments are for life and seek those who are more comfortable for the patient.

The ARBS may be useful as potent immunomodulatory agents, regardless of their current indications as drugs that act on the cardiovascular system.
The first choice in essential hypertension are blocking AT-1 receptor, whose standard is the result losartan Pathogenesis normotensores
Normalizes blood pressure, does not cause hypotension, or coughing, and dosage must be owner, according to the patient, ie 50 mg blocked 40% of AT-1 receptor and if uncontrolled blood pressure, according to the degree hypertension with a dose of 50mg every 12 hours will get more stable concentrations of the antagonist and a block of approximately 80% of AT-1 receptor and increased blood pressure control of cardiovascular hypertrophy, atherosclerosis and coronary and cerebral arterioloesclerosis .

Making losartan? :
In short blocking AT-1 receptor reverses or prevents most of the complications of the disease known as essential hypertension and inflammatory processes in other fibrotic diseases such as those caused by diabetes, glomerulonephritis, myocarditis, pulmonary fibrosis amiodarone.
Losartan, a blocker SPECIFIC RECEIVER AT-1 RESET MULTIPLE ALTERATIONS pathophysiological

BENEFITS OF THE COMBINATION OF THE LOSARTAN with atorvastatin treatment of hypertension and atherosclerosis
Among the acquired risk factors predisposing to atherosclerosis diseases are highly prevalent in the population such as hypertension, hypercholesterolemia and diabetes
= Reversible atherosclerosis disease characterized by an inflammatory process by deposition of cholesterol in the vascular intima followed by fibrosis and calcification, which can lead to arterial obstruction.
Although hypertension is usually treated with a blocker of the AT-1 receptor, such as losartan and hypercholesterolaemia with an inhibitor of cholesterol synthesis such as atorvastatin, the mechanisms of action of both drugs on the prevention of atherosclerosis are different .
Since hypertension and dyslipidemia often associated with an increase in insulin resistance, endothelial dysfunction associated with increased thickness of the intima (IMT, injury proaterogénica) the combined effects of LOSARTAN + atorvastatin, has a synergistic and administration is justified in protecting vascular of diabetes, hypertension and hypercholesterolemia, both reverse the inflammatory process even when arterial fibrosis and calcification is present.

 

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