Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.
Nitric oxide (NO), a multifunctional effector molecule that plays a central role in the maintenance of vascular homeostasis, regulates vascular tone and inhibits platelet and leukocyte adhesion to endothelial cells. NO status is related to the endothelial function. Patients with hypertension have lower levels of NO, increased free radical production, higher oxidative stress, augmented platelet aggregation, and a change in the arachidonic acid cascade metabolism, all leading to the acceleration of the atherosclerotic process. The study subjects included a group of 21 normotensive healthy subjects (8 males and 13 females) with a mean age of 39.2 +/- 1.8 years and a body mass index of 27.9 kg/m, and another group of 42 patients (19 males and 23 females) with untreated essential hypertension with a mean age of 47.6 +/- 1.7 years and a body mass index of 28.3 kg/m. Serum levels and urinary excretion of NO determined as combined nitrate/nitrite (NOx) and serum malondialdehyde (MDA) concentrations were measured in the 2 groups of subjects. The serum levels and 24-hour urinary excretion of NOx were significantly higher and the renal clearance of NO was lower in the normotensive group than in the hypertensive patients, indicating decreased NO status in hypertension. There was a negative correlation between serum NO levels and mean arterial pressure, suggesting that a decrease in NO availability is related to increase in blood pressure. Serum concentrations of MDA were higher in the hypertensive patients as compared with the normotensive individuals, suggesting increased oxidative stress in hypertensive patients. These results are in agreement with previous studies showing decreased NO and increased oxidative stress in hypertension. In conclusion, patients with essential hypertension as compared with normotensive individuals have lower NO status, which may contribute to the endothelial dysfunction in hypertension. Increased serum malondialdehyde in hypertensives suggests an association between increased oxidative stress with higher blood pressure.
Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT 1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT 2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT 1 and AT 2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT 2 receptor mediated the vasodepressor response to footshocks in the presence
The aim of this study was to evaluate the fibrinolytic system by measurement of fibrinogen, plasminogen, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in healthy normotensive subjects and in patients with essential hypertension. A group of 21 healthy normotensive subjects [age, 39.2 +/- 1.8 years; 8 males, 13 females; body mass index (BMI) = 27.9 kg/m] and 42 patients with untreated essential hypertension (age, 47.6 +/- 1.7 years; 19 males, 23 females; BMI = 28.3 kg/m) were studied. Blood samples and clinical measurement were taken between 7 am and 9 am by an observer in a blind fashion. The systolic/diastolic blood pressure of normotensive subjects was 121.3 +/- 2.5/78.4 +/- 1.3 mm Hg and that of hypertensive patients was 166.4 +/- 4.3/102.9 +/- 1.83 mm Hg, measured in the sitting position. Plasma fibrinogen levels in the normotensive and hypertensive individuals were 295.7 +/- 9.4 mg/dL and 305.67 +/- 10.9 mg/dL, respectively (P = 0.456). The corresponding values for plasminogen were 71.4 +/- 3.8% and 89.5 +/- 2.5%, (P = 0.0031), for t-PA were 6.3 +/- 0.5 ng/mL and 7.6 +/- 0.4 ng/mL (P = 0.0487), and for PAI-1 were 46.9 +/- 5.1 ng/mL and 63.0 +/- 5.6 ng/mL (P = 0.0324), respectively. In conclusion, patients with essential hypertension have disequilibrium in the fibrinolytic system with a tendency toward a hypercoagulability state when compared with normotensive subjects. This state could explain, in part, the thrombotic complications that occur with a higher frequency in hypertensive patients as compared with normotensive subjects.
The present study was carried out to assess whether endogenous angiotensin II (Ang II) supports sympathetically mediated cardiovascular response to stress in conscious unrestrained rats, using experimental models in which the renin-angiotensin-system was reduced or blocked. Footshock-stress increased mean arterial pressure (MAP) and heart rate (HR). Inhibition of angiotensin-converting enzyme with captopril or blockade of AT 1 angiotensin receptor with losartan, attenuated vasopressor responses to footshocks, while heart rate response was not altered. Bilateral nephrectomy suppressed vasopressor response as well the elevation of
The objective of this study was to investigate the effects of losartan (100 mg) plus hydrochlorothiazide (HCTZ; 25 mg) on nitric oxide (NO) production and blood pressure (BP) in "nondipper" severe hypertensive patients. Twelve hypertensive "nondipper patients" (6 of each gender) with sitting systolic/diastolic BP of 188.0 +/- 5.2/116.2 +/- 1.2 mm Hg were studied by 24-hour ambulatory blood pressure monitoring (ABPM) after daily administration of 100 mg losartan plus 25 mg HCTZ for a period of 12 weeks. Office and mean 24-hour, as well as mean awake- and sleep-time systolic/diastolic BP, serum NO levels, and urinary excretion of NO were measured after the placebo period (3 weeks) and after 12 weeks of therapy. At the end of the 12-week treatment period, the mean 24-hour systolic/diastolic BP decreased significantly from 158.6 +/- 4.7/102.2 +/- 2.6 mm Hg (placebo period) to 140.3 +/- 4.8/90.9 +/- 3.3 mm Hg (P = 0.001/< or = 0.002). The mean BP (systolic/diastolic) during the waking period was reduced from 159.3 +/- 4.4/103.0 +/- 2.5 mm Hg to 135.0 +/- 4.4/88.2 +/- 3.1 (P < or = 0.007/P < or = 0.002), whereas the mean BP (systolic/diastolic) during the sleeping hours changed from 154.9 +/- 5.3/98.9 +/- 3.1 to 140.9 +/- 4.6 (P = 0.035)/91.7 +/- 3.2 mm Hg (P = 0.035/P = 0.051). Serum NO levels increased from 40.89 +/- 5.69 microM/L (placebo period) to 67.35 +/- 6.96 microM/L (posttreatment; P < or = 0.007), whereas the 24-hour urinary NO excretion did not change significantly (69.71 +/- 3.68 microM/L [placebo period] vs 79.64 +/- 4.25 microM/L [posttreatment]; P < or = 0.16). Urinary clearance of NO also did not change. Serum NO levels increased significantly without a significant change in urinary NO excretion. BP was significantly reduced but without modifying the nondipper pattern in these patients.
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