Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the AT1 receptor which can be blocked by losartan and its analogues (the 'sartan family'), and the AT2 receptor that does not react with the above antagonists but which can be blocked by different compounds, such as PD123319. AT1 receptor blockade has proven to be a highly effective means of interference with the renin-angiotensin system (RAS) and hence of reducing high blood pressure. As a result of the terminal blockade of the RAS cascade, circulating Ang II levels tend to rise two- to threefold. The free access of such enhanced levels to uninhibited AT2 receptors may be clinically relevant, as argued in the present review. The most extensive experimental and clinical experience with AT1 receptor blockade so far has been obtained with the pioneer drug losartan, although major contributions have also been made on candesartan cilexetil, irbesartan and valsartan. All of these four drugs have been instrumental in substantial clinical trials, serving as sources of information in the clinically oriented part of this review. AT1 receptor blocking drugs generally provide a relatively gradual decrease in blood pressure, which is comparable to that obtained with conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack of drug-related adverse effects, scoring even better than placebo in terms of frequencies and sometimes patterns. The trough/peak ratio on single dosages seems to have been mastered, particularly with the second generation of AT1 receptor blockers, as is evident from 24 h ambulatory blood pressure monitoring. Combination with low-dose thiazide regimens is well established. Intermediate endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be controllable. Morbid cardiovascular sequelae are currently under study in comparison with beta- and calcium channel blockade.
The role of fluid overload in the pathogenesis of hypertension in hemodialysis patients is not clear. One problem is the lack of techniques to determine the fluid state. Recent new noninvasive techniques have become available which make it possible to accurately determine the dry weight in these patients. Therefore, we studied the influence of interdialytic weight gain on interdialytic blood pressure in 10 normotensive and 10 hypertensive hemodialysis patients without antihypertensive medication. The dry weight was determined with echography of the vena cava. The blood pressure was measured during 2-day and 3-day interdialytic periods using Spacelabs 90207 ambulatory blood pressure monitors. Mean systolic and diastolic blood pressures of the last day of the interdialytic period were compared with mean systolic and diastolic blood pressures of the 1st day of the interdialytic period. Although the interdialytic weight gain in the normotensive and hypertensive patients was greater during the 3-day than during the 2-day interdialytic period, the interdialytic systolic and diastolic blood pressure changes were not greater during the 3-day period. Also, the interdialytic blood pressure rise did not correlate significantly with weight gain, neither in the normotensive nor in hypertensive patients. No significant interdialytic blood pressure changes were found between the normotensive and the hypertensive patients. We conclude that fluid overload does not seem to play a major role in interdialytic blood pressure control in normotensive and hypertensive hemodialysis patients.
The analysis of low-frequency fluctuations in the carotid artery diameter demonstrates that aging as well as hypertension are associated with impaired neural control of the baroreflex. Beyond 50 years of age the effect of hypertension cannot be distinguished from the effect of aging.
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