Hypertension
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The Laragh Method for correcting BP
While there are many factors that influence blood pressure over the short term, body salt and plasma renin are the two prevailing forces that work together to determine long-term blood pressure levels and tissue blood flow. All antihypertensive drugs act either by reducing body salt-volume or by reducing/blocking plasma renin activity. Blood pressure is essentially regulated by: Volume (V): Salt content determines the amount of water in the body. High blood pressure can develop if the kidneys fail to excrete enough salt. Excess body salt results in increased in the concentration of sodium in extracellular water. In response the kidneys retain more water, thereby restoring the sodium concentration but at the same time increasing the extracellular fluid volume. This results in expansion of the arterial fluid volume and causes blood pressure to rise. This type of hypertension is called V hypertension because it is associated with an increase in body sodium-volume. Patients with V hypertension have low plasma renin activity (PRA) because the kidneys react to the increased arterial sodium-volume content and the higher blood pressure by suppressing renal renin secretion. Thus, a low PRA identifies this type of hypertension. Renin-angiotensin (R): Renin dependent hypertension is related to V hypertension. R hypertension develops when circulating renin levels (PRA) do not fall enough when the arterial sodium-volume expands. The reason renin secretion does not fall appropriately is because there are millions of sources of renin in the kidney. Normally the rate of secretion of renin produces just enough circulating angiotensin II to appropriately constrict blood vessels and maintain the perfusion pressure to each nephron. Renin dependent hypertension develops when a few nephrons become ischemic and then try to correct their under perfusion by increasing their secretion of renin. As plasma Ang II levels rise and hypertension develops the remaining normal nephrons become over-perfused and try to compensate by turning off their renin secretion, but to no avail. The PRA level becomes too high for the body sodium-volume content and arterial blood pressure rises. R hypertensive patients have medium to high plasma renin levels. The treatment of hypertensive patients would be easy if you could always correct high blood pressure by treating V patients with a natriuretic-diuretic drug and R patients with an anti-renin system drug (ACEI, ARB, beta blocker). In fact, successful treatment with monotherapy is achieved in large numbers of patients using this approach. But, not all. That is because when BP is reduced by antihypertensive drugs the ischemic nephrons become under-perfused again and further increase their renin secretion in an attempt to maintain adequate perfusion pressure. The result is that PRA levels rise to even higher levels, sometimes so high that they must be further blocked to reduce blood pressure into the normal range. Hypertensive patients differ markedly in the degree to which renin secretion rises in response to antihypertensive drugs. If the PRA rise is small enough blood pressure usually falls. But if the increase in PRA is too high it has to be blocked for BP to be controlled. When a V patient is sufficiently volume depleted and blood pressure falls to normal, PRA levels rise into the normal range. But, if the patient is insufficiently volume depleted for blood pressure to be normalized PRA levels will remain suppressed. A medium to high on-treatment PRA level in a patient who remains hypertensive indicates that BP was not controlled because renin was incompletely blocked, and a suppressed PRA level indicates that the patient was not sufficiently volume depleted. The former patient needs further renin system blockade, the latter needs greater sodium-volume depletion. The derivation of sodium-volume from plasma renin levels using the blood pressure equation - BP = V x R: As just discussed, long term blood pressure is determined by the interaction of arterial sodium volume (V) with plasma renin activity (R) levels. In other words, BP = V x R. We can measure blood pressure and we can measure PRA but there is no simple way to measure the arterial blood volume. With the blood pressure equation it becomes possible to derive the sodium-volume component from BP and PRA levels. In other words V = BP/R, or for a given level of blood pressure arterial sodium-volume is reciprocally related to PRA. Thus, if PRA is low and BP is either normal or high then long term BP is being sustained by arterial sodium-volume V and not by renin. If BP is not elevated and PRA is in the medium range, the arterial sodium-volume V is also in the medium range. But, if BP is high and PRA is in the medium range the arterial sodium-volume V is now elevated. If BP is not elevated and PRA is high then arterial sodium volume is reciprocally low. The subject is normotensive but volume depleted and long term BP is being sustained at least in part by renin. But, if BP is elevated and PRA is high and then arterial sodium volume could be either low, or medium and the high BP is being primarily sustained by excess renin. Thus, a low PRA level indicates that the body is volume overloaded and the kidney has turned off renin secretion to offset the rising BP. A medium PRA level in the presence of hypertension indicates that the kidneys were unable to suppress renin secretion appropriately as the body became volume expanded and the high blood pressure is due to both excess renin and excess sodium-volume. A high PRA level in the presence of hypertension indicates that the body may not be sodium-volume overloaded (it might even be volume depleted) and the kidneys are secreting renin at an inappropriately high rate and are the source of the hypertension. References: 1. Laragh JH. Vasoconstriction-volume analysis for understanding and treating hypertension: The use of renin and aldosterone profiles. Am J Med 1973;55:261-274 2. Laragh JH, Sealey JE, Niarchos AP, Pickering TG. The vasoconstriction-volume spectrum in normotension and in the pathogenesis of hypertension. Federation Proc. 1982;41:2415-2423 3. Laragh J. Laragh’s Lessons in Pathophysiology and Clinical Pearls for Treating Hypertension. Lesson XV: The volume-vasoconstriction equation that supports all normotension and hypertension. Amer J Hypertens 2001;14:397-404 4. Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body sodium-volume content and renin-angiotensin vasoconstriction to long term blood pressure. Am J Hypertens 2011;24:1164-1180 5. Gonzalez MD, Cohen HW, Sealey JE, Laragh JH, Alderman MH. Enduring direct association of baseline plasma renin activity with all-cause and cardiovascular mortality in hypertensive patients. Amer J Hypertens 2011;24:1181-86 |