Nephron heterogeneity: clue to the pathogenesis of essential hypertension and effectiveness of angiotensin-converting enzyme inhibitor treatment.
It is proposed that in essential hypertension there are two functionally abnormal populations of nephrons. One is ischemic; chronically hypersecreting renin and underexcreting sodium. The other, the larger population, is in adaptive hypernatriuresis with its renin secretion chronically suppressed. Nephrons in these two populations, each with its own detector-effector apparatus for renin secretion and sodium excretion, behave according to their individual needs, producing a physiologic discordance expressed in high blood pressure even with plasma renin levels in the so-called "normal" range. The unsuppressed and inappropriate renin secretion from the ischemic nephrons impairs renal function in ischemic and hyperfiltering nephrons alike, but in very different ways. To maintain glomerular filtration rate and an adequate excretion of sodium, the ischemic nephrons require a higher rate of renin secretion than they are actually receiving, because at low perfusion pressures maximal angiotensin II-induced efferent arteriolar constriction is needed to maintain glomerular filtration rate. On the other hand, the compensating hypernatriuretic nephrons become unable fully to excrete dietary sodium because they are exposed to an unwanted, inappropriately high angiotensin II level coming from the ischemic nephrons. This angiotensin II impairs sodium excretion (adaptive hypernatriuresis) from unaffected, adapting nephrons by promoting proximal sodium reabsorption and by inducing afferent constriction. The net result is that all nephrons are exposed to angiotensin II levels inappropriate for their needs. This leads to impaired ability to excrete sodium by both populations of nephrons, with sodium retention in the presence of abnormal renin secretion and perpetuation of the hypertension. The hypothesis is consistent with the hallmark pathology of multifocal afferent arteriolar narrowing seen in essential hypertension as well as with the characteristic renal hemodynamic pattern of vasoconstriction with reduced renal blood flow but with maintained glomerular filtration rate. The "normal" glomerular filtration rate as well as the often "normal" plasma renin activity may be seen as the sum of effects on the two abnormally acting populations of nephrons. Further, since any circulating renin is inappropriate in the presence of hypertension, the hypothesis helps explain why angiotensin-converting enzyme inhibitors reduce blood pressure even when renin levels are not elevated.
Laragh
J H
JH
Cardiovascular Center, New York Hospital-Cornell Medical Center, New York, New York 10021.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D009399:Nephrons / Q000378:metabolism / Q000503:physiopathology*; D011311:Pressoreceptors / Q000503:physiopathology; D012083:Renin / Q000493:pharmacokinetics; D012964:Sodium / Q000493:pharmacokinetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D012964:Sodium; D012083:Renin