Renal alpha-adrenergic receptor alterations: a cause of essential hypertension?
Based on a review of literature in various fields of research related to hypertension, we develop a new working hypothesis on the pathophysiology of genetically determined increases in blood pressure. According to our hypothesis, the primary defect is located in the kidneys. Renal alpha-adrenergic receptor density is increased in the early stages of the disease, before increases in blood pressure occur. Most renal alpha-adrenergic receptors are located in the proximal tubules and enhance Na+ reabsorption. A genetically determined increase of alpha 1- or alpha 2- or of both alpha-adrenergic receptor subtypes would impair Na+ excretion and, together with increased Na+ intake, would lead to positive Na+ balance. Subsequently, various mechanisms would be activated to restore a neutral Na+ balance, including the secretion of a natriuretic factor that inhibits Na+/K+-ATPase. Inhibition of Na+/K+-ATPase in extrarenal tissues would increase the intracellular concentration of Na+ and, via Na+/Ca2+ exchange, of Ca2+. Elevated intracellular Ca2+ would enhance vascular smooth muscle contractility and neuronal transmitter release, thereby leading to vasoconstriction and to increases in blood pressure. We thus hypothesize that hypertension is a homeostatic response designed to protect blood volume from a genetically determined renal alpha-adrenergic receptor-mediated increase in Na+ retention.
Michel
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MC
Department of Pharmacology, University of California, San Diego, La Jolla 92093.
Insel
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PA
Brodde
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OE
D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012964:Sodium / Q000502:physiology
D011942:Receptors, Adrenergic, alpha; D012964:Sodium