Purpose of review: Internal environment regulation, particularly volume and osmoregulation, has been a fundamental concept important to physiologists and clinicians for almost two centuries. Na balance, intracellular K homeostasis, the crucial role of the Na,K-ATPase pump, osmotic forces, and the overriding effect of the kidney on maintaining homeostasis are notions that have been taught by many and accepted by most for over 50 years. Nevertheless, contradictory findings, problems with simplistic balance explanations, and the notion of salt-sensitive and salt-resistant hypertension have been nagging headaches in the straightforward, two-compartment model of electrolyte balance.
Recent findings: Na can be accumulated without commensurate water retention in the interstitium of the skin, and this skin Na storage is paralleled by increased polymerization and sulfation of glycosaminoglycans in the Na reservoir. Subcutaneous tissue macrophages express the transcription factor tonicity enhancer binding protein in response to Na-mediated interstitial osmotic stress and thereby secrete vascular endothelial growth factor C, which stimulates lymphatic formation and endothelial nitric oxide synthase expression, suggesting that the immune system is a regulator of volume and blood pressure homeostasis.
Summary: Our findings do not abrogate the notion of pressure natriuresis and renal regulatory function. However, we do suggest that extracellular Na, volume and blood pressure homeostasis cannot be maintained without extrarenal regulatory mechanisms.