Hyponatremia is the most common electrolyte abnormality in hospitalized patients, with incidences ranging from 15% to 22% if defined as a serum Na+ <135 mmol/L, decreasing to 1% to 4% if defined as a serum Na+<130 mmol/L. Severe hyponatremia is associated with significant morbidity and mortality. It is common in congestive cardiac failure, cirrhosis, plasma volume contraction, and the syndrome of inappropriate antidiuretic hormone secretion. In the past, hyponatremia was interpreted as a secondary event in heart failure, but is now viewed as deleterious in its own right. In a series of studies in cultured vascular smooth muscle cells, Okada et al from Tochigi, Japan, have shown that hyponatremia per se decreases Na+/Ca2+ exchange, resulting in an increase in intracellular free ionized calcium and, ultimately, an increase in peripheral vascular resistance. Multiple changes in intracellular enzymes take place as a result of hyponatremic cell swelling, compounding the metabolic dysfunction of cardiomyocytes in heart failure. These changes reverse after correction of hyponatremia. Pathophysiology of hyponatremia Extra- and intracellular fluids, including plasma, are hypoosmolar in hyponatremic patients, ie, hyponatremia is a plasma osmolality disorder. Under physiologic conditions, the balance between fluid intake, controlled by thirst, and renal water excretion, controlled mainly by vasopressin, holds plasma Na+ levels (and effective plasma osmolality) within the narrow range 135 mmol/L to 148 mmol/L. In hyponatremia an imbalance between thirst and vasopressin results in hvpoosmolality. Hyponatremic patients in advanced heart failure often have inappropriately elevated plasma arginine vasopressin levels, which fail to fully suppress even after acute water loading. The condition is termed nonosmotic vasopressin secretion. It occurs because, in advanced heart failure, the low cardiac output underfills the arterial compartment, thus unloading the baroceptors which respond by activating the renin-angiotensin-aldosterone system, sympathetic nervous system, and arginine vasopressin secretion in an attempt to increase vascular resistance and enhance renal Na+ and water retention. Thus, despite a generalized hypervolemic edematous state, avid renal Na+ and water retention seeks to maintain an effective arterial blood volume. Nonosmotic vasopressin secretion alone is insufficient to produce hyponatremia. For instance, if fluid intake is lowered to match involuntary daily losses (about 800 mL in an afebrile human), water balance, plasma osmolality and serum Na+ concentration remain unaltered. Animal models of elevated serum vasopressin require a simultaneous increase in fluid intake to produce hyponatremia. Hyponatremic patients also have a high daily fluid intake, around 2 L to 2.5 L, ie, they have nonosmotic thirst in addition to nonosmotic vasopressin secretion. Treatment Physicians have two options in treating hyponatremia: Restrict fluid intake. Lower the levels of vasopressin or block its renal effect. Fluid restriction to levels below insensible + renal free water losses is the current mainstay of treatment. It induces a negative water balance, with increases in plasma osmolality and serum Na+ levels. However, it is impractical, inefficient, and difficult for physician and patient alike. Arginine vasopressin V2 receptor antagonists (vap-tans) are promising agents that block the action of arginine-vasopressin at the V2 receptors in the collecting ducts of the kidney. These agents, therefore, have the potential to increase free water clearance in states of arginine vasopressin excess, regardless of their cause. Arginine vasopressin is synthesized in the magnocel-lular neurosecretory cells of the hypothalamic paraventricular and supraoptic nuclei and excreted by the posterior pituitary. It is released into the circulation in response to an increase in plasma osmolality (mediated by osmoreceptors) or a decrease in plasma volume or blood pressure (mediated by baroceptors). It acts as an antidiuretic hormone at physiologic plasma concentrations and as a vasoconstrictor pressor hormone at higher plasma levels. However, there are other stimuli for arginine vasopressin release, including norepinephrine, angiotensin II, emotion, nausea and vomiting, and fever. There are two classes of arginine vasopressin receptors, Vj and V2, and two V, subclasses, V,A and V1B. V1A receptors are found on platelets, where they mediate platelet aggregation. V1B receptors are located in the anterior pituitary and mediate adrenocorticotropic hormone release. V2 receptors are located in the collecting ducts of the kidney; they are functionally coupled to aquaporin (water) channels and modulate free water clearance. Nonpeptide arginine vasopressin V2 antagonists produce dose-dependent aquaresis in both dehydrated and normally hydrated animals. Studies in heart failure patients are just beginning. Martin and Abraham's group in Denver showed the V2 receptor antagonist WAY-VPA 985 to be effective in a randomized, phase II, placebo-controlled single-dose study in hypona-tremic (<132 mmol/L) patients with New York Heart Association (NYHA) class II-III congestive heart failure. The drug was given orally for up to 7 days at dosages of 50 or 100 mg twice a day. All 14 patients were on a restricted fluid intake of 1200 mL/day. The V, receptor antagonist significantly increased serum Na+ levels vs placebo; the high dose even normalized serum Na+ levels and decreased urinary osmolality by approximately 50%. There was no evidence of tachyphylaxis over the 7 days, nor any significant side effect, in particular no evidence of hypernatremia. The Denver group has also reported safe and significant elevation of serum Na+ levels in response to the nonspecific V1A/V2 vasopressin receptor antagonist conivaptan (YM 087) in severe heart failure with hyponatremia. Conivaptan aquaresis has been confirmed in further studies. Conivaptan does not affect thirst. At Tufts University School of Medicine in Boston, Udelson et al showed that an intravenous bolus of conivaptan significantly decreased pulmonary capillary wedge pressure and right atrial pressure in patients with NYHA III-IV congestive heart failure vs placebo, with no effects on systemic blood pressure or heart rate. A note of caution is required with regard to heart failure. Specific V2 receptor antagonists have been found to increase plasma vasopressin levels, leading to concern about the possibility of unopposed V, receptor stimulation in such patients. This could be counterproductive in congestive heart failure. Nonspecific V]A/V2 receptor antagonists may therefore have advantages over specific V2 receptor antagonists in the heart failure setting. Short-term studies suggest that nonpeptide arginine vasopressin receptor antagonists can normalize plasma osmolality while lowering the requirement for restricted fluid intake, making the therapy of chronic hyponatremia much simpler and more effective than at present. However, the use of such drugs is contraindicated in hypovolemic patients, and requires caution as to the rate at which they correct hyponatremia. A potential complication of too-rapid correction, especially of severe hyponatremia, is pontine and extrapontine myelolysis, a demyelinating brain disease with substantial neurologic morbidity and mortality. Demyelination can occur independently of the method used to correct hyponatremia. Although correction of plasma Na+ in patients with acute hyponatremia carries little, if any, risk of demyelination, Further Readino Martin PY, Abraham WT, Lieming X, et al. Selective V2-receptor vasopressin antagonism decreases urinary aquaporin-2 excretion in patients with chronic heart failure. J Am Soc Nephrol. 1999; 10:2165-2170. Palm C, Reimann D, Gross P. The role of V2 vasopressin antagonists in hyponatremia. Cardiovasc Res. 2001 ;51:403-408 patients with more chronic hyponatremia (>48 hours) can develop demyelination after rapid correction because of greater brain volume changes induced by electrolyte and osmolyte losses. There is no indication for rapid correction in such patients, regardless of the initial plasma Na+ concentration.
U del son JE, Smith WB, Hendrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V(1 A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation. 2001;104:2417-2423.
Wong LL, Verbalis JG. Vasopressin V2 receptor antagonists. Cardiovasc Res. 2001;51:391-402.
biochemistry; hyponatremia; pathophysiology; prognosis; treatment; arginine vasopressin; neuroendocrine factor