Vasopressin Antagonists in Physiology and Disease

2.1

Inhibition of Vasopressin Release

The maintenance of serum tonicity, and therefore serum sodium concentration, within a very narrow physiologic range between 138 and 142 mEq/L is a reflection of the sensitive osmotic regulation of arginine vasopressin (AVP) secretion, a fact already recognized since the pioneering observations of Verney, almost 70 years ago. As such, vasopressin is a component of the intricate neuroendocrine system that controls body fluid homeostasis. The development of a radioimmunoassay for the hormone in the 1970s by Robertson and colleagues defined the high osmotic sensitivity of vasopressin release which translated into large changes in renal water excretion. While the cells that secrete vasopressin are the magnocellular neurons of the supraoptic and paraventricular nuclei in the hypothalamus, the sensing of osmolality is in close proximity but distinct from these neurons and probably resides in the anterior hypothalamus in the vicinity of the organum vasculosum of the lamina terminalis (OVLT).

The osmotic threshold, as well as the sensitivity for vasopressin release, is determined by genetic factors providing significant intraindividual variability. Nonetheless, this variability is modulated by a number of other factors, most of which such as pregnancy and aging either decrease the threshold or increase the sensitivity of the hormone’s release, respectively. In terms of inhibitory pathways, a decrement in plasma osmolality as small as 1%, with water intake, by causing swelling of osmoreceptor cells, is a powerful suppressor of vasopressin release. This process allows for dilution of the urine and the excretion of the water that was ingested. Thus, a decrease in osmolality is the most physiologic of all inhibitors of vasopressin release. A number of neurotransmitters have been implicated in osmoregulatory function. In this regard, the supraoptic nuclei are innervated by numerous pathways, including catecholamines, opioids, γ-aminobutyric acid (GABA), cholinergics, to name a few, all of which probably interact with the osmotic input to provide an integrated response.

In addition to the osmotic pathways, the secretion of vasopressin is impacted by nonosmotic stimuli as well. Of these, changes in hemodynamics are probably the most important. While significant (5%–7%) decrements in volume and perhaps as much as 20% decrements in pressure are required to activate vasopressin secretion, once activated these stimuli powerfully stimulate the release of the hormone in an exponential manner. Although less well characterized, an increase in blood volume and/or blood pressure seems to have the opposite effect, namely to reduce vasopressin secretion. These hemodynamic alterations appear to be mediated by changes in parasympathetic and sympathetic tone as the hypothalamus is richly innervated by these neural pathways. Thus, for example, the diuresis that accompanies acute left atrial distention is mediated by stimulation of the vagal afferents. Vasopressin secretion is also suppressed by alpha adrenergic stimulation, but this is mediated by the increment in blood pressure rather than a direct effect on the hypothalamus. In addition, sensory afferents from the oropharynx via the glossopharyngeal nerve are felt to mediate the decrease in vasopressin associated with the act of drinking, which occurs independent of any decrease in tonicity.

A number of hormones and drugs have been reported to inhibit vasopressin secretion. These are listed in Table 7.1 . The ability of ethanol to suppress the secretion of the hormone has been known for a long time and served to establish bioassays. Some hormones, such as the aforementioned norepinephrine, do so by indirect mechanisms. In low doses, a number of opioid agonists, including morphine, met-enkephalin, and kappa receptor agonists, inhibit both basal and stimulated vasopressin secretion. The dopamine antagonists, such as promethazine and haloperidol, most likely act by suppressing the effects of the emetic center which, via the chemoreceptor trigger zone, is a powerful stimulating pathway for hormone release. The effect of clonidine is most likely mediated by peripheral and central adrenoreceptors.

2.2

Inhibition of Vasopressin Action

The cellular response to vasopressin in the principal cells of the mammalian collecting duct is critical to the generation of a concentrated urine. The sequence of events that follows the binding of the hormone to its receptor in the basolateral membrane that ultimately culminate in the insertion of aquaporin 2 into the luminal membrane and render the tubule permeable to water is illustrated in the top panel A of Fig. 7.1 , have been well described. Genetic disorders that result in loss of function of the receptor and the water channel cause resistance to the hormone. In addition, there are other pathophysiologic and pharmacologic settings that also inhibit the hydroosmotic response to the hormone resulting in renal concentrating defects. There is no identifiable counterregulatory hormone to the action of vasopressin, but several autacoids, such as prostaglandins and endothelin, as well as alpha adrenergic stimulation, have been shown to antagonize the hydroosmostic properties of the hormone, thereby increasing water excretion. A number of pharmacologic agents that have been associated with this disorder are listed in Table 7.2 . Not all the listed drugs cause the disorder by directly antagonizing vasopressin action, as other mechanisms such as failure to generate interstitial hypertonicity may be operant with some. Two of the pharmacologic agents deserve particular mention—lithium and demeclocycline.

By virtue of its widespread use in the treatment of affective disorders, lithium has emerged as perhaps the most common cause of nephrogenic diabetes insipidus, affecting as many as 50% of patients on the drug. There is no evidence that lithium impairs vasopressin release. In terms of the mechanism of its renal action, lithium does not interfere with accumulation of medullary solutes, thus, an intrinsic tubular defect is postulated. In this regard, lithium decreases vasopressin-stimulated water transport in the perfused cortical collecting duct. An inhibition in adenylate cyclase and cAMP generation is observed in human tissue and cultured cells exposed to the cation as well as animals chronically treated with lithium. A downregulation of aquaporin-2 (AQP2) and aquaporin-3 (AQP3) has been described in lithium-treated rats. It is of interest that the aquaporin levels remained low after removal of lithium, in line with slow recovery of concentrating ability seen in humans. More recently, an effect of lithium on the epithelial sodium channel has also been described, which may explain the natriuresis that contributes to the polyuria. In fact lithium enters the cell by this channel explaining the efficacy of amiloride, an inhibitor of the epithelial sodium channel (ENaC), to ameliorate the concentrating defect and diminish the polyuria in patients on lithium.

Since it was first recognized as a cause of nephrogenic diabetes insipidus, demeclocycline has become the drug of choice for the treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). It has yet to be determined if demeclocycline reduces AVP secretion. It is clear, however, that demeclocycline induces dose-dependent decreases in human renal medullary adenylate cyclase activity. Because the drug decreases not only vasopressin but also cAMP-stimulated water flow, a post-cAMP defect may be operant. The precise biochemical mechanism of demeclocycline, however, has eluded elucidation.

Hypokalemia has long been known to cause polyuria as a consequence of a vasopressin-resistant renal concentrating defect. Initially, the polyuria results from a primary effect of potassium depletion to stimulate water intake. A renal concentrating defect that is independent of the high rate of water intake eventually supervenes. The defect is in part caused by a decrement in tonicity in the medullary interstitial, which most likely relates to a decrease in sodium chloride reabsorption in the thick ascending limb. The elaboration of vasopressin-resistant hypotonic urine suggests, however, a defect in the collecting duct’s response to vasopressin, independent of the decreased medullary tonicity. A direct effect of hypokalemia on the collecting tubule is supported by studies in the toad bladder that show a decrease in cAMP and vasopressin-stimulated water flow when potassium is removed from the bathing solution. These findings suggest both a pre-cAMP and post-cAMP defect. The hypokalemia-induced resistance to vasopressin is associated with a decreased cAMP accumulation, apparently owing to decreased adenylate cyclase activity. A profound decrement in the vasopressin-sensitive water channel (aquaporin-2) has been described in the hypokalemic rats. Hypokalemia from any cause (e.g., diarrhea, chronic diuretic use, or primary aldosteronism) may be associated with a urinary concentrating defect. The defect generally is reversible but required a longer time (1–3 months) than would be expected from a purely functional defect.

Hypercalcemia is another well-recognized cause of impaired urinary concentrating ability. A decrement in medullary interstitial tonicity clearly is present with hypercalcemia, which may be related to diminished solute reabsorption in the thick ascending limb. This defect is associated with a decrement in AVP-stimulated adenylate cyclase in this nephron segment. The concentrating defect, however, is multifactorial, because the elaboration of a vasopressin-resistant hypotonic urine implies an intrinsic defect in the collecting tubule. In this regard, studies in isolated toad bladders, as well as papillary collecting ducts, revealed a decreased response to vasopressin in hypercalcemia. A similar inhibition of cAMP accumulation and hydroosmotic response to AVP is seen with maneuvers that increase cell calcium. Two studies have examined the effect of hypercalcemia in AQP2 expression employing a vitamin D-treated rat. Both revealed a decrement in AQP2.