Neurohormonal antagonism in heart failure; beneficial effects of vasopressin V1a and V2 receptor blockade and ACE inhibition

Naitoh, Motoko; Risvanis, John; Balding, Leanne C.; Johnston, Colin I.; Burrell, Louise M.

doi:10.1016/s0008-6363(02)00244-4

Cited by 34 publications

(27 citation statements)

References 32 publications

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“…The effects of conivaptan on urinary parameters in rat models have included an increase in both urine volume and sodium concentration compared with placebo. 45 Decreased Tolvaptan, a selective nonpeptide V2 receptor antagonist, has potent aquaretic properties in animal models. 46,47 In cloned human receptors, the V2:V1a receptor selectivity was 29:1.…”

Section: Vasopressin Antagonists In Developmentmentioning

confidence: 99%

“…In a double-blind study conducted in 254 stable chronic HF patients (regardless of LV ejection fraction), 3 oral doses of tolvaptan (30,45, or 60 mg) given daily for 25 days were compared with placebo administration. 38 Throughout the full course of therapy, a significant decrease in body weight and edema was observed, as was an increased urinary volume.…”

Section: Hf With Hyponatremiamentioning

confidence: 99%

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Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

2008

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A rginine vasopressin has attracted attention as a potentially important neurohormonal mediator of the heart failure (HF) syndrome and hyponatremic states in humans 1 because vasopressin influences renal handling of free water, vasoconstriction, and myocyte biology. 2,3 Several vasopressin antagonists are under development, 4 and one of these agents, conivaptan, recently received US Food and Drug Administration approval for short-term intravenous treatment in patients with euvolemic or hypervolemic hyponatremia. The Role of Vasopressin in HF and HyponatremiaA neurohypophysial hormone, vasopressin (also called antidiuretic hormone [ADH]), affects free water reabsorption by the kidney, body fluid osmolality, blood volume, vasoconstriction, and myocardial contractile function. 2,3 Vasopressin is synthesized by neurosecretory cells located predominantly in the supraoptic and paraventricular hypothalamic nuclei. These neurons have axons terminating in the neural lobe of the posterior pituitary (neurohypophysis) that release vasopressin and oxytocin. 5

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Section: Vasopressin Antagonists In Developmentmentioning

confidence: 99%

Section: Hf With Hyponatremiamentioning

confidence: 99%

Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

2008

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“…Intracerebroventricular infusion of spironolactone prevents the progressive increase in plasma TNF-␣ level (11). Effects of central treatments on plasma vasopressin levels post-MI also may contribute to the extent of LV remodeling and dysfunction (29).…”

Section: Discussionmentioning

confidence: 99%

Blockade of brain mineralocorticoid receptors or Na⁺ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

Huang¹,

Leenen²

2005

American Journal of Physiology-Heart and Circulatory Physiology

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In rats postmyocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na ϩ channels, presumably epithelial Na ϩ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na ϩ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or its vehicle, or with benzamil (4 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the ␣ 2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (ϳ31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na ϩ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction. myocardial infarction; cardiac dysfunction; aldosterone RECENT STUDIES DEMONSTRATED that the central mechanisms leading to sympathetic hyperactivity in rats post-MI resemble those contributing to salt-sensitive hypertension in Dahl saltsensitive (S) rats. In Dahl S rats on high salt intake, blockade of brain ouabain-like compounds (OLC) or of the brain reninangiotensin system (RAS) prevents sympathetic hyperactivity and impairment of arterial baroreflex function and prevents salt-induced hypertension (19). Gomez-Sanchez and colleagues demonstrated that blockade of brain aldosterone biosynthesis with the 3␤-hydroxysteroid dehydrogenase inhibitor trilostane (17), of brain mineralocorticoid receptors (MR) with spironolactone (15), or of brain amiloride-sensitive Na ϩ channels with the amiloride analog benzamil (16) also prevents hypertension in Dahl S rats on high salt (15). In rats, responses to intracerebroventricular infusion of aldosterone can be blocked by intracerebroventricular infusion of a MR antagonist (14), benzamil, or antibody Fab fragments binding brain OLC (39). These findings suggest that in the brain, increased binding of aldosterone to MR increases activity of amiloride-sensitive Na ϩ channels, likely epithelial Na ϩ channels (ENaC), and thereby increases brain OLC and activity of the brain RAS (39). We proposed that in Dahl S rats on high salt, increased bindin...

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“…Conivaptan (YM087) is a high-affinity nonpeptide antagonist of AVP V 2 and V 1A receptors that produces aquaresis, the renal excretion of solute-free water that is electrolyte sparing [13, 14]. Orally and intravenously administered conivaptan increased plasma osmolality (P osm ) and decreased urine osmolality (U osm ) and AVP-induced skin vasoconstriction in normal individuals [15].…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

et al. 2007

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Background: Most cases of hyponatremia – serum sodium concentration ([Na⁺]) <135 mEq/l (<135 mM) – are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V_1A/V₂-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. Methods: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na⁺] 115 to <130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na⁺], measured by the baseline-adjusted area under the [Na⁺]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na⁺] increase, total time patients had serum [Na⁺] ≧4 mEq/l higher than baseline, change in serum [Na⁺] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na⁺] or normal [Na⁺] (≧135 mEq/l). Results: Both conivaptan doses increased area under the [Na⁺]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean ± standard error serum [Na⁺] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. Conclusion: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na⁺] and was well tolerated.

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Neurohormonal antagonism in heart failure; beneficial effects of vasopressin V1a and V2 receptor blockade and ACE inhibition

Cited by 34 publications

References 32 publications

Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

Blockade of brain mineralocorticoid receptors or Na⁺ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

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Neurohormonal antagonism in heart failure; beneficial effects of vasopressin V1a and V2 receptor blockade and ACE inhibition

Cited by 34 publications

References 32 publications

Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

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Blockade of brain mineralocorticoid receptors or Na⁺ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI