Dual PDE3/4 Inhibition Attenuates Lithium‐Induced Nephrogenic Diabetes Insipidus

Abstract

Acquired nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine and is often an effect of some drug therapies, including a common treatment for bipolar disorder, lithium. Approximately 40% of lithium‐treated patients have polyuria and it is thought that the decreased capacity to concentrate urine in these patients is due to the lithium‐mediated disruption of the cAMP pathway that regulates urea transporter (UT‐A1) and water channel (AQP2) expression and function in the renal medulla. The aim of our study is to identify a mechanism to restore renal cAMP levels in the lithium‐treated kidney and preserve urine concentration capacity. Aged‐matched Sprague‐Dawley (SD) rats were pair‐fed either a standard rodent diet or a diet supplemented with lithium carbonate (40 mmol/kg) for 2 weeks. After treatment, urinary cAMP levels are dampened in lithium‐treated rats and total cAMP‐phosphodiesterase (PDE) activity and mRNA expression of PDE3 and PDE4 isoforms are increased in the inner medulla of lithium‐treated rats. Because PDEs are enzymes that degrade cAMP, inhibition of PDE3 and/or PDE4 could attenuate lithium‐induced NDI. SD rats were treated for two as follows: 1) standard diet, vehicle; 2) standard diet, milrinone (PDE3 inhibitor); 3) standard diet, rolipram (PDE4 inhibitor); 4) standard diet, milrinone, rolipram; 5) lithium diet, vehicle; 6) lithium diet, milrinone (PDE3 inhibitor); 7) lithium diet, rolipram (PDE4 inhibitor); and, 8) lithium diet, milrinone, rolipram. Milrinone treatment of lithium‐fed rats did not prevent polyuria in these animals and did not preserve UT‐A1 and AQP2 expression in the medulla. Similarly, rolipram treatment of lithium‐fed rats yields the same results. When PDE3 and PDE4 are simultaneously inhibited, urine osmolality of lithium‐fed rats is increased compared to vehicle‐treated lithium‐fed rats and UT‐A1 and AQP2 expression is restored to endogenous levels. In summary, lithium lowers renal cAMP and increases cAMP PDE activity and expression. Dual PDE3/PDE4 inhibition attenuates lithium‐induced polyuria in rats – a finding that may allow patients to continue lithium therapy without renal side effects in the future.