A Rationale for Epigenetic Repurposing of Hydralazine in Chronic Heart and Kidney Failure

The hydrazinophthalazines-derivates (syn. hydrazine) hydralazine and dihydralazine were approved by the FDA as anti-hypertensives in 1953 – and because they are both effective and safe they are among the oldest drugs which have kept their place in clinical practice. While hydrazine was originally discovered as potent vasodilatator which lowered blood pressure and increased renal perfusion, it received renewed recognition in the 1980s due to its effectiveness for the treatment of heart failure and further reconsideration in the 2000s due to its effectiveness to reverse epigenetic DNA methylation in cancer. In light of recent advances in the understanding of cardio-renal interactions and contribution of epigenetics to chronic heart and kidney failure, we here re-visit rationales for use of hydrazine in clinical care. Received: January 08, 2016; Accepted: January 18, 2016; Published: January 25, 2016 Hydrazinophthalazines-Derivates Hydralazine and Dihydralazine The hydrazinophthalazines-derivates hydralazine (C8H8N4, syn. 1(2H)-phthalazinone, hydrazine, 1-hydrazinophthalazine, hydralazine mono-hydrochloride, hydralazine hydrochloride) and dihydralazine (C8H10N6, syn. 1,4-phthalazinedione, 2,3-dihydro-, dihydrazone, 1,4-dihydrazinonaphthalazine, dihydralazine sulfate, dihydrazinophthalazin) were discovered more than 50 years ago as potent vasodilators which lowered blood pressure and increased renal perfusion [1-3]. While the two substances are considered fully interchangeable regarding their biological activity, they have slightly different pharmacokinetics. Dihydralazine’s half-life of 4.8 hours is almost twice as long as the half-life of hydralazinehydrochloride (2.5 hours) and dihydralazine is typically taken on a twice daily regimen compared to threeor four-times a day regimen with hydralazine [4]. There is some confusion in the literature, because “hydralazine”, “hydrazine” and “dihydralazine” are being used synonymously, whereas distinct substances are being historically used in different countries: While in the U.S. the hydrazinophthalazines-derivate hydralazine is being used (marketed as “Apresoline”), in Europe dihydralazine (“Nepresol”) is available. For practical purposes we will adhere here to the term “hydrazine” if no further specification between hydralazine and dihydralazine is warranted. Hydrazine for Anti-hypertensive Therapy Hydrazine was first introduced to clinical application in 1952 for its blood pressure lowering effect (which had been consistently documented in animal studies) [1]. Of note, despite being already in clinical use, it was first tested in a controlled, double-blinded clinical study in 1964, which confirmed its safety and effectiveness [5]. Through observational studies, evidence for the benefit of combination therapy of hydrazine with an inhibitor of the betaadrenergic system and a diuretic emerged, and by the late 1970s such “triple therapy” was standard of care for the treatment of essential hypertension [6, 7]. Hydrazine has kept its role as thirdline anti-hypertensive in patients with severe hypertension and due to its benign side effects it still has its place in pregnancy hypertension [8, 9]. Due to its reliable vasodilatory effect it is