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L-Citrulline versus Spironolactone in a Rat Model of Hypertension: New Insights into their Therapeutic Effects

Author(s): P. P. Shivgunde* and Vandana Nade
Department of Pharmacology, Maratha Vidya Prasarak Samaj's College of Pharmacy, MVP Campus, Nashik, Maharashtra 422002, India

Correspondence Address:
P. P. Shivgunde, Department of Pharmacology, Maratha Vidya Prasarak Samaj's College of Pharmacy, MVP Campus, Nashik, Maharashtra 422002, India, E-mail:

L-citrulline, a natural antioxidant and nitric oxide donor, has beneficial cardiovascular properties. The present study investigated the differences in the outcomes between L-citrulline monotherapy and combination therapy with spironolactone as initial treatments for test animals with deoxycorticosterone acetate saltinduced hypertension. Deoxycorticosterone acetate salt (20 mg/kg, s.c.) was administered twice a week in male Wistar rats for 4 w with daily drinking water containing sodium chloride (1 %) and potassium chloride (0.2 %) to develop hypertension. In the development period, treatment groups received a daily dose of L-citrulline (50 or 100 mg/kg, p.o.) alone or in spironolactone (50 or 100 mg/kg, p.o.) combination. Treatment effects assessed by measuring non-invasive and invasive blood pressure, body and heart weight, vascular reactivity to catecholamines, acetylcholine-induced vasorelaxation in the isolated artery, and oxidative stress in heart specimens. Compared to the deoxycorticosterone acetate group, the L-citrulline and spironolactone combination therapy dose-dependently ameliorated the elevated levels of different blood pressure parameters, improved cardiac hypertrophy, vascular reactivity, aorta relaxant responses and attenuated oxidative stress. In addition, L-citrulline low and high-dose monotherapy demonstrated significant improvements in all evaluated parameters except vascular reactivity. However, compared to combination therapy, the performance of L-citrulline or spironolactone alone treatment is slightly inferior. Our results conclude that L-citrulline is a promising treatment option for treating hypertension, and L-citrulline can be combined with spironolactone to get a synergistic effect in treating hypertension.

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