Effects of V2-receptor antagonist tolvaptan and the loop diuretic furosemide in rats with heart failure.
Diuretics are frequently required to treat fluid retention in patients with chronic heart failure (CHF). Unfortunately, they can lead to a decline in renal function, electrolyte depletion, and neurohormonal activation. Arginine vasopressin (AVP) promotes renal water reabsorption via the V(2) receptor (V(2)R) and its levels are increased in CHF. This study was conducted to characterize the diuretic effect of tolvaptan, a non-peptide AVP V(2)R antagonist, and furosemide, a loop diuretic in a rat model of CHF after experimental autoimmune myocarditis. CHF was elicited in Lewis rats by immunization with porcine cardiac myosin, and 28 days after immunization rats were treated for 28 days with oral tolvaptan, and furosemide. CHF was characterized by left ventricular remodeling and impaired systolic and diastolic function. Tolvaptan produces a diuresis comparable to furosemide. Unlike tolvaptan, furosemide significantly increased urinary sodium and potassium excretion. Tolvaptan markedly elevated electrolyte-free water clearance (E-CH(2)O) or aquaresis to a positive value and increased urinary AVP excretion. In contrast to tolvaptan, furosemide elevated only electrolyte clearance (E-Cosm) but not E-CH(2)O. The differences in diuretic profile reflected the changes in plasma sodium and hormone levels. Tolvaptan dose dependently elevated plasma sodium concentration, but furosemide tended to decrease it. Furosemide significantly elevated plasma renin activity and aldosterone concentration. On the other hand, tolvaptan did not affect these parameters. Our results suggest that, tolvaptan have a potential medical benefit for the treatment of edematous conditions in CHF by removing excess water from the body without activating the RAAS or causing serum electrolyte imbalances.
Veeraveedu
Punniyakoti T
PT
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima Akiha-ku, Niigata City, Niigata 956-8603, Japan.
Watanabe
Kenichi
K
Ma
Meilei
M
Palaniyandi
Suresh S
SS
Yamaguchi
Ken'ichi
K
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D000450:Aldosterone / Q000097:blood; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000652:urine; D001552:Benzazepines / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004232:Diuretics / Q000627:therapeutic use*; D004452:Echocardiography; D005665:Furosemide / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D011188:Potassium / Q000097:blood / Q000652:urine; D051381:Rats; D011917:Rats, Inbred Lew; D012083:Renin / Q000097:blood; D012964:Sodium / Q000097:blood / Q000652:urine; D000077602:Tolvaptan; D020257:Ventricular Remodeling / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D001127:Arginine Vasopressin; D000077602:Tolvaptan; D000450:Aldosterone; D005665:Furosemide; D012964:Sodium; D003404:Creatinine; D012083:Renin; D011188:Potassium