Chronic administration of oral vasopressin type 2 receptor antagonist tolvaptan exerts both myocardial and renal protective effects in rats with hypertensive heart failure.
BACKGROUND
Although recent clinical trials have demonstrated the efficacy of the oral vasopressin (AVP) type 2 receptor (V2R) antagonist tolvaptan, its long-term effects on the myocardium and kidney in heart failure (HF) are not clear. We examined the chronic effects of tolvaptan administration on both the myocardium and kidney in a rat hypertensive HF model.


RESULTS
Not only circulating AVP level but also myocardial AVP and V1a receptor (V1aR) expressions, renal V1aR, and V2R expressions were significantly upregulated during the transition to HF. The animals were chronically treated with low-dose or high-dose (HD) tolvaptan or vehicle from the left ventricular (LV) hypertrophic stage. Chronic tolvaptan treatment persistently increased urine volume but did not affect blood pressure. In the HD group, the animal survival significantly improved (log-rank test, P<0.01). At the HF stage, the progression of LV dysfunction was prevented and lung congestion was suppressed. Activation of atrial natriuretic peptide, endothelin-1, AVP, and V1aR mRNA levels were significantly suppressed in the LV myocardium. Meanwhile, renal histopathologic damage was ameliorated and renal function was improved in the HD group at the HF stage. Concomitantly, not only activation of aquaporin-2 but also those of V2R, V1aR, renin, and endothelin-1 in the kidney were significantly suppressed (all P<0.05).


CONCLUSIONS
These results indicate that chronic tolvaptan treatment has beneficial effects by preventing not only the progression of LV dysfunction but also that of renal injury in hypertensive rats with HF. The underlying mechanism may be related to the suppression of myocardial and renal neurohumoral activation.
Division of Cardiology, Department of Internal Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
Hanako
H
Morooka
Yoshitaka
Y
Iwanaga
Yodo
Y
Tamaki
Toru
T
Takase
Yasumitsu
Y
Akahoshi
Yoshimasa
Y
Nakano
Hiroyuki
H
Fujiki
Shunichi
S
Miyazaki
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000097:blood; D001552:Benzazepines / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006727:Hormone Antagonists / Q000008:administration & dosage*; D006973:Hypertension / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D045265:Natriuretic Peptides / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D000077602:Tolvaptan; D014463:Ultrasonography; D014554:Urination / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D015415:Biomarkers; D006727:Hormone Antagonists; D045265:Natriuretic Peptides; D012333:RNA, Messenger; D017483:Receptors, Vasopressin; D017673:Sodium Chloride, Dietary; D001127:Arginine Vasopressin; D000077602:Tolvaptan