Renoprotective effect of angiotensin-converting enzyme inhibitor combined with alpha1-adrenergic antagonist in spontaneously hypertensive rats with renal ablation.
To assess the renal benefits of combined angiotensin-converting enzyme inhibition and alpha(1)-adrenergic antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone and in combination with doxazosin (DOX) in spontaneously hypertensive rats (SHR)/Izumo rats with renal ablation. Five-Sixths-nephrectomized rats were assigned to receive TMP (10 mg/kg/day) (TMP group), TMP plus DOX (2 mg/kg/day) (TMP+DOX group), or vehicle (control group) orally for 12 weeks. Both systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) in the control group progressively increased during the experimental period and were significantly higher than in sham-operated rats. Treatment with either TMP or TMP plus DOX had similar antihypertensive effects in this rat model. Twelve weeks after initiation of treatment, the SBP values in the control, TMP, and TMP+DOX groups were 265+/-8, 157+/-4, and 163+/-3 mmHg, respectively, in comparison with 233+/-4 mmHg in sham-operated rats (p<0.0001 control vs. sham, p<0.001 TMP vs. control, p<0.001 TMP+DOX vs. control). UalbV, serum creatinine (Scr), blood urea nitrogen (BUN), and heart weight/body weight (HW/BW) ratio were significantly lower in the TMP and TMP+DOX groups than in the control group (UalbV: p<0.05; Scr: p<0.01; [BUN, HW/BW ratio]: p<0.0001; and [UalbV, Scr, BUN, HW/BW ratio]: p<0.0001 vs. control, respectively). The index of glomerular sclerosis (IGS) and relative interstitial volume (RIV) were significantly lower in the TMP+DOX group than in the control group (IGS: p<0.05; RIV: p<0.01). Especially, UalbV, IGS, and RIV were significantly better in the TMP+DOX group than in the TMP group ([IGS, RIV]: p<0.05; UalbV: p<0.01). These results suggest that simultaneous administration of TMP and DOX provides greater renoprotective effects than administration of TMP alone.
Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Sendai, Japan. makanaza@sm.rim.or.jp
Masayuki
M
Kanazawa
Masahiro
M
Kohzuki
Hajime
H
Kurosawa
Naoyoshi
N
Minami
Osamu
O
Ito
Takao
T
Saito
Minoru
M
Yasujima
Keishi
K
Abe
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000419:Albuminuria; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017292:Doxazosin / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007672:Kidney Cortex / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D051381:Rats; D011918:Rats, Inbred SHR; D012598:Sclerosis; D013841:Thiazepines / Q000627:therapeutic use*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D013841:Thiazepines; C055603:temocapril hydrochloride; D017292:Doxazosin