Beneficial and adverse renal and vascular effects of the vasopeptidase inhibitor omapatrilat in renovascular hypertensive rats.
BACKGROUND
Vasopeptidase inhibitors are a new class of compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase. This study determined whether treatment with the vasopeptidase inhibitor omapatrilat (OMA) produced different effects on renal and cardiovascular structure compared with inhibition of ACE by enalapril (ENP) in rats with two-kidney, one clip hypertension (2K1C).


METHODS
Hypertensive 2K1C rats were randomized into four groups and studied for another 8 weeks: no treatment, OMA, ENP or ENP combined with the diuretic hydrochlorothiazide (ENP + HCTZ). Albuminuria, vascular and renal histology as well as glomerular expression of transforming growth factor-beta (TGF-beta) were determined at the end of the experiment.


RESULTS
OMA decreased blood pressure slightly better than ENP. However, combination of ENP with a diuretic lowered blood pressure equally effective as OMA. OMA was numerically more efficient in reducing cardiovascular and renal hypertensive changes compared with ENP. In contrast, the combination of ENP + HCTZ was as efficient as OMA. However, OMA lowered overexpression of TGF-beta in the non-clipped kidney better than ENP or ENP +HCTZ. Antihypertensive therapy surprisingly decreased renal function as shown by increased plasma creatinine and urea and decreased creatinine clearance.


CONCLUSIONS
OMA is marginally more potent compared with ENP alone in lowering blood pressure and preventing cardiovascular and renal injury. This effect may be due to slightly better blood pressure reduction because addition of HCTZ enhances the cardio- and nephroprotective capacity of ENP. In contrast, OMA reduces TGF-beta overexpression in the non-clipped kidney better than ENP or ENP + HCTZ. Therefore, vasopeptidase inhibition is not superior to ACE inhibition in the prevention of cardiovascular and renal damage Goldblatt hypertension.
D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D004195:Disease Models, Animal; D004656:Enalapril / Q000009:adverse effects / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011336:Probability; D011480:Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects; D015996:Survival Rate; D013841:Thiazepines / Q000009:adverse effects* / Q000494:pharmacology*
D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D004656:Enalapril