Enalapril attenuates endothelin-1-induced hypertension via increased kinin survival.
Recent studies have shown that angiotensin-converting enzyme (ACE) inhibitors attenuate endothelin-1 (ET-1)-induced hypertension, but the mechanisms for this effect have not been clarified. Initial experiments were conducted to contrast the effect of the ACE inhibitor enalapril, the combined ACE-neutral endopeptidase inhibitor omapatrilat, and the angiotensin II receptor antagonist candesartan on the hypertensive and renal response to ET-1 in anesthetized Sprague-Dawley rats. Acute intravenous infusion of ET-1 (10 pmol x kg(-1) x min(-1)) for 60 min significantly increased mean arterial pressure (MAP) from 125 +/- 8 to 145 +/- 8 mmHg (P < 0.05) and significantly decreased glomerular filtration rate (GFR) from 0.31 +/- 0.09 to 0.13 +/- 0.05 ml x min(-1) x 100 g kidney wt(-1). Pretreatment with enalapril (10 mg/kg iv) before ET-1 infusion inhibited the increase in MAP (121 +/- 4 vs. 126 +/- 4 mmHg) before and during ET-1 infusion, respectively (P < 0.05) without blocking the effect of ET-1 on GFR. In contrast, neither omapatrilat (30 mg/kg) nor candesartan (10 mg/kg) had any effect on ET-1-induced increases in MAP or decreases in GFR. To determine whether the effect of enalapril was due to the decrease in angiotensin II or increase in kinin formation, rats were given REF-000359 (1 mg/kg iv), a selective B(2) receptor antagonist, with or without enalapril before ET-1 infusion. REF-000359 completely blocked the effect of enalapril on ET-1 infusion (MAP was 117 +/- 5 vs. 135 +/- 5 mmHg before and during ET-1 infusion, respectively, P < 0.05). REF-000359 alone had no effect on the response to ET-1 infusion (MAP was 117 +/- 4 vs. 144 +/- 4 mmHg before and during ET-1 infusion, respectively, P < 0.05). REF-000359 with or without enalapril had no significant effect on the ability of ET-1 infusion to decrease GFR. These findings support the hypothesis that decreased catabolism of bradykinin and its subsequent vasodilator activity oppose the actions of ET-1 to increase MAP.
Elmarakby
Ahmed A
AA
Department of Pharmacology and Toxicology, Vascular Biology Center, Medical College of Georgia, Augusta 30912, USA.
Morsing
Peter
P
Pollock
David M
DM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D065168:Bradykinin Receptor Antagonists; D004656:Enalapril / Q000494:pharmacology*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006400:Hematocrit; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D007705:Kinins / Q000378:metabolism*; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D014563:Urodynamics / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D019332:Endothelin-1; D007705:Kinins; D011480:Protease Inhibitors; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D004656:Enalapril; C081643:candesartan