Effects of bradykinin B2 receptor antagonism on the hypotensive effects of ACE inhibition.
1. The aim of this study was to determine the participation of endogenous bradykinin (BK) in the antihypertensive effects of the angiotensin converting enzyme inhibitor (ACEI), perindoprilat, in the spontaneously hypertensive rat (SHR) on different salt diets. 2. Conscious SHRs receiving either a low or a high NaCl diet were used in order to evaluate the respective roles of angiotensin II suppression and bradykinin stimulation in the acute hypotensive effects of perindoprilat. Two different B2 receptor antagonists (B 4146 and Hoe 140) were used after bolus administration of 7 mg kg-1 of the ACEI, perindoprilat. In separate animals, Hoe 140 was administered before the injection of perindoprilat. In other experiments, the effects of Hoe 140 on the hypotensive effects of the calcium antagonist, nicardipine, were tested. 3. The different NaCl diets had no effect on baseline blood pressure. Hoe 140 injection before ACE inhibition did not modify blood pressure. Perindoprilat caused more marked hypotension in the low salt-fed rats than in the high salt animals (P < 0.01). Administration of Hoe 140 or B4146 after perindoprilat significantly reduced the antihypertensive effects of perindoprilat in the different groups, but this effect was more pronounced in high salt-fed rats. However, in SHRs receiving Hoe 140 before perindoprilat, the antihypertensive effect of perindoprilat was completely abolished in both high or low salt diet rats. In separate experiments we confirmed that Hoe 140 did not affect the hypotensive efficacy of the calcium antagonist, nicardipine. 4. Our study shows that inhibition of endogenous bradykinin degradation participates in the acute antihypertensive effects of perindoprilat in SHRs. The role of bradykinin is more pronounced following exposure to a high salt diet i.e., when the renin-angiotensin system is suppressed. Blockade of bradykinin B2 receptors by Hoe 140 before administration of perindoprilat completely abolished the hypotensive effect of perindoprilat suggesting an increased role of bradykinin in the onset of hypotensive action of ACE inhibitors. However, the exact mechanism of this interaction remains unclear.
Department of Internal Medicine, Broussais Hospital, Paris, France.
H
H
Bouaziz
Y
Y
Joulin
M
M
Safar
A
A
Benetos
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D007211:Indoles; C053500:perindoprilat; C065679:icatibant; D001920:Bradykinin