Role of bradykinin in the vasodilator effects of losartan and enalapril in patients with heart failure.
BACKGROUND
ACE inhibitors have been shown to potentiate the effects of exogenous bradykinin by inhibition of its breakdown. Despite this, there is little evidence that inhibition of endogenous bradykinin breakdown actually contributes to the effects of ACE inhibitors, or indeed, other inhibitors of the renin-angiotensin system, such as angiotensin II type I receptor (AT(1)) antagonists, and no evidence at all that it does so in patients with heart failure.


RESULTS
Twelve patients with heart failure (11 male, 1 female, ages 59 to 81 years) were randomized to double-blind crossover treatment with enalapril 10 mg BID followed by losartan 25 mg BID, or the reverse, each for 5 weeks. At the end of each treatment period, forearm blood flow was measured by venous occlusion plethysmography during an intrabrachial infusion of bradykinin before and after an intrabrachial infusion of Hoe-140 (a potent, selective, and long-acting bradykinin antagonist). Bradykinin caused profound vasodilatation after enalapril (peak, 357+/-67%) and less after losartan (peak, 230+/-46%). Despite this, Hoe-140 had no discernible effects after enalapril or losartan. Similarly, this was despite the finding that Hoe-140 significantly reduced vasodilatation to bradykinin after enalapril (peak, 192+/-35%) and losartan (peak, 66+/-13%).


CONCLUSIONS
Inhibition of endogenous bradykinin breakdown does not appear to contribute to the effects of ACE inhibition or AT(1) antagonism in the forearm of patients with heart failure at rest, despite the very obvious effects of ACE inhibition compared with AT(1) antagonism on exogenous bradykinin.
Medical Research Council Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, UK. a.davie@bio.gla.ac.uk
A P
AP
Davie
H J
HJ
Dargie
J J
JJ
McMurray
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014665:Vasodilator Agents / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014665:Vasodilator Agents; D004656:Enalapril; C065679:icatibant; D019808:Losartan; D001920:Bradykinin