Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P

被引:96
作者
Emanueli, C
Grady, EF
Madeddu, P
Figini, M
Bunnett, NW
Parisi, D
Regoli, D
Geppetti, P
机构
[1] Univ Ferrara, Dept Expt & Clin Med, Pharmacol Unit, I-44100 Ferrara, Italy
[2] Univ Ferrara, Inst Surg, I-44100 Ferrara, Italy
[3] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
关键词
angiotensin-converting enzyme; captopril; plasma; bradykinin; substance P;
D O I
10.1161/01.HYP.31.6.1299
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
The use of angiotensin-converting enzyme (ACE) has been associated with the occurrence of adverse effects, including cough and angioneurotic edema. Accumulation of kinins has been suggested to play a major role in these adverse effects of ACE inhibitor, although conclusive evidence for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of neurogenic inflammatory mechanisms. Intravenous captopril and enalapril increased the extravasation of Evans blue dye in all tissues examined (trachea, stomach, duodenum, and pancreas). This effect was evident 15 minutes after drug administration. The particulate dye Monastral blue identified the sites of captopril-induced leakage in the microvasculature. Pretreatment with the bradykinin B-2 receptor antagonist Hoe 140 or with the tachykinin NK1 receptor antagonist SR 140333 inhibited captopril-evoked increase in plasma extravasation. In mice in which the gene encoding the bradykinin B-2 receptor was disrupted by gene targeting, neither bradykinin nor captopril increased plasma extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive response induced by captopril. The present findings suggest that ACE inhibition increases kinin levels in tissues and/or plasma. These increased kinin levels increase microvascular leakage in mouse airways and digestive tract via the release of tachykinins from terminals of primary sensory neurons. Exaggerated kinin production and the subsequent stimulation of peptide release from sensory nerves may be involved in adverse effects of ACE inhibitors.
引用
收藏
页码:1299 / 1304
页数:6
相关论文
共 27 条
[21]  
REGOLI D, 1980, PHARMACOL REV, V32, P1
[22]  
ROQUES BP, 1993, PHARMACOL REV, V45, P87
[23]   PROTECTIVE ROLE OF BRADYKININ IN CARDIAC ANAPHYLAXIS - CORONARY-VASODILATING AND ANTIARRHYTHMIC ACTIVITIES MEDIATED BY AUTOCRINE PARACRINE MECHANISMS [J].
RUBIN, LE ;
LEVI, R .
CIRCULATION RESEARCH, 1995, 76 (03) :434-440
[24]  
Skidgel R.A., 1987, NEUROPEPTIDES THEIR, P165
[25]  
TURNER AJ, 1987, NEUROPEPTIDES THEIR, P183
[26]   RAMIPRILAT ENHANCES ENDOTHELIAL AUTOCOID FORMATION BY INHIBITING BREAKDOWN OF ENDOTHELIUM-DERIVED BRADYKININ [J].
WIEMER, G ;
SCHOLKENS, BA ;
BECKER, RHA ;
BUSSE, R .
HYPERTENSION, 1991, 18 (04) :558-563
[27]   ENHANCEMENT OF CYTOSOLIC CALCIUM, PROSTACYCLIN AND NITRIC-OXIDE BY BRADYKININ AND THE ACE-INHIBITOR RAMIPRILAT IN PORCINE BRAIN CAPILLARY ENDOTHELIAL-CELLS [J].
WIEMER, G ;
POPP, R ;
SCHOLKENS, BA ;
GOGELEIN, H .
BRAIN RESEARCH, 1994, 638 (1-2) :261-266