Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice.
- Flow-dependent dilation is a fundamental mechanism by which large arteries ensure appropriate blood supply to tissues. We investigated whether or not the vascular kallikrein-kinin system, especially tissue kallikrein (TK), contributes to flow-dependent dilation by comparing wild-type and TK-knockout mice in which the presence or absence of TK expression was verified. We examined in vitro changes in the outer diameter of perfused carotid arteries from TK(+/+) and TK(-/-) mice. In both groups, exogenous bradykinin caused a similar dilation that was abolished by the B(2) receptor antagonist HOE-140, as well as by the NO synthase inhibitor N:(omega)-nitro-L-arginine methyl ester. However, purified kininogen dilated only TK(+/+) arteries, demonstrating the essential role of TK in the vascular formation of kinins. In TK(+/+) arteries, increasing intraluminal flow caused a larger endothelium-dependent dilation than that seen in TK(-/-). In both strains the flow response was mediated by NO and by endothelium-derived hyperpolarizing factor, whereas in TK(-/-) vasoconstrictor prostanoids participated as well. HOE-140 impaired flow-dependent dilation in TK(+/+) arteries while showing no effect in TK(-/-). This compound reduced the flow response in TK(+/+) arteries to a level similar to that in TK(-/-). After NO synthase inhibition, HOE-140 no longer affected the response of TK(+/+). Impaired flow-dependent dilation was also observed in arteries from knockout mice lacking bradykinin B(2) receptors as compared with wild-type animals. This study demonstrates the active contribution of the vascular kallikrein-kinin system to one-third of the flow-dependent dilation response via activation of B(2) receptors coupled to endothelial NO release.
Institut National de la Santé et de la Recherche Médicale, Unit 541 Hôpital Lariboisière, Paris, France.
S
S
Bergaya
P
P
Meneton
M
M
Bloch-Faure
E
E
Mathieu
F
F
Alhenc-Gelas
B I
BI
Lévy
C M
CM
Boulanger
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D015870:Gene Expression; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D020840:Tissue Kallikreins / Q000235:genetics* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D018076:DNA, Complementary; D004008:Diclofenac; D009599:Nitroprusside; D010656:Phenylephrine; C065679:icatibant; D020840:Tissue Kallikreins; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester