Contractile effects of angiotensin peptides in rat aorta are differentially dependent on tyrosine kinase activity

Abstract

It has been suggested that tyrosine kinase activity participates in the regulation of signal transduction associated with angiotensin II (Ang II)-induced pharmaco-mechanical coupling in rat aortic smooth muscle. We further tested the effects of genistein, a tyrosine-kinase inhibitor, and its inactive analogue, daidzein, on angiotensin I (Ang I), angiotensin III (Ang III) and angiotensin IV (Ang IV) contractions, as compared with those on Ang II. Genistein partially inhibited Ang II- and Ang I-induced contractions. The genistein-induced inhibition was more evident on Ang III and especially important on Ang IV contractile effects. Thus, Ang IV- and Ang III-induced contractions seem to be more dependent on tyrosine kinase activity than those evoked by Ang II or Ang I. Daidzein did not significantly affect the contractile effects of any of angiotensin peptides tested. These results clearly suggest that the inhibition of the action of angiotensin peptides actions by genistein is mediated by inhibition of endogenous tyrosine kinase activity. Furthermore, our data show that the type and/or intensity of tyrosine kinase activity is differentially associated with the contractile effects of different angiotensin peptides in rat aorta. Nifedipine, a blocker of membrane L-type Ca2+ channels, strongly inhibited Ang IV-induced contractions. At the same time, it significantly inhibited Ang III contractile effects as compared with Ang II and Ang I contractions. Meanwhile, we observed a close relationship between calcium influx and tyrosine kinase phosphorylation activity under the stimulatory effects of angiotensin peptides. Furthermore, genistein did not significantly influence the phasic contractions induced by angiotensin peptides in Ca2+-free Krebs-Henseleit solution. Thus, it appears that Ca2+ influx, rather than the release of Ca2+ from IP3-sensitive stores, may play a major role in the contractile effects of angiotensin peptides in rat aorta via tyrosine kinase activation. One argument against a direct action of genistein on the Ca2+ channel itself is that it did not markedly affect the K+-induced contraction (depolarisation) in rat aorta. At the same time, a potential role for tyrosine kinase activity in the process of calcium entry is suggested. An elevation of intracellular calcium via tyrosine kinase-mediated processes may mediate the actions of G-protein coupled receptor agonists in smooth muscle, including angiotensin peptides.

Mechanism of attenuation of pro-inflammatory Ang II-induced NF-κB activation by genistein in the kidneys of male rats during aging

“…Genistein protects cells against ROS by scavenging free radicals and partially inhibiting Ang II-induced contractions and oxidative damage by modulating tyrosine kinase activity. In contrast, daidzein and glycitein were shown to have no significant effect on the Ang II-induced intracellular response (Petrescu et al 2001). In agreement with these findings, the chronic administration of genistein has been found to improves endothelial dysfunction in Ang II-related spontaneously hypertensive rats via regulation of the NADPH oxidase (Rivas et al 2002).…”

Angiotensin IV Activates the Nuclear Transcription Factor-κB and Related Proinflammatory Genes in Vascular Smooth Muscle Cells

“…42,43 Ang IV activates several protein kinases. 44,45 In endothelial cells, Ang IV increases PI3K, PI-dependent kinase-1 (PDK-1), extracellular signal-related kinases (ERK1/2), protein kinase B-␣/Akt (PKB-␣), and p70 ribosomal S6 kinase (p70S6K) activities. 46 Endotheliumdependent vasodilation is mediated by NO and cGMP production, 30 intracellular calcium release, and activation phospholipase C and PI3K.…”

“…29 In rat aorta, PTK inhibition and membrane L-type Ca 2ϩ channels blockade diminished Ang IV contractile effects. 44 In tubular cells, Ang IV increases tyrosine phosphorylation of the focal adhesion-associated proteins, p125-FAK and paxillin. However, Ang IV does not affect cAMP or cGMP production and does not increase cytosolic calcium concentrations.…”

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

“…26,[66][67][68][69] Of note, Ang IV activates the inflammatory NF-κB pathway in vascular smooth muscle cells, which leads to the production of pro-inflammatory factors such as IL-6, TNFα and ICAM-1. 30 We therefore investigated any potential modulatory effect of Ang IV (and the Ang IV-analogue AL-11) on the NF-κB pathway in macrophages.…”