In vivo effects of angiotensin II on vascular smooth muscle contraction and blood pressure are mediated through a protein tyrosine-kinase-dependent mechanism.

The effects of in vivo angiotensin II (AII) treatment on protein tyrosine kinase (PTK) levels were examined. It was found that administration of AII to normotensive Wistar-Kyoto rats induced tyrosine phosphorylation in aorta in a time-dependent manner. There was a rapid increase in phosphotyrosine content as early as 1 min, with peak phosphorylation occurring between 5 and 10 min. The response was also dose dependent, with increases in phosphorylation levels from 1 to 1000 micrograms/kg AII. Tyrosine phosphorylation was blocked using the angiotensin type 1 receptor antagonist losartan (10 mg/kg), suggesting that the effects are receptor mediated. Tyrphostin-25 (100 microM), a selective inhibitor of PTKs, when given in vivo was also able to attenuate phosphorylation by AII, further suggesting a PTK-mediated event. To couple these biochemical changes with physiological events, we also examined the ability of AII to induce vasoconstriction and raise systolic blood pressure through a PTK-mediated mechanism. In addition to increasing phosphorylation levels, AII caused a rise in systolic pressure in vivo and induced contraction in vitro. Both of these responses could be attenuated by pretreatment with losartan or tyrphostin-25. This is the first demonstration of the effects of AII on tyrosine phosphorylation in vivo. The data suggest that AII may induce a pressor response at least in part through activation of PTKs and subsequent phosphorylation of smooth muscle contractile proteins or activation of other protein kinases.

The anti-tumor agent, taxol, attenuates contractile activity in rat aortic smooth muscle.

Using 16-20 week old female spontaneously hypertensive rats (SHRs), the effects of the antitumor agent, taxol, on vascular reactivity were examined. Taxol significantly inhibited contraction induced by phenylephrine, angiotensin II, phorbol 12,13-dibutyrate and increasing concentrations of calcium. The data suggest that taxol does not augment hypersensitivity of the vascular, but instead attenuates contractile activity and may have important implications with respect to treatment of women with both cancer and cardiovascular disease.