These results compare favorably with other methods of treating AGI, especially in patients with multilevel occlusive disease. Principle advantages include acceptable perioperative mortality, low amputation rate, superior durability with excellent long-term patency, and freedom from secondary interventions and recurrent infections.

Angiotensin II (Ang II) type 1 receptors (AT1Rs) activate tyrosine kinases, including Src. Whether or not tyrosine kinase activation by AT1R occurs independently of heterotrimeric G protein coupling and, if so, the cellular function of such a mechanism are unknown. To address these questions, we used an AT1aR intracellular second loop mutant, which lacks heterotrimeric G protein coupling (AT1a-i2m). Surprisingly, Ang II-induced Src activation was preserved in AT1a-i2m, which was not attenuated by inhibiting protein kinase C and Ca 2؉or by inhibiting G␣ i or G␣ q in CHO-K1 cells. By contrast, Ang II-induced Src activation was abolished in a C-terminally truncated AT1a-(1-309), where Ang II-induced inositol phosphate response was preserved. Ang II activates ERKs via a Src-Ras-dependent mechanism in AT1a-i2m. ERKs activated by AT1a-i2m phosphorylate their cytoplasmic targets, including p90 RSK , but fail to translocate into the nucleus or to cause cell proliferation. Ang II-induced nuclear translocation of ERKs by wild type AT1aR was inhibited by overexpression of nuclear exportin Crm-1, while that by AT1a-i2m was restored by leptomycin B, an inhibitor of Crm-1. In summary, while Src and ERKs are activated by Ang II even without heterotrimeric G protein coupling, the carboxyl terminus of the AT1 receptor is required for activation of Src. Interestingly, ERKs activated by heterotrimeric G protein-independent mechanisms fail to phosphorylate nuclear targets due to lack of inhibition of Crm-1-induced nuclear export of ERKs. These results suggest that heterotrimeric G protein-dependent and -independent signaling mechanisms play distinct roles in Ang II-mediated cellular responses.The signaling mechanism of the angiotensin II (Ang II) 1 type 1 (AT1) receptor has traditionally been portrayed as being dependent on heterotrimeric G proteins (1). The AT1 receptor activates phospholipase C␤ (PLC␤) via G␣ q proteins. This causes generation of inositol trisphosphates as well as diacylglycerol, which in turn causes release of Ca 2ϩ from the intracellular Ca 2ϩ store sites and activation of protein kinase C (PKC), respectively. The AT1 receptor also couples to G␣ i , thereby regulating adenylyl cyclase (2). Besides coupling with the heterotrimeric G proteins, activation of tyrosine kinases is also intimately involved in the AT1 receptor signaling (3, 4). Both nonreceptor type tyrosine kinases (Src, Fyn, Yes, Pyk2, focal adhesion kinase, and JAK2) and receptor type tyrosine kinases (EGF and platelet-derived growth factor receptors) are activated by the AT1 receptor (5-8). These tyrosine kinases regulate downstream signaling mechanisms, including PLC␥, Ras-Raf-MEK-ERK, and STAT (6, 9, 10), thereby playing a critical role in cell growth responses by Ang II.Several mechanisms have been shown to mediate tyrosine kinase activation by heterotrimeric G protein-coupled receptors (GPCRs; reviewed in Refs. 11-13). First, the downstream effectors of G␣ and G␤␥ mediate tyrosine kinase activation. For example, Ca 2ϩ and PKC activated through ...

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To determine whether hemodynamic changes can modulate insulin action in vivo, we administered angiotensin II (A,,) to normal men under three separate, euglycemic conditions. First, in the presence of physiological hyperinsulinemia (-115 5,U/ml), infusion of A,, at rates of 2, 10, and 20 ng/min per kg caused significant elevations of blood pressure, whole-body glucose clearance, and plasma insulin concentrations in an Al, dose-dependent manner. Second, in the presence of plasma insulin concentrations that stimulate glucose transport maximally (-5,000 ,U/ml), A,, infusions increased whole-body glucose clearance without enhancing glucose extraction across the leg.Third, in the presence of basal insulin concentrations (.13 igU/ml), A,, infusions had no effect on whole-body glucose turnover or leg glucose extraction. Thus, A,, enhanced whole-body glucose utilization without directly stimulating glucose transport in a major skeletal muscle bed. To evaluate a possible hemodynamic mechanism for the effects of A,, on glucose utilization, we measured blood flow to two areas that differ in their sensitivity to insulin: the kidneys and the leg. We found that A,, redistributed blood flow away from the predominantly insulinindependent tissues of the kidney and toward the insulin-sensitive tissues of the leg during both sham and hyperinsulinemic glucose clamps. The redistribution of flow had no effect on whole-body glucose turnover when leg glucose uptake was unstimulated (sham clamps). However, when leg glucose uptake was activated by insulin, the redistribution of flow caused a net increase in whole-body glucose utilization. Our findings indicate that hemodynamic factors can modulate insulin action in vivo. Furthermore, our results suggest that variable activity of the renin-angiotensin system may contribute to inconsistencies in the association between insulin resistance and hypertension.

Although CAS may currently be performed for high-risk patients, it is still infrequently used in patients who require concurrent carotid and coronary interventions. In the United States, patients who undergo CAS-CABG have significantly decreased in-hospital stroke rates compared with patients undergoing CEA-CABG but similar in-hospital mortality. CAS may provide a safer carotid revascularization option for patients who require CABG.