Cellular mechanism of vasoconstriction induced by angiotensin II: it remains to be determined.

In this issue of Circulation Research , using mouse large conduit arteries, Zhou et al1 have provided direct evidence that AT1b, a subtype of angiotensin (Ang) II type 1 (AT1) receptors, predominantly mediates contractions induced by Ang II. In Figure 3, when 100 nmol/L Ang II was applied to the abdominal aorta and the femoral artery of knockout mice for AT1a, biphasic responses in tension appeared. Tension rose rapidly and transiently peaked in a few minutes, and then declined to a lower steady level (close to the preapplication level) at 10 to 20 minutes. Thus, Ang II causes a rapid contraction that attenuates significantly after several minutes even in the continued presence of agonist. However, the mechanisms underlying the biphasic response to Ang II are not explained in the report. Stimulation of AT1 receptors leads to activation, via the G protein Gq, of phospholipase C, which hydrolyzes phosphatidylinositol-4,5-bisphosphate to generate inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DG). IP3 triggers the intracellular release of Ca2+, and additional Ca2+ enters the cell from outside due to opening of Ca2+ channels located in the cell membrane. Ca2+/calmodulin-dependent myosin light chain kinase (MLCK) can switch on MLC phosphorylation and tension development. The extent of MLC phosphorylation reflects the activities of both MLCK and MLC phosphatase (MLCP). Thus, at constant Ca2+ and MLCK activity, inhibition of MLCP will cause an increase in MLC phosphorylation and tension, a phenomenon called Ca2+ sensitization. There are two well-described myosin phosphatase inhibitory pathways.2 The first is the RhoA/Rho-kinase pathway that either directly or indirectly acts on the regulatory phosphatase subunit to inhibit phosphatase activity (see Figure). The second is the protein kinase C (PKC)/CPI-17 pathway that inhibits the catalytic subunit of myosin phosphatase. In the latter pathway, PKC inhibits …