Angiotensin II type 1 receptor activation increases microvascular permeability via a calcium dependent process

Elevated serum angiotensin II (Ang II) has been implicated in the endothelial barrier dysfunction associated with shock. We hypothesized that the increase in microvascular permeability seen with activation of the type 1 (AT1) receptor is a calcium dependent process.

Microvascular hydraulic permeability (Lp) was measured in rat mesenteric venules using the Landis micro-occlusion model. A 100 mm KCl (HK) solution was used to negate the electrochemical potential of calcium influx, and measures of Lp were obtained before and after 20 ng/ml Ang II plus HK solution (n = 5). Intracellular calcium dependence on AT1 activation was evaluated two ways: 1) Lp changes were measured in response to 10 microm of the type 1 receptor agonist [SAR] [1]-angiotensin II in HK solution (n = 6), and 2) Lp changes were measured in response to 25 microg/ml of the type 2 (AT2) receptor blocker PD-123319 (PD) plus 20 ng/ml Ang II in HK solution (n = 6).

As expected, HK perfusion (P < 0.08) and Ang II plus HK solution (P < 0.42) did not affect Lp. Although perfusion of [SAR] [1]-angiotensin II in HK solution (P < 0.001) and PD plus Ang II in HK solution (P < 0.003) both significantly increased Lp, the magnitude of this response was less than that observed with Ang II alone.

Abrogation of intracellular calcium influx during AT1 activation blunted the known Ang II induced increase in microvascular permeability. Although the effect observed during AT1 activation was blunted by the HK solution, a significant elevation of Lp was still observed. This suggests that Ang II activation of the AT1 receptor increases microvascular permeability primarily, but not exclusively, via modulation of endothelial intracellular calcium ion levels.