The influence of angiotensin II and cyclic nucleotide second messenger signal transduction on ischemia-reperfusion-induced elevations in microvascular hydraulic permeability

Introduction: Intravascular volume loss from ischemia-reperfusion injury is a major clinical concern. We hypothesize that angiotensin II influences the ischemia-reperfusion-associated microvascular fluid leak through cyclic nucleotide second messenger signal transduction mechanisms. The purposes are to determine hydraulic permeability after ischemia-reperfusion of venules treated with 1) angiotensin II, 2) a cAMP synthesis inhibitor, 3) a cGMP inhibitor, and 4) simultaneous administration of angiotensin II and either a cAMP synthesis inhibitor or a cGMP synthesis inhibitor. Methods: Rat mesenteric postcapillary venules were micro-cannulated to measure hydraulic permeability (Lp). Ischemia-reperfusion was achieved by placing animals in a 5% oxygen environment and preventing venular flow followed by allowing blood flow to resume. Lp was measured after ischemia-reperfusion and treatment with 1) angiotensin II (20nM), 2) cAMP synthesis inhibitor (DDA,10uM), 3) cGMP synthesis inhibitor (LY83583, 10uM), and 4) angiotensin II plus either cAMP inhibition or cGMP inhibition, (n=6 in each group). Results: Compared to the 7-fold increase in Lp due to ischemia-reperfusion alone: 1) angiotensin II attenuated the 7-fold increase by 50% (p<0.001), 2) cAMP inhibition attenuated the 7-fold increase by 45% (p<0.001), 3) cGMP inhibition completed blocked any elevation in Lp due to ischemia-reperfusion (p<0.001), and 4) angiotensin II + cAMP inhibition was not statistically different from angiotensin II alone (p=0.16) while angiotensin II + cGMP inhibition attenuated the 7-fold increase in Lp due to ischemia-reperfusion by 65% (p<0.001). Conclusion: Treatment with angiotensin II attenuated increases in hydraulic permeability due to ischemia-reperfusion by 50%. Inhibition of cGMP synthesis completely blocked any increase in permeability due to ischemia-reperfusion while cAMP inhibition appears to play a lesser role. This emphasizes the major impact that cyclic nucleotide second messengers play in ischemia-reperfusion. A better understanding of mediators that reduce intravascular fluid loss from IR-induced microvascular dysfunction may help clinicians treat uncontrolled fluid extravasation that occurs during shock and sepsis.