In AMTG and AM+/-, we evaluated the hemodynamic parameters, including blood pressure and heart rate, by intraarterial cannulation
(Shindo et al., 2000; Shindo et al., 2001). Blood pressure was significantly lower in AMTG than in WT littermates (mean blood pressure: AMTG 109.3 +- 4.7 vs WT 124.4 +- 2.7 mm Hg). No significant change in heart rate accompanying the reduction in blood pressure was observed. To determine the extent to which the reduced blood pressure seen in AMTG was due to increased NO release, we studied the effects of A^-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, on blood pressure. The pressor response elicited by intravenous injection of L-NMMA was significantly higher in AMTG (AMTG 21.1 +- 3.3 vs WT 10.7 +- 1.3%; p<0.01); in fact, it offset the difference in blood pressure between the two groups. Plasma cGMP concentrations were significantly higher in AMTG than in WT mice, which is indicative of steady-state activation of the NO-cGMP pathway.
We also measured blood pressures in AM+/- mice and found them to be significantly higher than in WT (mean blood pressure: AM+/-128.4+-2.2 vsWT 118.7+-2.4 mm Hg).
We next examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AMTG, AM+/-and WT (Nishimatsu et al., 2002). Baseline RPP was significantly lower in AMTG than in AM+/-, and WT mice (AM+/- 93.4+-4.6, WT 85.8+-4.2, AMTG 72.4+-2.4 mm Hg, p<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in AMTG than that in AM+/- and WT (% RPP 10"7mol/L ACh: AM+/- 48.1+-3.9, WT 57.5+-5.6, AMTG 22.8+-4.8%, p<0.01). L-NAME caused greater vasoconstriction in AMTG (% RPP 10"4 mol/L L-NAME: AM+/- 33.1+-3.3, WT 55.5+-7.2, AMTG 152.6+21.2%, p<0.01). Both AM antagonists increased RPP in AMTG to a greater extent compared with AM+/- and WT (% RPP 10"6mol/L
CGRP(8-37): AM+/- 12.8+-2.6, WT 19.4+-3.6, AMTG 41.8+-8.7%, p<0.01).
We also evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes. In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in AMTG and greater values in AM+/- mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. Therefore, AM plays a role in the physiological regulation of the vascular tone and AM protects tissues from ischemia/reperfusion injury through its NO releasing activity.
Finally, our studies using transgenic and knockout mice demonstrated that AM has hypotensive and protective effects on organ and vasculature at postnatal stages as well as an important role in morphogenesis during the embyronic stage and in the maintenance of pregnancy. Further investigation is required on the underlying precise mechanisms of its diverse roles from embryo to adults.
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