Differential [[[Ca.sup.2+]].sub.i] signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats

Vascular resistance and blood pressure (BP) are reduced during late normal pregnancy (Norm-Preg). In contrast, studies in human preeclampsia and in animal models of hypertension in pregnancy (HTN-Preg) have suggested that localized reduction in uterine perfusion pressure (RUPP) in late pregnancy is associated with increased systemic vascular resistance and BP: however, the vascular mechanisms involved are unclear. Because [Ca.sup.2+] is a major determinant of vascular contraction, we hypothesized that the intracellular free calcium concentration ([[[Ca.sup.2+]].sub.i]) signaling of vasoconstriction is differentially regulated in systemic microvessels during normal and RUPP in late pregnancy. Pressurized mesenteric microvessels from Norm-Preg and RUPP rats were loaded with fura 2 in preparation for simultaneous measurement of diameter and [[[Ca.sup.2+]].sub.i] (presented as fura 2 340/380 ratio). Basal [[[Ca.sup.2+]].sub.i] was lower in RUPP (0.73 [+ or -] 0.03) compared with Norm-Preg rats (0.82 [+ or -] 0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, [10.sup.-5] M), angiotensin II (ANG II, [10.sup.-7] M), or endothelin-1 (ET-1, [10.sup.-7] M) caused an initial peak followed by maintained vasoconstriction and [[[Ca.sup.2+]].sub.i]. KCl caused similar peak vasoconstriction and [[[Ca.sup.2+]].sub.i] in Norm-Preg (45.5 [+ or -] 3.3 and 0.89 [+ or -] 0.02%) and RUPP rats (46.3 [+ or -] 2.1 and 0.87 [+ or -] 0.01%). Maximum vasoconstriction to Phe, ANG II, and ET-1 was not significantly different between Norm-Preg (28.6 [+ or -] 4.8, 32.5 [+ or -] 6.3, and 40 [+ or -] 4.6%, respectively) and RUPP rats (27.8 [+ or -] 5.9, 34.4 [+ or -] 4.3, and 38.8 [+ or -] 4.1%, respectively). In contrast, the initial Phe-, ANG II-, and ET-1-induced 340/380 ratio ([[[Ca.sup.2+]].sub.i]) was reduced in RUPP (0.83 [+ or -] 0.02, 0.82 [+ or -] 0.02, and 0.83 [+ or -] 0.03. respectively) compared with Norm-Preg rats (0.95 [+ or -] 0.04, 0.93 [+ or -] 0.01, and 0.92 [+ or -] 0.02, respectively). Also, the [[[Ca.sup.2+]].sub.i]-vasoconstriction relationship was similar in KCl-treated but shifted to the left in Phe-, ANG II-, and ET-1-treated microvessels of RUPP compared with Norm-Preg rats. The lower agonist-induced [[[Ca.sup.2+]].sub.i] signal of vasoconstriction and the leftward shift in the [[[Ca.sup.2+]].sub.i]-vasoconstriction relationship in microvessels of RUPP compared with Norm-Preg rats suggest activation of [[[Ca.sup.2+]].sub.i] sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such a [[[Ca.sup.2+]].sub.i] sensitization pathway(s) may also provide a feedback effect on [Ca.sup.2+] mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in systemic microvessels during RUPP in late pregnancy. resistance vessels; vascular smooth muscle; intracellular free calcium concentration; preeclampsia