Large conductance Ca2+-activated K+ channels modulate uterine α1-adrenergic sensitivity in ovine pregnancy

Abstract

The uteroplacental vasculature is refractory to α-adrenergic stimulation, and large conductance Ca(2+)-activated K(+) channels (BK(Ca)) may contribute. We examined the effects of uterine artery (UA) BK(Ca) inhibition with tetraethylammonium (TEA) on hemodynamic responses to phenylephrine (PE) at 101 to 117 days and 135 to 147 days of ovine gestation, obtaining dose responses for mean arterial pressure (MAP), heart rate (HR), and uteroplacental blood flow (UPBF) and vascular resistance (UPVR) before and during UA TEA infusions. The UA α(1)-adrenergic receptors (α1-ARs) were assessed. The PE increased MAP and UPVR and decreased HR and UPBF dose dependently at both gestations (P < .001, analysis of variance). The %▵MAP was less at 135 to 147 days before and during TEA infusions (P ≤ .008); however, responses during TEA were greater (P ≤ .002). The PE increased %▵UPVR>>%▵MAP, thus %▵UPBF fell. The TEA enhanced PE-mediated increases in %▵UPVR at 135 to 147 days (P ≤ .03). The UA α(1)-AR expression was unchanged in pregnancy. Uterine vascular responses to PE exceed systemic vascular responses throughout pregnancy and are attenuated by BK(Ca) activation, suggesting BK(Ca) protect UPBF.

Keywords: pressor responses; uteroplacental blood flow; vascular sensitivity; α1-adrenergic receptors.

Figure 1.

Representative recording of the effects of a unilateral uterine arterial infusion of TEA (0.04 mmol/L) on mean arterial pressure, heart rate, and left and right uterine blood flow in a term pregnant ewe before and during the cumulative PE dose response. Responses shown are at 10 minutes of PE infusion ± 2 minutes. TEA indicates tetraethylammonium; PE, phenylephrine.

Figure 2.

Comparison of PE-induced increases in mean arterial pressure in pregnant sheep at 101 to 117 days (▵, ▴) and 135 to 147 days (^, •) gestation in the absence (A, open symbols) and presence (B, solid symbols) of uterine artery TEA infusion. Data are the percentage change, analyzed by 2-way ANOVA and are shown as means ± SEM. The PE responses are dose dependent (P < .001, ANOVA), modified by gestational age (P ≤ .008, ANOVA), and increased in the presence of TEA. TEA indicates tetraethylammonium; PE, phenylephrine; SEM, standard error of mean; ANOVA, analysis of variance.

Figure 3.

Comparison of the simultaneous relative changes in uteroplacental vascular resistance (UPVR, ^), mean arterial pressure (MAP, ▵), and uteroplacental blood flow (UPBF, □) during systemic PE infusions in the absence (A) and presence (B) of UA infusions of TEA at 101 to 117 days of gestation. Data were analyzed by 2-way ANOVA and are shown as means ± SEM. The PE increased UPVR and MAP and decreased UPBF dose dependently without and with TEA (P < .0001, ANOVA), and %▵UPVR exceeded %▵MAP at the doses noted (*P ≤ .008, **P ≤ .01; Holm-Sidak method). TEA indicates tetraethylammonium; PE, phenylephrine; SEM, standard error of mean; ANOVA, analysis of variance; UA, uterine artery.

Figure 4.

Comparison of the simultaneous relative changes in uteroplacental vascular resistance (UPVR, •), mean arterial pressure (MAP, ▴), and uteroplacental blood flow (UPBF, ▪) during systemic PE infusions in the absence (A) and presence (B) of UA infusions of TEA at 135 to 147 days of gestation. Data were analyzed by 2-way ANOVA and are shown as means ± SEM. The PE increased UPVR and MAP and decreased UPBF dose dependently without and with TEA (P < .0001, ANOVA), and %▵UPVR exceeded %▵MAP at the doses noted (*P < .001; **P ≤ .002; Holm-Sidak method). TEA indicates tetraethylammonium; PE, phenylephrine; SEM, standard error of mean; ANOVA, analysis of variance; UA, uterine artery.

Figure 5.

Immunoblot analysis of α₁-adrenergic receptor expression in proximal third generation uterine artery smooth muscle from nonpregnant and term pregnant ewes. α-smooth muscle actin was the loading protein. P = .5, independent samples t test.

Figure 6.

Immunoblot analysis of α₁-adrenergic receptor expression in proximal third-generation uterine and cotyledon/placental arterial smooth muscle from term pregnant ewes. α-smooth muscle actin was the loading protein. P = .4, independent samples t test.