Characterization of changes in mechanical responses to histamine in omental resistance arteries in pre-eclampsia

Abstract

Changes in the effect of histamine on the smooth muscle of resistance arteries in pre-eclampsia were investigated by measuring isometric contractions in endothelium-denuded strips of omental resistance arteries from pre-eclamptic and normotensive pregnant women (pregnancy-term matched). Histamine (0.03 -1 microM) caused concentration-dependent relaxation of the contraction induced by 9, 11-epithio-11,12-methano-thromboxane A(2) (STA(2)) in strips from both groups. Sensitivity (for pre-eclampsia: pD(2)=6.66+/-0.04, n=5 and for normotensive pregnant women: pD(2)=7.07+/-0.03, n=10, P<0.001) was lower and the maximum response (90.6+/-0.6% vs 95.5+/-1.1%, P<0.05) was smaller in strips from pre-eclamptic women. Although 8-bromoadenosine-3', 5'-cyclic monophosphorothioate (Sp-isomer: Sp-8-Br-cAMPS, 0.1 - 0.3 mM), a phosphodiesterase (PDE)-resistant activator of adenosine-3',5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase, concentration-dependently attenuated the contraction induced by STA(2) in strips from both groups, the sensitivity (for pre-eclampsia: pD(2)=3.68+/-0.04, n=5 and for normotensive pregnant women: 3.94+/-0.09, n=7, P:=0.02) was lower and the maximum response (64.2+/-2.4% vs 74.9+/-4.4%, P:<0.05) was smaller in pre-eclampsia. In beta-escin-skinned strips, the pD(2) value for the contraction-inducing effect of Ca(2+) did not differ significantly between the two groups (for pre-eclampsia, n=6; for normotensive pregnant women, n=6). Thus, omental resistance arteries from human subjects with pre-eclampsia showed (i) a weaker H(2)-receptor-mediated relaxation to histamine and (ii) a weaker cyclic AMP-analogue-induced relaxation, suggesting that the reduced action of histamine may be partly due to a decreased effect of cyclic AMP.

Figure 1

Concentration-dependent effects of 9,11-epithio-11,12-methano-thromboxane A₂ (STA₂) in endothelium-denuded strips from normotensive pregnant and pre-eclamptic women. STA₂ (0.003–10 nM) was applied cumulatively from low to high concentration in strips from normotensive pregnant (n=4) and pre-eclamptic (n=4) women. The maximum amplitude of contraction induced by 10 nM STA₂ was normalized as a relative tension of 1.0 for each strip. Mean of data with s.e. shown by vertical line. ^**P<0.001 vs corresponding value for normotensive pregnant women.

Figure 2

Concentration-dependent relaxing effect of histamine on contraction induced by STA₂ in endothelium-denuded strips of human omental resistance artery. The concentration of STA₂ was 3 nM for strips obtained from normotensive pregnant women (n=10) and 1 nM for those from pre-eclamptic women (n=5). Histamine was applied in a step-wise fashion from low to high concentration during the maintained contraction observed in the presence of STA₂. Mean of data with s.e. shown by vertical line. ^*P<0.05, ^**P<0.01, significantly different from corresponding value in normotensive pregnant group (two-way repeated measures ANOVA with Scheffé's F-test).

Figure 3

Actual tracings of the effect of famotidine (3 μM) on the relaxation induced by histamine (1 μM) in the presence of STA₂ in endothelium-denuded strips from normotensive pregnant (a) and pre-eclamptic women (b). Each agent was applied as indicated by the bar. Famotidine (3 μM) was applied in the presence of histamine at the peak of the histamine-induced relaxation observed in the presence of STA₂. The concentration of STA₂ was 3 nM for the strip obtained from a normotensive pregnant woman and 1 nM for the strip from a pre-eclamptic woman.

Figure 4

Concentration-dependent relaxing effect of Sp-8-Br-cAMPS on contraction induced by STA₂ in endothelium-denuded strips from human omental resistance artery. (A) Actual tracing of the effects of Sp-8-Br-cAMPS in strips obtained from a normotensive pregnant woman (a) and from a pre-eclamptic woman (b). STA₂ was applied for 6 min at 45 min intervals. Sp-8-Br-cAMPS was pre-treated for 30 min and was present during the subsequent application of STA₂. (B) Summary of the effects of Sp-8-Br-cAMPS. The concentration of STA₂ was 3 nM in strips obtained from normotensive pregnant women and 1 nM in those from pre-eclamptic women. Mean of data with s.e. shown by vertical line. ^*P<0.05, ^**P<0.01, significantly different from corresponding value in normotensive pregnant group (two-way repeated measures ANOVA with Scheffé's F-test).

Figure 5

Ca²⁺-tension relationship in β-escin-skinned strips of omental resistance arteries obtained from normotensive pregnant and pre-eclamptic women. (A) Actual tracing of the effect of Ca²⁺ on contraction in β-escin-skinned strip from a pre-eclamptic woman. (B) Summary of the Ca²⁺-tension relationship in β-escin-skinned strips from normotensive pregnant women (n=6) or pre-eclamptic women (n=5). Mean of data is shown; s.e. did not exceed the diameter of the symbols.