Role of potassium and calcium channels in sevoflurane-mediated vasodilation in the foeto-placental circulation

Abstract

Background: Sevoflurane has been demonstrated to vasodilate the foeto-placental vasculature. We aimed to determine the contribution of modulation of potassium and calcium channel function to the vasodilatory effect of sevoflurane in isolated human chorionic plate arterial rings.

Methods: Quadruplicate ex vivo human chorionic plate arterial rings were used in all studies. Series 1 and 2 examined the role of the K+ channel in sevoflurane-mediated vasodilation. Separate experiments examined whether tetraethylammonium, which blocks large conductance calcium activated K+ (KCa++) channels (Series 1A+B) or glibenclamide, which blocks the ATP sensitive K+ (KATP) channel (Series 2), modulated sevoflurane-mediated vasodilation. Series 3 - 5 examined the role of the Ca++ channel in sevoflurane induced vasodilation. Separate experiments examined whether verapamil, which blocks the sarcolemmal voltage-operated Ca++ channel (Series 3), SK&F 96365 an inhibitor of sarcolemmal voltage-independent Ca++ channels (Series 4A+B), or ryanodine an inhibitor of the sarcoplasmic reticulum Ca++ channel (Series 5A+B), modulated sevoflurane-mediated vasodilation.

Results: Sevoflurane produced dose dependent vasodilatation of chorionic plate arterial rings in all studies. Prior blockade of the KCa++ and KATP channels augmented the vasodilator effects of sevoflurane. Furthermore, exposure of rings to sevoflurane in advance of TEA occluded the effects of TEA. Taken together, these findings suggest that sevoflurane blocks K+ channels. Blockade of the voltage-operated Ca++channels inhibited the vasodilator effects of sevoflurane. In contrast, blockade of the voltage-independent and sarcoplasmic reticulum Ca++channels did not alter sevoflurane vasodilation.

Conclusion: Sevoflurane appears to block chorionic arterial KCa++ and KATP channels. Sevoflurane also blocks voltage-operated calcium channels, and exerts a net vasodilatory effect in the in vitro foeto-placental circulation.

Figure 1

Schematic representation of the ex vivo incubation model system used in the isolated vessel experiments.

Figure 2

Schematic representation of the experimental design used in each experimental series, with the exception of series 1B.

Figure 3

Blockade of K_Ca++ channels enhances the vasodilatory effect of sevoflurane. Sevoflurane produced significant dose dependent vasodilation of chorionic plate arterial rings compared to control conditions. Prior blockade of K_Ca++ channels by incubation in 1 × 10^-2 M tetraethylammonium (n = 10 rings per group) enhanced the vasodilatory effect of sevoflurane. *P < 0.05 compared to rings exposed to control conditions. (Two way RM-ANOVA). † P < 0.05 compared to rings exposed to sevoflurane plus vehicle at graded sevoflurane concentrations (post hoc between group t test).

Figure 4

Prior exposure of chorionic rings to sevoflurane blocks the effect of tetraethylammonium. Exposure of rings to 1 × 10^-2 M tetraethylammonium transiently enhances resting tone. This effect is abolished following prior incubation in sevoflurane, demonstrating that sevoflurane blocks K_Ca++ channels (n = 10 rings per group). *P < 0.05 compared to control (Two way RM-ANOVA). † P < 0.05 compared to control at each timepoint (post hoc between group t test).

Figure 5

Blockade of K_ATP channels enhances the vasodilatory effect of sevoflurane. Sevoflurane produced significant dose dependent vasodilation of chorionic plate arterial rings compared to control conditions. Prior blockade of K_ATP channels by incubation in 1 × 10^-5 M glibenclamide (n = 10 rings per group) enhanced the vasodilatory effect of sevoflurane. *P < 0.05 compared to rings exposed to control conditions. (Two way RM-ANOVA). † P < 0.05 compared to rings exposed to sevoflurane plus vehicle at graded sevoflurane concentrations (post hoc between group t test).

Figure 6

Blockade of sarcolemmal voltage-operated Ca⁺⁺ channel (VOCC) attenuates the vasodilatory effect of sevoflurane. Sevoflurane produced significant dose dependent vasodilation of chorionic plate arterial rings compared to control conditions. Prior blockade of VOCC's by incubation in 1 × 10^-6 M verapamil (n = 10 rings per group) reduced the vasodilatory effect of sevoflurane. *P < 0.05 compared to rings exposed to control conditions. (Two way RM-ANOVA). † P < 0.05 compared to rings exposed to sevoflurane plus verapamil at graded sevoflurane concentrations (post hoc between group t test).

Figure 7

Blockade of sarcolemmal voltage-independent Ca⁺⁺ channels (VICC), by prior incubation with 1 × 10^-4 M SK&F 96365 (n = 10 rings per group), does not alter sevoflurane mediated vasodilation. Sevoflurane produced significant dose dependent vasodilation compared to control conditions, which was not modulated by SK&F 96365. *P < 0.05 compared to rings exposed to control conditions. (Two way RM-ANOVA).

Figure 8

Blockade of sarcoplasmic reticulum Ca⁺⁺ channel, by prior incubation with 5 × 10^-5 M ryanodine (n = 10 rings per group), does not alter sevoflurane mediated vasodilation. Sevoflurane produced significant dose dependent vasodilation compared to control conditions, which was not modulated by ryanodine. *P < 0.05 compared to rings exposed to control conditions. (Two way RM-ANOVA).