Figure 1

Rho-kinase inhibitors reverse ET-1-induced constriction. A) Effect of 10 nmol/L endothelin-1 (ET-1) on the cytosolic Ca²⁺ concentration ([Ca²⁺]_i) and the vascular diameter of the spiral modiolar artery. Note that ET-1 caused a transient increase in [Ca²⁺]_i and a sustained vasoconstriction and increase in vasomotion. This constriction outlasted the stimulation with ET-1. Increasing extracellular Ca²⁺ concentration ([Ca²⁺]_ex) to 10 mmol/L ("Ca") induced an increase in [Ca²⁺]_i with parallel vasoconstriction. This increase of the [Ca²⁺]_ex from 1 to 10 mmol/L ("Ca") served as a control experiment. Measurements of [Ca²⁺]_i were normalized to the value obtained prior to the admission of ET-1 (value at time 'x' was set to 1). B) In the presence of 10 nmol/L ET-1, increasing concentrations of fasudil (1–100 μmol/L) induce dose-dependent relaxation. [Ca²⁺]_i values were normalized, with the baseline value prior to application of ET-1 designated as 1.0 (denoted as "x"). C) Dose-response curves for Y-27632-, fasudil- and hydroxy-fasudil-induced reversal of ET-1 (10 nmol/L) -mediated vasoconstriction. C) ET-1 stimulated a significant increase in VSMC contractile apparatus Ca²⁺ sensitivity. D) Fasudil completely reversed the ET-1-induced Ca²⁺-sensitization.