Flosequinan, a Vasodilator with a Novel Mechanism of Action

1. The mechanism of action of flosequinan was investigated in ferret aortic smooth muscle by the simultaneous measurement of aequorin luminescence and isometric force. 2. The control calcium-force curve was obtained by plotting the calibrated aequorin luminescence against the force from potassium-depolarized muscles. Flosequinan relaxed potassium-depolarized muscles by causing parallel changes in [Ca2+]i and force with no shift in the control [Ca2+]i-force relationship. 3. The [Ca2+]i-force relationship in the presence of a maximally effective concentration of phenylephrine was significantly shifted to the left of that for the control, potassium-depolarized muscle. Flosequinan relaxed the phenylephrine-contracted muscle by causing a large decrease in force with only a minimal decrease in [Ca2+]i, resulting in an apparent rightward shift of the [Ca2+]i-force relationship, toward the control curve. 4. In comparison, sodium nitroprusside caused relaxation of either the potassium- or phenylephrine-induced contraction solely by a decrease in [Ca2+]i with no shift in either calcium-force relationship. 5. Milrinone caused no significant rightward shift of the calcium-force relationship during phenylephrine- or potassium-induced contractions, but when milrinone was added in the absence of vasoconstrictors, relaxation was obtained with no significant decrease in [Ca2+]i. 6. Flosequinan appears to differ in mechanism of action from both nitroprusside and milrinone. It relaxes depolarization-mediated contractions solely by decreasing [Ca2+]i but also appears to be capable of reversing the apparent calcium sensitizing action of phenylephrine.