Ontazolast

Objective—To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and to identify hemodynamic effects of ontazolast.Animals—28 Beagles.Procedure—Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1, or 3 mg/kg of body weight, IV) and for 1 hour in anesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/kg, IV).Results—Ontazolast prolonged QT interval and QT interval corrected for heart rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both variables remained prolonged but tended to decrease. In conscious dogs, ontazolast increased QT interval and QTc 15 minutes after administration, but both variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and increased tau, indicating a decreased rate of relaxation. One conscious dog receiving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondary components in their T waves.Conclusion and Clinical Relevance—Ontazolast possesses potent class-III antiarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dosedependent prolongation of QT interval in all instances, ontazolast may serve as a positive-control compound for studying other compounds that are believed to prolong the QT interval. (Am J Vet Res 2000;61:1364–1368)

We investigated the contractile effects of both activated and unactivated polymorphonuclear leukocytes (PMNs) on human vascular tissue to characterize the influence of human PMNs on vascular tone. PMNs were added either unactivated or after f-met-leu-phe (fMLP) activation (10(-8) M), into tissue chambers containing human umbilical vein segments under either control or cytokine-treated conditions. The activation state of different PMN preparations was measured by immunofluorescence staining of the adhesion glycoproteins Mac-1 and L-selectin. Both unactivated and activated PMNs induced a cell number-dependent (1.5 x 10(5) to 2 x 10(6) cells/ml) vasoconstriction in human umbilical vein segments. This PMN-induced response was not inhibited by treatment with indomethacin (10(-5) M), superoxide dismutase (2 x 10(-7) M) or L-nitro-monomethyl arginine (10(-4) M). However, treatment of PMNs with the leukotriene biosynthesis inhibitor BIRM-270 partially inhibited (-61 +/- 19%, P <.05) the contraction induced only by unactivated PMNs. Moreover, the supernatant from unactivated, but not that from activated, PMNs elicited a contractile response comparable to that from the addition of cells. We observed a significant correlation between the Mac-1/L-selectin ratio of activated PMNs and the contractile response they generated (r = 0.77, P <.05). The activated PMN response had an endothelium-dependent component, whereas the unactivated PMN response was endothelium-independent. These results suggest that human PMNs of varying activation states have the capacity to modulate vascular smooth muscle tone via distinct mechanisms. Unactivated PMNs appear to modulate tone via a secreted product, whereas the more activated phenotype modulates vascular tone via a cognate interaction with the endothelium.