Nupafant, a PAF-antagonist prototype for suppression of ventricular fibrillation without liability for QT prolongation?

Abstract

Background and purpose: PAF antagonists inhibit ischaemia-induced ventricular fibrillation (VF) in animals. However, unfavourable ancillary actions (on QT interval and coronary flow) have been reported with the PAF antagonist, BN-50739. If these are class actions, they would preclude development of PAF antagonists as novel anti-VF drugs. Our purpose was to examine this proposition using the hitherto untested PAF antagonist, nupafant.

Experimental approach: Two rat heart preparations (Langendorff and 'dual coronary' perfusion) were used to assay nupafant's effects on ischaemia-induced VF, coronary flow and QT interval, and to test for the site-selectivity necessary if any effects on VF are caused by PAF antagonism.

Key results: Global (whole-heart) delivery of 10 microM nupafant, reduced the incidence of ischaemia-induced VF and widened QT interval without affecting coronary flow. Importantly, lower concentrations (0.1 and 1 microM) had no effect on VF, yet widened QT almost identically to 10 microM nupafant. When nupafant was delivered selectively to (and entrapped within) the involved region it partially protected against VF (P<0.05). This occurred without change in QT interval. Selective nupafant delivery to the uninvolved region was without effect.

Conclusions and implications: Nupafant protects against ischaemia-induced VF primarily by site-selective actions in the ischaemic region but, unlike BN-50739, the effect is unrelated to its QT widening action, and is not compromised by any effect on coronary flow. This establishes proof of concept that VF suppression by PAF antagonism need not invariably be associated with QT prolongation or vasodilatation, justifying further development of this drug class.

Figure 1

The chemical structure of nupafant (N-4-(1-H-2-methylimidazo[4,5-c]pyridylmethyl)phenylsulphonyl-L-leucinyl ethyl ether hydrochloride).

Figure 2

Effects of nupafant on the QT interval in Langendorff perfused rat hearts after coronary artery occlusion. The QT interval was measured at 90% repolarization. Nupafant (10 μM) or vehicle delivery (‘test') began 10 min before onset of ischaemia. ^*P<0.05 versus control (n=12). Involved zone sizes were 45±1% of total ventricular weight in the nupafant group and 44±1% in controls. Data for 0.1 and 1 μM PAF were similar to data for the 10 μM group and have been omitted for clarity.

Figure 3

Group incidence (%) of VF during 30 min of ischaemia (dual perfusion experiment) in rat perfused hearts Krebs containing vehicle or nupafant was delivered to both coronary beds, selectively to the coronary bed or selectively to the right coronary bed using the dual perfusion cannula; n=12 per group. Delivery to the two sites is indicated (‘yes' or ‘no'). ^*P<0.05 versus control (no nupafant in left or right perfusion bed).

Figure 4

Effect of nupafant on VF onset and incidence in discrete time bins. In (a) VF onset time (mean sec) and in (b), Group incidence (%) of VF during 30 min of ischaemia in discrete time bins. Krebs containing vehicle or nupafant was delivered selectively to the left coronary bed in hearts perfused with the dual perfusion cannula; n=12 per group. ^* P<0.05 versus control.