Coronary and Systemic Arterial Physiology and Immunohistochemical Markers Related to Early Coronary Arterial Lesions in Beagle Dogs Given the Potassium Channel Opener, ZD6169, or the Endothelin Receptor Antagonist, ZD1611

Abstract

We evaluated immunohistochemistry (von Willebrand Factor [vWF] or fibrinogen) and systemic and coronary arterial physiological parameters in beagle dogs to investigate early arterial lesions induced by the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611. Dogs given an oral dose of ZD6169 (experiment 1) were terminated 1 day later and showed arterial and myocardial lesions. Minimal arterial lesions exhibited few condensed medial smooth muscle cells only, with others showing segmental medial necrosis occasionally with medial/adventitial acute inflammation. Intercellular immunostaining was seen in ostensibly normal tissue, where no pathology was present in conventionally stained sections. vWF and fibrinogen are valuable tools for detecting disruption of arterial integrity. In experiment 2, 2 dogs were given a single high dose of ZD6169 or ZD1611 and BP/HR monitored by conventional measures or telemetry. Substantially reduced systolic/diastolic BP and increased HR occurred within 10 min of ZD6169 infusion: ZD1611 caused minor BP decrease and HR increase. In experiment 3, both drugs given to anaesthetized dogs induced markedly exaggerated systolic phasic forward and reverse flow in left descending and right coronary arteries. Diastolic coronary artery flows were unaffected with ZD1611 and increased slightly with ZD6169. In both coronary arteries, the ZD1611-induced increase in flows paralleled decreased resistance.

Evaluation of von Willebrand Factor and von Willebrand Factor Propeptide in Models of Vascular Endothelial Cell Activation, Perturbation, and/or Injury

“…That is, because, in response to vascular injury, VWF will bind to platelets and subendothelial collagen as it forms the hemostatic plug to seal the site of vascular damage and prevent further blood loss (Van Buul-Wortelboer et al 1989). Our data as well as that from other reports (Brott et al 2005; Brott, Richards, and Louden 2012; Jones, Bjökman, and Schofield 2013) support this hypothesis because in the extravascular space, significant extracellular matrix VWF was detected by immunohistochemistry in damaged vascular wall. It has also been suggested that during the process of DIVI damaged ECs are released from the site of injury into systemic circulation (McFarland et al 2004; Scicchitano et al 2003; Zhang et al 2010) and this may further deplete the limited cellular source of available VWF proteins.…”

Hemodynamic Correlates of Drug-induced Vascular Injury in the Rat Using High-frequency Ultrasound Imaging

“…It is also not known whether the flow pattern in the SMA in the current study was disturbed, or the magnitude of the disturbance. A recent study in dogs administered the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611, demonstrated that both drugs induced very substantial changes in bidirectional oscillatory flow patterns in coronary blood vessels with increased velocity during the cardiac cycle that preceded vascular injury (Jones, Bjorkman, and Schofield 2013). Because all the compounds tested here are vasodilators, and rat mesenteric resistance arteries are sensitive to vasodilators (Lappe, Todt, and Wendt 1986), we suspect that the secondary and lesser branches of the mesenteric vascular bed are likely dilated.…”