Pharmacological inhibition of the hypertensive response to combretastatin A-4 phosphate in rats

Abstract

Combretastatin A-4 phosphate (CA4P) is a novel and promising anti-neoplastic agent. However, it is associated with transient hypertension in both animal and human models. In this study, we examined the potential cardiac toxicity and hypertensive effects of CA4P, and defined the most effective pharmacological inhibition of CA4P-induced hypertension in rats. There was a significant, concentration dependent increase in mean arterial blood pressure with a maximum increase of about 60% of the baseline MAP at 30 mg/kg of CA4P compared to the saline control. However, there was no significant increase in the cardiac troponin I level after CA4P injection. Nitroglycerin and the calcium channel blocker diltiazem effectively blocked the hypertensive effects of CA4P while the beta blocker metoprolol was ineffective. Furthermore, sublingual nitroglycerin administration demonstrated an additional anti-hypertensive effect in a setting of a low dose diltiazem infusion (10 µg/kg/min). We conclude that CA4P treatment resulted in a concentration dependent increase in blood pressure without significant myocardial damage in healthy rats. The hypertensive effect of CA4P was effectively blocked by both nitroglycerin and diltiazem, but not metoprolol.