Cardiovascular Toxicity of a Selective Akt Inhibitor: Hypotension and Bradycardia in Conscious Rats due to Inhibition of the Autonomic Nervous System.

摘要

Akt is a serine-threonine kinase that has been shown to be amplified in a variety of human cancers and has become an important therapeutic target for intervention. As with a large number of anticancer agents, some Akt inhibitors have produced a variety of functional toxicities that may limit their clinical benefit. Although these toxicities are often identified in preclinical animal studies, the mechanism(s) responsible are often not fully characterized. This study utilized a potent and selective Akt inhibitor that produced significant hypotension and bradycardia in conscious Sprague Dawley rats. In vitro assays, including the use of isolated rat right atrial tissue and isolated rat thoracic aortic rings, were used to investigate effects on cardiac and vascular tissue, respectively. In addition, rats surgically prepared with telemetry units for continuously monitoring blood pressure and heart rate were used to identify in vivo hemodynamic effects and to investigate the role of autonomic ganglia. The in vitro studies showed that the Akt inhibitor did not produce a direct effect on heart rate or cardiac contractility but could produce vasorelaxation of vascular smooth muscle. Furthermore, in conscious rats, the Akt inhibitor completely eliminated the neural pressor response to the known nicotinic acetylcholine receptor agonist dimethylphenylpiperazinium (DMPP). In fact, the response observed with the Akt inhibitor was comparable to the response observed with the known ganglionic blocker hexamethonium. The results of this study indicate that the hypotension and bradycardia produced by the Akt inhibitor is primarily due to blockade of nAChRs in autonomic ganglia and highlight the importance of evaluating the autonomic nervous system in cardiovascular toxicities associated with new chemical entities.