title: A selective Akt inhibitor produces hypotension and bradycardia in conscious rats due to inhibition of the autonomic nervous system.
abstract: Akt is a serine-threonine kinase that is amplified in a variety of human cancers, and as with other anticancer agents, some Akt inhibitors have produced functional cardiovascular effects such as marked hypotension that may limit their clinical benefit. Although identified in preclinical studies, the mechanism(s) responsible for these effects are often not fully characterized; potential targets include Akt signaling disruption in cardiac tissue, vascular smooth muscle, and/or autonomic system signaling. A selective Akt inhibitor was found to produce a rapid and marked hypotension and bradycardia in conscious rats. Isolated right atrial tissue and isolated thoracic aortic rings were used to examine direct effects of Akt inhibition on cardiac and vascular tissues, respectively. In addition, rats surgically prepared with telemetry units for monitoring blood pressure and heart rate were used to investigate potential effects on the autonomic nervous system (ANS). Whereas this Akt inhibitor did not produce any significant effect on atrial tissue, it did cause vasorelaxation of aortic rings. More significantly, in conscious rats, the Akt inhibitor inhibited the neural pressor response to the known nicotinic acetylcholine receptor (nAchR) agonist dimethylphenylpiperazinium (DMPP). In fact, the response observed was comparable to the response observed with the known ganglionic blocker hexamethonium. Thus, the hypotension and bradycardia produced by the Akt inhibitor is primarily due to blockade of nAchRs in autonomic ganglia. This finding highlights the importance of evaluating the ANS for cardiovascular effects associated with new chemical entities as well as suggesting a novel direct effect of an Akt inhibitor on nAchRs.
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences, Philadelphia, Pennsylvania 19104, USA. jon.p.renninger@gsk.com
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Renninger
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Murphy
authors.forename: Diane W
authors.initials: DW
authors.lastname: Morel
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory; D001919:Bradycardia / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005725:Ganglia, Autonomic / Q000187:drug effects / Q000503:physiopathology; D005730:Ganglionic Blockers / Q000633:toxicity*; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013686:Telemetry; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000322:Adrenergic Agonists; D005730:Ganglionic Blockers; D005731:Ganglionic Stimulants; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt