A selective Akt inhibitor produces hypotension and bradycardia in conscious rats due to inhibition of the autonomic nervous system.
Toxicol Sci
; 125(2): 578-85, 2012 Feb.
Article
in En
| MEDLINE
| ID: mdl-22094455
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autonomic Nervous System
/
Blood Pressure
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Bradycardia
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Nicotinic Antagonists
/
Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-akt
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Ganglionic Blockers
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Heart Rate
/
Hypotension
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Toxicol Sci
Journal subject:
TOXICOLOGIA
Year:
2012
Document type:
Article
Affiliation country:
United States