A selective Akt inhibitor produces hypotension and bradycardia in conscious rats due to inhibition of the autonomic nervous system.

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.

Differences in effects on myocardium and mitochondria by angiogenic inhibitors suggest separate mechanisms of cardiotoxicity.

Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine.

Respiratory inductive plethysmography as a method for measuring ventilatory parameters in conscious, non-restrained dogs.

Introduction: Assessing the effects of new chemical entities on respiratory function in animal models is an essential component of preclinical drug safety evaluation. Methods currently available for measuring ventilatory parameters in conscious dogs generally utilize a plethysmograph chamber or a face mask equipped with a pneumotachograph attached to the snout of the animal. These methods require restraint and allow for only short, periodic measurements.

Head-out plethysmography in safety pharmacology assessment.

The importance of the ability to accurately evaluate respiratory function in animals has been underscored by the classification of the respiratory system as a vital organ system by regulatory agencies in the United States, the European Union, and Japan. A comprehensive assessment of respiratory function should include an evaluation of ventilatory function, including rate and volume measurements, overall pulmonary ventilation (i.e.

A model of orthostatic hypotension in the conscious monkey using lower body negative pressure.

Introduction: Methods most commonly used for detecting susceptibility to orthostatic hypotension in humans include head-up tilt and the application of lower body negative pressure (LBNP). The objective of this study was to evaluate the use of LBNP for detecting drug-induced changes in susceptibility to orthostatic hypotension in conscious monkeys (Macaca fascicularis).

Methods: Orthostatic responses were produced using an airtight chamber, which sealed around the stomach (umbilical area) and enclosed the lower body, to which were applied successive decrements of 10 mmHg chamber pressure every 5 min until the orthostatic response was observed.