Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation.

Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM-1). Recently, we reported that ICAM-1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC-MR-/-) and wild-type littermate controls (EC-MR+/+). MR was specifically deleted in heart EC, and in EC-containing tissues, but not in leukocytes of TAC EC-MR-/- mice. While EC-MR-/- TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNFα and the endothelin receptors in the LV as compared to EC-MR+/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM-1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC-MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload.

Behavioral effects on rats of motion within a high static magnetic field.

Some human subjects report vestibular disturbances such as vertigo, apparent motion, and nausea around or within high strength MRI systems operating at 4 T to 9.4 T. These vestibular effects have been ascribed to the consequences of movement through the high magnetic field. We have previously found that exposure to magnetic fields above 7 T suppresses rearing, causes locomotor circling, and induces conditioned taste aversion (CTA) in rodents. The present experiments were designed to test the effects on rats of motion through the magnetic field of the 14.1 T superconducting magnet. In Experiment 1, we compared the effects of multiple rapid insertions and removals from the center of the magnet to the effects of continuous exposure. Repeated traversal of the magnetic field gradient with only momentary exposure to 14.1 T was sufficient to suppress rearing and induce a significant CTA. Repeated insertion and removal from the magnet, however, did not have a greater effect than a single 30-min exposure on either acute locomotor behavior or CTA acquisition. Prolonged exposure was required to induce locomotor circling. In the second series of experiments, we controlled the rate of insertion and removal by means of an electric motor. Locomotor circling appeared to be dependent on the speed of insertion and removal, but the suppression of rearing and the acquisition of CTA were independent of speed of insertion and removal. In Experiment 3, we inserted rats into the center of the magnet and then rotated them about their rostral-caudal axis during a 30-min 14.1 T exposure. Rotation within the magnet did not modulate the behavioral effects of exposure. We conclude that, in rats, movement through the steep gradient of a high magnetic field has some behavioral effects, but sustained exposure to the homogenous center of the field is required for the full behavioral consequences.

Repeated exposure attenuates the behavioral response of rats to static high magnetic fields.

Exposure of rats to high strength static magnetic fields of 7 T or above has behavioral effects such as the induction of locomotor circling, the suppression of rearing, and the acquisition of conditioned taste aversion (CTA). To determine if habituation occurs across magnetic field exposures, rats were pre-exposed two times to a 14 T static magnetic field for 30 min on two consecutive days; on the third day, rats were given access to a novel 0.125% saccharin prior to a third 30-min exposure to the 14 T magnetic field. Compared to sham-exposed rats, pre-exposed rats showed less locomotor circling and an attenuated CTA. Rearing was suppressed in all magnet-exposed groups regardless of pre-exposure, suggesting that the suppression of rearing is more sensitive than other behavioral responses to magnet exposure. Habituation was also observed when rats underwent pre-exposures at 2-3h intervals on a single day. Components of the habituation were also long-lasting; a diminished circling response was observed when rats were exposed to magnetic field 36 days after 2 pre-exposures. To control for possible effects of unconditioned stimulus pre-exposure, rats were also tested in a similar experimental design with two injections of LiCl prior to the pairing of saccharin with a third injection of LiCl. Pre-exposure to LiCl did not attenuate the LiCl-induced CTA, suggesting that 2 pre-exposures to an unconditioned stimulus are not sufficient to explain the habituation to magnet exposure. Because the effects of magnetic field exposure are dependent on an intact vestibular apparatus, and because the vestibular system can habituate to many forms of perturbation, habituation to magnetic field exposure is consistent with mediation of magnetic field effects by the vestibular system.