LOSARTAN IMPROVES VENTILATION IN DYSTROPHIC HAMSTERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The BIO 14.6 hamster, an animal model of limb-girdle muscular dystrophy demonstrates compromised ventilation resulting in hypoxemia that may exacerbate cardiac and skeletal muscle dysfunction. This animal model also exhibits levels of angiotensin II and angiotensin AT1 receptors. Not only is this system active as a classic endocrine, it is also found in the central nervous system where it modulates CNS function including dopaminergic neuron integrity, tyrosine hydroxylase expression, dopaminergic release and dopaminergic receptor function. The purpose of this proposal is to test the hypothesis that chronic losartan (an AT1 receptor antagonist) administration will improve ventilation in dystrophic hamsters by 1. improving diaphragmatic structure and function (as suggested by the recent study by Cohn and colleagues) and 2. decreasing TH expression, dopamine production, and normalizing dopamine receptor function. Another factor that may affect ventilation is that losartan augments cardiovascular function in dystrophic hamsters. Although this is well documented, we will also determine if structural changes in the dystrophic heart such as increased fibrosis are also improved by losartan function.