This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Chronic beta-blocker treatment in heart failure is associated with increases in systolic function, improvement in hemodynamics, reversal of pathologic remodeling, improvement of symptoms, a reduction in hospitalization and a reduction in mortality. The clinical evidence for the long-term benefit of beta-blocker therapy is so strong that it is now recommended therapy in all patients with class II or III heart failure symptoms who do not have specific contraindications. This study will investigate whether tolerance to the alpha 1-adrenoceptor blocking effects of carvedilol develops with chronic carvedilol therapy. We will measure the blood pressure and heart rate response to phenylephrine (a pure alpha 1-agonist) infusions in 17 subjects with heart failure. These measurements will be made prior to the initiation of carvedilol therapy, during the uptitration of carvedilol, and after 6 months of continuous carvedilol therapy. The dose of phenylephrine required to increase systolic blood pressure by 20 mm Hg (PS20) and the dose of phenylephrine required to increase diastolic blood pressure by 20 mm Hg (PD20) will be measured. Dose ratios at these doses will be calculated and compared. Prior to enrollment, a blood sample will be obtained to analyze alpha 1-adrenoceptor polymorphisms that could affect the individual's response to phenylephrine.
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