• To define in normal controls, human PSD, PDD, the actions of acute SQ BNP on the cardiorenal and humoral function and the integrated response to acute sodium loading dose [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  

• Subjects with PSD, PDD, acute SQ BNP administration will result in improved renal response to acute sodium loading with an increase in urinary sodium excretion, urine flow, glomerular filtration rate, effective renal plasma flow as compared to placebo [ Time Frame: 5 ] [ Designated as safety issue: Yes ]
  
• Subjects with PSD,PDD, acute SQ BNP administration will result in improved humoral response to acute sodium loading with greater suppression of plasma renin activity, plasma angiotensin II, plasma aldosterone, plasma catecholamines as compared to placebo [ Time Frame: 5 ] [ Designated as safety issue: No ]
  
• Subjects with PSD and PDD, acute SQ BNP will respond to acute sodium loading by increased cardiac output, improved diastolic filling, less of an increase in filling pressures and improved cardiac response compared to controls. [ Time Frame: 5 ] [ Designated as safety issue: No ]
  

The broad objective of this project is to advance our understanding of the integrative biology of the natriuretic peptide system (NPS) in the regulation of ventricular, renal, and humoral function in human preclinical left ventricular dysfunction, and to evaluate chronic peptide therapy with BNP as an effective strategy in preclinical ventricular dysfunction. Specifically, we will focus on human preclinical left ventricular systolic dysfunction (PSD) and human preclinical left ventricular diastolic dysfunction (PDD). Our studies recognize that the number of persons with congestive heart failure (CHF) continues to rise, and despite recent advances in the treatment of overt symptomatic CHF, mortality and morbidity remain high, and the potential for retarding progression to terminal CHF is limited. Studies have established that 40-50% of incident CHF cases are due primarily to abnormal diastolic function. The need to understand the biology and to identify effective therapy for preclinical left ventricular dysfunction is now a priority in efforts to delay the progression of CHF. The importance of recognizing and treating preclinical left ventricular dysfunction has been likened to well-recognized strategies in the field of oncology, where an emphasis on recognition and treatment of preclinical disease has been adapted. The natriuretic peptides (NPs) are a family of structurally similar but genetically distinct peptides with vasodilating, natriuretic, renin inhibiting, and lusitropic properties. Acute peptide therapy with brain natriuretic peptide (BNP) infusion has recently been approved by the FDA as a therapeutic strategy for the treatment of acute human decompensated CHF. We will determine the effects of acute SQ BNP or placebo administration on the integrated cardiorenal and humoral response to acute sodium load (sodium chloride 0.9% 0.25 ml/kg/min for 1 hour) in three groups of subjects: Group 1 normal controls, Group 2 with PSD, and Group 3 with PDD. Doppler echocardiography and tonometry will be used to measure cardiac and vascular function before and during the sodium load. Renal function studies will assess sodium excretion, renal plasma flow, and glomerular filtration rate at baseline, during, and after the sodium load. Blood will be drawn for humoral analysis including catecholamines, renin, aldosterone, angiotensin II, atrial natriuretic peptide (ANP), BNP, and cyclic guanosine monophosphate (cGMP) at baseline, during, and after the sodium load. Collection of blood at baseline, during, and after sodium load to store for future DNA/Protein analysis.