Additional rationale for this project is based on recent 24-hour urine results for creatinine clearance and total protein excretion from 97 patients with sickle cell anemia (Hb SS) and sickle beta zero thalassemia (SB0-thalassemia) followed in the Augusta Sickle Cell Clinic. These patients ranged in age from 19-63 years (52 females, 45 males). Of these, 17 (18%) had microalbuminuria as defined by a 24-hour albumin excretion of 150-300 mg, 34 (36%) had macroalbuminuria (>300 mg albumin excretion/24-hours), thus 54% of the patients had microalbuminuria or macroalbuminuria and only 46% were normo albuminuric. 58 patients (58%) were on chronic hydroxyurea therapy. 9 patients were on angiotensin converting enzyme inhibitors (ACEi) and 20 were on angiotensin receptor blockers (ARBs) (total 30%). 55 patients (57%) had glomerular hyperfiltration (creatinine clearance of >120 ml/min). There was an age related decline in the glomerular filtration rate (GFR) observed. The number of patients with normo albuminuria shows a sharp decline by age indicative of the progression of sickle nephropathy. Recent studies of pain in SCD have led to a change in perception. Approximately 50% of the patients reported experiencing daily, chronic pain. In addition, issues related to centralization and neuropathic pain in this patient population has begun to gain increasing attention. A large body of evidence suggests that endothelin-1 plays an important role in enhancing pain stimuli and nociception in various conditions. This is mediated by ETA receptor. Berkeley SCD transgenic mice do have hyperalgesia as shown in the rationale preliminary data section of Aim 2 and ETA receptor blockade reverses this hyperalgesia towards normal. As part of an ongoing National Institute on Minority Health and Health Disparities (NIMHD) funded study of pain and its genetic correlates (study reference: 1 P20 MD003383-01), the investigators have found that SCD patients display significant hyperalgesia as measured by pressure pain algometer testing. The testing was done at three different anatomic sites in patients (n=38) and controls (n=20) and showed that SCD patients perceived pain at significantly lower pressures compared to controls (masseter: 157.7 kilopascal (kPa) for patients, 214.4 kPa for controls, p=0.017; ulna: 299.1 kPa for patients, 477.5 kPa for controls, p=0.0018; and trapezius: 290.1 kPa for patients, 462.8 kPa for controls, p=0.02). These data suggest that hyperalgesia is present in the vast majority of SCD patients and will constitute an objective parameter to monitor during the study.