OBJECTIVE: Clinical observations point towards heterogeneity in patients' responses to antihypertensive drugs. As our earlier work showed that angiotensin II (AngII) sensitivity is associated with the A1166C polymorphism of the AngII type 1 receptor (AT1R) gene, we conducted the present study in which the responses to acute AT1R blockade were evaluated. METHODS: After 7 days of low and high sodium diet, the hormonal as well as systemic and renal hemodynamic responses to acute AT1R blockade with EXP3174 (active metabolite of losartan) were studied in 15 AA and 14 CC essential hypertensive patients. By means of platelet-binding studies the baseline AT1R density (Bmax) and affinity (KD) was tested. RESULTS: During low and high salt diet, baseline Bmax and KD were comparable between both genotype groups. At baseline, during low salt diet, CC patients had significantly lower glomerular filtration rate and a trend towards lower effective renal plasma flow (ERPF) compared to AA patients. Blood pressure responses to EXP3174 during high salt were significantly blunted in CC patients compared to AA patients (mean arterial pressure: 1.8 versus 7.5%; P < 0.05). During low salt the increase in ERPF (12.9 versus 16.1%; P = 0.08), as well as the decrease in filtration fraction (9.0 versus 14.0%; P = 0.05) and renal vascular resistance (7.5 versus 15.1%; P = 0.06) were blunted in CC patients compared to AA patients. Humoral effects did not differ between the groups. CONCLUSION: This study shows that the systemic and renal hemodynamic responses to acute AT1R blockade are, at least in part, genetically determined.
OBJECTIVE: Clinical observations point towards heterogeneity in patients' responses to antihypertensive drugs. As our earlier work showed that angiotensin II (AngII) sensitivity is associated with the A1166C polymorphism of the AngII type 1 receptor (AT1R) gene, we conducted the present study in which the responses to acute AT1R blockade were evaluated. METHODS: After 7 days of low and high sodium diet, the hormonal as well as systemic and renal hemodynamic responses to acute AT1R blockade with EXP3174 (active metabolite of losartan) were studied in 15 AA and 14 CC essential hypertensivepatients. By means of platelet-binding studies the baseline AT1R density (Bmax) and affinity (KD) was tested. RESULTS: During low and high salt diet, baseline Bmax and KD were comparable between both genotype groups. At baseline, during low salt diet, CC patients had significantly lower glomerular filtration rate and a trend towards lower effective renal plasma flow (ERPF) compared to AA patients. Blood pressure responses to EXP3174 during high salt were significantly blunted in CC patients compared to AA patients (mean arterial pressure: 1.8 versus 7.5%; P < 0.05). During low salt the increase in ERPF (12.9 versus 16.1%; P = 0.08), as well as the decrease in filtration fraction (9.0 versus 14.0%; P = 0.05) and renal vascular resistance (7.5 versus 15.1%; P = 0.06) were blunted in CC patients compared to AA patients. Humoral effects did not differ between the groups. CONCLUSION: This study shows that the systemic and renal hemodynamic responses to acute AT1R blockade are, at least in part, genetically determined.
Authors: Mickey M Martin; Jessica A Buckenberger; Jinmai Jiang; Geraldine E Malana; Gerard J Nuovo; Maqsood Chotani; David S Feldman; Thomas D Schmittgen; Terry S Elton Journal: J Biol Chem Date: 2007-06-22 Impact factor: 5.157