Deficiency in angiotensin AT1a receptors prevents diabetes-induced hypertension.
The renin-angiotensin system has been implicated in the etiology of the cardiovascular complications of diabetes. Our studies extend these findings to show a specific role for angiotensin AT1a receptors in mediating diabetes-induced hypertension. Male angiotensin AT1a knockout (AT1aKO) and wild-type (AT1aWT) mice with arterial telemetric catheters were injected with streptozotocin (STZ; 150 mg/kg ip). The STZ dose was selected on the basis of a dose-response experiment in C57/BL mice. Blood glucose, water intake, body weight, blood pressure (BP), and heart rate (HR) were measured over a 2-wk period. Estimates of BP and HR variance (BPV and HRV) and their low- and high-frequency domains were also determined. STZ induced similar levels of hyperglycemia and polydypsia in the groups. Mean arterial pressure (MAP) was increased from 100 +/- 6 to 124 +/- 6 mmHg in diabetic AT1aWT. MAP was unchanged in AT1aKO (80 +/- 4 vs. 85 +/- 5 mmHg, basal vs. STZ). Treatment with an ACE inhibitor, captopril, produced a greater reduction in MAP (-18%) in diabetic AT1aWT than in AT1aKO (-3.4%). BPV was lower in AT1aKO (19 +/- 0.5 vs. 9 +/- 2 mmHg(2), AT1aWT vs. AT1aKO). Diabetes reduced BPV but only in AT1aWT (19 +/- 0.5 vs. 8 +/- 1 mmHg(2), basal vs. STZ). There were no changes in HR in either group. In AT1aKO, STZ increased HRV and its high-frequency domain with no changes seen in AT1aWT. Results document that ANG AT1a receptors are critical in diabetes-induced hypertension and in cardiac autonomic responses.
Wichi
Rogerio B
RB
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA.
Farah
Vera
V
Chen
Yanfang
Y
Irigoyen
Maria Claudia
MC
Morris
Mariana
M
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D044140:Receptor, Angiotensin, Type 1; D013311:Streptozocin