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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Deficiency in angiotensin AT1a receptors prevents diabetes-induced hypertension

¹Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio; ²Laboratory of Human Movement, São Judas Tadeu University, São Paulo, Brazil; ³Mackenzie University, São Paulo, Brazil; and ⁴Laboratory of Experimental Hypertension, Heart Institute (InCor), São Paulo University Medical School, São Paulo, Brazil

Submitted 21 July 2006 ; accepted in final form 10 November 2006

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 mmHg², AT1aWT vs. AT1aKO). Diabetes reduced BPV but only in AT1aWT (19 ± 0.5 vs. 8 ± 1 mmHg², 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.

cardiovascular; heart rate; blood pressure; renin-angiotensin system; mice; autonomic function; streptozotocin; diabetes

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