Background Obesity can cause hypertension and exacerbates sleep-disordered breathing
(SDB). Leptin is an adipocyte-produced hormone, which increases metabolic rate, suppresses
appetite, modulates control of breathing, and increases blood pressure. Obese individuals
with high circulating levels of leptin are resistant to metabolic and respiratory
effects of leptin, but they appear to be sensitive to hypertensive effects of this
hormone. Obesity-induced hypertension has been associated with hyperleptinemia. New
Zealand obese (NZO) mice, a model of polygenic obesity, have high levels of circulating
leptin and hypertension, and are prone to develop SDB, similarly to human obesity.
We hypothesize that systemic leptin receptor blocker Allo-aca will treat hypertension
in NZO mice without any effect on body weight, food intake, or breathing. Methods
Male NZO mice, 12-13 weeks of age, were treated with Allo-aca (n = 6) or a control
peptide Gly11 (n = 12) for 8 consecutive days. Doses of 0.2 mg/kg were administered
subcutaneously 2x/day, at 10 AM and 6 PM. Blood pressure was measured by telemetry
for 48 h before and during peptide infusion. Ventilation was assessed by whole-body
barometric plethysmography, control of breathing was examined by assessing the hypoxic
ventilatory response (HVR), and polysomnography was performed during light-phase at
baseline and during treatment. Heart rate variability analyses were performed to estimate
the cardiac autonomic balance. Results Systemic leptin receptor blockade with Allo-aca
did not affect body weight, body temperature, and food intake in NZO mice. Plasma
levels of leptin did not change after the treatment with either Allo-aca or the control
peptide Gy11. NZO mice were hypertensive at baseline and leptin receptor blocker Allo-aca
significantly reduced the mean arterial pressure from 134.9 +/- 3.1 to 124.9 +/- 5.7
mmHg during the light phase (P < 0.05), whereas the control peptide had no effect.
Leptin receptor blockade did not change the heart rate or cardiac autonomic balance.
Allo-aca did not affect minute ventilation under normoxic or hypoxic conditions and
HVR. Ventilation, apnea index, and oxygen desaturation during NREM and REM sleep did
not change with leptin receptor blockade. Conclusion Systemic leptin receptor blockade
attenuates hypertension in NZO mice, but does not exacerbate obesity and SDB. Thus,
leptin receptor blockade represents a potential pharmacotherapy for obesity-associated
hypertension.
