Leptin Receptor Blockade Abolished Hypertension and Decreased Hypoxic Ventilatory Response in a Model of Obesity‐Related Hypertension

Abstract

INTRODUCTIONObesity causes hypertension and exacerbates sleep disordered breathing. Leptin is an adipocyte produced hormone which is implicated in regulation of metabolic rate, food intake, control of breathing and blood pressure. Obese individuals are resistant to metabolic and respiratory effects of leptin, but appeared to be sensitive to hypertensive effects of the hormone. We hypothesized that New Zealand obese mice (NZO), which are resistant to metabolic effects of leptin, remain susceptible to cardiovascular, but not respiratory, effects of this hormone.METHODSMale NZO mice of 12–13 weeks‐old were treated with leptin receptor blockers Allo‐aca (n=5) or control peptide Gly11 (n=3) for 9 consecutive days. Doses of 0.2mg/kg were administered 2x/day, at 10AM and 6PM subcutaneously. Blood pressure was measured by telemetry. Ventilation was assessed by whole‐body barometric plethysmography and control of breathing was examined by assessing the hypoxic ventilatory response (HVR). Sleep studies were conducted by full‐polysomnography.RESULTSSystemic leptin receptor blocker Allo‐aca did not affect body weight and food intake in NZO mice. In contrast, it induced a decrease in the mean arterial blood pressure from 132.9±5.9 mmHg to 121.2±11.3 mmHg during the light phase (P<0.001). Allo‐aca did not affect baseline minute ventilation in awake mice, but decreased HVR (P<0.05). There was a trend for systemic blockade of leptin receptors with Allo‐aca to suppress minute ventilation during NREM and REM sleep, whereas the control peptide Gly11 had no effect.CONCLUSIONSNZO mice were resistant to metabolic effects of leptin, but they were sensitive to the hypertensive and respiratory effects of the hormone. Thus, leptin receptor blockers can be used for pharmacotherapy for obesity‐associated hypertension, but sleep‐related hypoventilation should be considered as a potential side effect.Support or Funding InformationNIH R01s HL128970 and HL133100 to Dr. Vsevolod Y. Polotsky. Dr. Tufik and Dr. Andersen are CNPq fellowship (Brazil) recipients. Dr. Lenise Jihe Kim was supported by Associação Fundo de Incentivo à Pesquisa (AFIP, Brazil).