CMT‐3, an anti‐inflammatory, non‐antibiotic tetracycline, attenuates AngII‐induced hypertension

Abstract

BackgroundOur previous studies have established that activation of microglial cells and neuro‐inflammation in autonomic brain regions, particularly in the paraventricular nucleus (PVN) of the hypothalamus, plays a critical role in hypertension (HTN). This conclusion is primarily based on the evidence that the tetracycline antibiotic minocycline (Mino) inhibits microglial activation and attenuates HTN. Since Mino has both anti‐inflammatory and antibiotic properties, we sought to determine the property responsible for its antihypertensive effects using the chemically modified tetracycline‐3 (CMT‐3), that has no antibiotic activity.ObjectiveWe hypothesized that central administration of CMT‐3, would inhibit microglial activation, neuro‐inflammation and attenuate HTN.MethodsSix‐week‐old male SD rats (n=8–12/group) were implanted with telemetry transducers. Ten days after surgery, 2 osmotic minipumps were implanted to subcutaneously infuse AngII (200ng/kg/min,) or vehicle and intracerebroventricularly infuse CMT‐3 (3.5μg/hr) or vehicle. Mean arterial pressure (MAP) was recorded weekly; after 4 weeks of AngII treatment, spectral analysis of was performed for autonomic nerve activity and anti‐Iba1 immunostaining was carried out to quantitate activated microglia in the brain.ResultsCMT‐3 significantly attenuated the AngII‐induced increase in MAP both in light: (Con:102±3, CMT‐3:101±4, AngII:158±23, AngII+CMT‐3:125±20 mmHg) and dark cycles (Con:102±2, CMT‐3: 102±3, AngII: 174±20, AngII+CMT‐3:145±28 mmHg). The heart to body weight ratio was similarly decreased (Con:2.9±0.3, CMT‐3:2.9±0.1, AngII:3.9±0.4, AngII+CMT‐3:3.3±0.2 mg/g; p<0.05) with CMT‐3. CMT‐3 normalized AngII perturbed autonomic activity, as measured by LF/HF of SBP (Con:1.8±0.7, CMT‐3:2.0±1.6, AngII:5.4±4, AngII+CMT‐3:2.9±1.9; p<0.001)). Furthermore, AngII increased activated microglial cells ~2.5‐fold, predominantly in the PVN, and CMT‐3 significantly attenuated this increase (p<0.01).ConclusionThese data indicate that inhibition of neuro‐inflammation is key in correction of autonomic dysregulation and attenuation of HTN. They suggest that the anti‐inflammatory, rather than the antibiotic property, of Mino mediates these effects. Thus, CMT‐3 may be a better therapeutic candidate for neurogenic resistant hypertension in humans as it circumvents the problems associated with continuous antibiotic administration.Support or Funding InformationThis work is supported by NIH grant R01HL033610