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

• DOI: 10.1096/fasebj.31.1_supplement.1071.9
• Publication Date: 2023-11-26T17:16:59Z
• Authors: Ravindra K Sharma; Monica Santisteban; Gilberto O Lobaton; Elaine M Richards; Mohan K Raizada
• Keywords: Minocycline

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