Introduction Insular stroke results in marked cardiovascular changes, and the mechanisms need to be investigated. We have recently developed a murine model of hemorrhagic insular stroke that can help us understand such mechanisms [Fontes MAP et al. (2024). Clin Auton Res 34(6), 549-560; Marins FR et al. (2020). Auton Neurosci 227, 102695]. Rilmenidine, a centrally acting antihypertensive drug, is known to reduce sympathetic activity. Previous evidence suggests that rilmenidine effects result from activation of imidazoline receptors located in premotor sympathetic neurons at the rostral ventrolateral medulla. Thus, exploring the effects of rilmenidine in rats subjected to insular stroke may help: 1) to confirm that insular stroke generates a central abnormal sympathetic tone and 2) to identify benefits of rilmenidine that may potentially attenuate post-insular stroke cardiovascular alterations.
Aims This study evaluated the effects of rilmenidine on cardiovascular, neurobehavioral and cardiac norepinephrine levels in our newly developed rat model of insular hemorrhagic stroke (ICH).
Methods Ethics approval CEUA UFMG 109/2022. Male Wistar rats were anesthetized, instrumented for injection into the insular cortex of autologous blood (ICH, 200 nL) or vehicle (saline 0.9%, IC-Sal, 200 nL; central volume control) and prepared for recording of mean arterial pressure (MAP) and heart rate (HR). Three groups (n=8-9 each) were subjected to three days of intraperitoneal treatment as follows; 1) IC-Sal treated with vehicle (NaCl 0.9%, 0.1ml /100g); 2) ICH treated with vehicle (ICH-Sal, NaCl 0.9%, 0.1ml /100g); 3) ICH treated with rilmenidine (ICH-Ril 10 μg/kg). Anxiety, activity and muscle strength were evaluated. Cardiac norepinhephrine was quantified by HPLC. One-way ANOVA was used for statistical analysis.
Results ICH-Sal rats exhibited higher baseline MAP (IC-Sal: 104±4 mmHg vs. ICH-Sal: 120±14 mmHg; p<0.01) and HR (IC-Sal: 314±21 bpm vs. ICH-Sal: 460±41 bpm; p<0.01). Rilmenidine completely prevented the ICH-evoked increases in MAP and HR (ICH-Ril: MAP: 103±5 mmHg; HR: 295±22 bpm; p<0.01). No significant neurobehavioral changes were observed. ICH increased norepinephrine cardiac levels (IC-Sal: 17±9 ng.mg-1 vs. ICH-Sal: 37±4 ng.mg-1; p=0.0101), that were normalized with rilmenidine (ICH-Sal: 37±4 ng.mg-1 vs. ICH-Ril: 7±7ng.mg-1; p=0.0007).
Conclusions Our findings with rilmenidine suggest that insular stroke generates a centrally mediated abnormal sympathetic tone. Rilmenidine prevented the cardiovascular alterations resulting from insular hemorrhagic insular stroke via reduction of noradrenergic input to the heart. Our data indicates that rilmenidine may reduce post-stroke acute cardiovascular risk. (Support: FAPEMIG APQ-01128-21; CNPq MAPF PQ 301556/2026-1; ACVG 165774/2021-5; CNPq INCT 406792/2022-4).