Acetylcholinesterase Inhibition Attenuates Lipopolysaccharide‐Induced Hypotension in Unanesthetized Hypertensive Rats

Abstract

Background Hypertension and sepsis are highly prevalent clinical risk factors for morbidity and mortality. Administration of lipopolysaccharide (LPS) induces systemic inflammation (SI) and phathophysiological changes observed during sepsis, such as exacerbated release of inflammatory markers associated with hypotension, tachycardia, and hypothermia followed by fever. We have previously shown that both LPS-induced hypothesion and hypothermia are enhanced in hypertensive rats. Increased availability of acetylcholine may reduce inflammation. However, whether acetylcholinesterase inhibition modulates SI and its cardiovascular and thermorregulatory consequences in neurogenic hypertension remains unkonwn. Aim This study aimed to investigate the putative anti-inflammatory property of pyridostigmine (PIR), an acetylcholinesterase inhibitor, on cardiovascular and thermoregulatory changes observed during LPS-induced SI (at a septic-like model) in spontaneously hypertensive rats (SHR). Methods Wistar and SHR rats were used in the present study. Forty-eight hours before cardiovascular and deep body temperature (Tb) recordings, the animals underwent the surgery for femoral artery (for direct hemodynamic recordings) and vein catheterization for PIR (0.25 mg kg-1), LPS (1.5mg kg−1), or saline administration. In the same surgical procedure, an intraperitoneal temperature data-logger capsule was inserted for Tb recordings. We combined hemodynamic and thermoregulatory recordings after LPS administration and plasma measurements of interleukin (IL)-1β and IL-6. Results SI in Wistar rats was marked by a drop in blood pressure (2 ± 2 vs. −12 ± 2 mmHg, P < 0.0001). Compared with Wistar, LPS-induced drop in blood pressure was higher in SHR (−44 ± 4 vs. 2 ± 2 mmHg, P < 0.0001). PIR attenuated LPS-induced hypotension in Wistar (-12 ± 2 vs. 4 ± 3 mmHg, P = 0.0048) and SHR rats (-44 ± 4 vs. -23 ± 4 mmHg, P = 0.0016). LPS induced hypothermia followed by fever in Wistar rats (37.5 ± 0.2 vs. 38.9 ± 0.2ºC, P < 0.0001), whereas, in SHR, a maintained hypothermia without fever was observed (36.4 ± 0.2ºC). PIR attenuated fever in Wistar rats (38.9 ± 0.2 vs. 38.0 vs. 0.2ºC, P = 0.0015), but did not affect LPS-induced hypothermia in SHR (36.6 ± 0.1ºC). After LPS administration, Wistar rats showed significant plasma IL-1β (1393 ± 218 vs. 49 ± 12 pg mL−1, P < 0.0001) and IL-6 surges (44732 ± 5870 vs. 144 ± 13, P < 0.0001), and this increase was prevented by PIR pretreatment (1393 ± 218 vs. 430 vs. 98 pg mL−1, P = 0.0018 and 44732 ± 5870 vs. 18280 vs. 4123 pg mL−1, P = 0.0438). This anti-inflammatory effect of PIR was not observed in SHR. Conclusion The findings of the present study are consistent with the notion that pretreatment with an acetylcholinesterase inhibitor (PIR) attenuates the plasma IL-1β and IL-6 surges, hypotension, and fever in Wistar rats. On the other hand, PIR attenuated hypotension without preventing hypothermia, and plasma pro-inflammatory cytokines surges in SHR. We suggest that increased acetylcholine availability reduces LPS-induced SI in Wistar, but not in SHR. These findings reveal a novel effect of acetylcholinesterase inhibition during SI in normotensive and hypertensive rats.