The Influence of Anesthesia on the Cardiovascular Effects of Centrally Administered Clonidine

Abstract

The α2 adrenergic receptor (α2AR) agonists are known to induce hypotensive responses when administered via intracerebroventricular (icv) route in normotensive rats anesthetized with either pentobarbital or urethane. However, the icv injection of α2AR agonists such as clonidine (CLO) produces hypertensive responses in normotensive conscious rats. To date, the effects icv administration of CLO in normotensive rats under ketamine/xylazine anesthesia, a commonly used anesthetic combination in experimental studies, is still unknown. We hypothesized that anesthetic drugs differentially modulate cardiovascular responses to centrally administered CLO. To evaluate this hypothesis, we assessed blood pressure (BP) and heart rate (HR) of normotensive male rats anesthetized with pentobarbital or ketamine/xylazine, both under mechanical ventilation. These animals received CLO (10 μg/5 μL) or dexmedetomidine (DEX; 0.6 μg/5 μL) by icv route. In additional experiments, yohimbine (5 μg/5 μL), a selective α2AR antagonist, was given by icv route 15 min before a second injection of CLO or DEX in ketamine/xylazine anesthetized rats. As widely described, the icv microinjection of CLO decreased the mean arterial pressure (MAP) and HR by 40.73 ± 6.3 mmHg and 134 ± 15 bpm in pentobarbital anesthetized rats (n = 5). On the other hand, in ketamine/xylazine anesthetized rats (n = 6) CLO increased MAP by 29.4 ± 5.1 mmHg and decreased HR by 34 ± 5 bpm, a less pronounced effect when compared with the pentobarbital group (p < 0.0001). Similarly, the icv microinjection of DEX in ketamine/xylazine anesthetized rats (n = 6) increased MAP by 20.8 ± 3.2 mmHg and decreased HR by 51 ± 16 bpm. Notably, yohimbine generated a pattern of hypotensive responses comparable to CLO and DEX. Additionally, after yohimbine administration, both CLO- and DEX-increased MAP were reduced to 9.9 ± 2.3 mmHg and 6.7 ± 1.1 mmHg, respectively (n = 6, p < 0.05), despite the lack of influence of yohimbine in the bradycardia induced by these α2AR agonists in ketamine/xylazine anesthetized rats. This study discloses that in normotensive rats under ketamine/xylazine anesthesia, central administration of CLO produces a hypertensive effect, opposing the findings obtained in pentobarbital-anesthetized rats and resembling the vascular responses described in conscious animals. This data was reproduced by DEX and reduced by yohimbine, suggesting that stimulation of central α2AR takes a preponderant role in this effect. Our results reinforce the relevance regarding the influence of anesthetic choice for studies involving cardiovascular parameters.