Renal sympathetic nerve activity and vascular reactivity to phenylephrine after lipopolysaccharide administration in conscious rats

Abstract

It has been proposed that sympathoexcitation is responsible for vascular desensitization to α 1‐adrenoceptor stimulation during lipopolysaccharide (LPS)‐induced systemic inflammation. The present study tested this hypothesis by examining the effects of sympatho‐deactivation with the α 2‐adrenoceptor agonist, dexmedetomidine, on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and vascular reactivity to phenylephrine in conscious rats with cardiac autonomic blockade (methylatropine and atenolol) following LPS administration. In male, adult Sprague‐Dawley rats (n = 5 per group), RSNA and MAP were continuously recorded over 1‐h periods, before and after LPS administration (20 mg/kg iv), and finally after infusion of either saline or dexmedetomidine (5 μg/kg, then 5 μg/kg/h iv). A full dose–response curve to phenylephrine was constructed under each condition. After pooling data from both groups of rats (n = 10), LPS significantly (P = 0.005) decreased MAP (from 115 ± 1 to 107 ± 2 mmHg), increased RSNA (to 403 ± 46% of baseline values) and induced 4 to 5‐fold increases in the half‐maximal effective dose (ED 50) of phenylephrine (from 1.02 ± 0.09 to 4.76 ± 0.51 μg/kg). During saline infusion, RSNA progressively decreased while vascular reactivity did not improve. Treatment with dexmedetomidine decreased MAP, returned RSNA to near pre‐endotoxemic levels, but only partially restored vascular reactivity to phenylephrine (ED 50 was still threefold increased as compared with baseline values). These findings indicate that only part of the decrease in vascular reactivity to α 1‐adrenoceptor stimulation during endotoxemia can be accounted for by sympathetic activation, at least on a short‐term basis.

Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

“…This is likely due to an effect of a 2 -adrenergic receptor agonists to improve vascular reactivity to catecholamines and angiotensin II. 19,24,25 Likewise, in a recent prospective crossover clinical study, in 38 sedated septic patients, switching from standard-of-care propofol to DEX (0.7 mg/kg per h) significantly reduced norepinephrine requirements (0.7 AE 0.6 to 0.3 AE 0.2 mg/kg per min) to attain target blood pressure, an effect maintained up to 8 hours after replacing DEX with propofol. 22 Even when given alone, DEX prevented the further deterioration in MAP seen in the vehicle-time control group, an effect associated with vasoconstriction as shown by the reductions in total peripheral and renal vascular conductance.…”

“…17,18 Currently, DEX is not recommended as a standard-of-care sedative due to its central action to inhibit sympathetic nerve activity, 19,20 which would be expected to reduce blood pressure in sepsis. However, in both clinical [21][22][23] and experimental 19,24,25 sepsis, there is evidence that treatment with a 2 -adrenergic receptor agonists improves responsiveness to exogenous vasopressors such as norepinephrine, phenylephrine, and angiotensin II, which likely accounts for their ability to preserve blood pressure. A multinational, doubleblinded, randomized clinical trial is currently assessing DEX as a primary sedative agent, 26 making this agent of clinical interest and relevance.…”

Effect of dexmedetomidine anesthesia on respiratory function in pediatric patients undergoing retinoblastoma resection

“…It has excellent anti-anxiety as well as strong analgesic and sedative effects (23). According to literature, Dex can reduce the output of sympathetic nerves by increasing the output of parasympathetic nerves, thereby inhibiting the activity of sympathetic nerves (24). The use of Dex during the surgical procedure, can reduce the fluctuation of hemodynamic parameters due to intraoperative events such as intubation, extubation, awakening and stress response, and also relieve the respiratory depression associated with the action of other drugs (25).…”

Hypothesis: Fever control, a niche for alpha-2 agonists in the setting of septic shock and severe acute respiratory distress syndrome?

“…As septic shock involves many factors, other explanations are possible (NO, etc.) [78,79]: a) lowered temperature leading to vasoconstriction: this does not fit with the vasodilation generated by alpha-2 agonists b) normalization of an impaired micro-circulation (see below), leading to normalized local pH back toward normal, increased sensitivity to noradrenaline and reduced extravasation. Given the reduced requirement of vasopressor observed during hypothermia [38] or normothermia [3] in the absence of administration of alpha-2 agonists and the reduction in vasopressors requirement following administration of alpha-2 agonists [24,71], a combination of fever control and alpha-2 agonist may help in refractory septic shock.…”

“…A prospective randomized clinical trial e.g. in the setting of refractory 10 [88-90] septic shock should document the hypothesis [24,61,62,71,78,79].…”