Suppressed Prazosin‐Sensitive Cardiovascular Regulation in Central Nervous System During Early Sepsis
Authors: Matsubara Natália Kimie , da Silva-Santos José Eduardo 
Published: April 2020

Sepsis is the main cause of morbidity and mortality in ICU worldwide, with a resulting mortality rate of around 30–40%. The cardiovascular system in sepsis and septic shock is depressed, resulting in fluid‐refractory hypotension and hyporeactivity to vasoactive agents. In blood pressure (BP) neural control, tonic sympathetic nerve activity (SNA) through norepinephrine (NE) release is crucial for BP maintenance. Septic shock has been associated with SNA exacerbation, resulting in pro‐inflammatory activity and increased release of catecholamines. We hypothesized that α1‐adrenergic receptors (α1AR) in central nervous system (CNS) are less sensitive for NE in early sepsis, thus affecting autonomic modulation of cardiovascular function. To evaluate this hypothesis, we assessed BP and heart rate (HR) of anesthetized male rats subjected to cecal ligation puncture (CLP) model of sepsis, which was performed 6 h before the experiments. Control experiments were conducted in naïve rats. These animals received NE, administered by intracerebroventricular (icv; 10 μg/5 μL) or intravenous (iv; 3, 10, and 30 nmol/Kg) routes. In additional experiments, prazosin (5 μg/5 μL, icv), a selective α1AR antagonist, was given 15 min before a second icv administration of NE. In our experiments CLP generated a mortality rate of 50% in 36 h. Systemic administration of NE dose‐dependently increased the mean arterial pressure (MAP) by 9.2 ± 3.3, 74.6 ± 6.6 and 83.5 ± 4.6 mmHg in control group (n = 5), and by 8.9 ± 1.8, 48.9 ± 7.2 (p < 0.05), and 72.1 ± 11.7 mmHg in CLP animals (n = 4) for doses of 3, 10 and 30 nmol/Kg, respectively. When administered by iv route, NE‐increased BP was accompanied by increased HR, with no differences between control and CLP groups. Central microinjection of NE increased MAP and decreased HR of both control and CLP groups. However, responses were significantly depressed in septic animals. For instance, icv injection of NE increased MAP by 53.6 ± 3.3 mmHg in control (n = 5), and 18.9 ± 3.9 mmHg in CLP group (n = 8, p < 0.0001). Prazosin microinjection generated a similar pattern of slight and transitory reduction in BP of both control and CLP animals. In control animals, pretreatment with prazosin reduced NE‐increased MAP to 20.3 ± 2.6 mmHg (n = 5, p < 0.0001). However, icv administered NE maintained its pressor effect by 12.7 ± 1.4 mmHg in CLP subjected rats (n = 6) even after pretreatment with prazosin. Moreover, prazosin reversed the bradycardia induced by icv NE from −41 ± 12 bpm to 11 ± 21 bpm (n = 5, p < 0.05) in control animals, but had no effects in HR of CLP group. Our results disclose that mechanisms involved in tonic SNA stimulation by NE are depressed in CLP‐subjected rats during early sepsis stages, even before the establishment of hyporesponsiveness in peripheral cardiovascular system. The lack of prazosin effects in septic animals reinforces the development of neural sympathetic α1AR dysfunction and abnormal autonomic modulation of cardiovascular function in sepsis.

Support or Funding Information

Financial Support: CNPq (Brazil), with a Ph.D. fellowship to Matsubara, N. K. This study was approved by the Animal Ethics Committee of UFSC (6327180718).