Pralidoxime improves the hemodynamics and survival of rats with peritonitis-induced sepsis

Several studies have suggested that sympathetic overstimulation causes deleterious effects in septic shock. A previous study suggested that pralidoxime exerted a pressor effect through a mechanism unrelated to the sympathetic nervous system; this effect was buffered by the vasodepressor action of pralidoxime mediated through sympathoinhibition. In this study, we explored the effects of pralidoxime on hemodynamics and survival in rats with peritonitis-induced sepsis. This study consisted of two sub-studies: survival and hemodynamic studies. In the survival study, 66 rats, which survived for 10 hours after cecal ligation and puncture (CLP), randomly received saline placebo, pralidoxime, or norepinephrine treatment and were monitored for up to 24 hours. In the hemodynamic study, 44 rats were randomly assigned to sham, CLP-saline placebo, CLP-pralidoxime, or CLP-norepinephrine groups, and hemodynamic measurements were performed using a conductance catheter placed in the left ventricle. In the survival study, 6 (27.2%), 15 (68.1%), and 5 (22.7%) animals survived the entire 24-hour monitoring period in the saline, pralidoxime, and norepinephrine groups, respectively (log-rank test P = 0.006). In the hemodynamic study, pralidoxime but not norepinephrine increased end-diastolic volume (P <0.001), stroke volume (P = 0.002), cardiac output (P = 0.003), mean arterial pressure (P = 0.041), and stroke work (P <0.001). The pressor effect of norepinephrine was short-lived, such that by 60 minutes after the initiation of norepinephrine infusion, it no longer had any significant effect on mean arterial pressure. In addition, norepinephrine significantly increased heart rate (P <0.001) and the ratio of arterial elastance to ventricular end-systolic elastance (P = 0.010), but pralidoxime did not. In conclusion, pralidoxime improved the hemodynamics and 24-hour survival rate in rats with peritonitis-induced sepsis, but norepinephrine did not.

Aldosterone-induced hypertension is sex-dependent, mediated by T cells and sensitive to GPER activation

Aims The G protein-coupled estrogen receptor 1 (GPER) may modulate some effects of aldosterone. In addition, G-1 (a GPER agonist) can lower blood pressure (BP) and promote T cell-mediated anti-inflammatory responses. This study aimed to test the effects of G-1 and G-15 (a GPER antagonist) on aldosterone-induced hypertension in mice and to examine the cellular mechanisms involved. Methods and results C57Bl/6 (wild-type, WT), RAG1-deficient and GPER-deficient mice were infused with vehicle, aldosterone (0.72 mg/kg/day S.C. plus 0.9% NaCl for drinking) ± G-1 (0.03 mg/kg/day S.C.) ± G-15 (0.3 mg/kg/day S.C.) for 14 days. G-1 attenuated aldosterone-induced hypertension in male WT but not male GPER-deficient mice. G-15 alone did not alter hypertension but it prevented the anti-hypertensive effect of G-1. In intact female WT mice, aldosterone-induced hypertension was markedly delayed and suppressed compared with responses in males, with BP remaining unchanged until after Day 7. In contrast, co-administration of aldosterone and G-15 fully increased BP within 7 days in WT females. Similarly, aldosterone robustly increased BP by Day 7 in ovariectomized WT females, and in both sexes of GPER-deficient mice. Whereas aldosterone had virtually no effect on BP in RAG1-deficient mice, adoptive transfer of T cells from male WT or male GPER-deficient mice into male RAG1-deficient mice restored the pressor response to aldosterone. This pressor effect could be attenuated by G-1 in RAG1-deficient mice that were reconstituted with either WT or GPER-deficient T cells, suggesting that G-1 does not act via T cells to lower BP. Conclusion Our findings indicate that although aldosterone-induced hypertension is largely mediated by T cells, it can be attenuated by activation of GPER on non-T cells, which accounts for the sex difference in sensitivity to the pressor effect.

Activation of mGluR5 and NMDA Receptor Pathways in the Rostral Ventrolateral Medulla as a Central Mechanism for Methamphetamine-Induced Pressor Effect in Rats

Acute hypertension produced by methamphetamine (MA) is well known, mainly by the enhancement of catecholamine release from sympathetic terminals. However, the central pressor mechanism of the blood-brain-barrier-penetrating molecule remains unclear. We used radio-telemetry and femoral artery cannulation to monitor the mean arterial pressure (MAP) in conscious free-moving and urethane-anesthetized rats, respectively. Expression of Fos protein (Fos) and phosphorylation of N-methyl-D-aspartate receptor subunit GluN1 in the rostral ventrolateral medulla (RVLM) were detected using Western blot analysis. ELISA was carried out for detection of protein kinase C (PKC) activity in the RVLM. MA-induced glutamate release in the RVLM was assayed using in vivo microdialysis and HPLC. Systemic or intracerebroventricular (i.c.v.) administration of MA augments the MAP and increases Fos expression, PKC activity, and phosphorylated GluN1-ser 896 (pGluN1-ser 896) in the RVLM. However, direct microinjection of MA into the RVLM did not change the MAP. Unilateral microinjection of a PKC inhibitor or a metabotropic glutamate receptor 5 (mGluR5) antagonist into the RVLM dose-dependently attenuated the i.c.v. MA-induced increase in MAP and pGluN1-ser 896. Our data suggested that MA may give rise to glutamate release in the RVLM further to the activation of mGluR5-PKC pathways, which would serve as a central mechanism for the MA-induced pressor effect.

Abstract 360: Effects of Different Doses of Pralidoxime Administered During Cardiopulmonary Resuscitation and the Role of Alpha-Adrenergic Receptors in its Pressor Action

Introduction: We previously reported that pralidoxime potentiated the pressor effect of epinephrine and improved restoration of spontaneous circulation (ROSC) rate and short-term survival in pigs undergoing cardiopulmonary resuscitation (CPR). We sought to explore the optimal dose of pralidoxime to be used during CPR and to evaluate the involvement of α-adrenoceptors in its pressor action. Methods: In the first substudy, 44 pigs randomly received one of three doses of pralidoxime (40, 80, or 120 mg/kg) or saline placebo during CPR. All animals were given epinephrine every 3 minutes. In the second substudy, 49 rats were divided into 7 groups. In the first 4 groups, the effects of 40 mg/kg pralidoxime on arterial pressure were determined after pretreatment with saline, guanethidine, phenoxybenzamine, or phentolamine. In the other 3 groups, the effects of 200 mg/kg pralidoxime were determined after pretreatment with saline, propranolol, or phentolamine. Results: In the first substudy, 40 mg/kg pralidoxime resulted in the highest coronary perfusion pressure (CPP) among the groups, while 120 mg/kg pralidoxime resulted in the lowest CPP (group effect P <0.001). Sustained ROSC was attained in 4 (36.4%), 11 (100%), 9 (81.8%), and 3 (27.3%) animals in the saline, 40 mg/kg, 80 mg/kg, and 120 mg/kg groups, respectively ( P <0.001). In the second substudy, 40 mg/kg pralidoxime elicited a pressor response. Phenoxybenzamine completely inhibited the pressor response, but guanethidine and phentolamine did not. The pressor response of pralidoxime was even greater after pretreatment with guanethidine or phentolamine. Two-hundred mg/kg pralidoxime produced an initial vasodepressor response followed by a delayed pressor response. Phentolamine eliminated the initial vasodepressor response and reversed it into a pressor response. Conclusions: Forty mg/kg of pralidoxime administered with epinephrine led to a significantly higher ROSC rate by improving CPP in a pig model of cardiac arrest, whereas 120 mg/kg did not improve CPP or the ROSC rate. Our findings suggest that the pressor effect of pralidoxime is unrelated to α-adrenoceptors and that its pressor effect is buffered by its vasodepressor action mediated by the inhibition of the sympathetic nervous system.