The Protective Effect of Protein Kinase C and Adenosine Triphosphate-Sensitive Potassium Channel Agonists Against Inflammation in Rat Endothelium and Vascular Smooth Muscle In Vitro and In Vivo

Abstract

Volatile anesthetic pretreatment protects the vasculature from inflammation-induced injury via mechanisms involving the activation of adenosine triphosphate-sensitive potassium (K(ATP)) channels and/or protein kinase C (PKC). Therefore, we hypothesized that K(ATP) and PKC agonists may mimic the protective effects of volatile anesthetics in vitro and in vivo. In vitro, rat vascular smooth muscle cells (VSM) and aortic endothelial cells (AEC) were used to evaluate whether pretreatment with a K(ATP) agonist, cromakalim (CRK), or a PKC agonist, phorbol 12-myristate 13-acetate (PMA), decreases lipopolysaccharide (LPS)-induced cell injury. Cell survival was determined by trypan blue staining after 6 h. In vivo, rats received systemic LPS or saline with or without pretreatment with PMA or CRK. Mean arterial blood pressure, the response to endothelium-dependent (acetylcholine; ACH) and -independent (sodium nitroprusside) vasodilators, and arterial blood gases were determined after 6 h. Cell survival in VSM and AEC control cultures was more than 90%, which was not altered in the presence of PMA or CRK, whereas LPS significantly decreased cell survival. PMA (0.1-10 microM) significantly attenuated the LPS-induced decrease in cell survival by 28%-37% in VSM and 39%-53% in AEC, and CRK (1 mM) increased cell survival by 24% in VSM and 22% in AEC. In vivo, PMA and CRK pretreatment had no significant effect on measured variables in control rats. LPS decreased mean arterial blood pressure and vasodilation to ACH and sodium nitroprusside and caused hypoglycemia. PMA, but not CRK, increased ACH-dependent vasodilation (46%) at 6 h, but neither agonist altered the other detrimental effects of LPS. In conclusion, PKC and K(ATP) agonists appear to protect AEC and VSM cells against inflammation in vitro, but the systemic administration of PKC and K(ATP) agonists appeared to exert minimal or no protection in our in vivo model.

The beta‐adrenoceptor antagonist propranolol counteracts anti‐inflammatory effects of isoflurane in rat endotoxemia

“…As described for the pre‐conditioning properties of volatile anaesthetics in recent studies (26, 27), beta‐adrenoceptors seem to play an important role in the forwarding of the extracellular impact of volatile anaesthetics to the intracellular downstream signalling pathways during inflammation. Recent studies also suggest that other G‐protein coupled receptors such as adenosine receptors are involved in mediating the anti‐inflammatory effects of volatile anaesthetics (28, 29) and thereby may contribute to the anti‐inflammatory effects of volatile anaesthetics. The present study demonstrates, however, that during endotoxemia the beta‐adrenergic pathway and its blockade specifically modulate the anti‐inflammatory effects of isoflurane and cytokine release.…”

KATPChannel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine Induced Hypersensitivity, and Precipitated Withdrawal in Mice

“…In contrast, the cromakalim prodrug CF3-CKLP1 increased mechanical paw withdrawal thresholds only in the CFA mouse model of inflammatory pain, similar to CKLP1 and CKLP2. K ATP channel agonists have been shown to have anti-inflammatory properties, possibly due to inhibiting cytokine release from microglia (Plachinta et al, 2004; Virgili et al, 2011). This could explain why all three cromakalim prodrugs would increase the mechanical paw withdrawal thresholds in the inflammatory pain model, but not in the neuropathic pain model.…”

Pharmacokinetic and Pharmacodynamic Evaluation of the Suitability of Using Fluticasone and an Acute Rat Lung Inflammation Model to Differentiate Lung Versus Systemic Efficacy

“…This highly popular model was selected for the study because it provides two distinctive advantages. First, this acute animal model has been well studied by researchers and used to mimic human pulmonary inflammation and procedure is well reported 15–19. Secondly, compared with other animal models such as mouse ovalbumin model, rat LPS model offers the advantage of serial blood sampling and more precise delivery of drug into the lung via intratracheal dosing.…”