ABSTRACT
As powerful vasodilators, prostacyclin analogues are presently the mainstay in the treatment of severe pulmonary arterial hypertension. Although the hemodynamic effects of prostacyclin analogues are well known, the molecular mechanism of their acute effects on pulmonary vascular tone and systemic vascular tone remains poorly understood. Peroxisome proliferator-activated receptor-ß/δ (PPARß/δ) was previously identified as a putative receptor responsible for the modulation of target gene expression in response to prostacyclin analogues. The present study investigated the signaling pathway of prostacyclin in human pulmonary arterial smooth muscle cells (PASMCs), and sought to define the role of PPARß/δ in the acute vasodilating effect. In human PASMCs, prostacyclin rapidly activated TWIK-related acid-sensitive K channel 1 (TASK-1) and calcium-dependent potassium channels (K(Ca)). This pathway was mediated via the prostanoid I receptor-protein kinase A pathway. The silencing of PPARß/δ demonstrated that the downstream K(Ca) activation was exclusively dependent on PPARß/δ signaling, whereas the activation of TASK-1 was not. In addition, the PPARß/δ-induced activation of K(Ca) was independent of NO. The acute prostacyclin-induced K(Ca) activation is critically dependent on PPARß/δ as a rapid signaling factor. This accounts in part for the vasodilating effect of prostacyclin in pulmonary arteries, and provides insights into a new molecular explanation for the effects of prostanoids.
Subject(s)
Epoprostenol/analogs & derivatives , Iloprost/pharmacology , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/metabolism , PPAR delta/agonists , PPAR gamma/agonists , Potassium Channels, Calcium-Activated/drug effects , Signal Transduction/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Animals , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , Epoprostenol/pharmacology , Gene Silencing , Humans , Male , Membrane Potentials , Muscle, Smooth, Vascular/metabolism , Nerve Tissue Proteins/drug effects , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , PPAR delta/genetics , PPAR delta/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Potassium Channels, Calcium-Activated/genetics , Potassium Channels, Calcium-Activated/metabolism , Potassium Channels, Tandem Pore Domain/drug effects , Potassium Channels, Tandem Pore Domain/genetics , Potassium Channels, Tandem Pore Domain/metabolism , Pulmonary Artery/drug effects , Pulmonary Artery/metabolism , Rats , Rats, Wistar , Receptors, Epoprostenol , Receptors, Prostaglandin/drug effects , Receptors, Prostaglandin/metabolismABSTRACT
INTRODUCTION: The puff adder (Bitis arietans) is a venomous viper mainly found in sub-Saharan Africa. Due to its common occurrence and potent venom, it is considered to be the most dangerous snake in Africa, responsible for most snakebite fatalities there. Puff adder bites outside Africa are rare and involve captive vipers. We present the unusual case of puff adder envenomation in an Austrian man. CASE REPORT: A 26-year-old Austrian man was bitten by a puff adder that he kept illegally in his home. On admission he showed signs of local and systemic toxicity. He was stabilized with antivenom, intravenous fluids, catecholamines and packed platelets. Hyperbaric oxygenation was begun due to incipient compartment syndrome on the second day and continued until the eleventh day, when the patient had recovered completely and could be discharged. DISCUSSION: The venom of Bitis arietans can cause serious systemic and local complications. Our patient suffered from both. Systemic signs included hemodynamic as well as hemostaseologic impairment. Local effects included swelling and incipient compartment syndrome. Systemic and local treatment, including hyperbaric oxygenation, effected a full recovery. We suggest that, whenever feasible, hyperbaric oxygenation should be considered as adjunct treatment in snake bites to avert adverse outcomes.
