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Selective inhibition of receptor-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury
R C Mclntyre1, B Sheridan, J Agrafojo
1Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Abstract:
We hypothesized that pulmonary vasorelaxation mediated by receptors that require generation of cyclic adenosine monophosphate (cAMP) is impaired in endotoxin-induced acute lung injury. The purpose of this study was to determine the effect of endotoxin on the following pathways of pulmonary vasorelaxation that require the generation of cAMP: 1) beta-adrenoreceptor stimulation (response to isoproterenol, ISO), 2) P2 purinoreceptor stimulation (response to adenosine diphosphate, ADP), 3) H2-histamine receptor stimulation (response to dimaprit), 4) adenosine A2 receptor stimulation (response to adenosine, ADO), 5) type 2 E prostaglandin (EP2) receptor stimulation (response to prostaglandin E1, PGE1), and 6) direct adenylate cyclase stimulation (response to forskolin, FSK). We used isolated pulmonary artery rings harvested from rats injected with endotoxin or saline. We found that endotoxin impaired the response to beta-adrenoreceptor stimulation (ISO) and P2 purinoreceptor stimulation (ADP). Endotoxin converted the vasorelaxant effect of H2-histamine receptor stimulation (dimaprit) to vasoconstriction. On the other hand, the response to A2 receptor stimulation (ADO) and EP2 receptor stimulation (PGE1), was normal. The dose response to direct adenylate cyclase stimulation (FSK) was the same as control except at a single concentration (10(-7) M). These data suggest that endotoxin causes selective impairment of pulmonary vasorelaxation through receptors coupled to cAMP generation. This impaired pulmonary vasorelaxation may contribute to the increased pulmonary vascular resistance seen in acute lung injury. These data may lead to therapy that will prevent or improve the pathophysiologic pulmonary circulation in acute lung injury.
Insights
Endotoxin impairs pulmonary vasorelaxation pathways involving cyclic adenosine monophosphate (cAMP) generation, specifically beta-adrenoreceptor and P2 purinoreceptor stimulation. This selective impairment may worsen acute lung injury complications.
Area of Science:
- Pulmonary circulation physiology
- Cellular signaling pathways
- Pathophysiology of acute lung injury
Background:
- Acute lung injury (ALI) is associated with increased pulmonary vascular resistance.
- Pulmonary vasorelaxation mediated by cyclic adenosine monophosphate (cAMP) is crucial for maintaining normal vascular tone.
- The impact of endotoxin on specific cAMP-dependent vasorelaxation pathways in the pulmonary vasculature is not fully understood.
Purpose of the Study:
- To investigate the effect of endotoxin on pulmonary vasorelaxation mediated by various cAMP-generating receptors.
- To determine if endotoxin selectively impairs specific signaling pathways involved in pulmonary vasodilation.
Main Methods:
- Isolated rat pulmonary artery rings were used.
- Rings were harvested from rats injected with either endotoxin or saline (control).
- The vasorelaxant responses to stimulation of beta-adrenoreceptors (isoproterenol), P2 purinoreceptors (ADP), H2-histamine receptors (dimaprit), adenosine A2 receptors (adenosine), EP2 receptors (prostaglandin E1), and direct adenylate cyclase (forskolin) were measured.
Main Results:
- Endotoxin significantly impaired vasorelaxation induced by beta-adrenoreceptor (isoproterenol) and P2 purinoreceptor (ADP) stimulation.
- Endotoxin reversed the vasorelaxant effect of H2-histamine receptor stimulation (dimaprit) into vasoconstriction.
- Responses to adenosine A2 receptor (adenosine) and EP2 receptor (prostaglandin E1) stimulation remained normal.
- Direct adenylate cyclase stimulation (forskolin) showed similar dose-response curves to control, except at one concentration.
Conclusions:
- Endotoxin selectively impairs pulmonary vasorelaxation mediated by specific receptors coupled to cAMP generation.
- This selective impairment of vasorelaxation may contribute to the elevated pulmonary vascular resistance observed in acute lung injury.
- Understanding these selective pathway defects could inform therapeutic strategies for acute lung injury.