Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells.

Evangelia Pantazaka,Colin W Taylor,William G Bernard,Emily J A Taylor

doi:10.1111/bph.12239

Evangelia Pantazaka, Colin W Taylor + Show 2 more

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https://doi.org/10.1111/bph.12239

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Abstract

Background and PurposeHistamine and prostaglandin E2 (PGE2), directly and via their effects on other cells, regulate the behaviour of vascular smooth muscle (VSM), but their effects on human VSM are incompletely resolved.Experimental ApproachThe effects of PGE2 on histamine-evoked changes in intracellular free Ca2+ concentration ([Ca2+]i) and adenylyl cyclase activity were measured in populations of cultured human aortic smooth muscle cells (ASMCs). Selective ligands of histamine and EP receptors were used to identify the receptors that mediate the responses.Key ResultsHistamine, via H1 receptors, stimulates an increase in [Ca2+]i that is entirely mediated by activation of inositol 1,4,5-trisphosphate receptors. Selective stimulation of EP2 or EP4 receptors attenuates histamine-evoked Ca2+ signals, but the effects of PGE2 on both Ca2+ signals and AC activity are largely mediated by EP2 receptors.Conclusions and ImplicationsTwo important inflammatory mediators, histamine via H1 receptors and PGE2 acting largely via EP2 receptors, exert opposing effects on [Ca2+]i in human ASMCs.

Highlights

Histamine released from mast cells and basophils initiates inflammatory responses, notably in the vasculature where its most immediate effects are dilatation of small vessels causing increased blood flow to sites of injury
Histamine H1 receptors stimulate an increase in [intracellular free Ca2+ concentration (Ca2+]i) via inositol 1 (IP3). (A) Histamine (100 μM, bar) stimulates an increase in [Ca2+]i in populations of aortic smooth muscle cell (ASMC) incubated in HEPES-buffered saline (HBS) or Ca2+-free HBS
Caffeine (10 mM), which activates ryanodine receptors, had no effect on [Ca2+]i (Supporting Information Figure S3A), and the responses to histamine were unaffected by concentrations of either transNed-19 (1 μM, 5 min) that block responses to nicotinic acid adenine dinucleotide phosphate (NAADP) (Naylor et al, 2009; Brailoiu et al, 2010) or of ryanodine (100 μM, 5 min) that block ryanodine receptors (Zheng et al, 2005) (Figure 1E). These results demonstrate that activation of H1 receptors by histamine stimulates Ca2+ release via IP3 receptors in human ASMC, and that neither ryanodine receptors nor twopore channels contribute to the response

Summary

Introduction

Histamine released from mast cells and basophils initiates inflammatory responses, notably in the vasculature where its most immediate effects are dilatation of small vessels causing increased blood flow to sites of injury. These effects are mediated primarily by H1 histamine receptors on endothelial cells, which stimulate Gq and thereby phospholipase C (PLC) (Hill et al, 1997; Jones and Kearns, 2011). In animal models, prevention of histamine synthesis (Toda, 1987; Sasaguri et al, 2005) or competitive antagonists of H1 receptors (Miyazawa et al, 1998) reduce intimal thickening after vascular injury These observations implicate H1 receptors of VSM in both inflammatory responses and the development of atherosclerosis and restenosis. Selective ligands of histamine and EP receptors were used to identify the receptors that mediate the responses

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