ERK1/2 Inhibition Attenuates Cerebral Blood Flow Reduction and Abolishes ET_B and 5-HT_1B Receptor Upregulation after Subarachnoid Hemorrhage in Rat

Abstract

Upregulation of endothelin B (ET B ) and 5-hydroxytryptamine 1B (5-HT 1B ) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signalregulated kinase (ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ET B and 5-HT 1B receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ET A and ET B receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT 1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ET B and 5-HT 1B receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.

Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

“…More interestingly, there is induced upregulation of vasoconstrictive ET B receptor expression on porcine coronary artery smooth muscle cells in diet-induced hypercholesterolemia (Hasdai et al, 1997), in smoke exposed rats and in hypertension (Li et al, 2007), ischemic cardiovascular disease (Wackenfors et al, 2004), ischemic stroke (Povlsen et al, 2012) as well as in suspected acute coronary syndrome in patients (Dimitrijevic et al, 2009). Both ET-1 overexpression and vasoconstrictive ET B receptor upregulation contribute to vasospasms and decrease in local blood flow (Beg et al, 2006). Despite extensive knowledge of the physiology and pharmacology of vasoactive factors such as vasoconstrictors (ET-1 and thromboxane) and vasodilators (endothelium derived hyperpolarizing factor, NO and PGI 2 ), there is still plenty to find out about the ways in which synthesis or action of these mediators are selectively impaired in disease states; there is also still incomplete understanding of the nature of other endothelium-derived dilators and constrictors (Pearson, 2013).…”

Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries

“…The importance of this pathway has been illustrated by use of ERK1/2 inhibitors which attenuate cerebral blood flow reduction following SAH and brain tissue damage following MCAO. 8,26 . In addition there is phosphorylation of p38 and SAPK/JNK after cerebral ischemia and organ culture, however this occur at a later stage and is not Previous studies have revealed that cerebral ischemia (SAH and MCAO) and organ culture result in enhanced expression of endothelin, angiotensin and serotonin receptors in the arterial wall at both a molecular and a functional levels.…”

“…For a detailed description see Beg et al 8 . During the period of observation, the rat was monitored regularly and if it showed severe distress was killed prematurely (3 % mortality).…”

DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosumThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

“…5A). Because ET-1 also activates the mitogen-activated protein kinase (MAPK) signaling pathway and p44/42 isoforms of the extracellular signal-regulated kinase (ERK1/2) are involved in the contractile responses mediated by ET-1 (Kawanabe et al 2004;Beg et al 2006), we evaluated the responses to ET-1 after incubation with an ERK1/2 inhibitor, PD59089 (10 −6 mol/L). In this condition, no differences in ET-1-induced contractions were observed between cavernosal tissues from control and DOCA-salt mice, the inhibitor producing a greater attenuation of ET-1 responses in the DOCA-salt group (Fig.…”