Expressional Changes in Cerebrovascular Receptors after Experimental Transient Forebrain Ischemia

Abstract

BackgroundGlobal ischemic stroke is one of the most prominent consequences of cardiac arrest, since the diminished blood flow to the brain results in cell damage and sometimes permanently impaired neurological function. The post-arrest period is often characterised by cerebral hypoperfusion due to subacute hemodynamic disturbances, the pathophysiology of which are poorly understood. In two other types of stroke, focal ischemic stroke and subarachnoid hemorrhage, it has earlier been demonstrated that the expression of certain vasoconstrictor receptors is increased in cerebral arteries several days after the insult, a phenomenon that leads to increased contraction of cerebral arteries, reduced perfusion of the affected area and worsened ischemic damage. Based on these findings, the aim of the present study was to investigate if transient global cerebral ischemia is associated with upregulation of vasoconstrictive endothelin and 5-hydroxytryptamine receptors in cerebral arteries. Experimental transient forebrain ischemia of varying durations was induced in male wistar rats, followed by reperfusion for 48 hours. Neurological function was assessed daily by three different tests and cerebrovascular expression and contractile function of endothelin and 5-hydroxytryptamine receptors were evaluated by wire myography, immunohistochemistry and western blotting.ResultsTransient forebrain ischemia induced neurological deficits as well as functional upregulation of vasoconstrictive ETB and 5-HT1B receptors in cerebral arteries supplying mid- and forebrain regions. No receptor upregulation was seen in arteries supplying the hindbrain. Immunohistochemical stainings and western blotting demonstrated expressional upregulation of these receptor subtypes in the mid- and forebrain arteries and confirmed that the receptors were located in the smooth muscle layer of the cerebral arteries.ConclusionsThis study reveals a new pathophysiological aspect of global ischemic stroke, namely expressional upregulation of vasoconstrictor receptors in cerebral arteries two days after the insult, which might contribute to cerebral hypoperfusion and delayed neuronal damage after cardiac arrest.

In vivo experimental stroke and in vitro organ culture induce similar changes in vasoconstrictor receptors and intracellular calcium handling in rat cerebral arteries

“…Expressional upregulation of contractile ET B receptors has also been demonstrated following two other types of cerebral ischemia, namely global cerebral ischemia and subarachnoid hemorrhage (Hansen-Schwartz et al 2003a, b;Johansson et al 2010). Hence, we speculate that this upregulation is a general phenomenon characteristic for the response of cerebral arteries to situations of dramatic drops in intraluminal pressure and vascular wall tension such as during a stroke.…”

“…The 5-HT 1B receptor is another GPCR that has been shown to be upregulated in cerebral arteries after experiment subarachnoid hemorrhage (Ansar et al 2007) and global ischemic stroke (Johansson et al 2010). Organ culture-induced upregulation of contractile 5-HT 1B receptors has been reported; however, this appears to be a more delayed response, which is only evident after 48 h of organ culture (Hoel et al 2001;Hansen-Schwartz et al 2002).…”

“…After subarachnoid hemorrhage, increased expression of contractile ET B , 5-HT 1B , AT 1, and TX A2 receptors has been shown (Hansen-Schwartz et al 2003a, b;Ansar et al 2007Ansar et al , 2010, and after global ischemic stroke, cerebral arteries upregulate SMCs contractile ET B and 5-HT 1B receptors (Johansson et al 2010). After focal ischemic stroke, two previous studies revealed upregulation of contractile ET B (Stenman et al 2002) and AT 1 (Stenman and Edvinsson 2004) receptors in the occluded MCA 48 h after transient MCA occlusion (tMCAO) in rats.…”

Vascular plasticity in cerebrovascular disorders

“…This causes cerebral ischemia mainly in the forebrain, whereas the posterior brain parts supplied by the vertebral arteries appears almost unaffected by the insult (Smith et al, 1984). In this model, significant upregulation of contractile ET B and 5-HT 1B receptors in cerebral artery smooth muscles was recently demonstrated after 15 minutes carotid occlusion and hypovolemia followed by 48 hours of reperfusion (Johansson et al, 2011). Other receptor subtypes, such as the ET A and 5-HT 2A receptors, were unchanged by the ischemia.…”

Permanent Distal Occlusion of Middle Cerebral Artery in Rat Causes Local Increased ET_B, 5-HT_1B and AT₁ Receptor-Mediated Contractility Downstream of Occlusion

“…Thus, functional and expressional upregulation of contractile endothelin B (ET B ), angiotensin type 1 (AT 1 ), and 5-hydroxytryptamine 1B (5-HT 1B ) receptors have been shown in the smooth muscle cells (SMCs) of cerebral arteries following experimental subarachnoid haemorrhage (SAH) [1,2], focal cerebral ischemia with reperfusion [3,4,5] and transient forebrain ischemia [6]. The pathophysiological impact of these changes is a worsening of the ischemic brain damage caused by a suspected cerebrovascular hypercontractility leading to a further hypoperfusion of the already deprived brain area [2,7].…”