Mechanisms of Enhanced Basal Tone of Brain Parenchymal Arterioles During Early Postischemic Reperfusion: Role of ET-1-Induced Peroxynitrite Generation

Abstract

The contributions of vasoconstrictors (endothelin-1 (ET-1), peroxynitrite) and endothelium-dependent vasodilatory mechanisms to basal tone were investigated in parenchymal arterioles (PAs) after early postischemic reperfusion. Transient middle cerebral artery occlusion (tMCAO) was induced for 2 hours with 30 minutes reperfusion in male Wistar rats and compared with ischemia alone (permanent MCAO (pMCAO); 2.5 hours) or sham controls. Changes in lumen diameter of isolated and pressurized PAs were compared. Quantitative PCR was used to measure endothelin type B (ETB) receptors. Constriction to intravascular pressure ('basal tone') was not affected by tMCAO or pMCAO. However, constriction to inhibitors of endothelial cell, small- (SK) and intermediate- (IK) conductance, Ca(2+)-sensitive K(+) channels (apamin and TRAM-34, respectively) were significantly enhanced in PAs from tMCAO compared with pMCAO or sham. Addition of the ETB agonist sarafotoxin caused constriction in PAs from tMCAO but not from sham animals (21 ± 4% versus 3 ± 3% at 1 nmol/L; P<0.01) that was inhibited by the peroxynitrite scavenger FeTMPyP (5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride) (100 μmol/L). Expression of ETB receptors was not found on PA smooth muscle, suggesting that constriction to sarafotoxin after tMCAO was due to peroxynitrite and not ETB receptor expression. The maintenance of basal tone in PAs after tMCAO may restrict flow to the ischemic region and contribute to infarct expansion.

Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity

“…Sensitivity to nifedipine and electrophysiological properties of VDCC from PAs and MCAs. It is well-established that pressure-induced vasoconstriction involves VSM membrane depolarization that opens VDCC (6). It is therefore possible that differences in VDCC activity contribute to the increase in tone in PAs compared with MCAs.…”

“…In addition, PAs have greater myogenic tone at lower pressures compared with pial arteries (4,5) due to smooth muscle that is more depolarized (16,21) and large-conductance calcium-activated potassium channels (BK Ca ) that are uncoupled from ryanodine receptors and calcium sparks (7). Furthermore, under pathologic conditions such as ischemic stroke, pial arteries including the middle cerebral artery (MCA) have progressive loss of myogenic tone, whereas PAs have increased tone (6). The pronounced and persistent myogenic tone of PAs during pathologic conditions when other vessels dilate, makes them the "bottleneck" to flow in the cerebral cortex (20) and an important therapeutic target for conditions such as ischemic stroke, hypertension, and subarachnoid hemorrhage (3,5,6,21).…”

“…Furthermore, under pathologic conditions such as ischemic stroke, pial arteries including the middle cerebral artery (MCA) have progressive loss of myogenic tone, whereas PAs have increased tone (6). The pronounced and persistent myogenic tone of PAs during pathologic conditions when other vessels dilate, makes them the "bottleneck" to flow in the cerebral cortex (20) and an important therapeutic target for conditions such as ischemic stroke, hypertension, and subarachnoid hemorrhage (3,5,6,21). VSM calcium has a central role in the myogenic response (16).…”

Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

“…Specifically, ET-1-induced peroxynitrite generation in the brain has been shown to mediate arteriolar tone during postischemic reperfusion (Cipolla et al, 2013). Results from the ipsilateral tissue revealed a marked induction of Ifnb (3 Â at 24 h), Tnf (2.7 Â at 4 h, 2.7 Â at 24 h), and Il6 (8.5 Â at 4 h, 33.2 Â at 24 h) (Fig.…”

Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

“…25,26 Increased ET B R-mediated constrictions have also been shown in rat parenchymal arterioles after cerebral ischemia and reperfusion. 27 Additionally, upregulation of cerebral and peripheral vessel VSM ET B R has been observed in numerous disease models. 22,23,[28][29][30][31][32] Endothelin-1 signaling is also enhanced after CIH; however, the effects appear to primarily involve ET A R rather than ET B R. Chronic intermittent hypoxia is another model commonly used to evaluate the hypoxic component of sleep apnea.…”