Postischemic Reperfusion Causes Smooth Muscle Calcium Sensitization and Vasoconstriction of Parenchymal Arterioles

Cipolla, Marilyn J.; Chan, Siu‐Lung; Sweet, Julie G.; Tavares, Matthew; Gokina, Natalia I.; Brayden, Joseph E.

doi:10.1161/strokeaha.114.005888

Cited by 50 publications

(73 citation statements)

References 40 publications

(51 reference statements)

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“…Parenchymal arterioles develop substantial myogenic tone 26-28 and are key contributors to overall cerebral vascular resistance 29 . In the current study, parenchymal arterioles generated spontaneous tone once pressurized (37.1±3.0% of maximum diameter; n=10 arterioles) to a baseline diameter of 17±2 μm (active diameter).…”

Section: Resultsmentioning

confidence: 99%

Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

Silva

Kinzenbaw²,

Modrick

et al. 2016

Hypertension

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Rho kinase (ROCK) has been implicated in physiological and pathophysiological processes, including regulation of vascular function. ROCK signaling is thought to be a critical contributor to cardiovascular disease, including hypertension and effects of angiotensin II (Ang II). Two isoforms of ROCK (1 and 2) have been identified, and are expressed in vascular cells. In this study, we examined the importance of ROCK2 in relation to vessel function using several models and a novel inhibitor of ROCK2. First, incubation of carotid arteries with the direct RhoA activator CN-03 or Ang II impaired endothelium-dependent relaxation by approximately 40-50% (P<0.05) without altering endothelium-independent relaxation. Both CN-03- and Ang II-induced endothelial dysfunction was prevented by Y-27632 (an inhibitor of both ROCK isoforms) or the selective ROCK2 inhibitor SLX-2119. In contrast, SLX-2119 had little effect on contraction of carotid arteries to receptor-mediated agonists (serotonin, phenylephrine, vasopressin or U46619). Second, in basilar arteries, SLX-2119 inhibited constriction to Ang II by approximately 90% without significantly affecting responses to serotonin or KCl. Third, in isolated pressurized brain parenchymal arterioles, SLX-2119 inhibited myogenic tone in a concentration-dependent manner (eg, 1 μmol/L SLX-2119 dilated by 79±4%). Lastly, SLX-2119 dilated small pial arterioles in vivo, an effect that was augmented by inhibition of NO synthase. These findings suggest that ROCK2 has major, but heterogeneous, effects on function of endothelium and vascular muscle. The data support the concept that aberrant ROCK2 signaling may be a key contributor to select aspects of large and small vessel disease including Ang II-induced endothelial dysfunction.

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Section: Resultsmentioning

confidence: 99%

Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

Silva

Kinzenbaw²,

Modrick

et al. 2016

Hypertension

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“…However, it should be noted that the large network of capillaries is not the site of greatest resistance to flow in the brain and therefore targeting capillary reductions in flow may not be as beneficial as targeting upstream parenchymal arterioles that are high resistance and the bottleneck to flow to the brain parenchyma [60-62]. In fact, studies have shown that parenchymal arterioles undergo vasoconstriction in response to early post-ischemic reperfusion, a time period important for preventing infarct expansion [63]. …”

Section: Targeting Recanalization and Reperfusion As A Neuroprotectivmentioning

confidence: 99%

“…Parenchymal arterioles undergo vasoconstriction in response to early post-ischemic reperfusion due to calcium sensitization of the vascular smooth muscle [63]. Parenchymal arterioles are unique vessels in the brain and have greater tone at lower pressures than pial arteries due to a lack of influence of the large-conductance calcium-activated potassium (BK) channel [64].…”

Section: Targeting Recanalization and Reperfusion As A Neuroprotectivmentioning

confidence: 99%

“…Thus, SK/IK channel activation may not only increase perfusion to the penumbra due to an effect on LMAs, but also improve post-ischemic reperfusion by decreasing small vessel resistance. Also similar to LMAs, ROCK inhibition may provide a selective target to decrease small vessel resistance during early reperfusion since its involvement in myogenic tone is through calcium sensitization of smooth muscle, the mechanism by which ischemia and reperfusion are increasing vasoconstriction [41,63]. …”

Section: Targeting Recanalization and Reperfusion As A Neuroprotectivmentioning

confidence: 99%

“…Baseline variability in CBF can result in differences in drug concentrations after IA injection; however, changes in CBF after IA injection in combination with ET is likely unique and will depend on the response of the various arterial segments to rapid reperfusion. For example, pial arteries and arterioles dilate in response to ischemia and reperfusion whereas parenchymal arterioles constrict, likely changing segmental vascular resistance that will influence blood flow and drug concentration [63,91,92]. In fact, high resting CBF is disadvantageous during IA drug delivery to the brain because it decreases peak drug concentrations due to dilution by the arterial blood, decreases drug transit time and augments efflux from the brain [72].…”

Section: Ia Treatment and Etmentioning

confidence: 99%

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Improving Reperfusion Therapies in the Era of Mechanical Thrombectomy

Linfante

Cipolla

2016

Transl. Stroke Res.

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Recent positive clinical trials using mechanical thrombectomy proved that endovascular recanalization is an effective treatment for patients with acute stroke secondary to large vessel occlusions. The trials offer definite evidence that in acute ischemia recanalization is a powerful predictor of good outcome. However, even in the era of rapid and effective recanalization using endovascular approaches, the percentage of patients with good outcomes varies between 33% and 71%. In addition, the number of patients who are eligible for endovascular thrombectomy is small and usually based on having salvageable tissue on imaging. There is therefore room for improvement to both enhance the effectiveness of current practice and expand treatment to a larger subset of stroke patients. In this review, we highlight some of the most promising approaches to improve endovascular therapy by combining with strategies to enhance collateral perfusion and vascular protection.

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Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy

Laredo¹,

Rodríguez

Oleaga

et al. 2022

Annals of Neurology

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Objective: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. Methods: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. Results: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). Interpretation: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity.

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Postischemic Reperfusion Causes Smooth Muscle Calcium Sensitization and Vasoconstriction of Parenchymal Arterioles

Cited by 50 publications

References 40 publications

Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

Improving Reperfusion Therapies in the Era of Mechanical Thrombectomy

Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy

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