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. 2012 Jan;114(1):200-4.
doi: 10.1213/ANE.0b013e31823a5d36. Epub 2011 Nov 10.

Salvinorin A Pretreatment Preserves Cerebrovascular Autoregulation After Brain Hypoxic/Ischemic Injury via Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase in Piglets

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Salvinorin A Pretreatment Preserves Cerebrovascular Autoregulation After Brain Hypoxic/Ischemic Injury via Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase in Piglets

Diansan Su et al. Anesth Analg. .
Free PMC article

Abstract

Background: Cerebral hypoxia/ischemia during infant congenital heart surgery is not uncommon and may induce devastating neurologic disabilities persistent over the lifespan. Hypoxia/ischemia-induced cerebrovascular dysfunction is thought to be an important contributor to neurological damage. No pharmacological agents have been found to prevent this. Mitogen activated protein kinase (MAPK), including extracellular signal regulated kinase (ERK), c-Jun-N-terminal kinase, and p38, is thought to contribute to ischemic preconditioning. We investigated whether pretreatment with salvinorin A, the only natural nonopioid κ receptor agonist, could preserve autoregulation of the pial artery via MAPK.

Methods: The response of the pial artery to hypotension and hypercapnia was monitored in piglets equipped with a closed cranial window before and after hypoxia and ischemia in the presence or absence of U0126, an inhibitor for the protein kinase upstream of ERK, sp600125, an inhibitor of c-Jun-N-terminal kinase or sb203580, an inhibitor of p38. Salvinorin A (10 μg/kg IV) was administered 30 minutes before hypoxia/ischemia in salvinorin-treated animals. Cerebrospinal fluid samples were collected before and 30 minutes after salvinorin A administration for the measurement of MAPK. Data (n = 5) were analyzed by repeated-measures analysis of variance.

Results: Pial artery dilation to hypercapnia and hypotension was blunted after hypoxia/ ischemia but preserved well by pretreatment with salvinorin A. U0126, but not sp600125 or sb203580, abolished the preservative effects of salvinorin A on cerebral vascular autoregulation to hypotension and hypercapnia. The ratio of pERK/ERK in cerebrospinal fluid increased significantly in salvinorin-treated animals, which was inhibited by U0126.

Conclusions: Salvinorin A pretreatment preserves autoregulation of the pial artery to hypotension and hypercapnia after hypoxia/ischemia via ERK in a piglet model.

Figures

Figure 1
Figure 1
Effects of hypotension on pial artery diameter before (baseline), after hypoxia/ischemia (H/I; PO2 of 35 mm Hg for 10 minutes followed by global cerebral ischemia for 20 minutes), after H/I pretreated with salvinorin A (10μg/kg IV; H/I+SA) 30 minutes before H/I, and after H/I pretreated with U0126 (1mg/kg, IV; H/I+SA+U0126), the antagonist of extracellular signal regulated kinase (ERK), 30 minutes before salvinorin A, SP600125 (1μM, administered topically; H/I+SA+SP600125), the antagonist of c-Jun-N-terminal kinase (JNK), 30 minutes before salvinorin A, SB203580 (10μM, administered topically; H/I+SA+SB203580), the antagonist of P38, 30 minutes before salvinorin A. Pretreatment with salvinorin A preserved the dilation response of the pial artery to hypotension, which is abolished by U0126. SA: Salvinorin A; H/I: Hypoxia/ischemia; Moderate: moderate hypotension (25 % decrease of mean arterial blood pressure [MAP]); Severe: severe hypotension (45% decrease of MAP). N= 5 each group; baseline bar represents the data from all 25 animals. All nonlisted corrected P-values >0.405. All corrected 95% confidence interval width <10.32
Figure 2
Figure 2
Effects of hypercarbia on pial artery diameter before (baseline), after hypoxia/ischemia (H/I; PO2 of 35 mm Hg for 10 minutes followed by global cerebral ischemia for 20 minutes), after H/I pretreated with salvinorin A (10μg/kg IV; H/I+SA) 30 minutes before H/I, and after H/I pretreated with U0126 (1mg/kg, IV; H/I+SA+U0126), the antagonist of extracellular signal regulated kinase (ERK), 30 minutes before salvinorin A, SP600125 (1μM, administered topically; H/I+SA+SP600125), the antagonist of c-Jun-N-terminal kinase (JNK), 30 minutes before salvinorin A, SB203580 (10μM, administered topically; H/I+SA+SB203580), the antagonist of P38, 30 minutes before salvinorin A. Pretreatment with salvinorin A preserved the dilation response of the pial artery to hypercarbia, which is abolished by U0126. SA: Salvinorin A; H/I: Hypoxia/ischemia; Moderate: moderate hypercapnia with PaCO2 of 50 to 60 mmHg; Severe: severe hypercapnia with PaCO2 of 70 to 80 mmHg. N= 5 each group; baseline bar represents the data from all 25 animals. All non-listed corrected P-values >0.108. All corrected 95% confidence interval width <10.43.
Figure 3
Figure 3
Effects of isoproterenol (10nM, 1μM) on pial artery diameter before (baseline) and after hypoxia/ischemia did not change significantly in the presence and absence of various interventions. SA: Salvinorin A; H/I: Hypoxia/ischemia. N= 5 each group; baseline bar represents the data from all 25 animals. All nonlisted corrected P-values =1. All corrected 95% confidence interval width <10.13.
Figure 4
Figure 4
The ratio of p extracellular signal regulated kinase (ERK)/ERK before administration of salvinorin A and 30 minutes after pretreatment of salvinorin A or U0126 plus salvinorin A. The ratio of pERK/ERK in cerebrospinal fluid (CSF) increased significantly 30 minutes in the salvinorin A pretreatment group; and such increase was abolished by the ERK antagonist (U0126) pretreatment SA: Salvinorin A. H/I: Hypoxia/ischemia. All nonlisted corrected P-values =1. All corrected 95% confidence interval width <0.33.

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