Bkca opener, NS1619 pretreatment protects against shock-induced vascular hyporeactivity through PDZ-Rho GEF-RhoA-Rho kinase pathway in rats.

Abstract

BACKGROUND:

Our previous study showed that the ischemic preconditioning and pretreatment of adenosine triphosphate-sensitive potassium channel (KATP) opener, pinacidil, may induce a good protective effect on shock-induced vascular hyporeactivity. Whether the pretreatment of opener/activator of the large-conductance calcium-activated potassium channel (Bkca), NS1619, can also induce a protective effect on vascular reactivity and play a beneficial effect on subsequent hemorrhagic shock is not clear.

METHODS:

With Sprague-Dawley rats subjected to hemorrhagic shock and their isolated superior mesenteric artery, the protective effect of NS1619 (0.5, 1, 2, and 4 mg/kg) pretreatment (30 minutes before hemorrhage shock) on vascular reactivity and the underlying mechanisms were observed.

RESULTS:

NS1619 pretreatment significantly improved the 72-hour survival of hemorrhagic shock rats, alleviated shock-induced decrease of vascular reactivity and calcium sensitivity, and increased the cardiac output and oxygen delivery. NS1619 2 mg/kg had the best effect. These protective effects of NS1619 pretreatment on vascular reactivity and calcium sensitivity were antagonized by RhoA inhibitor, C3 transferase, and Rho kinase antagonist, Y-27632. NS1619 pretreatment up-regulated the activities of RhoA, Rho-kinase, and PDZ-Rho GEF (guanine nucleotide exchange factor). These effects of NS1619 pretreatment were eliminated by RhoA inhibitor, C3 transferase.

CONCLUSION:

Bkca opener, NS1619 pretreatment has good protective effect on vascular reactivity and calcium sensitivity, which plays a good beneficial effect on hemorrhagic shock. The mechanism may be mainly through PDZ-Rho GEF-RhoA-Rho kinase pathway. Bkca channel may be a potential target for the treatment of shock-induced vascular hyporeactivity.

• Authors: Yi Hu, Guangming Yang, Xudong Xiao, Liangming Liu, Tao Li
• Journal: The journal of trauma and acute care surgery (J Trauma Acute Care Surg) Vol. 76 Issue 2 Pg. 394-401 (Feb 2014) ISSN: 2163-0763 [Electronic] United States
• PMID: 24398773 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Benzimidazoles
• Kcnma1 protein, rat
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
• Potassium Channels
• Pyridines
• Y 27632
• NS 1619
• rho-Associated Kinases
• rhoA GTP-Binding Protein
• Calcium

Topics

• Amides (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Calcium (metabolism)
• Dilatation, Pathologic (drug therapy, etiology)
• Disease Models, Animal
• Hemodynamics (drug effects)
• Injections, Intraperitoneal
• Ischemic Preconditioning (methods)
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
• Male
• Mesenteric Artery, Superior (drug effects, physiopathology)
• Potassium Channels (drug effects, metabolism)
• Pyridines (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reference Values
• Sensitivity and Specificity
• Shock, Hemorrhagic (complications, drug therapy, enzymology, mortality)
• Signal Transduction
• Survival Rate
• rho-Associated Kinases (antagonists & inhibitors, metabolism)
• rhoA GTP-Binding Protein (metabolism)