Role of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and mitogen-activated protein kinases in volatile anesthetic-induced relaxation in newborn rabbit pulmonary artery.
BACKGROUND
This study examined the responsiveness of skinned pulmonary arteries from newborn rabbit to volatile anesthetics and the role of protein kinase C (PKC), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the downstream effectors, mitogen-activated protein kinases (ERK1/2 and p38).


METHODS
Pulmonary arterial strips from 9- to 12-day-old rabbits were mounted on force transducers and treated with saponin ("skinned" strips). The skinned strips were activated by pCa 6.3 until force reached a steady state (control). Isoflurane or halothane was then administered. The result (test) was expressed as a percentage of the control. Inhibitors included bisindolylmaleimide (Ca2+-dependent and -independent PKC), Gö6976 (Ca2+-dependent PKC), CKIINtide (CaMKII), KN-93 (CaMKII), PD98059 (MEK/ERK1/2), and SB203580 (p38).


RESULTS
The anesthetics dose-dependently decreased pCa-induced force (4-32% for 1-5% isoflurane; 17-76% for 1-3% halothane). The inhibitors of PKC (bisindolylmaleimide and Gö6976) and MEK/ERK1/2 (PD98059) completely prevented the relaxation induced by 3% isoflurane and partially prevented that induced by 2% and 3% halothane with the same effective inhibitor concentrations. In contrast, the effective concentration of CaMKII inhibitors was a direct function of the anesthetic concentration for different inhibitors (KN-93 for isoflurane and CKIINtide for halothane), and that of the p38 inhibitor (SB20358) was a direct function of both anesthetics.


CONCLUSIONS
In Ca2+-clamped skinned pulmonary arterial strips from newborn rabbits, the anesthetics induce relaxation, which is prevented by the PKC inhibitors MEK/ERK/12, CaMKII, and p38. It is proposed that the anesthetic-induced relaxation is via cPKC/MEK/ERK1/2 and CaMKII/p38 pathways and, in addition, via CaMKII-p/MLCK-p(-)/MLC-p(-) for halothane.
Su
Judy Y
JY
Department of Anesthesiology, University of Washington, Seattle 98195, USA. jsu@u.washington.edu
Vo
Anhkiet C
AC
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects*; D011817:Rabbits; D048051:p38 Mitogen-Activated Protein Kinases
D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D007530:Isoflurane; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C088060:bisindolylmaleimide; D006221:Halothane