Inhibitory effects of etomidate and ketamine on endothelium-dependent relaxation in canine pulmonary artery.
BACKGROUND
The authors recently demonstrated that acetylcholine-induced pulmonary vasorelaxation had two primary components, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The goal was to investigate the effects of etomidate and ketamine on the NO- and EDHF-mediated components of pulmonary vasorelaxation in response to acetylcholine, bradykinin, and the calcium ionophore, A23187.


METHODS
Canine pulmonary arterial rings with an intact endothelium were suspended in organ chambers for isometric tension recording. The effects of etomidate and ketamine (10(-5) M and 10(-4) M) on vasorelaxation responses to acetylcholine, bradykinin, and A23187 were assessed in phenylephrine-contracted rings. The NO- and EDHF-mediated components of relaxation were assessed using a NO synthase inhibitor (N-nitro-L-arginine methylester [L-NAME]: 10(-4) M) and a Ca2+-activated potassium channel inhibitor (tetrabutylammonium hydrogen sulfate [TBA]: 10(-3) M) in rings pretreated with a cyclooxygenase inhibitor (ibuprofen: 10(-5) M). Intracellular calcium concentration ([Ca2+]i) was measured in cultured bovine pulmonary artery endothelial cells loaded with acetoxylmethyl ester of fura-2.


RESULTS
Etomidate and ketamine attenuated pulmonary vasorelaxation in response to acetylcholine and bradykinin, whereas they had no effect on the response to A23187. The relaxant responses to acetylcholine and bradykinin were attenuated by L-NAME or TBA alone and were abolished by combined inhibition in rings pretreated with ibuprofen. Etomidate and ketamine further attenuated both L-NAME-resistant and TBA-resistant relaxation. These anesthetics also inhibited increases in endothelial [Ca2+]i in response to bradykinin, but not A23187.


CONCLUSIONS
These results indicate that etomidate and ketamine attenuated vasorelaxant responses to acetylcholine and bradykinin by inhibiting both NO- and EDHF-mediated components. Moreover, our results suggest that these anesthetics do not directly suppress NO or EDHF activity, but rather inhibit the endothelial [Ca2+]i transient in response to receptor activation.
Ogawa
K
K
Center for Anesthesiology Research, The Cleveland Clinic Foundation, Ohio 44195, USA.
Tanaka
S
S
Murray
P A
PA
D000109:Acetylcholine / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D005045:Etomidate / Q000097:blood / Q000494:pharmacology*; D066298:In Vitro Techniques; D007649:Ketamine / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D000777:Anesthetics; D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D000001:Calcimycin; D007649:Ketamine; D000109:Acetylcholine; D002118:Calcium; D005045:Etomidate