Delayed thromboxane synthesis inhibition, but not cholinergic blockade, reverses group B streptococcus-induced pulmonary hypertension.
Anisodamine, an anticholinergic drug, is widely used in China for treatment of infants with septic shock and has been reported to inhibit thromboxane synthesis in cultured cells. Thromboxane A2 plays an important role in the early pulmonary hypertension in sepsis; however, the role of thromboxane A2 later in sepsis is unclear. We tested the hypothesis that thromboxane A2 synthesis inhibition with dazmegrel, and cholinergic blockade with anisodamine, would attenuate the later phase of pulmonary hypertension induced by 4 h of group B streptococcus (GBS) infusion. 1 mg/kg of dazmegrel reversed the pulmonary hypertension and slightly increased cardiac output; these hemodynamic improvements persisted for 30-60 min. Plasma thromboxane B2 levels returned toward pre-GBS baseline values after dazmegrel treatment. Thus, thromboxane A2 is still a major mediator of pulmonary hypertension in piglets after 4 h of continuous GBS infusion. 0.5 mg/kg of anisodamine had no significant hemodynamic effect. 2 and 4 mg/kg of anisodamine each caused transient, dose-related decreases in systemic artery pressure; cardiac output also fell after the highest anisodamine dose. Pulmonary hypertension was not alleviated by anisodamine. All hemodynamic changes induced by anisodamine were short-lived and returned to preanisodamine values within 10 min. Anisodamine did not ameliorate thromboxane-mediated pulmonary hypertension in this animal model, and therefore may not inhibit thromboxane synthesis in vivo. The results of this study do not support the use of anticholinergic therapy to improve hemodynamics in GBS sepsis, but do suggest that thromboxane synthesis inhibition may be a clinically useful therapy in advanced GBS sepsis.
Li
J X
JX
Department of Pediatrics, University of Alabama, Birmingham.
Gray
B M
BM
Oliver
J R
JR
Lu
C Y
CY
Philips
J B
JB
D000818:Animals; D001784:Blood Gas Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D007093:Imidazoles / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D012991:Solanaceous Alkaloids / Q000494:pharmacology; D013290:Streptococcal Infections / Q000150:complications*; D013292:Streptococcus agalactiae; D013552:Swine; D013928:Thromboxane A2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000096:biosynthesis*; D014665:Vasodilator Agents / Q000494:pharmacology
D007093:Imidazoles; D010276:Parasympatholytics; D012991:Solanaceous Alkaloids; D013931:Thromboxanes; D014665:Vasodilator Agents; C003922:anisodamine; C039242:dazmegrel; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase