title: Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs.
abstract: Severe blood loss is a major cause of death occurring within hours of traumatic injury. Na+/H+ exchange (NHE-1) activity is an important determinant of the extent of ischemic myocardial injury. The goal of the present study was to test the hypothesis that NHE-1 inhibition delays the onset of hypovolemic circulatory shock, thereby preventing early death due to severe hemorrhage in pigs. Severe hypovolemia was studied in 16 (25.2 kg) anesthetized male pigs in steps of 10-, 20-, 30-, 40-, and 50-mL kg(-1) blood loss, each in 30-min intervals. Shed blood resuscitation was started 30 min after 50 mL kg(-1) blood loss. The experiment was terminated after 3 h of resuscitation. Eight pigs were used as seline control. Eight pigs received 3 mg kg(-1) benzamide, N-(aminoiminomethyl)-4-[4-(2-furanylcarbonyl)-1-piperazinyl]-3-(methylsulfonyl), methanesulfonate (NHE-1 inhibitor) 15 min before hemorrhage. Seven control pigs died at 40- to 50-mL kg(-1) blood loss. One control pig survived initial resuscitation but died soon after. In contrast, all animals treated with NHE-1 inhibitor survived the entire protocol. In control animals, cardiac output and MAP gradually decreased at each step of blood loss with marked increase in heart rate. Cardiovascular decompensation occurred at 40 mL kg(-1) blood loss. Na+/H+ exchange inhibition increased oxygen delivery, attenuated cardiovascular decompensation, delayed the onset of irreversible hypovolemic circulatory shock, and enabled resuscitation to survival. Echocardiography analysis showed that myocardial hypercontracture gradually developed with each step of blood loss in control animals, but this hypercontracture was attenuated in the animals receiving the NHE-1 inhibitor. We conclude that NHE-1 inhibition attenuates ischemic myocardial hypercontracture, cardiovascular decompensation, delays the onset of hypovolemic circulatory shock, and prevents early death in severe hemorrhage.
authors.affiliation: Department of Research, Division of Neonatology, Mount Sinai Medical Canter, Miami Beach, Florida 33140, USA. dwu@msmc.com
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Arias
authors.forename: Jorge
authors.initials: J
authors.lastname: Bassuk
authors.forename: Henri
authors.initials: H
authors.lastname: Doods
authors.forename: Randolph
authors.initials: R
authors.lastname: Seidler
authors.forename: Jose A
authors.initials: JA
authors.lastname: Adams
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002302:Cardiac Output / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D004452:Echocardiography; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008698:Mesylates / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D012769:Shock / Q000503:physiopathology* / Q000517:prevention & control; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*; D013552:Swine
chemical_list: D001549:Benzamides; D008698:Mesylates; D017923:Sodium-Hydrogen Exchangers; C045880:methanesulfonic acid; C037689:benzamide