Many recent reports in the literature address the local anesthetics efficacy of tricyclic antidepressants (TCAs). Here we investigated whether nerve block from TCAs is prolonged by site 1 sodium channel blockers such as tetrodotoxin and saxitoxin, which are known to prolong block from conventional local anesthetics. Tetrodotoxin and saxitoxin greatly prolonged block from TCAs. For example, the median duration of thermal nociceptive blocks for 10 mM amitriptyline, nortriptyline and doxepin were 0, 0, and 124 min; co-injection with 20 microM TTX (median block duration=0), yielded blocks lasting 404, 325, and 697 min, respectively. Co-injection of 12 microM saxitoxin (median block duration=0) with 10 mM amitriptyline resulted in a thermal nociceptive block duration of 373 min. Co-injection of 7.7 mM bupivacaine and 7.7 mM amiptriptyline did not result in block prolongation. Systemic (subcutaneous) delivery of tetrodotoxin or amitriptyline did not result in prolongation of block from the other class of drug injected at the sciatic nerve. In TCA-containing formulations, motor blockade was consistently longer than thermal nociceptive block; motor blockade was also prolonged by tetrodotoxin and saxitoxin. In summary site 1 sodium channel blockers prolong the duration of TCAs via a locally mediated mechanism.
Neurotoxicity has been reported with tricyclic antidepressants (TCAs) used as local anesthetics. We examined the hypothesis that TCAs cause tissue injury, particularly myotoxicity, as occurs with many local anesthetics. Animals were given sciatic nerve injections with 0-80 mM doxepin, amitriptyline, or bupivacaine (1.5 mL for histological studies, 0.3 mL for neurobehavioral studies). Four days after injection, the TCAs caused ischemic tissue injury. Subcutaneous tissue showed expansion and hardening, with hemorrhage and adhesion to overlying skin. Muscle was diffusely pale. Histopathology showed coagulative necrosis of muscle and surrounding soft tissues, with thrombus formation in vasculature near affected areas. These findings were much reduced with bupivacaine. TCA-injected and bupivacaine-injected animals also developed characteristic local anesthetic myotoxicity. Amitriptyline proved less potent than bupivacaine as a local anesthetic: the concentrations required to provide 100 min of nerve block were 20 mM and 3 mM, respectively. Some animals receiving large concentrations of amitriptyline developed spontaneous recrudescence of nerve blockade or had irreversible nerve blockade, both of which may reflect nerve injury. Neither finding occurred in animals injected with bupivacaine. TCAs do not appear to offer any advantages over conventional local anesthetics and do appear to risk substantially increased toxicity.
Objective Corin is a natriuretic peptide converting enzyme that cleaves precursor pro-B-type natriuretic peptide (proBNP) to active BNP (diuretic, natriuretic, and vasodilatory properties). Increased plasma BNP is a known diagnostic and prognostic heart failure (HF) biomarker in ambulatory and surgical patients. Recent studies indicate that plasma corin is significantly decreased in chronic HF patients, yet perioperative plasma corin concentrations have not been assessed in cardiac surgical patients. The objectives of this study were to determine the effect of coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) on plasma corin concentrations and to assess the association between change in perioperative plasma corin concentration and long-term postoperative HF hospitalization or death. We hypothesized that plasma corin concentrations decrease significantly from preoperative baseline during postoperative days 1-4, and that hospitalization or death from HF during the 5 years after surgery is significantly associated with higher relative difference (preoperative baseline to postoperative nadir) in plasma corin concentrations. Design Prospective observational pilot study. Setting Two institutions: Brigham and Women’s Hospital, Boston, Massachusetts and the Texas Heart Institute, St. Luke’s Hospital, Houston, Texas. Patients 99 European ancestry subjects who underwent isolated primary CABG surgery with CPB. Intervention Non-emergency isolated primary CABG surgery with CPB. Measurements Plasma corin concentration was assessed preoperatively and at four postoperative time points (postoperative days 1-4). HF hospitalization or HF death events during the five years following surgery were identified by review of hospital and death records. Main Results Postoperative plasma corin concentrations were significantly lower than preoperative baseline concentrations (P<0.0001). Perioperative corin concentrations were significantly higher in males than in females (P<0.0001). 15 subjects experienced long-term postoperative HF events. Subjects who experienced HF hospitalization or HF death during study follow-up had significantly higher relative difference in plasma corin concentration (preoperative baseline to postoperative nadir) than subjects who did not experience HF events during study follow-up (P=0.03). Conclusions Plasma corin concentrations decrease significantly from preoperative concentrations following CABG surgery. HF hospitalization or HF death during the 5 years following CABG surgery with CPB is associated with larger relative decrease in plasma corin concentration from preoperative baseline. Further investigation is warranted to determine the role of corin in postoperative HF biology.
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