title: Impaired myocardial function and oxygen utilization due to protamine sulfate in an isolated rabbit heart preparation.
abstract: The myocardial effects of protamine, with and without heparin, were documented in this investigation. Isolated rabbit hearts (n = 30) were retrograde perfused with Krebs-Ringers bicarbonate solution aerated with 95% O2/5% CO2 through the aortic root (37 C, 80 mmHg). Developed left ventricular blood pressure, heart rate, coronary artery flow, contractility as reflected by peak +dp/dt, oxygen extraction (a-vO2), and oxygen consumption (VO2) were measured at baseline and continuously throughout the experiment. Protamine (25 micrograms, 50 micrograms, and 250 micrograms per mL of perfusate) was circulated in the Krebs-Ringers buffer to hearts perfused without heparin (groups I, II, and III) or hearts perfused with heparin added to the buffer solution, 0.1 IU/1.0 microgram protamine (groups IV, V, and VI). Blood pressure 4 minutes after protamine was less in groups III (-23 mmHg) and VI (-28 mmHg) than in groups I (-6 mmHg), II (-18 mmHg), IV (-1 mmHg), and V (-7 mmHg). Heart rate changes (beats/minute) at 4 minutes revealed similar dose-dependent reductions (III and VI: -51, -55; II and V: -36, -36; and I and IV: -20, -16, respectively). Coronary artery flow at 4 minutes was slightly increased in groups III (9 mL/minute) and VI (15 mL/minute), but was relatively unchanged in the other groups. Decreases in contractility were apparent in all groups 4 minutes after protamine was started: group I, -14%; II, -16%; III, -30%; IV, -7%; V, -15%; and VI, -34%. Similarly declines in oxygen extraction and consumption were noted in all groups at the same time period and were greater in groups III (-53%, -44%) and VI (-55%, -49%) than in groups I (-25%, -26%), II (-15%, -12%), IV (-48%, -49%) and V (-15%, -18%), with p less than or equal to 0.05 or p less than or equal to 0.01 compared to baseline. Three of ten hearts exposed to high-dose protamine stopped beating after 5 minutes. This investigation establishes, for the first time, that protamine has dose- and time-specific adverse effects on cardiac contractility. In addition protamine decreases myocardial a-vO2 and VO2. These changes may contribute to certain adverse events accompanying the clinical administration of protamine.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor.
authors.forename: T W
authors.initials: TW
authors.lastname: Wakefield
authors.forename: L E
authors.initials: LE
authors.lastname: Bies
authors.forename: S K
authors.initials: SK
authors.lastname: Wrobleski
authors.forename: S F
authors.initials: SF
authors.lastname: Bolling
authors.forename: J C
authors.initials: JC
authors.lastname: Stanley
authors.forename: M M
authors.initials: MM
authors.lastname: Kirsh
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects*; D011479:Protamines / Q000633:toxicity*; D011817:Rabbits
chemical_list: D011479:Protamines