title: Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle.
abstract: Protamine is a polycationic amine used clinically to reverse heparin overdose. Here we characterized the actions of protamine on the cardiovascular system of anesthetized rats and in isolated Langendorff rat hearts in order to define a possible mechanism of action on cardiovascular tissue. In anesthetized rats, protamine reduced blood pressure in a dose-dependent fashion and reduced heart rate. Only at a dose of 32 mg/kg did protamine increase the Q-aT interval of the electrocardiogram (EKG) to 62 +/- 6 msec from a control of 54 +/- 5 msec (p < 0.05). Protamine dose-dependently reduced cardiac output by 74 +/- 5% and stroke volume by 62 +/- 15 %, suggesting that it directly affects cardiac contractility. An analysis of blood chemistry suggests that protamine does not alter plasma electrolyte or serum enzyme levels at the doses administered. Protamine produced aberrant rhythms in normal rat hearts when administered between 1-32 mg/kg. The P-Q segment of the EKG for each of the arrhythmic complexes was reduced to 24 +/- 1 msec compared to 32 +/- 3 msec in normal EKG complexes suggestive of anomalous atrio-ventricular or pre-excitation conduction. Isolated rat heart studies confirmed that protamine produced a reduction in cardiac contractility. Our studies suggest that the cardiovascular depressant actions of protamine result from a direct effect on the heart and that protamine may produce aberrant conduction within the heart which may result in deleterious effects in heart function, especially conditions associated with myocardial disease.
authors.affiliation: Department of Pharmacology, XOMA (US) LLC, 2910 Seventh St., Berkeley, CA 94710, USA. pugsley@xoma.com
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
authors.forename: Vikram
authors.initials: V
authors.lastname: Kalra
authors.forename: Sarah
authors.initials: S
authors.lastname: Froebel-Wilson
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008970:Molecular Weight; D009200:Myocardial Contraction / Q000187:drug effects; D009924:Organ Culture Techniques; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000071228:Polyelectrolytes; D011479:Protamines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011073:Polyamines; D000071228:Polyelectrolytes; D011479:Protamines