Disease relevance of PRM1

• Protamine sulfate is commonly required during these surgical procedures but has been associated with left ventricular dysfunction [1].
• However, 40 micrograms/ml of protamine caused a more pronounced decline in myocyte function and beta-adrenergic responsiveness in the supraventricular tachycardia group [1].
• These results suggest that patients with underlying cardiac disease may have an increased susceptibility to a sudden compromise of left ventricular contractile performance after protamine administration [1].
• This study examined the direct effects of protamine on isolated myocyte contractile function in 10 control pigs and 10 pigs with dilated cardiomyopathy induced by supraventricular tachycardia (rapid atrial pacing at 240 beats/min for 3 weeks) [1].
• CONCLUSIONS: The loss of the normal force-frequency relation, partial depolarisation, rise in resting tension, and appearance of rested state rapid cooling contractures suggest that unbound protamine can lead to excess intracellular Ca2+, mediated by an alteration in membrane ionic conductances [2].

High impact information on PRM1

• Thus, the effects of PROT on myocyte contractile processes are not due simply to the high positive charge of the molecule [3].
• Direct effects of protamine sulfate on myocyte contractile processes. Cellular and molecular mechanisms [3].
• BACKGROUND: Administration of the arginine-rich, highly charged protamine (PROT) molecule has been associated with episodes of acute left ventricular (LV) dysfunction [3].
• In addition, cAMP production after stimulation with isoproterenol and forskolin was significantly blunted in the presence of PROT [3].
• In addition, PROT abolished the inotropic effects of ouabain on myocyte contractile function [3].

Chemical compound and disease context of PRM1

• Pulmonary hypertension developed and reached a peak within 2 min of protamine administration, often at the same time that L-670596 was administered in the treatment group [4].
• We tested the hypothesis that pulmonary hypertension and thromboxane A2 release after heparin neutralization by protamine are mediated by oxygen free radicals [5].
• Severe pulmonary hypertension and thromboxane A2 release after protamine were not prevented by either DMSO or SOD [5].
• The effect of left ventricular infusion of protamine on pulmonary hypertension as well as a possible role of platelet-activating factor (PAF) or histamine in the heparin-protamine reaction was investigated in 30 pigs in four different groups during general anesthesia [6].
• Thus, pulmonary hypertension associated with protamine reversal of heparinization is associated with prostaglandin release from the lung, and this does not require mediation of platelets or leukocytes [7].

Biological context of PRM1

• The nucleotide sequence of a boar protamine 1 cDNA [8].
• Variants of the PROT moelcule were constructed by specific amino acid substitutions and deletions, which provided a means to vary charge as well as structure [3].
• However, a PROT variant with an 18+ charge but different amino acid sequence induced significant negative effects on myocyte function and inotropic responsiveness [3].
• Although there was no significant phosphorylation of phosphorylase, phosphorylase b kinase, casein, phosvitin, and protamine, this kinase was found to be very active toward myelin basic protein and histones H1, 2A, and 2B [9].
• The addition of protamine to virus infusate resulted in a fivefold increase in transgene protein product in lung tissue assayed 72 hr after gene transfer [10].

Anatomical context of PRM1

• Microscopic examination revealed that PROT could traverse the vascular compartment of the myocardium and come in direct contact with the myocyte [3].
• Renal NO production may be modulated by the addition of L-arginine, arginine homopolymers (R2, R6, R10), and protamine, all of which can potentially transport across cellular membranes and provide a substrate for nitric oxide synthase within kidney parenchyma [11].
• These results do not support the hypothesis that protamine sensitizes vascular smooth muscle cells to the endothelium-derived relaxing factor, nitric oxide [12].
• Immunocytochemical localization of nuclear protamine in boar spermatozoa during epididymal transit [13].
• The protamine is present in the cytoplasm of elongating spermatids and it enters the nuclei throughout the elongation process after possible storage in the cytoplasm or in the nuclear envelope of spermatids, or both [14].

Associations of PRM1 with chemical compounds

• Ouabain receptor binding was 7.1 pmol/mg and decreased to 2.6 +/- 0.4 pmol/mg in the presence of PROT [3].
• Substitution of arginine with lysine in the PROT peptide sequence ameliorated the negative effects on myocyte contractile processes; despite identical overall charge (21+) [3].
• PROT reduced myocyte responsiveness to forskolin (100 mumol/L), which directly activates adenylate cyclase, by > 40% from forskolin [3].
• To further establish that PROT can contribute to changes in LV function in the clinical setting, fluorescein-labeled PROT was circulated in antegradely perfused rabbit hearts [3].
• To determine contributory mechanisms for the effects of PROT on myocyte sarcolemmal systems, beta-receptor- and cardiac glycoside-binding characteristics were determined in sarcolemmal preparations. beta-receptor binding was 175 +/- 10 fmol/mg and was reduced to 140 +/- 6 fmol/mg in the presence of PROT (P < .05) [3].

Other interactions of PRM1

• Two minutes after protamine administration, CD18 (beta-subunit of Mac-1) expression measured by immunofluorescence flow cytometry increased 128 +/- 9% (mean +/- SEM) over preprotamine levels in control piglets but remained unchanged in NPC piglets (99 +/- 2%, P < 0.05) [15].
• Furthermore, the endothelial cell-mediated acceleration of thrombin inactivation by antithrombin III was diminished by protamine sulfate, but was not affected by histidine-rich glycoprotein even at a histidine-rich glycoprotein/antithrombin III molar ratio of approximately 7:1 [16].
• Group IV animals were given superoxide dismutase (SOD) 5 min before protamine [5].
• Neutrophil activation mediates protamine-induced pulmonary hypertension [15].
• Choline acetyltransferase (CAT) was purified to homogeneity from 363 g of human neostriatum by means of ammonium sulfate and protamine sulfate fractionation, followed by chromatography on DEAE-Sephadex, hydroxyapatite, phosphocellulose, and agarose-hexane-Co A columns [17].

Analytical, diagnostic and therapeutic context of PRM1

• In the presence of 20 micrograms/ml of protamine, myocyte contractile function was unaffected in the control group but decreased by 40% from baseline values in the supraventricular tachycardia group [1].
• Myocyte contractile function was measured by videomicroscopy at baseline and with 10, 20, 40 or 80 micrograms/ml of protamine [1].
• Vertebrate protamine gene evolution I. Sequence alignments and gene structure [18].
• Protamine P1 genes have been sequenced following PCR amplification from 11 mammals representing five major mammalian orders: Rodentia (rat and guinea pig), Carnivora (cat and bear), Proboscidea (elephant), Perissodactyla (horse), and Artiodactyla (camel, deer, elk, moose, and gazelle) [19].
• OBJECTIVES: To evaluate the therapeutic efficacy and applicability of a heparin removal device (HRD) based on plasma separation and poly-L-lysine (PLL) affinity adsorption as an alternative to protamine in reversing systemic heparinization following cardiopulmonary bypass (CPB) [20].

References