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PubMed1981

Effects of hyaluronidase and protamine on resistance and transport after coronary flow reduction in heparinized dogs.

We have measured the effects of hyaluronidase, protamine and a mixture of the two drugs on coronary flow resistance and transcapillary exchange in 20 heparinized, anesthetized dogs in which flow to the left anterior descending coronary artery was supplied through an extracorporeal shunt from the carotid artery. Multiple-tracer measurements were made by injecting a mixture of isotopes into the shunt and sampling from the coronary sinus. These were carried out under base-line conditions, after 1 hr of reduced flow to the left anterior descending coronary artery and after a 2nd hr during which the drug under study was infused into the ischemic zone. The results of multiple-tracer measurements were expressed as extravascular water volume (VT), extravascular sucrose volume (VS) and microvascular permeability surface area for sucrose. It was found that flow reduction significantly reduced VT, VS and permeability surface area. Resistance increased during the period of reduced flow after an initial decrease immediately upon flow reduction. In five dogs, a mixture of hyaluronidase and protamine significantly lowered coronary flow resistance and increased permeability surface are, VT, VS and VS/VT compared to preinfusion, reduced flow values. Infusion of hyaluronidase alone had significantly less effect in five other dogs, whereas infusion of protamine alone (N = 5) and saline (N = 5) did not affect resistance or transport. It is concluded that protamine enhances the effects of hyaluronidase when heparin is present, probably by preventing its blockade of hyaluronidase action.

Animals↗
PubMed1995

Studies on the neutralizing effects of protamine on unfractionated and low molecular weight heparin (Fragmin) at the site of activation of the coagulation system in man.

In a double-blind, randomized, cross-over study the neutralizing action of protamine towards unfractionated heparin (UFH, 150 U/kg i.v.) and a low molecular weight heparin (LMWH, Fragmin, 100 anti-Xa U/kg i.v.) was investigated in 15 healthy subjects in vitro by measuring activated partial thromboplastin time (APTT), thrombin time (TT) and anti factor Xa activity (anti-Xa) in venous blood and in vivo by determination of prothrombin fragment 1.2 (f1.2) and thrombin-antithrombin III complexes (TAT) in venous blood and in shed blood. UFH and LMWH caused a prolongation of APTT and TT, an increase in anti-Xa and significantly inhibited f1.2 and TAT formation in shed blood, whereas only a minimal effect on TAT and f1.2 formation in venous blood was noted. Administration of 1 mg protamine/100 U UFH resulted in a near complete reversal of APTT, TT and anti-Xa, whereas lower doses (0.25 and 0.5 mg) were less effective. The effects of UFH on f1.2 and TAT generation in shed blood were partially (60-70%) neutralized only by the high dose (1.0 mg). Application of 1 mg protamine/100 anti-Xa U LMWH caused a near complete reversal of both APTT and TT but had only a weak effect on anti-Xa. In shed blood, the effect of LMWH on TAT and f1.2 formation was reversed by protamine only by 14% and 23% respectively. Our data do not support the concept that to reduce the incidence of protamine's potential clinical side effects, the administration of a lower dose of protamine than 1 mg protamine/100 U UFH is justified.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Direct sequencing of the human protamine P1 gene and application in forensic medicine.

Protamines are among the most variable nuclear proteins known in eukaryotes. In order to learn more about their evolution and function in humans and to explore the possibility of potential applications in forensic medicine we have developed a rapid method to amplify and directly sequence the protamine P1 gene simultaneously in many different samples. The method takes only 3.5 h from genomic DNA to the sequencing reactions. Despite the high variability of these genes only one polymorphic site was detected at the coding region level in different individuals. This polymorphic variation does not create a change in the amino-acid sequence of the protamine. Because all the protamine genes sequenced from different species are markedly different among them as well as to the human sequence, amplification and direct sequencing of this gene can be used to unequivocally identify the human or animal origin of biological specimens. Furthermore, the single polymorphic site detected in the human P1 gene could be useful in conjunction with other markers in identification studies in humans.

Amino Acid Sequence↗
PubMedDate not supplied

Can protamine be used during perfusion with heparin surface coated equipment?

Left heart bypass (LHBP) with heparin coated perfusion equipment including an arterial filter (pore size: 40 microns) was performed in five canine experiments after full systemic heparinization (heparin 300 IU/kg; activated coagulation time [ACT] > 480 sec). The heparin coated filter was replaced after 45 min with a second heparin coated filter. Protamine (1:1) was added after 45 min and perfusion was continued for another 45 min before the second filter was replaced with an uncoated control filter. In addition to continuous hemodynamic monitoring, all filters were disassembled and analyzed morphometrically with a scanning electron microscope (deposits on screens were expressed as percent of surface covered with fibrin or number of cells/100 micron 2, respectively). For the first heparin coated filter (ACT > 480), 0.3 +/- 0.5% of the surface was covered with fibrin, 0.7 +/- 0.7% with platelets, and 0.02 +/- 0.0% with red cells. For the second heparin coated filter exposed to neutralization of heparin with protamine, surface coverage was fibrin in 22 +/- 15%, platelets in 3.2 +/- 0.8%, and red cells in 0.2 +/- 0.1% (p < 0.05 for all comparisons with filter 1). For uncoated control filters (ACT = 120), surface coverage was fibrin in 31 +/- 33%, platelets in 3.7 +/- 2.9%, and red cells in 0.2 +/- 0.1% (not significant [NS] for all comparisons with filter 2). Although all arterial filters used in this study remained patent throughout the scheduled period, it became clear that protamine given during perfusion reduces the antithrombotic activity of bonded heparin. Hence, protaminization during perfusion with heparin coated equipment cannot be recommended.

Animals↗
PubMed1993

[Human male sterility can be caused by mutations in the protamine P2 gene].

The sperm of fertile and infertile human males was treated with 0.25 n. HCl or 1% CTAB. Relative proportions of various protamine fractions in the obtained extracts were determined by scanning microdensitometry following electrophoresis of the total protamine in polyacrilamide gels. The findings were as follow. 1. The share of protamine P(2 + 3) in the sperm obtained from infertile males was lower than that of fertile males. 2. Protamine P2 in infertile males has a reduced affinity to DNA. It is suggested that in some cases the human male infertility may be due to some mutations within the P2 gene.

Cell Count↗
PubMedDate not supplied

[The effect of protamine on cholesterol, triglycerides and blood serum proteins during the dynamics of experimental hypercholesterolemia].

Content of total proteins, cholesterol, and triglycerides was studied in the blood serum and lipoprotein fractions of rabbits after administration of protamine within 1, 3 and 7 months of hypercholesterolemia development. The protamine effect was accompanied by "equalization" of cholesterol and triglyceride concentrations, as compared with their alteration in hypercholesterolemia, by stabilization of their content in various periods of the disease, but at the higher level than that of intact animals. The phenomenon observed occurred mainly in lipid components of LDL and VLDL subfractions. Analysis of alterations in the content of cholesterol and proteins in HDL and apo B-containing fractions showed that administration of protamine during long-term hypercholesterolemia led to development of antiatherogenic symptoms. Proatherogenic alterations in lipoprotein composition, developed during hypercholesterolemia, appear to be inhibited by protamine.

Animals↗
PubMed1993

Vitamin D status and hypocalcemic response to protamine in exercised and non-exercised dairy cows.

Bone resorption was studied in post parturient cows using intravenous injection of protamine. Protamine inhibits bone resorption and the protamine-induced hypocalcemia can be taken as a measure of this process. The studies were performed in a herd where half of the cows had been tied indoors for 2 1/2 years, the other half had been given daily exercise during the same period. All animals were fed in the same way. The hypocalcemic response to protamine was the same in both groups, which indicates that exercise did not change bone resorption. The serum levels of calcium, inorganic phosphorus and magnesium around parturition did not differ. The daily exposure to daylight increased the serum level of 25-(OH)-cholecalciferol in late summer in the exercised group.

Animals↗
PubMed1996

Antagonism of SR 90107A/Org 31540-induced bleeding by protamine sulfate in rats and mice.

The neutralization by protamine sulfate of bleeding enhancement induced by the potent anti-factor Xa pentasaccharide SR 90107A/Org 31540 and by heparin has been studied in rats and mice. Bleeding, as measured by transection of the tail of anaesthetised rats or mice, was increased following the administration of heparin and very high doses of SR 90107A/Org 31540. In rats, i.v. doses of 0.6 mg/kg heparin or 15 mg/kg SR 90107A/Org 31540 were required to enhance bleeding time to approximately the same extent (5- or 7-fold increase), whereas in mice a 13-fold increase in blood loss was observed with i.v. doses of 3 mg/kg heparin or 10 mg/kg SR 90107A/Org 31540. Protamine sulfate (10 mg/kg i.v.) reduced bleeding in rats and mice induced by both compounds. It also neutralized the anti-factor Xa activity as well as the antithrombotic activity of heparin as observed in venous thrombosis models in both species. However, protamine sulfate neither affected the anti-factor Xa activity nor the antithrombotic activity of SR 90107A/Org 31540 in rats and mice. The present results suggest that protamine sulfate may be regarded as a potential antidote to neutralize bleeding side-effects in cases of SR 90107A/Org 31540 overdosing.

Animals↗
PubMed1976

Removal of heparin and protamine from plasma.

A simple chromatographic technique for rapid adsorption of heparin and protamine from plasma samples is described, allowing accurate interpretation of coagulation screening tests and specific clotting factor assays. With the use of columns of ECTEOLA-cellulose, up to 300 U. of heparin could be completely adsorbed from a 1 ml. plasma sample. When citrated nonheparinized plasma was passed over the ECTEOLA-cellulose columns, the thrombin, prothrombin, and partial thromboplastin times were unaffected. Levels of fibrinogen, prothrombin, and factors V, VII, VIII, IX, and XI average within 90 per cent of control, nonchromatographed samples. When heparinized plasma samples (0.1 and 1.0 U. per milliliter) were passed over columns, heparin was completely removed and the results of the screening tests and the specific factor assays were the same as for the chromatographed nonheparinized samples. In addition, heparinized samples with decreased factor VIII activity maintained their pretreatment factor VII activities after heparin removal. Blood samples containing heparin were obtained from two patients during open-heart surgery. Following heparin adsorption on ECTEOLA-cellulose columns, factor VIII activity levels remained above 60 per cent during cardiopulmonary by-pass. The presence of protamine sulfate in plasma samples prolonged the prothrombin and partial thromboplastin times while slightly shortening the thrombin time. The protamine effect persisted after ECTEOLA-cellulose, but could be removed by a similar column of carboxymethyl-cellulose. The latter resin had no effect on screening tests or on assays of factors VIII or IX activity. The combination of the two resins was then used to remove the separate inhibitory effects from heparinized plasma samples to which protamine had been added.

Adsorption↗
PubMed1981

Intraaortic administration of protamine: Method for heparin neutralization after cardiopulmonary bypass.

In neutralizing heparin with intravenous protamine sulfate, hypotension may be prevented by administering the drug intraarterially. Forty patients underwent cardiac surgery with extracorporeal circulation in our hospital; each received a rapid injection of nondiluted protamine sulfate in the aortic root to reverse the effects of heparin. To maintain the blood volume at a constant level, volume expanders and inotropic drugs were avoided. The intraaortic injections ranged in duration from 0.2 min to 2.8 min, with a mean of 1.1 min. The mean systolic pressure only dropped from 92 mm Hg (SD +/- 21) before protamine injection to 85 mm Hg (SD +/- 23) after injection (p < 0.0001). In seven patients (18%), no hypotension was evident; in the remaining patients, the systolic pressure returned to preinjection values within a mean of 2.2 min. Coagulation was observed within 3 to 4 min (mean = 2.2 min) after the initiation of injection. This study indicates that intraaortic administration of protamine is a rapid and safe technique for heparin reversal after cardiopulmonary bypass.

Journal Article↗
PubMed1991

Characterization of a cAMP-independent Ca2(+)-inhibited protamine kinase from Candida lipolytica.

A cAMP-independent protamine kinase has been purified from extracts of the yeast Candida lipolytica by ion-exchange and affinity chromatography. Two subunits with apparent Mr's of 52,000 and 36,000 were resolved by SDS-PAGE. The purified kinase exhibited about 20% activity with casein and histone Type VII-S as substrates relative to protamine. The enzyme was inactive against other protein substrates tested, and was essentially insensitive to AMP, cAMP, cGMP up to 0.2 mM, the polyamines spermine and spermidine up to 1 mM, N-ethylmaleimide (5 mM), 2-mercaptoethanol (20 mM), or dithiothreitol (2 mM), and several cations like Zn2+, N1+, or Co2+ at 0.1 mM each. Ca2+ at 3 mM inhibited protamine kinase activity by 50%, which was reversed by EGTA.

Calcium↗
PubMed2001

Nuclear transfer of mouse follicular epithelial cells pretreated with spermine, protamine, or putrescine.

The in vitro and in vivo developmental potential of nuclear transferred embryos receiving follicular epithelial cells pretreated with spermine (5 and 20 mM), protamine (0.25 and 25 mg/ml), or putrescine (1 and 100 microg/ml) at room and reduced temperatures was examined in the mouse. The pretreated donor cells were first fused with enucleated oocytes, and then nuclei from reconstituted eggs at the two-cell stage were fused with the enucleated fertilized two-cell embryos. The proportion of reconstituted embryos that developed into blastocysts was not significantly different among groups. After transfer to recipients, implantation rates were not different between groups and fetuses were obtained in protamine- and spermine-treated groups as well as in control groups. These results demonstrate that pretreatment of nuclear donor cells with spermine, protamine, or putrescine does not enhance the developmental potential in vitro or in vivo in the mouse. J. Exp. Zool. 289:208-212, 2001.

Animals↗
PubMed2000

Lead effects on protamine-DNA binding.

BACKGROUND: Lead impairs male fertility and may affect offspring of exposed males, but the mechanisms for this impairment are not completely clear. Protamine P1 and P2 families pack and protect mammalian sperm DNA. Human HP2 is a zinc-protein and may have an important role in fertility. As lead has affinity for zinc-containing proteins, we evaluated its ability in vitro to bind to HP2 and its effects on HP2-DNA binding. Methods and Results UV/VIS spectroscopic data indicated that HP2 binds both Pb(2+) and Zn(2+)(as chloride salts). They also provided evidence that thiol groups mainly participate for Zn(2+)-binding; however, HP2 has additional binding sites for Pb(2+). The mobility shift assay showed that lead interaction with HP2 caused a dose-dependent decrease on HP2 binding to DNA, suggesting that lead may alter chromatin stability. CONCLUSIONS: These in vitro results demonstrate that lead can interact with HP2 altering the DNA-protamine binding. This chemical interaction of lead with protamines may result in chromatin alterations, which in turn may lead to male fertility problems and eventually to DNA damage.

Chromatin↗
PubMedDate not supplied

Anticoagulation with heparin during cardiac catheterization and its reversal by protamine.

The duration of effective anticoagulation with heparin during cardiac catheterization and angiography was determined in 201 patients. Effective anticoagulation was defined as prolongation of the activated partial thromboplastin time (APTT) by 2 or more times the upper limit of normal. When the procedure was completed within 40 min of heparin administration, all patients were anticoagulated adequately. The incidence of inadequate anticoagulation ranged from 9% to 25% as the time from heparin administration increased to 89 min. Procedures completed more than 90 min after heparin administration had a 58% incidence of inadequate anticoagulation. A protocol to estimate the appropriate protamine dose was developed based on experience accumulated in the first 78 patients and tested subsequently in 101 consecutive patients. Clotting studies returned to the normal range in 92% of the patients. The mean APTT decreased from 84.1 +/- 19.4 to 27.4 +/- 2.5 sec (p less than .001) after protamine. Patients who did not correct to normal after protamine remained only 2.8 +/- 1.4 sec (range 0.7-5.5 sec) above normal. These data provide an estimate of the duration of anticoagulation during cardiac catheterization and angiography and demonstrate the feasibility of a simple and reliable method to reverse the effects of heparin.

Adult↗
PubMed1984

Adverse reactions to protamine sulfate following cardiac surgery.

We report four patients who developed severe adverse reactions to protamine sulfate following cardiac surgery. Two types of reactions were seen. First, an immediate anaphylaxis which is a complement-dependent IgG antibody-mediated reaction. In the literature, 80% of patients who had similar reactions have had previous exposure to protamine. All patients adequately tested had positive skin tests and there is 6% mortality. The second reaction to protamine during cardiac surgery is characterized by delayed onset and profound vascular damage presenting as noncardiogenic pulmonary edema or total vascular collapse with prolonged hypotension and anasarca. These patients have negative skin tests and in our studies, no evidence of antibody mediated reaction, suggesting some other mechanisms may play a part. The mortality is high (30% of patients reported) and survivors have significant morbidity.

Aged↗
PubMed1978

Proteolytic degradation of protamine during thiol-induced nuclear decondensation in rabbit spermatozoa.

Rabbit sperm nuclei decondensed when incubated with dithiothreitol and Triton X-100. Protamine isolated from these nuclei during the course of treatment exhibited marked and progressive degradation. Timed interval experiments revealed that the degradation of protamine significantly preceded sperm nuclear decondensation and reached its maximum extent before decondensation was completed. Studies with protease inhibitors demonstrated that proteolysis was involved in both nuclear decondensation and protamine degradation.

Animals↗
PubMed1987

Protamine polymorphism in Xenopus laevis laevis.

Protamines from individual frogs of the subspecies Xenopus laevis laevis were compared by electrophoresis on polyacrylamide gels containing acetic acid, urea, and Triton X-100 to determine if the expression of protamine genes differs among individuals. Two electrophoretic bands, SP2a and SP2b, appeared to be expressed as allelic variants. Of 33 frogs, 19 expressed only SP2a, 11 expressed both SP2a and SP2b, and three expressed only SP2b. Electrophoretic analysis of partial V8 protease digests could not distinguish the peptides released from SP2a and SP2b. Differences in sperm development between individuals were not detected by light or electron microscopy. The results suggest that protamine polymorphism can exist among individuals of a species without an apparent effect on sperm development or sperm function.

Animals↗
PubMed1993

Differences in chromatin condensation during spermiogenesis in two species of fish with distinct protamines.

The sperm cells of Mullus surmuletus (family Mullidae, order Perciformes) and Dicentrarchus labrax (family Percichthyidae, order Perciformes) belong respectively to "type I" and "type II" spermiogenesis categorized by Mattei ('70). The protein content in their sperm nuclei consists of two histone-like proteins (Mullus surmuletus) and one typical protamine (D. labrax). In order to correlate the molecular characteristics of these proteins with their function, we have analyzed the molecules in detail and studied at the ultrastructural level the condensation of chromatin during the spermiogenesis in both species. D. labrax has a true protamine of 34 amino acid residues and its sequence (PR4QASRPVR5TR2STAER5V2R4) contains four arginine clusters. The sperm proteins of M. surmuletus contain 110 and 115 amino acid residues and , by their composition (23-24% Lys, 21-22% Arg, 11-12% Ala), they are similar to protamine-like molecules from sperm of molluscs. During the spermiogenesis of D. Labrax, chromatin condensation progresses from small fibro-granular structures (25 +/- 5 nm in diameter), to larger granules (150 +/- 50 nm diameter). M. surmuletus accumulates 25 +/- 5 nm diameter structures in the basal pole of the nucleus; these structures grow till they reach a diameter of 50 +/- 10 nm and finally go through a process of fusion that changes the condensation of chromatin in sperm nuclei, acquiring a homogeneous aspect. These observations show that during spermiogenesis in the studied types, the last stages of chromatin condensation are dependent on the type of nuclear proteins.

Amino Acid Sequence↗