Follow-up after liver transplantation for primary sclerosing cholangitis: effects on survival, quality of life, and colitis.

BACKGROUND: Except for primary biliary cirrhosis, primary sclerosing cholangitis (PSC) is now the commonest indication for liver transplantation in Sweden. There are several specific problems related to post-transplantation life in these patients. METHODS: We analyzed a 10-year cohort of 47 patients transplanted at our center. RESULTS: Incidental biliary carcinoma was diagnosed in 13%,, with a 2-year survival of only 17%, compared with 70% in the other patients. The 2-year survival has improved considerably (to 82%) in recent years. Quality of life was much or slightly improved in 80%. The colitis was much or slightly improved in 65%, with some deterioration in only 6%. No patient developed colonic carcinoma. Previous biliary tract surgery was identified as a risk factor for a worse 1-year mortality. CONCLUSIONS: Liver transplantation for PSC is now associated with a high survival rate and an improvement in the quality of life and course of ulcerative colitis. Previous biliary tract surgery is a risk factor for non-survival.

Replacement of L-Lys by D-Lys(NH2) in peptide Ala-Arg-Pro-Ala-Lys (peptide 6A) increases its coronary blood flow-promoting properties.

Peptide 6A, a degradation of B beta chain of fibrinogen, is known to increase coronary and femoral blood flow. In this study, we examined the effects of peptide 32, an analogue of peptide 6A on coronary blood flow in anesthetized dogs. Intracoronary administration of equimolar amounts of peptide 32 and peptide 6A showed a greater (p < 0.05) increase in blood flow with peptide 32. Intravenous administration of peptide 32 also resulted in greater and longer-lasting increase in coronary blood flow. The greater blood flow enhancing effect of peptide 32 than that of peptide 6A may relate to absence of its degradation by angiotensin converting enzyme.

Fibrin(ogen) degradation product peptide 6A increases femoral artery blood flow in dogs.

To determine the effects of peptide 6A (a fibrinogen-degradation product) on femoral blood flow, anaesthetized dogs were given saline or peptide 6A intravenously in random order. Bolus injection of peptide 6A (10, 20 or 50 mumoles) caused a short-lasting dose-dependent decrease in femoral bed resistance and an increase in femoral blood flow. Continuous infusion of peptide 6A (50 mumoles min-1) resulted in a sustained decrease in resistance and an increase in femoral artery blood flow (54 +/- 33%), with a small, insignificant decrease in femoral artery mean pressure. Indomethacin pretreatment caused only slight attenuation of the peptide 6A-induced increase in femoral blood flow. In in vitro experiments, peptide 6A relaxed rings of femoral artery, and this effect was associated with an increase in 6-keto-PGF1 alpha in the vascular ring supernatants and in the tissue cyclic GMP concentrations. Peptide 6A-induced relaxation was abolished by de-endothelialization, but not by treatment with indomethacin. These observations suggest that peptide 6A induces vasorelaxation largely by stimulating release of endothelium-derived relaxing factor. PGI2 release appears to play only a minor role in the vasodilator effects of peptide 6A in the femoral bed.

Effect of L-arginine and an arginine-containing pentapeptide on canine femoral arterial blood flow.

The amino acid L-arginine is a precursor of endothelium derived relaxing factor (EDRF). The pentapeptide 6A (Ala-Arg-Pro-Ala-Lys) released by plasmin degradation of fibrinogen also contains arginine and relaxes vascular smooth muscle by releasing EDRF (nitric oxide). To determine and compare the effects of L-arginine, peptide 6A and a combination of L-arginine and peptide 6A on femoral artery blood flow and vascular resistance, anesthetized mongrel dog were administered saline, L-arginine, D-arginine, peptide 6A and L-arginine + peptide 6A in a random order. L-arginine and peptide 6A both induced an immediate dose-dependent short-lasting increase in femoral blood flow and a decrease in vascular resistance. Peptide 6A exerted a much greater (P less than 0.01) vasodilatory effect than did L-arginine at the same molar concentration suggesting that properties besides the arginine content are important in the effect of the pentapeptide. D-arginine had much less effect than L-arginine, indicating that the effect of L-arginine may be related to its utilization for synthesis of EDRF. When the peptide 6A was given soon after L-arginine, its effect on blood flow was not greater than that of L-arginine alone suggesting that L-arginine in a large amount makes guanylate cyclase less available for the more active peptide.

Omega-3 polyunsaturated fatty acids augment endothelium-dependent vasorelaxation by enhanced release of EDRF and vasodilator prostaglandins.

Dietary supplementation with fish oil results in augmentation of endothelium-dependent vasorelaxation in experimental animals. The present study was designed to evaluate the direct in vitro effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) on vascular reactivity in isolated rat aortic rings. Aortic rings were incubated with the omega-6PUFA arachidonic acid (AA, 10(-7) M) or the omega-3 PUFAs eicosapentaenoic acid (EPA, 10(-7) M) and docosahexaenoic acid (DHA, 10(-7) M) in an organ bath at 37 degrees C. Following contraction with norepinephrine, changes in isometric force were measured in response to the endothelium-dependent vasodilators acetylcholine (ACh, 10(-10) to 10(-5) M) or the calcium ionophore A23187 (10(-10) to 10(-5) M). Parallel sets of vascular rings were pretreated with the cyclooxygenase inhibitor indomethacin (10(-5) M) or the inhibitor of nitric oxide synthesis NG-monomethyl L-arginine (L-NMMA 5 x 10(-5) M) prior to treatment with AA or EPA. Treatment of rings with EPA resulted in an increase (P less than 0.05) in ACh-mediated vasorelaxation compared both to AA-treated and buffer-treated rings (maximum relaxation 83 +/- 5% vs 46 +/- 5% and 63 +/- 4%, respectively). A similar augmentation was observed in DHA-treated rings. Pretreatment of rings with indomethacin or I-NMMA decreased (P less than 0.05) the ACh-mediated vasorelaxation, although EPA-treated rings showed less (P less than 0.05) attenuation of ACh response compared to AA-treated or untreated control rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of a peptide derived from fibrinogen degraded by leukocyte elastase on isolated bovine mesenteric arteries.

A peptide derived from fibrinogen degraded by leukocyte elastase, and corresponding to amino acids 30-43 in the B beta-chain of fibrinogen, was evaluated concerning its effects on isolated bovine mesenteric arteries. This peptide induced dilation of the arteries and an increase in both cyclic AMP and cyclic GMP in the vessels. In addition there was an increase in 6-keto-PGF1 alpha indicating an increased release of prostacyclin. The increase in cyclic nucleotides and 6-keto-PGF1 alpha was inhibited by indomethacin, as was the vasodilation. The increase in cyclic GMP was much larger than the increase in cyclic AMP. The effects of the studied peptide are similar to the effects of other vasoactive peptides with a similar structure, such as bradykinin, neurotensin and substance P. The increase in cyclic AMP is probably caused by prostacyclin, a probable mediator of vasodilation. In addition, in certain species vasodilation may be caused by an increase in cyclic GMP.

Effect of a fibrin-derived vasoactive peptide on pulmonary angiotensin converting enzyme activity and on pressure responses to bradykinin.

Decreased angiotensin converting enzyme (ACE) activity is a common finding in patients with adult respiratory distress syndrome and in animal models of lung injury. The nature of this effect is unknown. Intravascular fibrin, also a common finding in lung injury, is degraded to small peptides by proteolytic enzymes. Peptide 6A, corresponding to amino acid residues 43 to 47 of the B beta chain of fibrin(ogen), is produced by plasmin degradation of fibrin and has been shown to inhibit ACE in vitro. We investigated the effect of this peptide on the pulmonary hydrolysis of a synthetic ACE substrate, benzoyl-phenylalanyl-alanyl-proline, in anesthetized rabbits and in isolated, perfused rabbit lungs. Peptide 6A caused a reversible, dose-dependent inhibition of benzoyl-phenylalanyl-alanyl-proline hydrolysis. It also potentiated the increase in pulmonary arterial pressure and the decrease in systemic arterial pressure due to bradykinin (BK), as well as the increase in pulmonary artery pressure due to BK in isolated lungs. The amount of BK needed to increase pulmonary arterial pressure was about 1000-fold larger in the isolated lung than in the intact animal. Peptides of this type might contribute to decreased ACE activity in patients with adult respiratory distress syndrome and may potentiate BK-mediated hemodynamic changes in these patients.

Pulmonary vascular effects of a fibrin(ogen)-derived vasoactive peptide.

We examined the effects of the 5 amino acid fibrin(ogen)-degradation product Ala-Arg-Pro-Ala-Lys (Peptide 6A) on pulmonary hemodynamics and vascular permeability in the isolated-perfused guinea pig lung. Infusion of this peptide (100 mumoles) resulted in a small increase in pulmonary vascular resistance. The pulmonary vasoconstrictor responses was not mediated by histamine or cyclooxygenase metabolites since neither H1 blockers nor meclofenamate inhibited the response. The capillary filtration coefficient (a measure of water transvascular permeability) did not change after Peptide 6A infusion. Small molecular weight fibrin(ogen)-degradation products may contribute to increased pulmonary vascular resistance associated with pulmonary intravascular coagulation, but not to the increase in lung hydraulic conductivity.

Peptide 6A, a fibrin(ogen) degradation product, increases coronary blood flow.

The coronary hemodynamic effects of intracoronary administration of a fibrin(ogen)-derived pentapeptide, Ala-Arg-Pro-Ala-Lys (peptide 6A), were evaluated in open-chest anesthetized dogs. With administration of peptide 6A (2.5-30 mumol), coronary blood flow increased and coronary vascular resistance decreased promptly in a dose-related manner. Increase in coronary blood flow was independent of any change in indexes of myocardial O2 demand, indicating the peptide 6A exerts direct effects on coronary arterial tone. Systemic arterial and left ventricular end-diastolic pressures remained unchanged with smaller doses but decreased when higher doses of peptide 6A (greater than or equal to 20 mumol) were administered. Plasma concentrations of 6-ketoprostaglandin F1 alpha, stable hydrolysis product of prostacyclin, increased in coronary sinus blood samples in conjunction with increase in coronary blood flow. Administration of indomethacin (5 mg/kg iv) inhibited peptide 6A-induced release of prostacyclin and significantly attenuated the effects of peptide 6A on coronary hemodynamics. Pretreatment of animals with H2-receptor blocker cimetidine (500 mg iv) or with H1-and H2-receptor blocker diphenhydramine (50 mg iv) had no significant effects on peptide 6A-induced increase in coronary blood flow. This study suggests that this fibrin(ogen)-derived peptide has potent vasodilator effects on the coronary vascular bed of the dog, and these effects are in part mediated by stimulation of prostacyclin release.

Fibrin(ogen)-derived peptide B beta 30-43 increases coronary blood flow in the anesthetized dog.

The hemodynamic effects of intracoronary administration of a fibrin (ogen)-derived peptide B beta 30-43 (Arg-Pro-Ala-Pro-Pro-Pro-Ile-Ser-Gly-Gly-Gly-Tyr-Arg-Ala) were evaluated in open-chest anesthetized dogs. Coronary blood flow (CBF) increased and coronary vascular resistance (CVR) decreased with intracoronary administration of peptide B beta 30-43. These changes were dependent on the amount of the peptide B beta 30-43 administered. There were no significant effects of peptide B beta 30-43 on aortic & left ventricular end-diastolic pressures. Plasma 6-keto-PGF1 alpha (stable hydrolysis product of PGI2) concentrations increased in coronary sinus blood samples in conjunction with increase in CBF. Intravenous administration of indomethacin (5 mg/kg) inhibited the release of PGI2 and almost completely abolished the effects of the fibrin(ogen)-derived peptide on CBF. This study suggests that this fibrin (ogen)-derived peptide has potent effects on the coronary vascular bed of the dog, and that these effects are in large part mediated through PGI2 release. These coronary hemodynamic effects of fibrin(ogen)-derived products may have important autoregulatory effects in atheromatous coronary circulation, wherein thrombi may form spontaneously.

Effect of a fibrin(ogen)-derived vasoactive peptide on polymorphonuclear leukocyte emigration.

A vasoactive peptide known to increase vascular permeability and corresponding to residues 30-43 of the human fibrinogen B beta-chain induced polymorphonuclear leukocyte emigration in rabbit skin in vivo. The leukocyte emigration was much stronger after 2 h than after 0.5 h. Addition of prostaglandin E2 (PGE2) did not influence the chemotactic activity, which might possibly be explained by a known PGI2 releasing capacity of this peptide. PGE2 enhanced the leukocyte emigration due to leukotriene B4.

A fibrin(ogen) derived pentapeptide induces vasodilation, prostacyclin release and an increase in cyclic AMP.

A pentapeptide derived from fibrin(ogen), Ala-Arg-Pro-Ala-Lys, is known to increase microvascular permeability. This peptide induced dilation of bovine mesenteric arteries and caused a release of prostacyclin and an increase in cyclic AMP in these vessels. These changes were abolished by pretreatment with indomethacin, indicating that the vasodilation and the increase in cyclic AMP are due to the prostacyclin release. One mechanism underlying the effect of this peptide on microvascular permeability might thus be a triggering of the arachidonic acid cascade, with release of prostacyclin and an increased blood flow, which may potentiate the effect of other substances with a direct effect on vascular endothelium, e.g. histamine. The pentapeptide is known to release histamine from mast cells.

Fibrin-derived vasoactive peptides release histamine.

Two fibrin-derived peptides. Ala-Arg-Pro-Ala-Lys and Ser-Gln-Leu-Gln-Lys-Val-Pro-Pro-Glu-Trp-Lys, increase microvascular permeability in rat skin. In the present investigation it is shown that they release histamine from rat mast cells and that their effect on microvascular permeability can be inhibited by previous histamine depletion of the skin or treatment with an antihistamine, the H1-blocker mepyramine maleate. It is concluded that histamine release contributes to the permeability-increasing effect of these peptides as well as of the structurally similar peptides bradykinin, substance P and neurotensin.