Search

The vasorelaxant effects of milrinone and amrinone in canine coronary, cerebral, and renal arterial rings or strips contracted by either K+-depolarization, U46619 (a thromboxane mimetic), or prostaglandin F2 alpha (PGF 2 alpha) were quantitated. Milrinone was more potent as a vasorelaxant in coronary arteries relative to cerebral or renal arteries regardless of the mode of contraction; amrinone was coronary selective with K+ contraction only. When comparing potency in arteries contracted by different agonists, milrinone was significantly more potent as a vasorelaxant in all three arteries contracted by either U46619 or PGF2 alpha than in arteries contracted by K+ depolarization, whereas amrinone was only selective for U46619-induced contractions in cerebral arteries. This profile of activity for milrinone was similar to that of sodium nitrite and isoproterenol and dissimilar from the calcium entry blocking agents nimodipine and nifedipine. In conclusion, this study shows that coronary vascular selectivity exists for milrinone and amrinone. Moreover, the relaxant profiles of milrinone and amrinone, with different sources of vascular smooth muscle, are unlike those of calcium entry blocking agents and more similar to the profiles of agents that modulate cyclic nucleotide levels.

Interleukin-1 (IL-1) is the name given to a family of related proteins showing a variety of activities. It was originally shown to be produced by monocytes and macrophages but is now known to be produced by numerous cell types, including synovial cells. From the point of view of arthritis, its most interesting activities are those on connective tissue cells in vitro. These include stimulation of production of prostaglandins, plasminogen activator and metalloproteinases such as collagenase and proteoglycanase. IL-1 is also mitogenic for synoviocytes and bone cells, and can alter rates of production of extracellular matrix constituents. The presence of IL-1 in synovial fluids from rheumatoid and osteoarthritic joints and its actions on connective tissues in vitro suggest that IL-1 may play an important role in the pathogenesis of arthritis. There are several potential cellular sources of IL-1 in the inflamed rheumatoid joint and interactions between these cells, T lymphocytes and plasma cells may continually induce IL-1 so contributing to the chronicity of the disease. The mechanism of action of IL-1 on connective tissue cells is at present uncertain though preliminary studies suggest that IL-1 may induce cellular responses by stimulating phosphoinositide turnover and possibly protein kinase C activity.

Using a sensitive enzyme amplified immunoassay for TSH, the evening rise and pulsatile release of TSH were studied in 10 men with chronic renal failure treated by haemodialysis. Compared to euthyroid male controls the evening rise of TSH was attenuated (median 0.066 vs 0.195 mU/l/h, P less than 0.01) and the rate of rise correlated with the TSH response to TRH (r = 0.93, P less than 0.001). All subjects showed TSH pulsatility in at least one method of data analysis but the less sensitive incremental method showed no significant difference in pulse frequency and amplitude between the two groups. However, with time series analysis, periodicity was shorter (median 45 vs 95 min, P = 0.013) and pulse amplitude smaller (median 0.06 vs 0.175 mU/l, P = 0.017) in renal patients. Pulse amplitude, but not periodicity, correlated with the TSH response to TRH (r = 0.68, P less than 0.05). In addition, serum total thyroxine, free thyroxine and free triiodothyronine concentrations were reduced, while serum prolactin and 17 beta-oestradiol concentrations were raised. These changes in TSH evening surge and pulsatile release may contribute to the reduction in thyroidal hormone concentrations seen in renal failure and emphasize the value of sensitive methods of hormone and pulse data analysis.

The anti-arrhythmic action of 2,3-cis-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-butylamino)propoxy]2,3-naphthalenediol (nadolol) was evaluated and compared with that of propranolol in several experimental models of cardiac arrhythmias. Both nadolol and propranolol antagonized isoproterenol-induced tachycardia and ouabain-induced arrhythmias in cats, antagonized coronary artery ligation-induced ventricular fibrillation and suppressed ventricular ectopic activity during vagal stimulation in dogs. In contrast to propranolol, nadolol was considerably weaker in suppressing existing digoxin-induced arrhythmias, lacked local anesthetic activity and did not depress the heart in dogs. Because of these findings, it is concluded that the anti-arrhythmic activity of nadolol is apparently related to blockade of beta-adrenergic receptors.

Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Although the 4,6-dimethyl analogue 6a retained most of the activity of 5a, the 4-methyl analogue 8a was substantially less potent. The synthesis and structure-activity relationships are discussed.

Seven patients on dialysis with renal failure received transplants from mismatched cadaver donors and were treated with cyclosporin A (CyA), initially as the sole immunosuppressive agent. CyA was effective in inhibiting rejection but there was clear evidence of both nephrotoxicity and hepatotoxicity. A cyclophosphamide analogue was added to the CyA treatment in six of the patients. Five patients are out of hospital with functioning allografts, and two of these have received no steroids. One patient required an allograft nephrectomy because of pyelonephritis in the graft. Another died of systemic aspergillus and candida infection. Further careful study of this potentially valuable drug will by required before it can be recommended in clinical practice.

Increasingly patients whose first renal transplant fails are being re-transplanted. A study of patients in one unit was undertaken to assess whether second kidney grafts were as successful as first allografts and whether certain factors determined the outcome of secondary transplants. Second and subsequent grafting can be performed with confidence of a successful outcome provided a careful selection of patients is made. The outcome of subsequent grafts should show no significant difference from the overall results of first renal allografts.

Fibronectin is a large, adhesive glycoprotein which self-associates on many cell surfaces. We have begun to study this reaction by determining the domains of fibronectin which interact with each other. To avoid possible solid-phase artifacts of affinity chromatography, we have devised a solution-phase assay in which the smallest fibronectin fragment is labeled with fluorescamine, mixed with unlabeled fibronectin, and complexation is observed by the appearance of a new higher-molecular-weight peak on gel high-performance liquid chromatography columns. The assay allowed use of excess unlabeled reactant, high-sensitivity, low background without removal of reagent, and fast analysis. Our results show that the amino- and carboxyl-terminal fibronectin fragments bind the native molecule in solution.

Two patients with primary hepatic malignancy were treated by hepatectomy and orthotopic liver transplantation. In both cases the donor liver was infused with cold solutions and kept chilled without continuous perfusion. There was immediate satisfactory hepatic function in both transplants.The first patient died after 11 weeks from overwhelming bacterial and fungal infections probably secondary to hepatic infarction due to thrombosis of the recipient hepatic artery. The thrombus occurred at the site of the arterial clamp. In an attempt to control the growth before transplantation, the patient had been treated with large doses of chlorambucil, which resulted in extreme marrow depression and septicaemia.The second patient developed cholestatic jaundice during the second and third weeks after transplantation, with histological evidence of mild rejection, which was controlled by increasing the dose of immunosuppressive agents. He is now well, having returned to work six weeks after the operation.Though the first patient showed no evidence of rejection, it is concluded that patients receiving liver allografts should receive immunosuppressive therapy.

Bresica-Cimino shunts inserted to facilitate intermittent dialysis may markedly increase the circulatory load on the heart. Three patients in whom there was evidence of overload are described. Thorough investigation of the cardiac output should be made in patients with fistulae of this kind, which should be closed as soon as practicable after transplantation.

Twenty-six renal grafts four months or more after transplantation have been shown to function satisfactorily when the donor's age has varied from 10 to 64 years and the period of warm ischaemia has been between 26 and 133 minutes. It is suggested that a more lenient view be adopted with respect to the age of the donor, but that a warm ischaemia time of two hours should not be exceeded.

Seven cases of erythraemia following successful renal transplantation are described. This complication was not necessarily associated with clinical evidence of rejection of the transplant, and the prognosis so far as rejection was concerned was excellent. Four patients, however, developed thromboembolic pulmonary complications, and two other patients had thrombotic episodes. Hence it is suggested that treatment either by anticoagulation or by venesection is indicated.

The experience gained from 13 hepatic transplant operations is described, with particular reference to the findings in nine patients who survived the immediate operative period. A major problem was found to be infection. Fulminant pneumonia caused death in two adults, at a time when liver function was virtually normal. Infection related to bile fistula and sepsis may be overcome by an improved method of biliary drainage by cholecyst-dochostomy, which was carried out in the last two patients. Jaundice in the second week due to rejection was observed in several patients. The striking histological change was centrilobular cholestasis. The jaundice, which was not prevented by administration of antilymphocyte globulin, was rapidly controlled by temporarily increasing die dose of prednisone. One patient who survived for four and a half months and who had a poor tissue match subsequently developed chronic rejection with progressive cholestatic jaundice. Five of the patients were able to go home and at time of publication two are alive and well 14 and 20 weeks after treatment.

The leucocyte migration test, an in-vitro measure of cellular immunity, has been used to follow the changes in cell-mediated hypersensitivity to kidney and histocompatibility antigens in three patients after renal transplantation.Inhibition of leucocyte migration, indicating strong sensitization to the antigens used, occurred in each patient, starting five to seven days after transplantation. Satisfactory renal function had not been established in any of the patients at this time. In one case inhibition of leucocyte migration persisted almost continuously until the 24th day and was associated with poor renal function proved histologically to be due to rejection. Treatment with increased dosage of prednisone was associated with a rapid reversion to normal of the migration index and improvement in renal function. Later, inhibition of migration occurred again, and shortly afterwards the graft ceased to function. In the other two cases the migration index became normal without alteration in immunosuppressive therapy and a satisfactory diuresis followed. It is suggested that this simple test should prove useful in the specific diagnosis of rejection and in control of immunosuppressive therapy.

The efficiency of haemodialysis has been determined when a Watson-Marlow (Kiil) dialyser was used repetitively without changing the membranes. Dialysis efficiency was assessed from the clearance of creatinine and of urea from the patient's blood. No significant deterioration in dialysis could be detected in six dialyses through the same membrane. Leaving the dialyser unit for up to eight hours before washing it out after the completion of each dialysis did not appear to have any effect on dialysis efficiency.It was concluded that repetitive haemodialysis through the same membranes is possible, but careful monitoring of the patient to assess suitability for such treatment, and subsequently at each dialysis, is essential.