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M L Foegh

Publications and source records attributed to M L Foegh.

At least 73 records · Page 4Linked to original sources
PubMed1990

Preservation of renal compensatory growth in uninephrectomized rats by low-dose cyclosporine.

The growth-inhibitory effect of prednisone is a serious drawback to its use in kidney graft recipients. At high doses, cyclosporine also inhibits somatic growth in animals. Furthermore, cyclosporine, in addition to being nephrotoxic in patients, is reported to inhibit compensatory renal growth in uninephrectomized rats. It is unclear whether the latter effect is specific to the kidney. In the present study, we have tested, in the uninephrectomized rat model, the effect of a low dose cyclosporine that is immunosuppressive but does not inhibit somatic growth. Compared with sham operation, uninephrectomy resulted in a significantly greater kidney-to-body weight ratio 2 and 7 days postsurgery. In uninephrectomized rats treated daily with 10 mg/kg cyclosporine s.c., compensatory renal growth was intact. Kidney wet weight, dry weight, and kidney-to-body weight ratios were similar in vehicle and cyclosporine treated, uninephrectomized animals. Similarly, body weight, food consumption, and size of other organs were not adversely affected by the 10 mg/kg/day cyclosporine treatment. Thus, by reducing cyclosporine to levels that are not generally toxic, renal growth is preserved. Our results suggest that the present trend toward using lower doses of cyclosporine in kidney transplant recipients will not only reduce nephrotoxicity, but will also be of benefit in terms of somatic and renal growth, which are important considerations in pediatric transplant patients.

Animals↗
PubMed1990

Attenuation of vascular relaxation and cyclic GMP responses by cyclosporin A.

The effect of Cyclosporin A (CsA) on vascular vasomotor responses was determined in two isolated tissue preparations. The first preparation was the rat mesenteric vascular bed which was constricted by phenylephrine (EC80) and perfused with CsA (8.32 x 10(-8) to 8.32 x 10(-6) M). Vasodilation responses to acetylcholine, bradykinin and the calcium ionophore, A23187, were impaired, as was the response to sodium nitroprusside at high CsA concentrations. Indomethacin had no effect suggesting that the CsA effect is unrelated to the synthesis of cyclooxygenase products. In the second preparation, thoracic aortic rings from rats treated with CsA (5-10 and 20-50 mg/kg/daily for 3 and 1 weeks, respectively) were used. Aorta rings precontracted by phenylephrine (EC80) also showed impaired responses to both endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators. Furthermore, a marked decrease of the guanosine 3',5'-cyclic monophosphate (cGMP) content in aortic preparations was found to accompany the in vivo effect of CsA on relaxation. In addition, exposure of aortic rings to CsA (8.32 x 10(-8) to 8.32 x 10(-6) M) in vitro, also inhibited markedly the cGMP response induced by acetylcholine or sodium nitroprusside. This effect of CsA was not modified by isobutyl methylxanthine, a phosphodiesterase inhibitor. We conclude that CsA acts directly on the vascular smooth muscle; and speculate that CsA may compromise the response to vasodilators by inhibiting cGMP formation.

Acetylcholine↗
PubMed1990

Mechanism of cyclosporin potentiation of vasoconstriction of the isolated rat mesenteric arterial bed: role of extracellular calcium.

Hypertension is a serious side-effect of the clinical use of Cyclosporin A (CsA). One notion is that alterations of vascular reactivity contribute to this hypertension. In this study we used the isolated rat mesenteric vascular bed to test the specific hypothesis that CsA modifies vascular calcium regulation to potentiate vascular contractility. Mesenteric vessels from CsA-treated rats (10 mg/kg/day i.m. for 7 days) exhibited significantly greater vasoconstrictor responses to exogenous norepinephrine (NE) and potassium-induced depolarization than those of vehicle-treated animals. Similarly, in vitro CsA (8.3 X 10(-8) to 8.3 X 10(-6) M) augmented in a concentration-dependent manner both the sensitivity and the maximum response to NE and potassium. This effect of CsA on vasoconstriction was critically dependent on the presence of external calcium [( Ca++]o). The degree of vasoconstriction potentiation correlated significantly with the [Ca++]o which was used during exposure of the mesenteric bed to CsA. Reapplication of external calcium in the presence of CsA to "calcium-depleted" preparations increased significantly the amplitude of subsequent NE responses in a calcium-free medium. Thus, CsA-potentiated NE responses, once established, were not reversed by removing external calcium; however, attenuation occurred with the intracellular calcium antagonist dantrolene. Verapamil and nifedipine blocked potassium-elicited responses, but failed to prevent the CsA effect on NE-induced vasoconstriction. We conclude that CsA potentiation of vasoconstriction depends on extracellular calcium, and results from an enhanced transmembrane calcium transport. We speculate that CsA also increases the filling of intracellular stores of releasable calcium. These effects lead to greater calcium influx and greater intracellular calcium release upon stimulation.

Animals↗
PubMed1989

Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034.

Proliferation of vascular smooth muscle is an early and major event in the formation of an atherosclerotic lesion. Here we report for the first time the inhibitory effects on myointimal proliferation of the rat carotid artery by a synthetic peptide, angiopeptin, and its closely related congener, BIM 23034. Proliferation was initiated in the carotid artery of anesthetized rats by air-drying of the endothelium. After 15 days the rats were killed and the carotid artery was pressure-fixed and subjected to morphologic analysis for evaluation of the degree of myointimal thickening. Five synthetic somatostatin-like peptides were tested by pretreating rats (20 and 50 micrograms/kg/rat s.c. daily) for 2 days prior to and for 5 days after the endothelial injury. Angiopeptin and the closely related octapeptide (BIM 23034) significantly inhibited myointimal thickening. Angiopeptin was also effective when the pretreatment period was reduced from 2 days to 30 min. The inhibitory effect of angiopeptin was further confirmed in an additional experiment involving [3H]thymidine incorporation. In this experiment angiopeptin (100 micrograms/kg/day s.c.) was also administered for 2 days prior to and five days following the endothelial injury and it significantly inhibited thymidine uptake. All the peptides tested inhibit the release of growth hormone. However, only angiopeptin and BIM 23034 inhibited myointimal proliferation. Thus the effect of angiopeptin and its congener is unlikely to be mediated through growth hormone. Since angiopeptin inhibits myointimal proliferation it may have clinical utility in preventing restenosis following angioplasty and coronary artery by-pass procedures.

Animals↗
PubMed1989

Inhibition of coronary artery transplant atherosclerosis in rabbits with angiopeptin, an octapeptide.

Accelerated coronary atherosclerosis of cardiac allograft occurs in 30-40% of cardiac transplant patients and remains an unsolved clinical problem. The etiology is unknown and anti-platelet drugs are used without conspicuous success. The inhibitory effect of the octapeptide, angiopeptin on coronary atherosclerosis was studied in a previously described rabbit heterotopic cardiac transplant model where allograft rejection is prevented by daily administration of cyclosporin A (CsA, 10 mg/kg per day s.c.). Twenty male New Zealand white rabbits (2.6-2.8 kg) received a heterotopic cardiac transplant from rabbits of the same strain. Donors and recipients were fed a 0.5% cholesterol diet 1 week prior to transplantation which was continued for the recipient until death 6 weeks later. The control group (n = 16) received CsA and saline injections twice daily and the treatment group (n = 4) received CsA and angiopeptin (60 micrograms/rabbit daily s.c.) in 2 divided doses. The treatment began after completion of the transplantation. Coronary artery transplant atherosclerosis was uniformly distributed (tubular) in the entire length of the coronary arteries. Angiopeptin inhibited the intimal hyperplasia in the transplanted heart from 47.5 +/- 2.4% (mean +/- SE) to 25.0 +/- 6.9% and in the native heart from 24.2 +/- 1.4% to 15.7 +/- 1.5%. The intimal hyperplasia is expressed as area of intimal hyperplasia/total vessel area x 100%. A similar inhibition by angiopeptin was seen in lipid deposition in the donor ascending aorta which is transplanted with the heart. Angiopeptin attenuated significantly the hyperplasia and the lipid deposition of the native coronary arteries and aorta but to a lesser extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1988

Eicosanoids and platelet activating factor mechanisms in organ rejection.

In summary, the eicosanoids and PAF modulate the immune response in vitro and in vivo. The PG seem to attenuate and TX, LT, and PAF to potentiate the cell-mediated immune response. In addition, these compounds have nonimmunologic effects that may modify the edema and decreased blood flow associated with the rejection process.

Animals↗