tacrolimus and 1-4-dihydropyridine

The ryanodine receptor is the main intracellular calcium release channel from the sarcoplasmic reticulum in striated muscle. It is the largest ion channel known, composed of four identical major subunits of 565 kDa and four smaller 12-kDa subunits, identified as FK-506 binding protein. The successful isolation of the ryanodine receptor together with the development of cryoelectron microscopy and single-particle image processing techniques have enabled major progress to be made in the determination of the receptor's structure over the past decade. Three-dimensional reconstruction shows the receptor to be composed of two main parts, a large square shaped cytoplasmic assembly and a smaller transmembrane assembly. The cytoplasmic assembly has an unusual architecture in which about 10 domain-like structures are interconnected in a loosely packed manner. Subsequent studies have started to reveal conformational changes associated with channel gating and the localization of binding sites for some proteins with which the receptor interacts (calmodulin, and FK-506 binding protein). It is becoming clear that long-range induced conformational changes must be involved in the mechanisms of modulation of the receptor's gating properties.

Topics: Animals; Calmodulin; Calsequestrin; Carrier Proteins; Dihydropyridines; DNA-Binding Proteins; Heat-Shock Proteins; Image Processing, Computer-Assisted; Microscopy, Electron; Models, Molecular; Muscle Proteins; Muscle, Skeletal; Protein Binding; Protein Conformation; Ryanodine Receptor Calcium Release Channel; Tacrolimus; Tacrolimus Binding Proteins

Transplant immunosuppression using either cyclosporine (CsA) or FK506 leads to renal vasoconstriction. To examine the role of endothelin (ET) in this process, we measured plasma and urinary ET before and at intervals for two years after liver transplantation. Urinary prostacyclin (as 6-keto-PG-F1 alpha), thromboxane, glomerular filtration rate and renal plasma flow were also measured. Forty-four patients were treated with CsA-based regimens and 31 patients with FK506-based regimens. Prednisone doses after one year were lower with FK506 (5.5 +/- 0.5 vs. 10.5 +/- 0.5 mg/day) by study design. Circulating plasma ET remained above normal, but not different from pre-transplant levels. Urinary ET was elevated before transplant (24.6 +/- 3.4 ng/day vs. normal 16 +/- 1.5 ng/day, P < 0.05) and rose further after transplantation (48.5 +/- 13 ng/day, P < 0.05), remaining elevated for two years. 6-keto-PG-F1 alpha fell from 2567 +/- 338 ng/day to subnormal levels and remained suppressed (1158 +/- 128 ng/day, P < 0.01). Over the same period GFR fell (84 +/- 3 ml/min to 60 +/- 3 ml/min, P < 0.01) and renal vascular resistance index rose (11,119 +/- 561 to 23,279 +/- 1692 d.s.cm-5.m-2, P < 0.01). Similar changes were observed both with CsA and FK506-based immunosuppression. No changes in ET were attributable to dihydropyridine calcium channel blockers. These results demonstrate that urinary ET changes independently from plasma ET after transplantation. Elevated ET and suppression of endothelium-derived prostacyclin persist with intense renal vasoconstriction for at least two years after transplant.

Topics: Cyclosporine; Dihydropyridines; Eicosanoids; Endothelins; Female; Hemodynamics; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Radioimmunoassay; Renal Circulation; Retrospective Studies; Tacrolimus; Vasoconstriction