title: Diltiazem modulates cyclosporin A induced renal hemodynamic effects but not its effect on plasma endothelin-1.
abstract: Cyclosporin A (CsA) has been reported to induce major acute renal hypoperfusion that may be antagonised by calcium channel blockers. The vasoconstrictive peptide endothelin-1 (ET-1) has been proposed as a mediator of CsA induced hypoperfusion. We investigated the acute effects of the new CsA formulation (Sandimmun Neoral) in 8 renal transplant patients on triple immunosuppressive therapy before and following slow-release diltiazem treatment in a dose of 90-120 mg b.i.d for 4 weeks. CsA significantly increased mean arterial blood pressure by 6 +/- 2 mmHg (p < 0.05) during the first 3 h after administration. This effect was abolished by diltiazem treatment, also reducing blood pressure by 12 +/- 3 mmHg (p < 0.05) 3-9 h after administration. CsA administration induced a maximum reduction in renal blood flow of 20 +/- 8% (p < 0.05) 5 h after ingestion and a concomitant reduction in glomerular filtration rate of 18 +/- 7% (p < 0.05). The filtration fraction increased by a maximum of 13 +/- 7% (p < 0.05) after 4 h as did the calculated fractional proximal reabsorption by 14 +/- 4% (p < 0.05). All these acute renal effects were abolished by diltiazem administration. Concurrent with the maximum renal hemodynamic effects, plasma ET-1 was elevated with a peak increase of about 40% 4-5 h after CsA ingestion. Diltiazem treatment had no effect on the increase in plasma ET-1 following CsA administration. These findings suggest that CsA induced acute vasoconstriction and renal hypoperfusion are mediated by ET-1 and that diltiazem treatment abolishes these pharmacodynamic effects of CsA despite persistent increase of plasma ET-1 levels.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Oslo, Norway. anderas@farmasi.uio.no
authors.forename: A
authors.initials: A
authors.lastname: Asberg
authors.forename: H
authors.initials: H
authors.lastname: Christensen
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
authors.forename: K J
authors.initials: KJ
authors.lastname: Berg
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D019332:Endothelin-1 / Q000097:blood* / Q000502:physiology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D004110:Diltiazem