Systemic vascular effects of cyclosporin A treatment in normotensive rats.
The immunosuppressive drug cyclosporin A (CsA) frequently induces hypertension, but the mechanism(s) is unknown. Thus, we examined the mechanism(s) by which CsA increases arterial blood pressure (MAP) in the normotensive rat. Three different treatment modalities were used. First, chronic CsA treatment (20 mg/kg/day, s.c., for 1 week) significantly increased MAP from 109.6 +/- 2.3 mm Hg to 125.8 +/- 2.9 mm Hg (P less than .05). Second, subacute i.v. infusion of CsA (20 mg/kg daily for 3 days) increased MAP to even higher values (140.5 +/- 2.3 mm Hg), which correlated significantly with the highest circulating values of the drug. The pressor effect after i.v. infusion appears to be unrelated to endogenous release of catecholamines, because phentolamine, which abolishes the response to exogenous norepinephrine, failed to prevent the CsA-induced pressor response. Third, i.v. bolus injections of CsA (10-20 mg/kg) evoked immediate, dose-dependent and short-lasting increases in MAP (+15-25 mm Hg) in both anesthetized and conscious rats. Ganglionic blockade did not prevent this effect, rather, a 2- to 3-fold increase in amplitude (+40-60 mm Hg) and duration (+30-45 min) of the CsA-induced pressor response was observed in anesthetized rats. Heart rate was not increased significantly by either acute or chronic administration of CsA. Our results suggest that both CsA-induced pressor responses and hypertension are due to a peripheral action unrelated to sympathetic outflow. Furthermore, CsA's hypertensive effect is accompanied by severe morphological changes in the vascular endothelium and smooth muscle cells. In addition, CsA-treated rats showed significantly attenuated vasodilatory responses to prostacyclin and sodium nitroprusside, and increased pressor responses to norepinephrine. Thus, a direct vascular action of CsA is likely to contribute to the alterations on systemic vascular responsiveness, as well as to the hypertensive effect of the drug.
Rego
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A
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC.
Vargas
R
R
Cathapermal
S
S
Kuwahara
M
M
Foegh
M L
ML
Ramwell
P W
PW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002319:Cardiovascular System / Q000187:drug effects*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D016572:Cyclosporine; D003404:Creatinine