Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats

Abstract

1 The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. 2 CsA (5.9 mg kg À1 bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. 3 Pretreatment with the angiotensin (AT 1 ) receptor antagonist, losartan, and the endothelin (ET A and ET B ) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the a-adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. 4 Tacrolimus (450 mg kg À1 bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. 5 Sirolimus (450 mg kg À1 bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. 6 The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects.

Calcineurin Inhibitor Nephrotoxicity

“…Animal studies have demonstrated that the vasoconstrictive effect of tacrolimus is weaker than of cyclosporine (205)(206)(207), and this was also confirmed in humans (208,209). Moreover, the fibrogenic potential of tacrolimus also appears to be lower (210), although these results could not be confirmed in a more recent study (135).…”

Sirolimus Causes Relaxation of Human Vascular Smooth Muscle: A Novel Action of Sirolimus Mediated via ATP-Sensitive Potassium Channels

“…Under in vivo conditions, however, i.v. injection of sirolimus into conscious rats caused a modest pressor response and decrease in regional blood flow (Gardiner et al, 2004), consistent with a vasoconstrictor effect. In light of the present results demonstrating that sirolimus causes endothelium-independent relaxation of human arteries, the importance of species differences and the need to assess the pharmacologic activity of vasoactive drugs in human tissues are readily apparent.…”

“…This is particularly notable since sirolimus is released directly into the circulation (Hiatt et al, 2001;Suzuki et al, 2001), where it could potentially alter blood flow and tissue perfusion in regions distal to the site of stent placement. A limited number of preliminary studies have attempted to address this issue by using animal models, but the results are conflicting (Corbin et al, 1994;Milliard et al, 1998;Jeanmart et al, 2002;Gardiner et al, 2004). Hence, the present study was designed to determine the vasomotor effects of sirolimus in human blood vessels.…”

Short-Term and Long-Term FK506 Treatment Alters the Vascular Reactivity of Renal and Mesenteric Vascular Beds

“…When given by bolus i.v. injection, FK506 causes a pressor effect, which is maximal when there is no significant regional vasoconstriction in conscious rats (25).…”

“…Alternatively, increased or impaired vascular reactivity caused by FK506 was unlikely to be the sole explanation for its hypertensive side effect. Gardiner et al (25) have reported that the blood pressure increasing effect of FK506 must be due to an increase in cardiac output. When given by bolus i.v.…”