Vasomotor responses in cyclosporin A-treated rats after chronic angiotensin blockade.

Abstract

Chronic angiotensin-converting enzyme (ACE) inhibition prevents endothelial dysfunction in hypertension and hypercholesterolemia. Long-term treatment with cyclosporin A impairs endothelium-dependent relaxations and augments contractions to angiotensin II in the rat aorta. The present study compares vasomotor responses to several vasoconstrictor and dilator stimuli after 6 weeks of oral treatment with either the angiotensin-converting enzyme inhibitor lisinopril (10 mg/kg per day), the angiotensin subtype 1 receptor antagonist D 8731 (10 mg/kg per day), cyclosporin A (15 mg/kg per day), or a combination of cyclosporin A with lisinopril or D 8731 (n=15 rats per group). Twenty-four hours after the last treatment, aortic rings were mounted in organ chambers for measurement of isometric force. Endotheliumdependent relaxations to acetylcholine and calcium ionophore were impaired by cyclosporin A but not affected by the vasodilators. Cyclosporin A-induced endothelial dysfunction was prevented by cotreatment with lisinopril or D 8731. C hronic angiotensin-converting enzyme (ACE)inhibition prevents endothelial dysfunction in animal models with hypertension and hypercholesterolemia. 13 Even in hypertensive animals the modulation of endothelial function is not exclusively explained by the reduction of blood pressure, since treatment with hydralazine does not modify endothelium-dependent relaxations to the same extent, if at all. 1Considering additional studies showing reduced intima formation after endothelial injury and reduced development of atherosclerosis during ACE inhibition, 46 it has been hypothesized that chronic ACE inhibition protects or restores endothelial function. Both reduced angiotensin II (Ang II) formation and bradykinin accumulation during ACE inhibition have been discussed as mechanisms contributing to these effects.Long-term treatment with cyclosporin A (CsA) impairs endothelium-dependent relaxations in rats and humans.7 " In the rat this effect is not a consequence of increased blood pressure, since CsA does not significantly increase blood pressure in normotensive rats. 10 -12 We chose this model to determine possible protective effects of chronic ACE inhibition on endothelial function, since CsA has been shown to augment selectively the effects of Ang II in rat vascular smooth muscle. cidate the contribution of Ang II to these effects. In addition, we assessed the modulation of vascular smooth muscle contractions to Ang II and other vasoconstrictors by these treatments. CsA dosage was reduced compared with previous studies to reduce toxic side effects and to reach blood concentrations close to the therapeutic range.7 ' 10

Effect of cyclosporin A and analogues on cytosolic calcium and vasoconstriction: possible lack of relationship to immunosuppressive activity

“…The relatively slow time course of both the establishment of the CsA-effect and its reversibility suggests a possible effect on gene expression. CsA could possibly increase the synthesis of hormone receptors as described for angiotensin II or endothelin receptors (Nambie et al, 1990;Iwai et al, 1993;Auch-Schwelk et al, 1994). As in our experiments CsA potentiated the cellular calcium response to four hormones as well as vasoconstriction due to noradrenaline, CsA should increase the synthesis of at least five receptors or activate a common component necessary for the synthesis of these receptors.…”

“…(2) Stimulation of the renin-angiotensin system has been described in hypertensive transplant recipients under CsA treatment (Julien et al, 1993) as well as in animals (Muller-Schweinitzer, 1988). (3) In vascular tissue of CsA-treated rats, an increased expression of angiotensin II and endothelin receptors (Iwai et al, 1993;Auch-Schwelk et al, 1994;Nambi et al, 1990) has been measured. (4) Increased levels of vasoconstrictor agents such as thromboxane or endothelin have been detected in plasma of CsA-treated patients (Grieff et al, 1993;Mouquet et al, 1994) as well as in in vitro models (Copeland & Yatscoff, 1992;Lanese & Conger, 1993;Conger et al, 1994).…”

Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration

“…4,5,22 In preclinical models, CsA promotes renal afferent arteriolar vasoconstriction 3 and increases the vasoactive response to several vasoconstrictors. 6–8 Additionally, CsA induces a Ca 2+ influx–dependent vasoconstriction in isolated mesenteric arteries, 23 and increases the perfusion pressure of the caudal artery. 24 This arterial vasoconstriction depends on extracellular Ca 2+ .…”

“…4 CsA increases noradrenaline-, angiotensin II (AngII)–, endothelin-, and vasopressin-induced vasoconstriction in rat arteries. 6–8 Despite these limitations, CsA is still very commonly used after organ transplantation, especially in low-income countries. Therefore, deciphering the mechanisms by which CsA promotes renal hemodynamic alterations is crucial to the development of new therapeutic strategies to prevent or ameliorate acute CIN.…”