The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

Abstract

Daily administration of prednisolone, but not the derivative NCX-1015 (or prednisolone 21-[4Ј-nitrooxymethyl]benzoate), to rats resulted in a time-and dose-dependent increase in mean arterial blood pressure (MABP), significant after 1 week for the dose of 6.9 mol/kg i.p. (n ϭ 10; P Ͻ 0.05), and 3 weeks for the lower dose of 1.38 mol/kg. A similar dichotomy of behavior was observed with respect to myocardial contractility and renal vascular resistance, in either case augmented by 3-week treatment with prednisolone but not NCX-1015. In contrast, both NCX-1015 and prednisolone reduced plasma levels of corticosterone in a dose-(dose range of 0.69 -6.9 mol/kg i.p.) and time-dependent (1-3 weeks) manner. Similar profiles were obtained for plasma nitrate values, although they were increased selectively after NCX-1015 administration. In contrast, prednisolone, but not NCX-1015, augmented plasma endothelin 1 (ET-1) with a profile that mirrored the changes observed in MABP and renal blood flow. Supply in the drinking water of the ET-1 receptor typeantagonists prevented the changes produced by a 21-day treatment with prednisolone. In conclusion, this study indicates 1) a lack of occurrence of cardiovascular alterations by nitro-releasing derivative of prednisolone (NCX-1015), and 2) a functional link between prednisolone effects and the endogenous endothelin-1 system. Glucocorticoids (GCs) have wide clinical applications for the management of a variety of disorders, including autoimmune, allergic, and lymphoproliferative diseases. In most of these pathologies, GC must be administered for long term, and this increases the likelihood of the appearance of major side effects, thus limiting further use (Whitworth, 1994;Saruta, 1996). Marked side effects include obesity with the classical "moon face"; hirsutism; cataracts; osteoporosis; diabetes mellitus; immune suppression; and cardiovascular disorders, including hypertension and atherosclerosis (Ross and Linch, 1982;Schä cke et al., 2002). Among these multiple effects, cardiovascular complications are an important factor for predicting the morbidity and mortality of patients overtreated with GCs (Ross and Linch, 1982). Plasma volume expansion due to sodium retention gives a minor contribution to GC cardiovascular effects (Whitworth et al., 1989;Whitworth, 1994;Saruta, 1996). In contrast, increase in peripheral vascular resistance, demonstrated by an augmented pressor response to catecholamines and angiotensin II, is a major contributor to the pathogenesis of hypertension after excess use of GCs (Pirpiris et al., 1992;Whitworth, 1994;Saruta, 1996). The molecular mechanism whereby GC excess causes the increase in vascular resistance and hypertension has not been fully elucidated, although a recent study has provided a functional link between dexamethasone administration and down-regulation of endothelial nitric-oxide (NO) synthase (Wallerath et al., 2004

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“…These data suggest that NCX-1015 is less likely to cause hypertension with long-term use than prednisolone. Both prednisolone and NCX-1015 reduced the levels of corticosterone [17], indicating that NCX-1015 retains the ability to inhibit the hypothalamo-pituitary axis. In the carageenan air-pouch rat model of acute inflammation, the injection of NO-flunisolide directly into the pouch inhibited leukocyte and fluid accumulation in the pouch, and was 41-fold more potent than flunisolide [18].…”

“…Prednisolone also increased renal vascular resistance to renal blood flow [17]. The plasma levels of the vasoconstrictor endothelin-1 were increased by prednisolone but not by NCX-1015 [17].…”

“…In the rat, prednisolone (but not NCX-1015) at 2.5 mg/kg/day for 3 weeks markedly increased blood pressure and myocardial contractility [17]. Prednisolone also increased renal vascular resistance to renal blood flow [17].…”

Therapeutic Potential of Nitrate Esters of Commonly Used Drugs

“…A study aimed to evaluate the cardiovascular effects of the treatment with NCX 1015 versus prednisolone was performed in rats. NCX 1015 did not induce blood pressure changes unlike prednisolone, which also induced alteration in the endothelin system [86]. Moreover, a protective action by the NO part in NCX 1015 molecule has also been claimed in a model of rat stomach ischemia-reperfusion injury to justify the lack of damage in this model [87].…”

NO donor hybrid compounds as multifunctional therapeutic agents

“…A study to evaluate the cardiovascular effects of NCX1015 versus prednisolone was performed in rats. Unlike prednisolone, NCX1015 did not induce blood pressure changes, which seriously induced alteration in the endothelin system [78] . Moreover, protective action by the NO part of the NCX1015 molecule has also been claimed in a model of rat stomach ischemia-reperfusion injury [79] .…”