Exacerbation by Nicotine of the Cyclosporine A‐induced Impairment of Β‐adrenoceptor‐mediated Renal Vasodilation in Rats

Abstract

Nicotine is implicated in smoking-related renovascular impairment and worsening of existing nephropathies. In the present study, we investigated whether nicotine aggravates the deleterious effect of the immunosuppressant drug cyclosporine A (CsA) on renal vasodilation induced by the beta-adrenoceptor agonist isoprenaline. Bolus isoprenaline (0.03-8.0 micromol) elicited dose-dependent vasodilation of phenylephrine-preconstricted perfused kidneys that was attenuated by infusion at 5 mL/min of nicotine (5 x 10(-4) mol/L) or CsA (2 micromol/L). Further, chronic administration of nicotine (0.4 mg/kg per day) or CsA (20 mg/kg per day) for 3 weeks reduced isoprenaline-induced vasodilation and elevated plasma urea and creatinine concentrations, effects that were magnified when both nicotine and CsA were administered concurrently. The role of endothelial and smooth muscle signalling in the acute nicotine/CsA renovascular interaction was investigated. Vasodilation caused by 0.25 micromol isoprenaline was attenuated by 6 micromol/L propranolol and 10 mmol/L tetraethylammonium (TEA), potentiated by 100 micromol/L hexamethonium and 7 micromol/L diclophenac, and virtually abolished in 80 mmol/L KCl-preconstricted tissues. N(G)-Nitro-L-arginine (L-NNA; 200 micromol/L), methylene blue (10 micromol/L), 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propane-sulphonate (CHAPS; 0.2% for 30 s), nifedipine (750 nmol/L), atropine (1 micromol/L) and SQ22536 (an adenylyl cyclase inhibitor; 3 x 10(-5) mol/L) had no effect on isoprenaline responses. Nicotine (5 x 10(-4) mol/L) reduced isoprenaline-induced vasodilation and this effect was potentiated by concurrent CsA (2 micromol/L) infusion. Nicotine-induced impairment of the vasodilator response to isoprenaline was reduced by hexamethonium and potentiated by L-NNA, methylene blue, CHAPS and nifedipine. Alternatively, CsA exacerbation of the nicotine-isoprenaline interaction was abolished by propranolol, L-NNA, methylene blue, CHAPS, L-arginine, TEA and nifedipine. 5. In summary, nicotine and CsA produce additive impairment of kidney function and beta-adrenoceptor-mediated renovascular control, nitric oxide (NO)-cGMP signalling tonically restrains nicotine-induced impairment of isoprenaline vasodilation and the endothelial NO-K+ pathway modulates the aggravating effect of CsA on nicotine-isoprenaline interactions.

Estrogen Provokes the Depressant Effect of Chronic Nicotine on Vagally Mediated Reflex Chronotropism in Female Rats

“…Because nicotine was administered in single daily doses, it could be argued that the rapid elimination of nicotine might have hampered the development of hypertension. Remarkably, the single daily-dose regimen has been repeatedly used for studying the biological effects of nicotine (Hui and Ogle, 1991;Ferrari and Fior-Chadi, 2007;El-Gowilly et al, 2008). Moreover, pharmacokinetic studies showed that, despite the relatively short half-life of nicotine (ϳ1 h), the half-life of cotinine, the principal metabolite and pharmacologically active form of nicotine, ranges from 10 to 24 h (Miller et al, 1977;Buccafusco and Terry, 2003).…”

PI3K/Akt-Independent NOS/HO Activation Accounts for the Facilitatory Effect of Nicotine on Acetylcholine Renal Vasodilations: Modulation by Ovarian Hormones

“…Nicotine also cause renal vasoconstriction and damage probably via increasing levels of vasoconstrictors, such as catecholamines, vasopressin and endothelin-1 [17]–[19]. Further, nicotine impairs NOS-dependent [20] and β-adrenoceptor vasoreactivity [21], [22] These discrepant vascular effects of nicotine could be attributed to differences in vascular beds or in the dose or duration of nicotine regimens.…”

“…It is worth mentioning that most of the published work on the vascular effects of nicotine has been conducted in the male population [11], [17], [21] or in pooled populations from both genders [16]–[19]. We have recently demonstrated that estrogen enhances the vasodilator effect of acute nicotine in the renal vasculature of female rats mainly through facilitation of NOS signaling [12].…”

Previous Exposure to Cigarette Smoke Aggravates Experimental Cyclosporine-Induced Nephrotoxicity

“…Similarly, only one experimental study has reported the simultaneous effects of CsA and nicotine on renal function [21]. These authors demonstrated that the concurrent administration of CsA and nicotine exacerbated functional vascular impairment and renal dysfunction as compared with the administration of each substance separately.…”