Abnormal growth of vascular smooth muscle cells (SMC) is frequently associated with hypertension and atherosclerosis, and homeostasis within a normal vessel is maintained by the balanced generation of both vasoconstrictors and vasodilators. Moreover, several endogenous vasoconstricting factors induce SMC growth, whereas several vasodilators inhibit SMC growth. Inasmuch as adenosine is a potent vasodilator, it is possible that it too could inhibit SMC growth. Hence, the effects of adenosine (10(-8) to 10(-3) mol/L), 2-chloroadenosine (a stable analogue of adenosine; 10(-8) to 10(-3) mol/L), and 8-bromo-cAMP (10(-8) to 10(-3) mol/L) on fetal calf serum (FCS; 2.5%)-induced growth of rat aortic SMC were evaluated. Growth was analyzed by assaying DNA synthesis (thymidine incorporation in SMC pulsed for 4 hours with 1 microCi/mL [3H]thymidine) and cell proliferation (change in cell number). Growth-arrested SMC were treated with 2.5% FCS in the presence and absence of adenosine, 2-chloroadenosine, or 8-bromo-cAMP for 24 hours for DNA synthesis or 4 days for cell proliferation. All three substances inhibited DNA synthesis and cell proliferation in a concentration-dependent manner. Compared with adenosine, 2-chloroadenosine was more potent in inhibiting growth. The inhibitory effects of 2-chloroadenosine were reversed by KF17837 (a specific A2 receptor antagonist) but not by DPCPX (a specific A1 receptor antagonist). Furthermore, the inhibitory effects of 2-chloroadenosine were not mimicked by CGS21680 (an A2a receptor agonist), and the effects of N6-cyclopentyladenosine (CPA; an A1 receptor agonist) were not markedly more potent than those of 2-chloroadenosine, suggesting that the inhibitory effects of adenosine are possibly mediated via A2b receptors. These studies provide evidence that adenosine inhibits SMC growth and suggest that a decrease in local levels of adenosine may initiate SMC growth and contribute to the vascular remodeling process observed in hypertension and atherosclerosis.
The antifungal effects of amphotericin B are believed to be due to two possibly interrelated mechanisms: an increase in permeation by binding to sterols in cellular membranes and a prooxidant effect causing oxidative damage in target cells. However, the seven conjugated double bonds in amphotericin B raise the possibility that it could be highly susceptible to autoxidation, causing an antioxidant effect. In the present study, we investigated the prooxidant and antioxidant properties of amphotericin B in a model system in which oxidation of a reporter molecule, cis-parinaric acid, was induced by azo initiators of peroxyl radicals. Since interactions of amphotericin B with sterols are essential for its pharmacological and toxic actions, we also studied the effects of cholesterol on the prooxidant and antioxidant properties of amphotericin B. Amphotericin B caused a noncollisional quenching of a characteristic fluorescence of cholesteryl cis-parinarate integrated in liposomes, suggesting the formation of amphotericin B-cholesteryl cis-parinarate complex. This effect of amphotericin B was ablated by increasing concentrations of cholesterol. We found that amphotericin B inhibited oxidation of cis-parinaric acid complexed with human serum albumin [using a water-soluble azo initiator, 2,2'-azobis(2aminopropane)dihydrochloride] and in liposomes [using a lipid-soluble azo initiator, 2,2'-azobis(2,4-dimethylvaleronitrile)]. The inhibitory effect of amphotericin B on 2,2'-azobis(2,4-dimethylvaleronitrile)-induced peroxidation of cis-parinaric acid in liposomes was also diminished by cholesterol. The antioxidant effect of amphotericin B in this model system suggests that amphotericin B does not exert its pharmacological and toxicological responses through a prooxidant effect to cause damage in target cells.
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