Regulation of Trypanosoma cruzi infectivity by alpha- and beta-adrenergic agonists: desensitization produced by prolonged treatments or increasing agonist concentrations.
We previously reported that blood forms of Trypanosoma cruzi express alpha- and beta-adrenergic receptors and that binding of specific agonists to these receptors modifies the infective capacity of the parasite in vitro. The present study has revealed that the inhibitory effect of the beta-adrenergic agonist L-isoproterenol and the stimulatory effect of the alpha-adrenergic agonist L-phenylephrine are not produced when the parasite is subjected to prolonged exposure to otherwise effective doses of these agonists or when supraoptimal doses of these agonists are used. We refer to these phenomena as 'desensitization' because of their analogy with vertebrate cells becoming desensitized by prolonged exposure to, or relatively high concentrations of, adrenergic agonists. At a constant agonist concentration, T. cruzi desensitization was time-dependent and, when the time of parasite treatment with the agonists was not changed, the higher concentrations of the agonist tested were the most effective in producing desensitization. The reduced infectivity resulting from treatment with optimal doses of L-isoproterenol was accompanied by elevated levels of cyclic adenosine monophosphate (cAMP) which were not detectable when L-isoproterenol concentrations producing desensitization were used. This finding implicated cAMP as a likely second signal in the inhibitory mechanisms of this agonist. No significant change in cAMP was detectable in parasites treated with L-phenylephrine, leaving open the question about how optimal doses of this alpha-adrenergic agonist enhance T. cruzi infectivity. Parasite responsiveness to alpha- and beta-adrenergic agonists as well as the desensitization effects define a system which regulates infectivity and could be modified at the host tissue level by naturally occurring agonists.
Ayala
A
A
Department of Microbiology and Public Health, Michigan State University, East Lansing 48824.
Kierszenbaum
F
F
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006790:Host-Parasite Interactions; D007545:Isoproterenol / Q000494:pharmacology*; D008264:Macrophages / Q000469:parasitology*; D051379:Mice; D008808:Mice, Inbred CBA; D010656:Phenylephrine / Q000494:pharmacology*; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000502:physiology
D010656:Phenylephrine; D000242:Cyclic AMP; D007545:Isoproterenol