The immunosuppressant drug cyclosporine A (CsA) is an important new cause of hypertension, and the principal investigator's previous work has implicated a major neurogenic component in the pathogenesis. During the first granting cycle, they demonstrated that acute CsA-induced hypertension in rats is caused by sympathetic activation, that persists for hours after a single dose of CsA. The principal investigator now wants to explore in-depth the underlying mechanisms. The central hypothesis is that the full expression of CsA-induced sympathetic activation requires the coactivation of peripheral reflex and central neural mechanisms. CsA-induced sympathetic activation: (a) is initiated reflexively by activation of excitatory subdiaphragmatic visceral afferents, and then (b) is amplified and maintained by central synaptic potentiation, which (c) involves the inhibition of calcineurin-mediated dephosphorylation of presynaptic proteins such as synapsins.
The specific aims are 3-fold. In rats, the principal investigator will determine if: (1) An excitatory reflex arising in subdiaphragmatic afferents initiates the sympathetic response to CsA but this reflex mechanism alone is not sufficient to sustain sympathetic activation. The maintenance, but not initiation, of CsA-induced sympathetic activation is closely coupled to inhibition of calcineurin. (2) Inhibition of neuronal calcineurin induces a marked central potentiation of the excitatory subdiaphragmatic afferent reflex and/or central attenuation of the inhibitory baroreceptor reflex. In mice, it will be determined if (3) synapsins play an important role in the central, calcineurin-sensitive component of CsA-induced sympathetic activation, which therefore is greatly attenuated in synapsin deficient mice. In contrast, CsA-induced renal afferent activation is well-preserved despite synapsin deficiency. The distinctive features of this application include: (1) the combination of afferent and efferent neural recordings in rodents to elucidate differential regulation of the induction and persistence of an acute neurogenic form of hypertension; and (2) the use of transgenic models to study the role of specific proteins, e.g., the synapsins, in the integrated neural control of blood pressure. A better understanding of the neural mechanisms underlying CsA-induced hypertension could possibly lead to the elimination of hypertension as the major side effect of clinical immunosuppressive treatment and may have much broader scientific implications regarding the pathogenesis and treatment of other forms of hypertension.
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