Abstract
Cardiovascular autonomic dysfunction, such as orthostatic hypotension consequent to baroreflex failure and cardiac sympathetic denervation, is frequently observed in the synucleinopathy Parkinson’s disease (PD). In the present study, the baroreceptor reflex was assessed in mice overexpressing human wildtype alpha-synuclein (Thy1-aSyn), a genetic mouse model of synucleinopathy. The beat-to-beat change in heart rate (HR), computed from R–R interval, in relation to blood pressure was measured in anesthetized and conscious mice equipped with arterial blood pressure telemetry transducers during transient bouts of hypertension and hypotension. Compared to wildtype, tachycardia following nitroprusside-induced hypotension was significantly reduced in Thy1-aSyn mice. Thy1-aSyn mice also showed an abnormal cardiovascular response (i.e., diminished tachycardia) to muscarinic blockade with atropine. We conclude that Thy1-aSyn mice have impaired basal and dynamic range of sympathetic and parasympathetic-mediated changes in HR and will be a useful model for long-term study of cardiovascular autonomic dysfunction associated with PD.
Highlights
Baroreflex failure is documented in patients with Parkinson’s disease (PD) and is often considered as the root cause for observed orthostatic hypotension [1, 2]
Baseline heart rate (HR) measures were significantly different between genotypes under anesthesia during the acute hemodynamic studies (Table 2); Thy1-aSyn mice had a higher HR compared to WT mice (p < 0.05)
In the present study we show that overexpression of human alpha-synuclein in mice leads to impaired baroreflex control of HR prior to changes in striatal dopamine content and reminiscent of the baroreflex dysfunction observed in PD [1, 2]
Summary
Baroreflex failure is documented in patients with Parkinson’s disease (PD) and is often considered as the root cause for observed orthostatic hypotension [1, 2]. Orthostatic hypotension, baroreflex failure, and sympathetic denervation have been reported to occur early in PD, before the onset of overt motor symptoms, making cardiovascular autonomic dysfunction a potential PD biomarker for the development of diseasemodifying treatments [3,4,5,6,7]. In this study we sought to characterize baroreceptor function in transgenic mice overexpressing alpha-synuclein under the Thy promoter [Thy1-aSyn; [16]]. These mice have increased alpha-synuclein levels in central and peripheral neurons and develop proteinase K-resistant alpha-synuclein aggregates in multiple brain regions, including the substantia nigra, locus coeruleus, and olfactory bulb [16,17,18]. We assessed morphometry parameters, baroreceptor reflex, and left ventricular contractility in Thy1-aSyn and wildtype (WT) mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
