Riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of striatonigral degeneration (parkinson variant of multiple system atrophy).

We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.

Vasoactive neuroendocrine responses associated with tolerance to lower body negative pressure in humans.

The purpose of this investigation was to test the hypothesis that peripheral vasoconstriction and orthostatic tolerance are associated with increased circulating plasma concentrations of noradrenaline, vasopressin and renin-angiotensin. Sixteen men were categorized as having high (HT, n=9) or low (LT, n=7) tolerance to lower body negative pressure (LBNP) based on whether the endpoint of their pre-syncopal-limited LBNP (peak LBNP) exposure exceeded -60 mmHg. The two groups were matched for age, height, weight, leg volume, blood volume and maximal oxygen uptake, as well as baseline blood volume and plasma concentrations of vasoactive hormones. Peak LBNP induced similar reductions in mean arterial pressure in both groups. The reduction in leg arterial pulse volume (measured by impedance rheography), an index of peripheral vascular constriction, from baseline to peak LBNP was greater (P<0.05) in the HT group (-0.041 +/- 0.005 ml 100 ml-1) compared to the reduction in the LT group (-0. 025 +/- 0.003 ml 100 ml-1). Greater peak LBNP in the HT group was associated with higher (P<0.05) average elevations in plasma concentrations of vasopressin (pVP, Delta=+7.2 +/- 2.0 pg ml-1) and plasma renin-angiotensin (PRA, Delta=+2.9 +/- 1.3 ng Ang II ml-1 h-1) compared to average elevations of pVP (+2.2 +/- 1.0 pg ml-1) and PRA (+0.1 +/- 0.1 ng Ang II ml-1 h-1) in the LT group. Plasma noradrenaline concentrations were increased (P<0.05) from baseline to peak LBNP in both HT and LT groups, with no statistically distinguishable difference between groups. These data suggest that the renin-angiotensin and vasopressin systems may contribute to sustaining arterial pressure and orthostatic tolerance by their vasoconstrictive actions.

Effects of cholinergic and beta-adrenergic blockade on orthostatic tolerance in healthy subjects.

Cardiovascular responses during a graded lower body negative pressure (LBNP) protocol were compared before and after atropine and propranolol administration to test the hypothesis that both sympathetic and parasympathetic control of cardio-acceleration are associated with syncopal predisposition to orthostatic stress in healthy subjects. Eleven men were categorized into two groups having high (HT, N = 6) or low (LT, N = 5) tolerance based on their total time before the onset of presyncopal symptoms. HT and LT groups were similar in physical characteristics, fitness, and baseline cardiovascular measurements. Atropine treatment had no effect on LBNP tolerance or mean arterial pressure at presyncope, despite an atropine-induced increase in heart rate. Propranolol treatment reduced (p<0.05) LBNP tolerance in both groups. Diminished LBNP tolerance after propranolol administration was associated with reductions in cardiac output, whereas increase in systemic peripheral resistance from baseline to presyncope was unaffected by propranolol. Reduction in cardiac output and LBNP tolerance after beta blockade reflected a chronotropic effect because lower LBNP tolerance for the HT (-50%) and LT (-39%) groups was associated with dramatic reductions (p <0.05) in the magnitude of LBNP-induced tachycardia without significant effects on stroke volume at presyncope. Absence of an atropine-induced difference in cardiac output and systemic peripheral resistance between HT and LT groups failed to support the notion that cardiac vagal withdrawal represents a predominant mechanism that could account for differences in orthostatic tolerance. Because a reduction in LBNP tolerance in both HT and LT groups after propranolol treatment was most closely associated with reduced tachycardia, the data suggest that a primary autonomically mediated mechanism for maintenance of mean arterial pressure and orthostatic tolerance in healthy subjects is beta adrenergic-induced tachycardia.

Aerobic fitness does not contribute to prediction of orthostatic intolerance.

Several investigations have suggested that orthostatic tolerance may be inversely related to aerobic fitness (VO2max). To test this hypothesis, 18 males (age 29 to 51 yr) underwent both treadmill VO2max determination and graded lower body negative pressures (LBNP) exposure to tolerance. VO2max was measured during the last minute of a Bruce treadmill protocol. LBNP was terminated based on pre-syncopal symptoms, and LBNP tolerance (peak LBNP) was expressed as the cumulative product of LBNP and time (torr-min). Changes in heart rate, stroke volume, cardiac output, blood pressure, and impedance rheographic indices of mid-thigh-leg fluid accumulation were measured at rest and during the final minute of LBNP. For all 18 subjects, mean (+/- SE) fluid accumulation index and leg venous compliance index at peak LBNP were 139 +/- 22 ml and 3.9 +/- 0.4 ml . 100 ml . torr-min-2 x 10(3), respectively. Pearson product-moment correlations and step-wise linear regression were used to investigate relationships with peak LBNP. Variables associated with endurance training, such as VO2max and percent body fat, were not found to correlate significantly (P less than 0.05) with peak LBNP and did not add sufficiently to the prediction of peak LBNP to be included in the step-wise regression model. The step-wise regression model included only fluid accumulation index, leg venous compliance index, and blood volume, and resulted in a squared multiple correlation coefficient of 0.978. These data do not support the hypothesis that orthostatic tolerance as measured by LBNP is lower in individuals with high aerobic fitness.

Cardiovascular dynamics associated with tolerance to lower body negative pressure.

The purpose of this investigation was to identify cardiovascular responses associated with tolerance to lower body negative pressure (LBNP). In this study, 18 men, ages 29-51 years, were categorized as high (HT) or low (LT) LBNP tolerant based on a graded presyncopal-limited LBNP exposure criterion of -60 mm Hg relative to ambient pressure. Groups were matched for physical characteristics and preLBNP cardiovascular measurements, with the exceptions of greater (p less than 0.05) end-diastolic volume and cardiac output in the HT group. During peak LBNP, cardiac output was similar (NS) in both groups, although the HT group displayed a greater heart rate (p less than 0.05). In both groups, venous return appeared to limit cardiac output resulting in decreased arterial pressure. Tolerance to LBNP did not appear solely dependent on the absolute amount of blood pooled in the legs since the HT group demonstrated a greater (p less than 0.05) peak LBNP-induced increase in midthigh-leg volume. Greater tolerance to LBNP was associated with a larger preLBNP cardiac output reserve and higher compensatory increases in heart rate and peripheral resistance.