Symptomatic orthostatic hypotension in Parkinson's disease patients: Prevalence, associated factors and its impact on balance confidence.

BACKGROUND: Orthostatic hypotension (OH) is a commonly reported sign of the cardiovascular autonomic dysfunctions associated with Parkinson's disease (PD). Patients might suffer from a variety of the clinical symptoms of OH, including dizziness, lightheadedness, or problems with vision and fatigue. OBJECTIVES: To determine the prevalence of, and factors associated with, symptomatic orthostatic hypotension (OH) in Parkinson's disease (PD) and to identify any relationships between the clinical symptoms of OH and balance confidence in this patient population. METHODS: Symptomatic OH was defined as a systolic or diastolic BP fall of ≥20 or ≥10mmHg respectively, within 3min of standing and an Orthostatic Hypotension Questionnaire (OHQ) score of more than zero. Factors related to symptomatic OH were identified from a multivariate logistic regression analysis. Pearson's correlation test was used to reveal any relationships between the clinical symptoms of OH and a patient's confidence in their ability to balance, assessed using the Activities-specific Balance Confidence (ABC) scale. RESULTS: 100 Thai PD patients were consecutively recruited into this study. The prevalence of symptomatic OH was 18%, asymptomatic OH was 4%, while 78% were patients without OH. Factors associated with symptomatic OH were age (OR, 95%CI: 1.06, 1.003-1.115, p=0.038) and hypertension (OR, 95%CI: 6.16, 1.171-32.440, p=0.032). A significant and negative correlation (r=-0.229, p=0.022) between OHQ composite scores and item 3 of the ABC scale (picking up slippers from floor), one of the movements in a vertical orientation, was found. CONCLUSION: Elderly PD patients and with a co-morbidity of essential hypertension should be closely evaluated for the presence of symptomatic OH. In addition, they should be advised to change positions slowly, especially those in a vertical orientation.

Association between Sleep Disturbances and Daytime Somnolence in Parkinson's Disease.

BACKGROUND: Sleep disturbance is a common problem among patients with Parkinson's disease (PD). OBJECTIVES: To investigate the prevalence of daytime somnolence and night-time sleep disturbances; to characterise the night-time sleep disturbance in patients with daytime somnolence; and to determine the correlation between daytime somnolence and night-time sleep disturbances. METHODS: One hundred and sixty patients with PD were included in the study. Each patient completed the Thai version of the Epworth Sleepiness Scale (ESS) questionnaire to evaluate excessive daytime sleepiness (EDS), and the PD Sleep Scale version-2 (PDSS-2) questionnaire to evaluate night-time sleep disturbance. Subjective sleep information and details about the presence or absence of sleep attack (SA) were also obtained from the patients. RESULTS: The types of daytime somnolence found in this study were EDS, SA, and combination of EDS and SA (EDS + SA) with the prevalence rates of 22.5, 3.1 and 6.3%, respectively. The prevalence of night-time sleep disturbance was 46.9%. The most common nocturnal disturbance (82.5%) was "get up at night to pass urine". There was a significant positive correlation between the ESS score and PDSS-2 total score with a correlation coefficient of 0.16 (p = 0.043). Patients with "EDS + SA" were the most affected by nocturnal disturbances, as they represented the largest group among those patients with night-time disturbances and had the highest PDSS-2 total score (p < 0.05). CONCLUSION: There are differences in nocturnal sleep disturbances among PD patients with different types of daytime somnolence. The significant positive correlation between the ESS and the PDSS-2 total scores suggests that night-time sleep disturbance may influence daytime somnolence.

Modulation of inducible nitric oxide synthase (iNOS) expression and cardiovascular responses during static exercise following iNOS antagonism within the ventrolateral medulla.

Previous reports indicate that inducible nitric oxide synthase (iNOS) blockade within the rostral ventrolateral medulla (RVLM) and caudal ventrolateral medulla (CVLM) differentially modulated cardiovascular responses, medullary glutamate, and GABA concentrations during static skeletal muscle contraction. In the current study, we determined the role of iNOS antagonism within the RVLM and CVLM on cardiovascular responses and iNOS protein expression during the exercise pressor reflex in anesthetized rats. Following 120 min of bilateral microdialysis of a selective iNOS antagonist, aminoguanidine (AGN; 10 µM), into the RVLM, the pressor responses were attenuated by 72 % and changes in heart rate were reduced by 38 % during a static muscle contraction. Furthermore, western blot analysis of iNOS protein abundance within the RVLM revealed a significant attenuation when compared to control animals. In contrast, bilateral administration of AGN (10 µM) into the CVLM augmented the increases in mean arterial pressure by 60 % and potentiated changes in heart rate by 61 % during muscle contractions, but did not alter expression of the iNOS protein within the CVLM. These results demonstrate that iNOS protein expression within the ventrolateral medulla is differentially regulated by iNOS blockade that may, in part, contribute to the modulation of cardiovascular responses during static exercise.

Effects of medullary administration of a nitric oxide precursor on cardiovascular responses and neurotransmission during static exercise following ischemic stroke.

We have reported that in rats with a 90 min left middle cerebral artery occlusion (MCAO) and 24 h reperfusion, pressor responses during muscle contractions were attenuated, as were glutamate concentrations in the left rostral ventrolateral medulla (RVLM) and left caudal VLM (CVLM), but gamma-aminobutyric acid (GABA) levels increased in left RVLM and CVLM. This study determined the effects of L-arginine, a nitric oxide (NO) precursor, within the RVLM and (or) CVLM on cardiovascular activity and glutamate/GABA levels during static exercise in left-sided MCAO rats. Microdialysis of L-arginine into left RVLM had a greater attenuation of cardiovascular responses, a larger decrease in glutamate, and a significant increase in GABA levels during muscle contractions in stroke rats. Administration of N(G)-monomethyl-L-arginine, an NO-synthase inhibitor, reversed the effects. In contrast, L-arginine administration into left CVLM evoked a greater potentiation of cardiovascular responses, increased glutamate, and decreased GABA levels during contractions in stroked rats. However, L-arginine administration into both left RVLM and left CVLM elicited responses similar to its infusion into the left RVLM. These results suggest that NO within the RVLM and CVLM modulates cardiovascular responses and glutamate/GABA neurotransmission during static exercise following stroke, and that a RVLM-NO mechanism has a dominant effect in the medullary regulation of cardiovascular function.

Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration.

Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs.

Ingestion of Mn and Pb by rats during and after pregnancy alters iron metabolism and behavior in offspring.

Manganese (Mn) and lead (Pb) exposures during developmental period can impair development by direct neurotoxicity or through interaction with iron metabolism. Therefore, we examined the effects of maternal ingestion of Mn or Pb in drinking water during gestation and lactation on iron metabolism as well as behavior in their offspring. Pregnant dams were given distilled water, 4.79mg/ml Mn, or 2.84mg/ml Pb in drinking water during gestation and lactation. Pups were studied at time of weaning for (59)Fe absorption from the gut, duodenal divalent metal transporter 1 (DMT1) expression, hematological parameters, and anxiety-related behavior using an Elevated Plus Maze (EPM) test. Metal-exposed pups had lower body weights and elevated blood and brain concentrations of the respective metal. Pb-exposed pups had lower hematocrits and higher blood Zn protoporphyrin levels. In contrast, Mn exposed pups had normal hematological parameters but significantly reduced Zn protoporphyrin. Pharmacokinetic studies using (59)Fe showed that intestinal absorption in metal-exposed pups was not different from controls, nor was it correlated with duodenal DMT1 expression. However, intravenously injected (59)Fe was cleared more slowly in Pb-exposed pups resulting in higher plasma levels. The overall tissue uptake of (59)Fe was lower in Mn-exposed and lower in the brain in Pb-exposed pups. The EPM test demonstrated that Mn-exposed, but not Pb-exposed, pups had lower anxiety-related behavior compared to controls. We conclude that gestational and lactational exposures to Mn or Pb differentially alter Fe metabolism and anxiety-related behavior. The data suggest that perturbation in Fe metabolism may contribute to the pathophysiologic consequences of Mn and Pb exposure during early development.

Cardiovascular responses and neurotransmitter changes during blockade of angiotensin II receptors within the ventrolateral medulla.

Angiotensin II (Ang II) receptors are located in different regions of the brain, particularly within the cardiovascular control centers in the brainstem. These Ang II receptors are divided into AT1 and AT2 subtypes. We investigated the role of AT1 receptor subtype within the rostral (RVLM) and caudal (CVLM) ventrolateral medulla on cardiovascular responses and glutamate/GABA neurotransmission during static exercise using microdialysis in anesthetized rats. Bilateral microdialysis of a selective AT1 receptor antagonist, ZD7155 (10 microM), for 30 min into the RVLM attenuated increases in mean arterial pressure (MAP) and heart rate (HR) during a static muscle contraction. Glutamate concentrations within the RVLM decreased while GABA levels increased simultaneously during the contraction period when compared to those before ZD7155. After 60 min of discontinuation of ZD7155, MAP, HR, glutamate, and GABA levels in response to another muscle contraction returned to baseline levels. Conversely, bilateral microdialysis of ZD7155 into the CVLM potentiated cardiovascular responses during a static muscle contraction; glutamate concentrations increased while GABA levels within the CVLM decreased. All responses recovered after 60 min of discontinuation of ZD7155. These results demonstrate that medullary AT1 receptors play an important role in modulating both neurotransmission and cardiovascular function during static exercise.

Neuronal nitric oxide synthase (nNOS) blockade within the ventrolateral medulla differentially modulates cardiovascular responses and nNOS expression during static skeletal muscle contraction.

Nitric oxide (NO) is synthesized from L-arginine through the activity of the enzyme, NO synthase (NOS). Previous studies have demonstrated the role of the 3 isoforms of NOS, namely endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) in cardiovascular regulation. Local blockade of nNOS in RVLM vs. CVLM differentially alters local glutamate and GABA release, and thereby results in opposite cardiovascular responses to static muscle contraction (Brain Res. 2003, 977, 80-89). In this study, we examined whether nNOS antagonism within the RVLM and CVLM affected cardiovascular responses during the exercise pressor reflex and simultaneously modulated medullary nNOS protein expression using anesthetized rats. Bilateral microdialysis of a selective nNOS antagonist, 1-(2-trifluoromethylphenyl)-imidazole (TRIM, 1.0 microM) for 120 min into the RVLM, potentiated cardiovascular responses during a static muscle contraction. Western blot analysis of nNOS expression within the RVLM showed significant attenuation of the protein when compared to the data obtained from control animals microdialyzed with vehicle. In contrast, bilateral application of TRIM into the CVLM attenuated cardiovascular responses during muscle contractions and increased nNOS protein expression within the CVLM. These results demonstrated that nNOS protein expression within the brainstem was pharmacologically altered by nNOS blockade within the RVLM or CVLM, which in turn might have contributed to the augmentation or attenuation of cardiovascular responses, respectively, during static exercise.

Cardiovascular responses and neurotransmitter changes during static muscle contraction following blockade of inducible nitric oxide synthase (iNOS) within the ventrolateral medulla.

The enzyme nitric oxide synthase (NOS) which is necessary for the production of nitric oxide from L-arginine exists in three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Our previous studies have demonstrated the roles of nNOS and eNOS within the rostral (RVLM) and caudal ventrolateral medulla (CVLM) in modulating cardiovascular responses during static skeletal muscle contraction via altering localized glutamate and GABA levels (Brain Res. 977 (2003) 80-89; Neuroscience Res. 52 (2005) 21-30). In this study, we investigated the role of iNOS within the RVLM and CVLM on cardiovascular responses and glutamatergic/GABAergic neurotransmission during the exercise pressor reflex. Bilateral microdialysis of a selective iNOS antagonist, aminoguanidine (AGN; 1.0 microM), for 60 min into the RVLM attenuated increases in mean arterial pressure (MAP), heart rate (HR), and extracellular glutamate levels during a static muscle contraction. Levels of GABA within the RVLM were increased. After 120 min of discontinuation of the drug, MAP and HR responses and glutamate/GABA concentrations recovered to baseline values during a subsequent muscle contraction. In contrast, bilateral application of AGN (1.0 microM) into CVLM potentiated cardiovascular responses and glutamate concentration while attenuating levels of GABA during a static muscle contraction. All values recovered after 120 min of discontinuation of the drug. These results demonstrate that iNOS within the ventrolateral medulla plays an important role in modulating cardiovascular responses and glutamatergic/GABAergic neurotransmission that regulates the exercise pressor reflex.