Biomedical subjects

Courtney Holmes

Publications and source records attributed to Courtney Holmes.

27 records · Page 2Linked to original sources

PubMed2003

Sympathoadrenal imbalance before neurocardiogenic syncope.

Neurocardiogenic syncope is the most common cause of acute loss of consciousness in adults. The present study attempted to identify neuroendocrine and hemodynamic changes before syncope that could therefore play a pathophysiologic role. Twenty-five patients referred for chronic orthostatic intolerance had plasma catecholamines measured serially; 21 patients during tilt-table testing (evoking syncope in 13) and 4 others with spontaneous syncope while supine. Forearm blood flow was measured by impedance plethysmography. All 12 patients with blood sampled before tilt-induced syncope had progressive, marked increases in plasma epinephrine levels (mean 11 times baseline, p <0.0001) before syncope. Simultaneously obtained norepinephrine levels increased to a much smaller extent than did epinephrine levels ("sympathoadrenal imbalance"). In the same patients, forearm vascular resistance decreased by 21% before syncope. Proportionate changes in forearm vascular resistance before syncope correlated negatively with those in the epinephrine:norepinephrine ratio (r = -0.75, p = 0.005). Patients without syncope had forearm vasoconstriction and no sympathoadrenal imbalance during tilt. Patients with syncope while supine also had sympathoadrenal imbalance before loss of consciousness. Sympathoadrenal imbalance precedes tilt-evoked and spontaneous neurocardiogenic syncope and correlates with concurrent skeletal muscle vasodilation. Sympathoadrenal imbalance may contribute to hemodynamic derangements precipitating neurocardiogenic syncope.

Adult↗

PubMed2003

Cerebrospinal fluid levels of catechols in patients with neurogenic orthostatic hypotension.

In multiple system atrophy (MSA) and pure autonomic failure (PAF), orthostatic hypotension (OH) results from deficient noradrenaline release from sympathetic nerves during standing. Post-mortem findings have indicated loss of central noradrenergic cells in both diseases. The present study sought in vivo neurochemical evidence for central noradrenergic deficiency in patients with OH due to MSA or PAF. A total of 28 patients with OH (18 with MSA; 10 with PAF) had cerebrospinal fluid and blood sampled for levels of noradrenaline and its neuronal metabolite dihydroxyphenylglycol. A control group of 44 subjects included 10 elderly normal volunteers, 10 patients with Alzheimer's disease, 18 patients with dysautonomia (postural tachycardia syndrome or neurocardiogenic syncope) and six patients with MSA in the absence of OH. Patients with OH had lower cerebrospinal fluid concentrations of noradrenaline (0.53+/-0.07 nmol/l) and dihydroxyphenylglycol (6.52+/-0.46 nmol/l) than did control subjects (0.90+/-0.09 and 9.64+/-0.46 nmol/l respectively; P =0.0001). The MSA+OH group had higher plasma levels of both catechols (noradrenaline, 1.31+/-0.16 nmol/l; dihydroxyphenylglycol, 5.08+/-0.43 nmol/l) than did the PAF group (noradrenaline, 0.38+/-0.08 nmol/l; dihydroxyphenylglycol, 2.53+/-0.30 nmol/l; P <0.001), despite similarly low cerebrospinal fluid levels. Among MSA patients, those with OH had lower cerebrospinal fluid levels of noradrenaline and dihydroxyphenylglycol than those without OH (noradrenaline, 1.71+/-0.64 nmol/l; dihydroxyphenylglycol, 10.41+/-1.77 nmol/l respectively; P =0.006). The findings are consistent with central noradrenergic deficiency in both MSA+OH and PAF. In MSA, central noradrenergic deficiency seems to relate specifically to OH.

Aged↗

PubMed2003

Tyrosinase: a developmentally specific major determinant of peripheral dopamine.

L-3,4-dihydroxyphenylalanine, the immediate precursor of dopamine, can be formed by two enzymes: tyrosine hydroxylase (TH) in catecholamine-producing neurons and chromaffin cells and tyrosinase in melanocytes. In this study we examined whether tyrosinase contributes to production of dopamine. Deficiency of TH caused marked reductions in norepinephrine in albino and pigmented 15-day-old mice. In contrast, peripheral levels of dopamine were reduced only in albino TH-deficient mice and were higher in pigmented than in albino mice, regardless of the presence or absence of TH. We next examined age-related changes in dopamine and cutaneous expression of tyrosinase and melanin in albino and pigmented TH wild-type mice. We found that the differences in peripheral dopamine between pigmented and albino mice disappeared with advancing age following changes in expression and function of tyrosinase. In young animals, tyrosinase was present in epidermis but did not produce detectable melanin. With advancing age, tyrosinase was localized only around hair follicles, melanin synthesis became more pronounced, and dopamine synthesis decreased. The data reveal a previously unrecognized TH-independent major pathway of peripheral dopamine synthesis in young, but not adult, mice. The transient nature of this source of dopamine reflects a developmental switch in tyrosinase-dependent production of dopamine to production of melanin.

Age Factors↗

PubMed2003

Aging-related changes in cardiac sympathetic function in humans, assessed by 6-18F-fluorodopamine PET scanning.

UNLABELLED: Sympathetic nerves play key roles in cardiac physiology and aging-related cardiovascular diseases. This study examined the effects of normal human aging on cardiac sympathetic innervation and function, including the neuronal uptake of catecholamines (uptake 1) via the cell membrane norepinephrine transporter. METHODS: Thirty-three healthy volunteers, 17 under 40 and 16 over 50 y old, underwent thoracic PET scanning after injection of the sympathoneural imaging agent 6-(18)F-fluorodopamine. Myocardial perfusion was estimated by (13)NH(3) scanning, and arterial blood was sampled for levels of 6-(18)F-fluorodopamine and 6-(18)F-fluorodopamine-derived radioactivity. RESULTS: The older group had more myocardial 6-(18)F-fluorodopamine-derived radioactivity than did the younger group. Myocardial perfusion was also greater in the older group, and arterial blood levels of 6-(18)F-fluorodopamine were also higher. After adjustment for delivery of the tracer, the estimated level of myocardial extraction of 6-(18)F-fluorodopamine was lower in the older group (48%) than in the younger group (74%) (P = 0.02). CONCLUSION: Cardiac uptake 1 activity decreases with normal human aging.

Adult↗

PubMed2002

Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes.

BACKGROUND: In postural tachycardia syndrome (POTS) and repeated neurocardiogenic presyncope (NCS), orthostatic intolerance occurs without persistent sympathetic neurocirculatory failure. Whether these conditions involve abnormal cardiac sympathetic innervation or function has been unclear. METHODS AND RESULTS: Patients with POTS or NCS underwent measurements of neurochemical indices of cardiac release, reuptake, and synthesis of the sympathetic neurotransmitter norepinephrine based on entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover), cardiac extraction of circulating (3)H-norepinephrine, and cardiac production of dihydroxyphenylalanine and measurement of left ventricular myocardial innervation density using 6-[(18)F]fluorodopamine positron emission tomographic scanning. Mean cardiac norepinephrine spillover in POTS (171+/-30 pmol/min, N=16) was higher and in NCS (62+/-9 pmol/min, N=20) was lower than in a large group of healthy volunteers (102+/-9 pmol/min, N=52) and in a subgroup of age-matched healthy women (106+/-18 pmol/min, N=11). Both patient groups had normal cardiac extraction of (3)H-norepinephrine, normal cardiac production of dihydroxyphenylalanine, and normal myocardial 6-[(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: POTS and NCS differ in tonic cardiac sympathetic function, with increased cardiac norepinephrine release in the former and decreased release in the latter. Both groups had normal values for indices of function of the cell membrane norepinephrine transporter, norepinephrine synthesis, and density of myocardial sympathetic innervation. Because POTS and NCS both include specific abnormalities of cardiac sympathetic function, both can be considered forms of dysautonomia.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed2002

Progressive loss of cardiac sympathetic innervation in Parkinson's disease.

This study addressed whether cardiac sympathetic denervation progresses over time in Parkinson's disease. In 9 patients without orthostatic hypotension, 6-[(18)F]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6-[(18)F]fluorodopamine-derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinson's disease, loss of cardiac sympathetic denervation progresses in a pattern of loss suggesting a dying-back mechanism.

Disease Progression↗

PubMed2002

Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor.

We report the case of a patient with chronic autonomic failure who had evidence of decreased postganglionic traffic to intact sympathetic nerve terminals. The patient complained mainly of decreased salivation, constipation, dry skin, and orthostatic intolerance. There was no evidence of central neurodegeneration. Autonomic function testing showed orthostatic hypotension without tachycardia and abnormal blood pressure and pulse rate responses to the Valsalva maneuver, indicating combined sympathetic and parasympathetic neurocirculatory failure. In contrast to patients with pure autonomic failure, the patient had normal left ventricular myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity, establishing intact postganglionic sympathetic innervation; and in contrast to patients with multiple system atrophy or baroreflex failure, the patient had a low plasma norepinephrine concentration and brisk norepinephrine response to orthostasis. These findings indicated an impediment to ganglionic neurotransmission. Serologic testing demonstrated a circulating antibody to the ganglionic nicotinic acetylcholine receptor. The findings in this case support the concept that circulating antibodies to this receptor can interfere with ganglionic neurotransmission and produce autoimmune autonomic neuropathy.

Adrenergic alpha-Agonists↗

PubMed2002

Local sympathetic denervation in painful diabetic neuropathy.

This study assessed whether painful diabetic neuropathy is associated with abnormal sympathetic nervous function in the affected limbs. Nine patients with diabetes (four men, five women; age 61 +/- 7 years) and painful peripheral neuropathy of the feet, but without evidence of generalized autonomic neuropathy, underwent intravenous infusion of tritiated norepinephrine (NE) and sampling of arterial and venous blood in both feet and in one arm to quantify the rate of entry of NE into the local venous plasma (NE spillover). In the same patients, positron emission tomography (PET) scanning after intravenous injection of the sympathoneural imaging agent 6-[(18)F]fluorodopamine was used to visualize sympathetic innervation and after intravenous [(13)N]ammonia to visualize local perfusion. The results were compared with those in the feet of normal volunteers and in an unaffected foot of patients with unilateral complex regional pain syndrome (CRPS). In addition, neurochemical results obtained in painful diabetic neuropathy were compared with those obtained in diabetic control patients with painless neuropathy and diabetic control patients without neuropathy. Local arteriovenous difference in plasma NE levels (DeltaNE(AV)) and NE spillover in the arms did not differ across the groups. However, DeltaNE(AV) in the feet was significantly less in the group with painful diabetic neuropathy than in the control groups. Also NE spillover in the feet tended to be lower in painful neuropathy. DeltaNE(AV) of diabetic control patients without neuropathy (n = 6) resembled values in the control groups without diabetes, whereas patients with painless diabetic neuropathy (n = 6) had evidence suggesting partial loss of sympathetic innervation. PET scanning revealed decreased flow-corrected 6-[(18)F]fluorodopamine-derived radioactivity in patients with painful diabetic neuropathy, compared with values in normal volunteers and patients with CRPS. The results provide neurochemical and neuroimaging evidence for regionally selective sympathetic denervation in the painful feet of patients with diabetic neuropathy.

Aged↗

PubMedDate not supplied

Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes.

BACKGROUND: Neurogenic orthostatic hypotension (OH) characterizes pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure. We used neuropharmacologic probes that might distinguish these diseases based on loss of sympathetic noradrenergic nerves in PAF and PD + OH but not in MSA, and related the results to neurochemical and neuroimaging findings in the same patients. METHODS: Patients with neurogenic OH (PD + OH; N = 35), MSA (N = 41), and PAF (N = 12) received iv trimethaphan (TRI), which inhibits sympathetic nerve traffic, or yohimbine (YOH), which stimulates sympathetic traffic. Dependent measures included blood pressure, plasma norepinephrine (NE) levels, and interventricular septal myocardial radioactivity after iv injection of the sympathoneural imaging agent, 6-[F]fluorodopamine. RESULTS: The PD + OH and PAF groups had smaller pressor responses to YOH (12 +/- 8 and 13 +/- 1 mm Hg) and depressor responses to TRI (-14 +/- 8 and -17 +/- 7 mm Hg) than did the MSA group (43 +/- 8 mm Hg, -57 +/- 8 mm Hg; P = 0.01, P = 0.03). The PD + OH and MSA groups did not differ in NE responses to YOH and TRI. The depressor response to TRI, the pressor response to YOH, and the blood pressure difference between YOH and TRI all correlated positively with myocardial 6-[F]fluorodopamine-derived radioactivity. CONCLUSIONS: The PD + OH resembles PAF and differs from MSA in hemodynamic responses to drugs that alter NE release from sympathetic nerves. The results fit with sympathetic noradrenergic denervation in PD + OH and PAF but not in MSA.

Blood Pressure↗