Acute nitric oxide synthase inhibition and cardiac conduction in persons with spinal cord injury: a short report.

NG-nitro L-arginine methyl ester (L-NAME) is a potent and non-specific inhibitor of nitric oxide synthase (NOS). NOS inhibition with L-NAME has been shown to adversely prolong electrocardiogram (ECG) intervals in an animal model, an observation which has yet to be evaluated in humans. We determined the effects of several weight-based L-NAME doses on ECG intervals in persons with tetraplegia and a neurologically-intact control group. This two-part investigation determined the effects of different weight-based doses of L-NAME in the supine (Study 1) and orthostatic position (Study 2). Subjects completed an open-label trial with intravenous administration of L-NAME at specific doses [i.e., 0, 1, 2 or 4 mg.kg-1] in the supine position. The SCI group completed an orthostatic challenge with or without il-NAME [i.e., 0, 1 or 2 mg.kg-'] and controls completed only a single visit [0 mg.kg-1]. Digital ECGs were obtained at baseline (BL), after infusion (60 minutes) and 1 hour post-infusion (120 minutes) in Study 1, and at BL, 60 minutes and at two, 10 minute post-infusion time points after head up tilt (Post-Tilt 1 and 2) in Study 2. Heart rate, PQ, QT, and heart rate corrected QT (QTC) intervals were determined. The groups were matched for demographics. Seven subjects with tetraplegia and 6 controls participated in Study 1; 7 subjects with tetraplegia and 7 controls participated in Study 2. No statistical differences were noted between or within groups at baseline on each study visit for the ECG variables. L-NAME, regardless of dose, did not significantly change any ECG interval. NOS inhibition with L-NAME, at the weight-based doses tested do not induce hypertensive crises and, did not adversely affect any ECG interval in persons with SCI or neurologically intact control subjects during supine rest or orthostatic provocation.

Orthostatic responses to nitric oxide synthase inhibition in persons with tetraplegia.

OBJECTIVES: To determine the effects of 1.0 mg/kg nitro-L-arginine methyl ester (L-NAME) on orthostatic mean arterial pressure (MAP), serum aldosterone, and plasma renin concentrations in persons with chronic tetraplegia compared with nonspinal cord-injured controls. DESIGN: Prospective placebo-controlled intervention study. SETTING: James J. Peters Veterans Affairs Medical Center. PARTICIPANTS: Patients (n=5) with tetraplegia and controls (n=7) participated. The groups were matched for age, height, and weight; the average duration of injury in the tetraplegia group was 22+/-14 years. INTERVENTION: Subjects with tetraplegia visited the laboratory twice, receiving placebo on day 1 and L-NAME (1.0 mg/kg) on day 2. The agents were infused via an intravenous catheter over 60 minutes with the patient in the supine position. Data were collected during the infusion and then during head-up tilt to 45 degrees for 30 minutes. Control subjects visited the laboratory once for placebo infusion and the head-up tilt maneuver. MAIN OUTCOME MEASURE: Orthostatic MAP. RESULTS: Orthostatic MAP was reduced after placebo infusion in subjects with tetraplegia compared with controls (69+/-11 vs 89+/-9 mmHg, respectively; P<.01) and compared with L-NAME infusion (90+/-16 mmHg; P<.01). Orthostatic MAP did not differ when comparing the tetraplegia group with controls after L-NAME infusion. Orthostatic aldosterone levels were increased after placebo compared with L-NAME infusion in persons with tetraplegia; plasma renin levels did not differ among the groups. CONCLUSIONS: These data suggest that nitric oxide synthase inhibition may have clinical potential for treatment of orthostatic hypotension in persons with chronic tetraplegia.

Direct and reflexive effects of nitric oxide synthase inhibition on blood pressure.

Direct effects of vasoactive substances on blood pressure can be examined in individuals with tetraplegia due to disruption of descending spinal pathways to sympathetic preganglionic neurons, as cervical lesions interfere with baroreceptor reflex buffering of sympathetic outflow. In this study, we assessed effects of the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) on mean arterial pressure, heart rate, and plasma norepinephrine concentrations in individuals with tetraplegia vs. effects shown in a neurologically intact control group. Seven individuals with tetraplegia and seven age-matched controls received, on separate visits and in the following order, placebo (30 ml normal saline) and 0.5, 1, 2, and 4 mg/kg L-NAME intravenously over 60 min. Supine hemodynamic data were collected, and blood was sampled at the end of each infusion and at 120, 180, and 240 min thereafter. L-NAME increased mean arterial pressure, and the relative increase was greater in the tetraplegia group than in the control group. Heart rate was reduced after L-NAME administration in both groups. L-NAME decreased plasma norepinephrine in the control group but not in the group with tetraplegia. These findings suggest that reflexive sympathoinhibition normally buffers the pressor response to nitric oxide synthase inhibition, an effect that is not evident in individuals with tetraplegia as a result of decentralized sympathetic vasomotor control.

Altered glycogen synthase and phosphorylase activities in skeletal muscle of tetraplegic patients.

Despite marked differences in both the extent of physical activity and in muscle metabolism and structure between tetraplegic and control subjects, the glycogen content in the skeletal muscle of both groups is similar. We determined whether this similarity could be explained by the activities of key enzymes of glycogen metabolism. Muscle biopsies were analysed for glycogen synthase (GS) and glycogen phosphorylase (GP) activities, as well as for metabolites. Glycogen content did not differ significantly between the two groups. Total glycogen synthase activity was reduced by almost 60 % in tetraplegics (P < 0.01), whereas total phosphorylase activity did not differ between groups. GS fractional activity did not differ between groups, whereas phosphorylase fractional activity (-/+ AMP) was significantly higher in the tetraplegics (0.08 +/- 0.01, control; 0.25 +/- 0.02, tetraplegics; P < 0.001). Neither uridine diphosphate (UDP)-glucose nor glucose 6-phosphate (G-6-P) content in muscle differed significantly between groups. These data demonstrate that, in tetraplegics, muscle glycogen content is preserved despite decreases in GS activity and increases in phosphorylase fractional activity. Muscle paralysis has differential effects on the activities of GS and GP. Experimental Physiology (2001) 86.2, 205-209.

Interstitial 7q deletion [46,XY,del (7) (pter----cen::q112----qter)] in a retarded quadriplegic boy with normal beta glucuronidase.

A 14-year-old severely retarded male with deletion of chromosomal band 7 cen----q112 is described. Clinical features include short stature, microcephaly, unusual facies with narrow forehead, short nose, malar hypoplasia, protruding alveolar ridges and incisors, receding chin, relatively long philtrum, and large ears. In addition, he had bilateral inguinal herniae cryptorchidism with hypogonadism, pulmonic stenosis, and spastic quadriplegia. Normal activity of beta-glucuronidase was found in the patient's leukocytes. This finding suggests that the gene is not in the deleted region, narrowing the smallest region of overlap to 7q112----q22.

Plasma renin and serum dopamine-beta-hydroxylase during orthostatic hypotension in quadriplegic man.

To determine whether orthostatic hypotension in patients with cervical spinal cord lesions is the result of impaired sympathetic nerve response and/or impaired renin release, serum dopamine-beta-hydroxylase (DbetaH) activity and plasma renin activity (PRA) were examined during passive tilting in 6 quadriplegic patients and in 6 able-bodied control subjects. Serum DbetaH was measured by an isotopic enzymatic method and PRA by radioimmunoassay. Following head-up tilting, quadriplegic subjects demonstrated a prompt, significant decrease in mean arterial pressure (MAP) and increase in heart rate (HR). DbetaH and PRA both increased significantly 15 minutes after tilt. In normal subjects, although HR increased, MAP was unchanged; DbetaH and PRA did not increase significantly during head-up tilt. The finding of increased DbetaH during tilt hypotension in quadriplegic patients provides evidence that reflex sympathetic nerve stimulation persists despite cervical cord transection. Increased PRA may be attributed to decreased renal perfusion pressure and increased sympathetic stimulation during tilt hypotension. These data suggest that orthostatic hypotension in quadriplegia patients cannot be attributed solely to failure of the sympathetic nervous system or the renin-angiotensin system to respond to the stimulus of orthostasis.

Histochemical and morphologic changes in skeletal muscle following cervical cord injury: a study of upper and lower motor neuron lesions.

The effects of upper and lower motor neuron lesions on human skeletal muscles and muscle spindles were studied using histochemical and morphometric techniques. In the lower motor neuron lesions, the muscle fibers showed group atrophy, fiber type grouping and target fibers. The muscle spindle demonstrated thickening of the capsule, degeneration of the nuclear chain fibers, targeting and splitting of the bag fibers. In the upper motor neuron lesion, the muscles showed group atrophy with histochemical evidence of preferential type II fiber involvement. Histometrics, however, failed to demonstrate type II fiber atrophy but showed hypertrophy of type I fibers. The muscle spindles only showed increased number of intrafusal fibers.