Biomedical subjects

D B MacLean

Publications and source records attributed to D B MacLean.

32 records · Page 2Linked to original sources

PubMed1987

Adrenocorticotropin-adrenal regulation of transported substance P in the vagus nerve of the rat.

The factors regulating substance P (SP) synthesis and quantity of transport in the sensory vagus nerve are unknown. To examine this issue rats were administered ACTH or corticosterone or subjected to adrenalectomy, and the quantity of peripherally directed transported SP was measured in those animals as an indication of neuropeptide synthesis. ACTH treatment (12 U/day, sc, for 14 days) resulted in significant adrenal hypertrophy and increased corticosterone levels. The 24-h accumulation of SP proximal to ligature in the cervical vagus was significantly reduced [mean net proximal segment content: controls, 529 +/- 42 (+/- SEM) pg/3 mm segment; ACTH, 282 +/- 44]. The content in the unligated nerve, one sixth or less than that proximal to ligature, was not different in the two groups. In a separate experiment, ACTH (6 U/day for 14 days) had no effect compared to controls, whereas 16 U/day reduced transported SP. The content in the unligated nerve was again not different in the two groups. In the same experiment, corticosterone (2.5 mg/100 g BW, sc, for 14 days) reduced the quantity of transported SP. Total protein content in proximal segments was reduced only in the corticosterone group and was identical in all groups in unligated nerve. Adrenalectomy modestly increased transport by 20% and contralateral unligated nerve content by a similar percentage. The quantity of transported somatostatin, another vagal neuropeptide partly derived from sensory cell bodies, was either increased or unaltered by the experimental manipulations. In summary, these studies demonstrate that the chronic administration of ACTH or corticosterone significantly decreases the quantity of peripherally transported SP in the sensory vagus nerve and, presumably, synthesis within the vagal sensory ganglia. Down-regulation of synthesized/transported neuropeptide suggests a mechanism by which the ACTH-adrenal axis, acting through visceral sensory nerves, may modulate autonomic or central nervous system vagally mediated reflex arcs.

Adrenal Glands↗

PubMed1987

Substance P and somatostatin content and transport in vagus and sciatic nerves of the streptozocin-induced diabetic rat.

Substance P (SP) and somatostatin (SS) are two widely distributed neuropeptides that within the vagus and sciatic nerves are localized predominantly in sensory fibers. The effect of diabetes mellitus on their content or transport in sensory nerves is unknown. With the nerve ligation technique, the peripheral orthograde 24-h transport of both peptides was quantified in the vagus nerve 3 days or 1 mo after induction of streptozocin (STZ) diabetes and in both the vagus and sciatic nerves after diabetes of 3 mo duration. In acute (3-day) diabetics, neuropeptide transport in the vagus was unaltered. After 1 mo, SP transport was significantly increased; content in unligated contralateral nerve was unaltered. Transport of SS was unchanged, and content in contralateral nerve was too low to reliably quantitate. After diabetes of 3-mo duration, transport of both peptides in the vagus nerve was increased in STZ-induced diabetic (STZ-D) rats versus both weight- and age-matched controls: SP 474 +/- 17 (N = 10) vs. 358 +/- 32 (N = 13) pg/24 h, STZ-D rats vs. controls, mean +/- SE, P less than .03; SS 29 +/- 4 vs. 20 +/- 3 pg/24 h, STZ-D rats vs. controls, P less than .02. In the sciatic nerve, SP transport and content were unaltered. SS content was significantly reduced: 17 +/- 3 vs. 30 +/- 3 pg/3-mm nerve segment, STZ-D rats vs. controls, P less than .01. SS transport in the sciatic nerve of diabetic rats was variably reduced (P less than .07), and transport rates were increased (1.41 +/- 0.13 vs. 0.96 +/- 0.10 mm/h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat.

Cholecystokinin (CCK) is a peripheral and central mediator of short-term satiety. When given i.p., CCK decreases food intake in previously fasted rats for a period of 30 min. The effect has been previously shown to be abolished by vagotomy and more specifically by severing of vagal sensory rootlets. These studies were designed to determine the effects on rat feeding behavior, and in particular CCK-satiety, of the sensory neurotoxin capsaicin. In neonates, capsaicin selectively and permanently destroys unmyelinated sensory fibers including those in the vagus nerve. Rat neonates were treated with capsaicin, 50 mg/kg or vehicle, and surviving females studied at 8-10 weeks of age. The weights, 24-h food intake, and feeding responses to insulin were the same in adult capsaicin treated (Cap Rx) and vehicle treated (Veh Rx) rats. CCK (8 micrograms/kg i.p.) reduced 30 min food intake 61 +/- 18% in Veh Rx animals (mean +/- S.D., P less than 0.01). In capsaicin denervated animals, CCK also significantly reduced 30 min food intake from 5.09 +/- 1.10 to 3.92 +/- 0.84 g (P less than 0.01), but the mean reduction, 23 +/- 6%, was significantly less than in Veh Rx rats (P less than 10(-4]. A separate group of females, similarly treated as neonates with capsaicin or vehicle, were subjected to bilateral lesioning of the ventromedial hypothalamus. Both Cap Rx and Veh Rx animals gained significantly and equally more than non-lesioned controls. 24 h vagal transport of substance P was reduced 70% in age matched capsaicin treated animals compared to controls. These studies demonstrate that peripheral CCK-satiety is partly mediated by capsaicin sensitive fibers, presumably in the vagus nerve. Substance P is one possible transmitter mediating this reflex. Further conclusions are that active inhibition of an intact peripheral CCK-stimulated reflex arc is not necessary for full expression of central inducers of feeding, e.g., insulin or lesioning of the ventromedial hypothalamus, and that destruction of these fibers does not alter long-term weight regulation in rats receiving a normal diet.

Aging↗

PubMed1984

De novo synthesis and axoplasmic transport of [35S]methionine-substance P in explants of nodose ganglion/vagus nerve.

The synthesis and transport of substance P, the widely distributed undecapeptide, was studied in the vagus nerve of the guinea pig. In preliminary in vivo studies, the cervical vagus nerve was ligated 2 cm distal to the nodose ganglion. Twenty-four hours later, the content of immunoreactive substance P (IR-SP) in the 3-mm nerve segment proximal to ligature was 2147 +/- 207 pg (mean +/- S.E.M.) vs 133 +/- 31 pg in an equal segment of unligated nerve or 243 +/- 55 pg in the nodose ganglion. When the vagus nerve was crushed above the ganglion and simultaneously ligated 2 cm distally, the IR-SP content proximal to the ligature was reduced 50% to 1131 +/- 99 pg (P less than 0.01), while nodose ganglion content increased to 420 +/- 140 pg (n.s.). To confirm that residual transport following supranodose crush was derived from nodose ganglion-synthesized SP, SP synthesis and transport were studied in explants of nodose ganglion and attached distal vagus nerve removed from perfused animals and maintained in vitro for up to 24 h. At the time of resection, nerves were ligated 1.5 cm distal to the ganglion. Twenty-four hours following explantation, IR-SP content in proximal segments was 1022 +/- 142 pg vs 155 +/- 22 pg in unligated segments and 560 +/- 72 pg in the nodose ganglion. Accumulation in the proximal segment was time dependent. In separate experiments, [35S]methionine was added to explant medium and the explants maintained for varying time intervals. Nerve tissue was extracted and subjected to either serial reverse phase high performance liquid chromatography (HPLC), or immunoprecipitation with SP antiserum followed by a single HPLC separation. By 4 h, radiolabeled SP was present in nodose ganglia and lesser amounts in the proximal segments. By 12 h, [35S]SP was present equally in ganglia and proximal segments whereas by 18 h, two-thirds or more of the newly synthesized peptide was present in proximal segments. At 18 h, the quantity of radiolabeled SP covaried with IR-SP content in the individual nerve segments. The addition of cycloheximide to explant medium reduced [35S]SP synthesis by 90%. These studies demonstrate that: (1) approximately 50% of immunoreactive SP transported efferently within the vagus nerve of the guinea pig is derived from the nodose ganglion, (2) de novo SP synthesis within and export from the nodose ganglion occurs within 4 h, (3) the changes in IR-SP content demonstrated in in vivo and in vitro ligation studies accurately reflect ongoing SP synthesis within the nodose ganglion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Axoplasmic transport of somatostatin and substance P in the vagus nerve of the rat, guinea pig and cat.

The axoplasmic transport of somatostatin (SS) and substance P (SP) in the cervical vagus nerve was studied in the rat, guinea pig and cat. In preliminary studies, neuropeptide immunoreactivity (IR-SS and IR-SP) was evaluated in extracts of nodose ganglion and vagus nerve using gel and reverse-phase high-performance liquid chromatography (HPLC). In each species, a single immunoreactive form of SP co-eluted with the synthetic undecapeptide on a Bio-Gel P-10 column. More than 95% of transported vagal IR-SS co-eluted with synthetic SS-14. A small percentage in each species co-eluted with SS-28. No larger form, corresponding to a prosomatostatin, was identified in any of the 3 species. On HPLC, IR-SP and IR-SS co-eluted with their synthetic forms. To quantify neuropeptide transport, the vagus nerve was ligated distal to the nodose ganglion. 24 h later in each species, the content of IR-SS and IR-SP was more than 6 times greater in a 3-mm segment of nerve proximal to the ligature than in equal length segments distal to ligature or in the unligated contralateral nerve. In the proximal segment, the net content of IR-SP (pg/3-mm segment, mean +/- S.E.M.) was 366 +/- 45 in the rat, 2038 +/- 184 in the guinea pig, and 912 +/- 108 in the cat. The content of IR-SS in the same segment was 36 +/- 4, 66 +/- 13, and 575 +/- 59 pg/3-mm, respectively. The apparent transport velocities were similar for each peptide and among species. The contribution of the nodose ganglion to transported neuropeptide was estimated by crushing the vagus above the nodose ganglion and simultaneously ligating the nerve distal to the ganglion. The percent contribution of the ganglion to transported IR-SS following this procedure was 50% in the rat, 73% in the guinea pig, and 16% in the cat. Nodose ganglion contribution to IR-SP transport was 31%, 50% and 74%, respectively. Estimated turnover of IR-SS and IR-SP within the ganglion ranged from 4.1 to 6.8 times per 24 h in each species.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Studies of the axoplasmic transport of somatostatin in the vagus nerve of the rat.

These studies were performed to examine the axoplasmic transport of somatostatin (SS) in the cervical vagus nerve of the rat. As a preliminary step, the immunoreactive SS (IR-SS) obtained from extracts of the vagal nodose ganglion and the vagus nerve was subjected to chromatographic analysis. On a Bio-Gel P-10 column, 92% of the nodose ganglion IR-SS and 98% of the vagal IR-SS coeluted with synthetic SS-14. The remaining immunoreactivity in both areas coeluted with synthetic SS-28. Vagal IR-SS demonstrated migratory characteristics identical to those of synthetic SS-14 on high performance liquid chromatography. A larger molecular weight form of IR-SS, which may correspond to prosomatostatin, was not identified in either site. When the vagus nerve was ligated distal to the nodose ganglion, the content of IR-SS increased in a time-dependent manner in the 3-mm segment of nerve proximal to the ligature. No increase in IR-SS was observed in an equal segment of nerve distal to the ligation or in the unligated contralateral nerve. Twenty-four hours after the ligation, the content of IR-SS (picograms per 3 mm; mean +/- SD) was: proximal segment, 33.9 +/- 9.6; distal segment, 3.4 +/- 3.0; and contralateral nerve, 1.7 +/- 0.7. The apparent transport velocity of IR-SS was estimated to be 2.1 +/- 1.5 mm/h. A variety of experimental approaches were used to characterize the mechanisms underlying the transport process and to define the anatomical sites of origin of the transported peptide. The application of colchicine to the vagus nerve resulted in an accumulation of IR-SS above the area which was not significantly different from that obtained after nerve ligation. When the vagus nerve was crushed above the nodose ganglion, the accumulation of IR-SS in the proximal segment was reduced by 50%, although the IR-SS content in the nodose ganglion and in the intervening nerve segments was unchanged by this procedure. The induction of a chemical sympathectomy with guanethidine had no effect on the accumulation of IR-SS. The administration of capsaicin during the neonatal period or in adult life had no effect on the transport of IR-SS, but greatly decreased the transport of substance P.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

The rat LTW(m) Leydig cell tumor: cancer anorexia due to estrogen.

Anorexia occurs in male rats bearing transplantable LTW(m) Leydig cell tumors. Previous studies had shown that this tumor caused decreased food consumption and weight loss within 2 weeks of implantation. Additional studies reported here demonstrate that this tumor had little anorectic effect in female rats, and that male rats with LTW(m) tumors had elevated concentrations of circulating estradiol and low levels of testosterone. The tumor was also anorexigenic in castrated male rats. Exogenous estrogen given in the form of sc implanted pellets of estradiol reduced weight gain in male rats in proportion to the dose of estradiol. Weight gain was reduced when the plasma estradiol concentration was as low as 49 +/- 3 pg/ml; control estradiol levels were 25 +/- 4 pg/ml. Similar effects were observed in male Zucker fatty rats. It was further demonstrated that the tumor is anorexigenic in ventromedial hypothalamus-lesioned rats, an effect previously observed in ventromedial hypothalamus-lesioned rats given exogenous estradiol. Carcass analysis revealed that tumor-bearing rats used a metabolic fuel mixture containing a higher percentage of fat-derived substrates compared to nonimplanted controls, suggesting that altered fuel utilization may contribute to the decreased weight gain of tumor-bearing rats. We conclude that the circulating substance responsible for LTW(m) tumor-induced anorexia in male rats is likely to be an estrogenic steroid.

Animals↗

PubMed1981

Normal immunoregulation of in vitro antibody secretion in autoimmune thyroid disease.

Defective suppressor cell function may be a causative factor in autoimmune disease in animals and man. In autoimmune thyroid disease, decreased suppressor cell activity could, under appropriate conditions, account for excess production of thyroid autoantibodies. We evaluated suppressor cell function in patients with Graves' disease and Hashimoto's thyroiditis and in normal controls. The method used is based on the principle that immunoglobulin synthesis by pokeweed mitogen (PWM)-stimulated lymphocytes is inhibited by Concanavalin A (Con A) stimulation of suppressor T cells. We studied suppressor cell control of polyclonal immunoglobulin G (IgG) and the thyroid-specific autoantibody, antimicrosomal antibody. PWM-stimulated IgG secretion (mean +/- SD) by lymphocytes from patients with Graves' disease (2797 +/- 718 ng/ml) and Hashimoto's thyroiditis (2201 +/- 423 ng/ml) did not differ from normal subjects (2431 +/- 485 ng/ml). The addition of Con A to PWM-stimulated lymphocytes suppressed IgG production in all three groups: Graves', 475 +/- 137 ng/ml; Hashimoto's, 507 +/- 74 ng/ml; and normal subjects, 460 +/- 156 ng/ml. The degree of suppression by the disease groups did not differ from the normal controls. Antimicrosomal antibody was detected in the concentrated, PWM-stimulated culture media of two of four Hashimoto's lymphocytes, three of five Graves' lymphocytes, and none of nine normal controls. Con A induced marked suppression of this organ-specific antibody in all cases. We conclude that Con A-stimulated lymphocytes from patients with Hashimoto's thyroiditis and Graves' disease can suppress antimicrosomal antibody and polyclonal IgG synthesis. These findings do not support the postulate of a generalized defect of suppressor cell function in these thyroid disorders.

Adult↗

PubMed1974