Biomedical subjects

E E Muller

Publications and source records attributed to E E Muller.

At least 19 recordsLinked to original sources

PubMed2006

TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity.

The vgf gene has been identified as an energy homeostasis regulator. Vgf encodes a 617-aa precursor protein that is processed to yield an incompletely characterized panel of neuropeptides. Until now, it was an unproved assumption that VGF-derived peptides could regulate metabolism. Here, a VGF peptide designated TLQP-21 was identified in rat brain extracts by means of immunoprecipitation, microcapillary liquid chromatography-tandem MS, and database searching algorithms. Chronic intracerebroventricular (i.c.v.) injection of TLQP-21 (15 mug/day for 14 days) increased resting energy expenditure (EE) and rectal temperature in mice. These effects were paralleled by increased epinephrine and up-regulation of brown adipose tissue beta2-AR (beta2 adrenergic receptor) and white adipose tissue (WAT) PPAR-delta (peroxisome proliferator-activated receptor delta), beta3-AR, and UCP1 (uncoupling protein 1) mRNAs and were independent of locomotor activity and thyroid hormones. Hypothalamic gene expression of orexigenic and anorexigenic neuropeptides was unchanged. Furthermore, in mice that were fed a high-fat diet for 14 days, TLQP-21 prevented the increase in body and WAT weight as well as hormonal changes that are associated with a high-fat regimen. Biochemical and molecular analyses suggest that TLQP-21 exerts its effects by stimulating autonomic activation of adrenal medulla and adipose tissues. In conclusion, we present here the identification in the CNS of a previously uncharacterized VGF-derived peptide and prove that its chronic i.c.v. infusion effected an increase in EE and limited the early phase of diet-induced obesity.

Adipose Tissue, Brown↗

PubMed2004

Elite volunteer athletes of different sport disciplines may have elevated baseline GH levels divorced from unaltered levels of both IGF-I and GH-dependent bone and collagen markers: a study on-the-field.

Seventy-seven Italian eliteathletes(42 M, 35 F, mean age +/- SE: 24.4-0.7 yr, age range: 17-47 yr) of different sport disciplines (sprinters, triathletes, middle-distance runners, road-walkers, cyclists, rowing athletes, skiers, roller hockey players, swimmers) were sampled on-the-field (before a training session) for the determination of basal GH, IGF-I, C-terminal cross-linked telopeptide of type I collagen (ICTP) and amino-terminal propeptide of type III procollagen (PIIINP) levels, two GH-dependent peripheral markers of bone and collagen turnover, respectively. Basal GH concentrations were significantly higher (p<0.001) in female (5.8 +/- 1.0 ng/ml) vs male athletes (1.8 +/- 0.5 ng/ml), with a large spread of values in either gender. Mean GH levels of athletes were significantly higher than those recorded in age-matched sedentary controls (females: 2.5 +/- 0.5 ng/ml, p<0.001; males: 0.5 +/- 0.2 ng/ml, p<0.05). Among female athletes, 7/35 had basal GH values higher than the upper limit of control values (>9.5 ng/ml), while among males 7/42 had values higher than the upper limit of male sedentary controls (>3.6 ng/ml). No significant differences in basal GH concentrations were found between females taking oral contraceptives (OC) and those who did not receive this treatment (5.0 +/- 2.1 vs 6.0 +/- 1.2 ng/ml). IGF-I levels (236.4 +/- 7.8 ng/ml) were in the normal range for age in all athletes (except for 1 athlete with slightly increased levels), no significant correlation being found between GH and IGF-I levels (R2=0.0393). Mean ICTP (4.6 +/- 0.2 ng/ml) and PIIINP (4.4-0.1 ng/ml) concentrations of elite athletes were not significantly different from those recorded in age and matched healthy sedentary subjects; 4 athletes showed increased PIIINP levels and 2 had increased ICTP levels. ICTP and PIIINP levels were positively correlated with chronological age (p<0.001), a positive correlation being also found between the two markers (p<0.001). On the contrary, no significant correlation was found between basal GH/IGF-I levels and ICTP/PIIINP levels. In conclusion, the present study demonstrates that: 1) elite athletes (particularly females), which have frequently increased basal GH on-the-field, have actually normal IGF-I levels; 2) ICTP and PIIINP levels of athletes are similar to those recorded in healthy sedentary, being significantly higher in younger subjects of both groups; 3) the presence of increased basal GH levels, being associated with normal IGF-I, ICTP and PIIINP levels, is probably the result of a transient GH peak in this study group. Further additional studies are requested to verify the possible use of these peripheral GH-dependent markers for detecting exogenous chronic administration of recombinant GH in athletes.

Adolescent↗

PubMed2004

Characterization of the resistance to the anorectic and endocrine effects of leptin in obesity-prone and obesity-resistant rats fed a high-fat diet.

Leptin produced by adipocytes controls body weight by restraining food intake and enhancing energy expenditure at the hypothalamic level. The diet-induced increase in fat mass is associated with the presence of elevated circulating leptin levels, suggesting the development of resistance to its anorectic effect. Rats, like humans, show different susceptibility to diet-induced obesity. The aim of the present study was to compare the degree of leptin resistance in obesity-prone (OP) vs obesity-resistant (OR) rats on a moderate high-fat (HF) diet and to establish if the effects of leptin on hypothalamo-pituitary endocrine functions were preserved. Starting from 6 weeks after birth, male Sprague-Dawley rats were fed on either a commercial HF diet (fat content: 20% of total calorie intake) or a standard pellet chow (CONT diet, fat content: 3%). After 12 weeks of diet, rats fed on HF diet were significantly heavier than rats fed on CONT diet. Animals fed on HF diet were ranked according to body weight; the two tails of the distribution were called OP and OR rats respectively. A polyethylene cannula was implanted into the right ventricle of rats 1 week before central leptin administration. After 12 weeks of HF feeding, both OR and OP rats were resistant to central leptin administration (10 mug, i.c.v.) (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 62 [50; 78]; OR, 93 [66; 118]; OP, 90 [70; 120] as medians and 95% confidence intervals (CIs) of six rats for each group). Conversely, after 32 weeks of diet both OR and OP rats were partially responsive to 10 mug leptin i.c.v. as compared with CONT rats (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 60 [50; 67]; OR, 65 [50; 80]; OP, 80 [60; 98] as medians and 95% CIs of six rats for each group); the decrease of food intake following 200 mug leptin i.p. administration was similar in all the three groups (calorie intake as a percent of vehicle-treated rats: 86 [80; 92] as median and 95% CI). The long-term intake of HF diet caused hyperleptinemia, hyperinsulinemia and higher plasma glucose levels in OP rats as compared with CONT rats. Plasma thyroxine (T4) was lower in all the rats fed the HF diet as compared with CONT. i.c.v. administration of leptin after 32 weeks of diet restored normal insulin levels in OP rats. Moreover, leptin increased plasma T4 concentration and strongly enhanced GH mRNA expression in the pituitary of OP as well as OR rats (180+/-10% vs vehicle-treated rats). In conclusion, long-term intake of HF diet induced a partial central resistance to the anorectic effect of leptin in both lean and fat animals; the neuroendocrine effects of leptin on T4 and GH were preserved.

Animals↗

PubMed2003

The GABAB receptor and recognition memory: possible modulation of its behavioral effects by the nitrergic system.

Functional activation of the GABA(B) receptor inhibits learning and memory processes, though discrepant findings, in this context, have also been reported. The present study was designed to investigate the role of the GABA(B) receptor on recognition memory in the rat. For this purpose, the effects induced by the GABA(B) agonist baclofen and the GABA(B) antagonist P-(3-aminopropyl)-P-diethoxymethylphosphinic acid (CGP 35348) on memory were assessed by using the object-recognition task. In addition, the possible involvement of the nitrergic system on GABA(B) receptor's effects was also evaluated by using the same behavioral procedure. This is a working-memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, baclofen (0.5, 2, and 4 mg/kg, i.p.), dose-dependently impaired animals' performance in this task, suggesting a modulation of acquisition and storage of information. CGP 35348 (100 and 300 mg/kg, i.p.), counteracted these baclofen-induced performance deficits. The nitric oxide donor molsidomine, at the dose of 4 but not 2 mg/kg, i.p, successfully antagonized the deficits on cognition induced by the highest dose of baclofen (4 mg/kg). These results indicate a) that the GABA(B) receptor is involved in recognition memory and b) that an NO component modulates the effects of the GABA(B) receptor on learning and memory.

Animals↗

PubMed2003

Long-term effects on bone of postnatal immunization against GHRH in female and male rats.

The effects of neonatal passive immunization against GHRH on bone was examined in male and female rats. Pups were treated subcutaneously with GHRH-antiserum (GHRH-Ab) from day 1 to day 10 of age. Bone mineral content (BMC) and bone mineral density (BMD) were evaluated at monthly intervals until 7 months. Markers of bone resorption (urinary lysylpyridinoline, LP), bone formation (serum osteocalcin, OC) and serum IGF-I were measured at 2, 3 and 7 months. In male rats, GHRH-Ab did not modify BMC and BMD when compared with controls. In contrast, female rats demonstrated lower whole body and femoral BMC and BMD from 2 to 7 months of age. Reduced bone growth in the females was associated with lower IGF-I levels than controls at 2 and 3 months of age, whereas in males IGF-I titers did not change during the period of the study. LP excretion was higher in GHRH-Ab-treated rats at 2 and 3 months in both sexes. In females, no difference in OC values was recorded, whereas in GHRH-Ab-treated males, there was an increase in OC levels at 2 and 3 months. These data indicate that transient GHRH deprivation induces an osteopenic effect in female rats which is not evident in male rats.

Amino Acids↗

PubMed2002

Bone effects of hexarelin, a GH-releasing peptide, in female rats: influence of estrogen milieu.

OBJECTIVE: The present study was performed to evaluate the potential influence of the estrogen milieu in modulating the effects of GH/IGF stimulation by a GH-releasing peptide, hexarelin (HEXA), on bone metabolism and mineral density in middle-aged female rats. METHODS: HEXA was administered for 60 days (50 microg/kg s.c. twice a day) to intact and ovariectomized (OVX) 11-month-old female rats and changes in bone parameters were evaluated with respect to those of the same rats under baseline conditions and with those of control rats (intact and OVX) administered isovolumetric amounts of physiological saline. Serum total alkaline phosphatase (ALP) and urinary deoxypyridinoline (Dpd) were measured before and at various times during HEXA treatment. Bone mineral content (BMC) and density of lumbar vertebrae and femoral mid-diaphyses were measured by dual energy X-ray absorptiometry before and after treatment. In all groups, serum IGF-I levels were determined before and during treatment and the GH secretory response to HEXA was assessed at the end of the experiment. RESULTS: In intact rats, HEXA did not modify Dpd urinary excretion, induced a trend toward an increase of serum ALP activity and significantly increased BMC (+6.5%) and bone area (+4.1%) only at lumbar vertebrae. In OVX rats, HEXA did not modify the OVX-induced increase in bone turnover markers (Dpd and ALP) and did not affect the OVX-induced vertebral bone loss, but significantly increased BMC (+7.2%) and bone area (+5.3%) at femoral mid-diaphyses. HEXA significantly increased serum IGF-I levels at day 14, but not at day 60, in both intact and OVX rats, whereas the GH secretory response to HEXA was higher in the former than in the latter. CONCLUSIONS: Overall, the present data demonstrate that chronic HEXA treatment increases BMC and bone area at lumbar vertebrae in intact rats and at femoral diaphyses in OVX rats. The different sensitivity to HEXA of the skeletal districts examined is related to the estrogen milieu and may reflect a complex interplay between estrogens and GH/IGF function.

Animals↗

PubMed2001

Glycosaminoglycan-promoted muscle reinnervation and insulin-like growth factor-I levels are affected by anti-growth hormone-releasing hormone exposure.

The present study shows that exposure to antibodies to growth hormone-releasing hormone (GHRH) partially counteracted the promoting effects of treatment with glycosaminoglycans (GAGs) on muscle reinnervation. Sciatic nerve crush was performed in 2-day-old rats, and reinnervation of the extensor digitorum longus muscle was monitored. The extent of reinnervation was rather poor in saline-treated rats, whereas in GAG-treated rats the extent of muscle reinnervation, the recovery of nerve-evoked muscle twitch tension, and the number of motor neurons reinnervating the extensor digitorum longus muscle were greatly enhanced. In addition, treatment with glycosaminoglycans increased markedly insulin-like growth factor-I (IGF-I) levels in denervated muscles. Both types of stimulatory action exerted by GAGs were affected by concomitant exposure to anti-GHRH, with abolition of IGF-I muscle increase and a smaller enhancement in muscle reinnervation.

Animals↗

PubMed2001

Effects of molsidomine on scopolamine-induced amnesia and hypermotility in the rat.

Nitric oxide (NO) is hypothesized to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit nitric oxide synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The aim of this study was to assess in the rat the effects of the NO donor molsidomine (2 and 4 mg/kg, i.p.) on memory deficits caused by scopolamine. For this purpose, the object recognition task and the step-through passive avoidance procedure were chosen. In addition, the effects of molsidomine in antagonizing the scopolamine-induced hypermotility were also examined. Scopolamine at 0.2 mg/kg (object recognition) and 0.75 mg/kg (passive avoidance) disrupted acquisition in both the tasks and induced locomotor hyperactivity at the dose of 0.2 mg/kg. Molsidomine at either dose reversed the scopolamine-induced deficits in the object recognition paradigm but did not counteract the hypermotility and the deficits occurred in the passive avoidance test. These results suggest that to some extent, the NO donor molsidomine is involved in memory processing.

Amnesia↗

PubMed2001

Penile erection induced by EP 80661 and other hexarelin peptide analogues: involvement of paraventricular nitric oxide.

The effect of GAB-D-Trp(2-Me)-D-Trp(2-Me)-LysNH(2) (EP 80661), GAB-D-Trp(2-Me)-D-Trp(2-Me)-D-Trp(2-Me)-LysNH(2) (EP 60761), GAB-D-Trp(2-Me)-LysNH(2) (EP 91071) and GAB-D-Trp(2-Me)-D-beta Nal-Phe-LysNH(2) (EP 50885), four hexarelin peptide analogues that induce penile erection when injected into the paraventricular nucleus of the hypothalamus of male rats, on the concentration of NO(2)(-) and NO(3)(-) in the paraventricular dialysate was studied in male rats. EP peptides (1 microg) induced penile erection and increased the concentration of NO(2)(-) and NO(3)(-) in the paraventricular dialysate. In contrast, hexarelin (1 microg) was ineffective on either penile erection or paraventricular NO(2)(-) and NO(3)(-). EP peptide-induced penile erection was prevented by the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methylester given into the paraventricular nucleus (20 microg), which also reduced the concomitant increase of NO(2)(-) and NO(3)(-) concentration in the paraventricular dialysate. In contrast, the oxytocin receptor antagonist [d(CH(2))(5)Tyr(Me)(2)-Orn(8)]vasotocin (1 microg) given into the paraventricular nucleus, was ineffective on penile erection and on the NO(2)(-) and NO(3)(-) increase induced by EP peptides, despite its ability to prevent the sexual response induced by the above peptides when given into the lateral ventricles. The present results show that EP peptides induce penile erection by activating nitric oxide synthase in the paraventricular nucleus of the hypothalamus, possibly in the cell bodies of oxytocinergic neurons that control penile erection.

Animals↗

PubMed2001

Recombinant human IGF-I does not modify the ACTH and cortisol responses to hCRH and hexarelin, a peptidyl GH secretagogue, in humans.

An inhibitory influence of insulin-like growth factor-I (IGF-I) on hypothalamus-pituitary-adrenal (HPA) axis has been hypothesized. In fact, it has been reported that the rhGH (recombinant human GH)-induced IGF-I increase inhibits both cortisol and GH response to MK-0677, a non-peptidyl GH secretagogue in animals. The aim of this study was to further clarify the inhibitory role, if any, of IGF-I on corticotroph function. We studied the effect of rhIGF-I (recombinant human IGF-I; 20 microg/kg s.c. at -180 min) or placebo on the ACTH and cortisol responses to hCRH (human CRH; 2.0 microg/kg i.v. at 0 min) or hexarelin (HEX; 2.0 microg/kg i.v. at 0 min), a peptidyl GHS, in normal young women. The effect of rhIGF-I on the GH response to HEX was also studied. The subjects were six normal young women [age: 26-35 yr; body mass index (BMI): 19-23 kg/m2] in their early follicular phase. The results showed that after s.c. rhIGF-I administration, circulating IGF-I levels increased approximately 77%, peaking at -60 min and persisting similar up to +120 min. The mean ACTH, cortisol and GH concentrations did not change from -180 to 0 min when evaluated after both placebo or rhIGF-I. CRH and HEX induced similar ACTH (peak vs baseline, mean+/-SE: 47.5+/-10.9 vs 21.3+/-3.0 pg/ml and 30.3+/-6.9 vs 19.2+/-3.8 pg/ml, respectively; p<0.04) and cortisol responses (177.5+/-5.4 vs 109.3+/-10.3 microg/l and 149.4+/-12.3 vs 119.8+/-16.4 microg/l, respectively, p<0.04). RhIGF-I pretreatment did not modify the ACTH and cortisol responses to hCRH (46.0+/-13.8 pg/ml and 181.1+/-16.9 microg/l, respectively) as well as those to HEX (28.8+/-5.0 pg/ml and 144.1+/-16.2 microg/l, respectively). On the other hand, the GH response to HEX was clearly reduced by rhIGF-I (23.9+/-4.7 vs 64.7+/-14.8 microg/l, p<0.05). Our findings show that rhIGF-I-induced increase of circulating IGF-I levels exerts negative feedback action on somatotroph secretion, while it does not modify the corticotroph and the adrenal responsiveness to CRH or hexarelin.

Adrenocorticotropic Hormone↗

PubMed2001

Effect of IGF-I administration on growth hormone secretion in obese subjects.

OBJECTIVE: The reduction of spontaneous and stimulated growth hormone (GH) secretion in obesity could reflect an increase of the inhibitory effect of insulin growth factor I (IGF-I) on somatotroph secretion. DESIGN: In the present study we aimed to verify the effect of low dose recombinant human IGF-I (20 microg/kg subcutaneously (s.c.) at 0 min) on 3 h-spontaneous GH secretion (mGHc, 0-180 min) and on the GH response to growth hormone releasing hormone (GHRH) (1 microg/kg i.v. at+180 min) in obesity. SUBJECTS: Five obese women with abdominal adiposity (OB, age, mean+/-s.e.m.: 31+/-7.13 y; BMI: 32.04+/-3.69 kg/m(2)) and eight age-matched lean women (NW, 28.3+/-1.2 y; 20.1+/-0.5 kg/m(2)) were studied. RESULTS: The mGHc and GHRH-induced GH response in OB (1.0+/-0.7 microg/l; AUC(180-270 min): 688.6+/-202.4 microg/l min, respectively) were lower than in NW (2.6+/-0.8 microg/l, 1315.9+/-189.9 microg/l min, respectively, P<0.05). The administration of rhIGF-I increased circulating IGF-I levels in OB and NW to the same extent (339.0+/-50.39 and 420.3+/-30.5 microg/l, respectively). The rhIGF-I administration did not affect mGHc in OB or NW (1.1+/-0.9 and 3.2+/-1.0 microg/l, respectively) but inhibited (P<0.05) the GH response to GHRH in OB (324.2+/-153.1 microg/l) and NW (730.2+/-288.1 microg/l). CONCLUSIONS: Our study shows that the administration of low dose rhIGF-I reduces the somatotroph responsiveness to GHRH in obesity as well as in normal subjects.

Adult↗

PubMed2001

Effects of recombinant human insulin-like growth factor I administration on the growth hormone (gh) response to GH-releasing hormone in obesity.

Circulating GH levels are reduced in obesity due to true reduction of the 24-h GH production rate. GH insufficiency in obesity might reflect neuroendocrine abnormalities and/or alterations in peripheral hormones and metabolic factors. The somatotroph response to provocative stimuli including GHRH is markedly blunted in obese patients. However, the somatotroph responsiveness to GHRH in obesity shows also peculiar refractoriness to the inhibitory effect of glucose load. In this present study we aimed at verifying the effect of low dose rhIGF-I (20 microgram/kg, sc, at 0 min) on the GH response to GHRH (1 microgram/kg, iv, at 180 min) in obesity. With this goal in mind, six obese women with abdominal adiposity [OB; age (mean +/- SEM), 32.3 +/- 4.4 yr; body mass index, 32.8 +/- 2.3 kg/m(2)] were studied. The effects of recombinant human insulin-like growth factor I (rhIGF-I) administration on circulating total IGF-I, insulin, and glucose levels were also evaluated. The results in OB were compared with those recorded in age-matched lean women (NW; age, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m(2)), in whom the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I levels in OB were similar to those in NW (199.7 +/- 33.3 vs. 274.4 +/- 25.3 microgram/L). The mean GH concentration over 3 h (from 0-180 min) in OB was lower than that in NW (0.9 +/- 0.4 vs. 2.6 +/- 0.8 microgram/L; P = NS). Administration of GHRH induced a GH response in OB lower than that in NW (area under the curve from 180-270 min, 576.5 +/- 137.5 vs. 1315.9 +/- 189.9 microgram/L.min; P < 0.02). Administration of rhIGF-I increased circulating IGF-I levels in both groups to the same percent extent (326.8 +/- 28.3 and 420.3 +/- 26.5 microgram/L in OB and NW, respectively). rhIGF-I administration inhibited the GH response to GHRH in OB (240.1 +/- 99.6 microgram/L; P < 0.05) as well as in NW (730.2 +/- 288.1 microgram/L; P < 0.05), although it failed to lower the mean GH concentration over 3 h in either OB or NW. After rhIGF-I the GH response to GHRH in OB was slight and was still lower (P < 0.05) than that in NW; in fact, the percent decreases were similar in both groups (44.21 +/- 14.06 and 48.21 +/- 13.95 microgram/L, in OB and NW, respectively). The mean insulin (107.1 +/- 21.9 and 36.8 +/- 7.2 pmol/L), but not glucose (4.0 +/- 0.3 and 4.1 +/- 0.1 mmol/L), levels calculated over 270 min, were higher (P = 0.005) in OB than in NW; rhIGF-I administration did not modify insulin and glucose levels in either group. Our study shows that the sc administration of a low rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese as well as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect of rhIGF-I is preserved in obesity.

Abdomen↗

PubMed2001

Effects of diet on the development of Schistosoma mansoni in Biomphalaria glabrata and on the neutral lipid content of the digestive gland-gonad complex of the snail.

In a previous study, when the snail Biomphalaria glabrata was infected with Schistosoma mansoni and maintained on a diet of hen's egg yolk, it produced fully developed cercariae in about one-half the time taken by snails fed Romaine lettuce. Increased lipids were also noted in the snails fed the yolk diet. The purpose of the present study was to further investigate nutritional effects of a high-lipid diet on larval schistosome development and to reexamine the time to cercarial patency in infected snails maintained on either the yolk or lettuce diet and to use high-performance thin-layer chromatography (HPTLC) to analyze the neutral lipids in the digestive gland-gonad complex (DGG) of snails maintained on both diets. Infected snails maintained at 26 C and fed either diet produced fully developed cercariae by 4 wk postinfection (PI). Likewise, infected snails maintained at 23 C and fed either diet produced fully developed cercariae by 6 wk PI. The contention that the yolk diet enhanced the time to cercarial patency was not confirmed. The HPTLC analysis of neutral lipids showed that the DGG of infected snails fed the yolk diet contained significantly greater amounts of free sterols and cholesteryl esters but not triacylglycerols than that of the infected snails fed the lettuce diet.

Animals↗

PubMed2000

EP 60761 and EP 50885, two hexarelin analogues, induce penile erection in rats.

The effect of hexarelin and four related peptide analogues, EP 40904, EP 40737, EP 50885 and EP 60761, injected into the paraventricular nucleus of the hypothalamus of male rats in doses between 2 and 2000 ng on spontaneous penile erection was studied. Of these peptides, EP 60761 and EP 50885, but not hexarelin, EP 40904 or EP 40737, increased dose-dependently the number of spontaneous penile erections. EP 60761 was active already at the dose of 20 ng, which induced the sexual response in 70% of the treated rats. The maximal response was induced by 200 ng of the peptide. EP 50885 was less potent than EP 60761, with 1000 ng being the minimal effective dose and 2000 ng as the dose required to induce the maximal response. At the doses used, both peptides also increased slightly the number of spontaneous yawning episodes. EP 60761- and EP 50885-induced penile erection was prevented by the oxytocin receptor antagonist [d(CH(2))(5)Tyr(Me)(2)-Orn(8)]vasotocin (0.1-1 microg) given intracerebroventricularly (i.c.v.), but not into the paraventricular nucleus (0.1-1 microg), by the competitive nitric oxide (NO) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) given either into the paraventricular nucleus (10-20 microg) or i.c.v. (75-150 microg), by the N-type Ca(2+) channel blocker omega-conotoxin-GVIA (2-5 ng) or by the opiate morphine (1-10 microg), but not by the dopamine receptor antagonist (Z)-4-[3-[2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl]-1-p ipe razine-ethanol (cis-flupenthixol) (10 microg) or by the N-methyl-D-aspartic acid (NMDA) receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ((+)-MK-801) (1 microg), all given into the paraventricular nucleus before either peptide. The present results show that EP 60761 and EP 50885 induced penile erection by increasing central oxytocin transmission, possibly by activating NO synthase in the cell bodies of oxytocinergic neurons located in the paraventricular nucleus that control penile erection.

Animals↗

PubMed2000

EP 60761- and EP 50885-induced penile erection: structure-activity studies and comparison with apomorphine, oxytocin and N-methyl-D-aspartic acid.

The effect of 10 peptides structurally related to the growth hormone (GH) releasing peptide hexarelin, injected into the paraventricular nucleus of the hypothalamus (PVN), on penile erection was studied in male rats. Six out of the 10 peptides tested induced penile erection in a dose-dependent manner. Among them, the most potent were EP 80661, EP 60761 and EP 91072, which were active at doses of 20-200 ng. The potency of these peptides in inducing penile erection is comparable to that of apomorphine, oxytocin and N-methyl-D-aspartic acid similarly injected into the PVN. Other peptides found active were EP 50885, EP 90101 and EP 91071, which induced penile erection at doses of 200-2000 ng. In contrast, EP 51322, EP 70555, EP 51216 and EP 91073 were inactive, as were hexarelin, EP 40904 and EP 40737 in a previous study. The majority of EP peptides found active when injected into the PVN induced penile erection, although to a lesser extent, also when given systemically (endovenously). The proerectile effect of EP peptides was prevented by the oxytocin receptor antagonist [d(CH2)5 Tyr(Me)2-Orn8]-vasotocin given into the lateral ventricles but not into the PVN, by the nitric oxide (NO) synthase inhibitor N(G)-nitro-1-arginine methyl ester given either into the lateral ventricles or into the PVN, by the N-type Ca2+ channel blocker omega-conotoxin GVIA and by morphine, but not by the dopamine receptor antagonist cis-flupenthixol or by the N-methyl-D-aspartic acid receptor antagonist dizolcipine, given into the PVN. As the structure-activity relationship of EP peptides for proerectile activity is different from those of other biological actions of these compounds, ie for GH release and eating behaviour, the present results suggest that EP peptides induce penile erection by acting on specific hypothalamic receptor sites that activate paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas that mediate this sexual function by a mechanism similar to that of dopamine receptor agonists, oxytocin and N-methyl-D-aspartic acid.

Animals↗

PubMed2000

Arginine counteracts the inhibitory effect of recombinant human insulin-like growth factor I on the somatotroph responsiveness to growth hormone-releasing hormone in humans.

Insulin-like growth factor I (IGF-I) exerts a negative feedback effect on GH secretion via either direct actions at the pituitary level or indirect ones at the hypothalamic level, through stimulation of somatostatin (SS) and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) in humans inhibits spontaneous GH secretion as well as the GH response to GHRH and even more to GH/GH-releasing peptides, whose main action is on the hypothalamus, antagonizing SS and enhancing GHRH activity. The aim of the present study was to further clarify in humans the mechanisms underlying IGF-I-induced inhibition of somatotroph secretion. In six normal young volunteers (all women; mean +/- SEM: age, 28.3+/-1.2 yr; body mass index, 21.3+/-1.2 kg/m2) we studied the GH response to GHRH (1 microg/kg, iv, at 0 min), both alone and combined with arginine (ARG; 0.5 g/kg, iv, from 0-30 min), which probably acts via inhibition of hypothalamic SS release, after pretreatment with rhIGF-I (20 microg/kg, sc, at -180 min) or placebo. rhIGF-I increased circulating IGF-I levels (peak at -60 vs. -180 min: 54.9+/-3.9 vs. 35.9+/-3.3 mmol/L; P < 0.05) to a reproducible extent, and these levels remained stable and within the normal range until 90 min. The mean GH concentration over 3 h (from -180 to 0 min) before ARG and/or GHRH was not modified by placebo or rhIGF-I. After placebo, the GH response to GHRH (peak, 23.6+/-2.9 microg/L) was strikingly enhanced (P < 0.05) by ARG coadministration (69.6+/-9.9 microg/L). rhIGF-I blunted the GH response to GHRH (13.1+/-4.5 microg/L; P < 0.05), whereas that to GHRH plus ARG was not modified (59.5+/-8.9 microg/L), although it occurred with some delay. Mean glucose and insulin concentrations were not modified by either placebo or rhIGF-I. In conclusion, ARG counteracts the inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH in humans. These findings suggest that the acute inhibitory effect of rhIGF-I on the GH response to GHRH takes place on the hypothalamus, possibly via enhancement of SS release, and that ARG overrides this action.

Adult↗

PubMed2000

Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats.

Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 microgram, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in ! lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexare! lin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Glycosaminoglycans treatment increases IGF-I muscle levels and counteracts motor neuron death: A novel nonanticoagulant action.

The present study shows that sciatic nerve crush in 2-day-old rats causes extensor digitorum longus (EDL) muscle atrophy and motor neuron loss and that treatment with glycosaminoglycans (GAGs) promotes muscle reinnervation, motor neuron survival, and markedly increases insulin-like growth factor-I (IGF-I) content in the denervated muscles. EDL muscle denervation-induced atrophy in saline-treated rats is progressive and reaches the greatest extent at 42 days after birth, which correlates with reduced EDL weight growth. There is also a partial reinnervation as shown by the number of reinnervated EDL muscle fibers (65.4% of control) and by the poor restoration of the indirect isometric twitch tension (62% of control) that is further reduced under tetanic stimulation (34% of control). The number of surviving motor neurons that innervate EDL muscle drops from 55 +/- 3 to 29 +/- 8. In GAGs-treated 42-day-old rats, the effects of neonatal nerve lesioning on EDL muscle atrophy and denervation are successfully reversed, and the isometric twitch tension and the capacity to hold tetanic stimulation are restored to almost control levels. The number of surviving EDL motor neurons is also increased to 43 +/- 4. Treatment with GAGs selectively affects IGF-I content in denervated hindlimb muscles, which is augmented from 7.02 +/- 0.71 ng/mg tissue to 25.72 +/- 0.7 in the EDL and from 3.2 +/- 0.18 to a robust 211 +/- 9.6 in the soleus.

Animals↗