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Biomedical subjects

E E Müller

Publications and source records attributed to E E Müller.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effects of recombinant human insulin-like growth factor I administration on spontaneous and growth hormone (GH)-releasing hormone-stimulated GH secretion in anorexia nervosa.

Exaggerated GH and reduced insulin-like growth factor I (IGF-I) levels are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 +/- 0.6 kg/m2] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0 microg/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 microg/kg, sc) significantly reduced mGHc in AN (P < 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups; mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P < 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P < 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.

Adolescent↗
PubMed1999

Effect of somatostatin infusion on the somatotrope responsiveness to growth hormone-releasing hormone in patients with anorexia nervosa.

BACKGROUND: According to the existence in anorexia nervosa (AN) of peripheral growth hormone (GH) resistance, low circulating insulinlike growth factor I (IGF-I) levels may be coupled with GH hypersecretion; however, there is also evidence for alterations in the neural control of GH secretion. In fact, reportedly GH secretion is partially refractory to the inhibitory effect of muscarinic cholinergic antagonists as well as to the stimulatory effect of muscarinic cholinergic agonists, which act via opposite modulation of hypothalamic somatostatin (SS) release. Thus, somatostatinergic activity could be impaired in AN. This could be due to an impaired hypothalamic SS release or, alternatively, an altered somatotroph sensitivity to SS. METHODS: We studied in 10 women with AN in acute phase (AN, age, mean +/- SEM: 18.7 +/- 0.8 years) the effect of exogenous SS1-14 (25 and 75 micrograms/hour i.v., infused from +15 to +75 min), at doses that had previously been shown capable of increasing circulating SS levels within the physiological range, on the GH response to GH-releasing hormone (GHRH) (1 microgram/kg i.v. at 0 min). The same study protocol was performed in 8 normal age-matched women (NW, 22.9 +/- 1.0 years). RESULTS: In AN patients, IGF-I levels were lower (p < .01) than those in NW, while basal GH levels were similar in both groups. The GHRH-induced GH rise in AN was higher (p < .01) than that in NW. In AN, the exaggerated GH response to GHRH was inhibited to the same extent by both SS doses (p < .05) and became similar to that after GHRH alone in NW. In NW both 25 and 75 micrograms/hour SS decreased the GHRH-induced GH response; however, the inhibitory effect of the lower dose did not attain statistical significance, whereas the higher dose did (p < .02). During SS infusion, the GHRH-induced GH response in NW was persistently lower (p < .02) than that in AN. The percent inhibitory effect of SS on the somatotroph responsiveness to GHRH was similar in both groups at each dose. CONCLUSIONS: Our present findings demonstrate that the sensitivity of somatotroph cells to exogenous SS given at physiological doses is preserved in patients with AN. It is noteworthy that, during the infusion of physiological SS doses, the GH response to GHRH in AN overlaps on that to GHRH alone under physiological conditions. Thus, in AN, the sensitivity of somatotroph cells to SS apparently being preserved, an impairment of somatostatinergic neurons cannot be ruled out.

Adolescent↗
PubMed1999

Nitric oxide modulation of the growth hormone-releasing activity of Hexarelin in young and old dogs.

The growth hormone (GH)-releasing activity of Hexarelin, a potent GH-releasing peptide (GHRP) analog, was evaluated in eight young (aged 1 to 6 years) and five old (10 to 16 years) beagle dogs pretreated with erythrityl tetranitrate, a liposoluble nitric oxide (NO) donor, and/or indomethacin, an inhibitor of cyclooxygenase enzymes, and N-nitro-L- or N-nitro-D-arginine methylester (L-NAME and D-NAME), active and inactive NO synthase (NOS) inhibitors, respectively. Erythrityl tetranitrate (0.3 mg x kg(-1) oral [p.o.]) strikingly potentiated Hexarelin-stimulated GH secretion (31.25 microg x kg(-1) intravenous [i.v.]) in both young (area under the time-concentration curve at 0 to 90 minutes AUC(0-90)] 878.50 +/- 267.02 v 1,994.04 +/- 434.20 ng x mL(-1) x h, P < .01) and aged animals (314.82 +/- 117.11 v 1,314.12 +/- 484.75 ng x mL(-1) x h, P < .01). The NO donor alone did not modify baseline GH levels in either young dogs (188.68 +/- 85.24 ng x mL(-1) x h) or old dogs (120.49 +/- 22.03 ng x mL(-1) x h). L-NAME (5 mg x kg(-1) x 2 i.v.) suppressed GH release induced by the peptide in young dogs (1,367.68 +/- 251.87 v 411.12 +/- 68.49 ng x mL(-1) x h, P < .01), but potentiated it in old dogs (314.73 +/- 117.10 v 1,103.97 +/- 374.11 ng x mL(-1) x h, P < .01). D-NAME (5 mg x kg(-1) x 2 i.v.) did not affect the GH response to Hexarelin in either young (1,328.68 +/- 433.54 ng x mL(-1) x h) or aged (342.32 +/- 84.82 ng x mL(-1) x h) dogs. Indomethacin (1.5 mg x kg(-1) i.m.) abolished the NO-donor potentiation of the GH response induced by Hexarelin in both young dogs (1,627.25 +/- 260.90 v 1,163.37 +/- 334.84 ng x mL(-1) x h, P < .05) and old dogs (1,061.47 +/- 210.38 v 365.69 +/- 79.27 ng x mL(-1) x h, P < .01) without affecting the plasma GH peak evoked by the peptide alone (young dogs, 786.04 +/- 153.44 v 960.04 +/- 444.44 ng x mL(-1) x h, P = NS; old dogs, 474.55 +/- 47.30 v 490.82 +/- 144.86 ng x mL(-1) x h, P = NS). In conclusion, (1) NO donors are capable to further increase the strong GH-releasing activity of Hexarelin in both young and old dogs, although the site(s) and mechanism(s) of action of NO is still obscure; (2) the different GH response to the peptide after NOS inhibition in young and old dogs signifies in the latter an alteration of the somatotrope function; and (3) prostaglandins are the downstream effectors of the chain of events triggered by activation of the NO-ergic system.

Aging↗
PubMed1999

Glycosaminoglycans boost insulin-like growth factor-I-promoted neuroprotection: blockade of motor neuron death in the wobbler mouse.

Wobbler mice display forelimb weakness, altered paw positioning, reduced running speed, muscle atrophy and motor neuron loss; co-treatment with glycosaminoglycans and insulin-like growth factor-I counteracts the progression of the disease. Reportedly, treatment with glycosaminoglycans or insulin-like growth factor-I slows the early stages of progressive forelimb dysfunction in wobbler mice. Our aim was to study whether the combination of these two drugs would result in greater neuroprotective effects. In a group of wobbler mice, combined treatment with daily s.c. administration of 20 microg/kg insulin-like growth factor-I and 1 mg/kg glycosaminoglycans was begun upon diagnosis at three weeks of age and continued for the next six weeks. This treatment halted motor neuron loss and markedly reduced the decay of forelimb muscle morphometry and function. Moreover, the mouse phenotype itself was strikingly improved. The effect of the combination treatment was significantly higher than that of the single drugs, even at a dosage as high as 1 mg/kg insulin-like growth factor-I. The ability of the insulin-like growth factor-I/glycosaminoglycans pharmacological cocktail to arrest the progression of motor neuron disease in wobbler mice and the safety of the low dose of insulin-like growth factor-I used hold promise that this combination might represent a novel approach for the treatment of motor neuron disease and peripheral neuropathies.

Aging↗
PubMed1999

Growth hormone and hexarelin prevent endothelial vasodilator dysfunction in aortic rings of the hypophysectomized rat.

The endothelial vasodilation mechanism(s) has been investigated in aortic rings of hypophysectomized male rats as well as hypophysectomized rats treated for 7 days with growth hormone (GH, 400 microg/kg, s.c.) or hexarelin (80 microg/kg, s.c.). Tissue preparations from intact animals were taken as controls. The results obtained indicate that the release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings of hypophysectomized rats was markedly reduced (51%; p<0.01) as compared with that of control preparations; the peak response to cumulative concentration of endothelin-1 (ET-1, from 10(-11) to 10(-5) M) was increased 2.4-fold (p<0.01) versus controls; the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) in norepinephrine-precontracted aortic rings was reduced by 39.5+/-4.4%. Pretreatment of hypophysectomized rats with GH or hexarelin markedly antagonized the hyperresponsiveness of the aortic tissue to ET-1 and allowed a consistent recovery of both the relaxant activity of ACh and the generation of 6-keto-PGF1alpha. Collectively these findings support the concept that dysfunction of vascular endothelial cells may be induced by a defective GH function. Because a replacement regimen of GH restored the somatotropic function and increased plasma insulin-like growth factor-I (IGF-I) concentrations in the hypophysectomized rats, it is suggested that IGF-I may have protected the vascular endothelium acting as a biologic mediator of GH action. In contrast to GH, hexarelin replacement neither increased body weight nor affected the plasma concentrations of IGF-I, indicating that its beneficial action on vascular endothelium was divorced from that on somatotropic function and was likely due to activation of specific endothelial receptors.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Neuroendocrine control of growth hormone secretion.

The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity. Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active, small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane domain receptors, whose natural ligands are not yet known.

Amino Acid Sequence↗
PubMed1999

Growth hormone-independent cardioprotective effects of hexarelin in the rat.

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 microg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 microg/kg sc) produced similar results, whereas administration of EP 51389 (80 microg/kg sc), another GH-releasing peptide that does not bind to the heart, was ineffective. In conclusion, we demonstrate that hexarelin prevents cardiac damage after ischemia-reperfusion, and that its action is not mediated by GH but likely occurs through activation of specific cardiac receptors.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Effects of recombinant human insulin-like growth factor I administration on growth hormone (GH) secretion, both spontaneous and stimulated by GH-releasing hormone or hexarelin, a peptidyl GH secretagogue, in humans.

The negative feedback exerted by insulin-like growth factor I (IGF-I) on GH secretion occurs at the pituitary, as well as the hypothalamic level, via stimulation of SS and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) administration inhibits basal GH secretion, at least in fasted humans, though its effect on the GH response to GHRH is still controversial. GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules that act on specific receptors at the pituitary and/or the hypothalamic level. Contrary to GHRH, the GH-releasing activity of GHS is strong, reproducible, and even partially refractory to inhibitory influences such as exogenous somatostatin. We studied the effects of rhIGF-I administration (20 microg/kg s.c. at 0 min) on GH secretion, either spontaneous or stimulated by GHRH (2 microg/kg i.v. at +180 min) or Hexarelin (HEX, 2.0 microg/kg i.v at +180 min), a GHS, in eight normal young women (age, mean +/- SEM, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m2). rhIGF-I administration increased IGF-I levels (peak vs. baseline: 420.3 +/- 30.5 vs. 274.4 +/- 25.3 microg/L, P < 0.05) within the physiological range from +120 to +300 min. No variation in glucose or insulin levels was recorded. rhIGF-I did not reduce spontaneous GH secretion [areas under curves (AUC)(0-300 min) 140.6 +/- 66.3 vs. 114.6 +/- 32.1 microg/L x h], whereas it inhibited the GH response to both GHRH (AUC(180-300 min) 447.7 +/- 159.4 vs. 715.9 +/- 104.3 microg/L x h, P < 0.05) and HEX (620.3 +/- 110.4 vs. 1705.9 +/- 328.9 microg/L x h, P < 0.03). The percent inhibitory effect of rhIGF-I on the GH response to GHRH (41.7 +/- 12.8%) was lower than that on the response to HEX (57.7 +/- 11.0%). In fact, the GH response to GHRH alone was clearly lower than that to HEX alone (P < 0.05), whereas the GH responses to GHRH and HEXwere similar after rhIGF-I. Our findings show that the sc administration of low rhIGF-I doses inhibits the GH response to GHRH and, even more, that to HEX; whereas, at least in this experimental design in fed conditions, it does not modify the spontaneous GH secretion. Because GHS generally show partial refractoriness to inhibitory inputs, including exogenous somatostatin, the present results point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.

Adult↗
PubMed1999

Somatostatin infusion withdrawal: studies in normal children and in children with growth hormone deficiency.

Withdrawal of a somatostatin infusion (SSIW) is followed by a rebound rise of GH in both animals and normal adult men, a phenomenon likely mediated by endogenous GHRH function. In the present study, we have evaluated the GH response to SSIW in a group of 28 prepubertal children (18 boys and 10 girls; aged 3.7-11.1 yr). Six children had GH deficiency [GHD; GH responses to pyridostigmine (PD)+GHRH and to clonidine <20 and <7 microg/L, respectively], 4 children had GH neurosecretory dysfunction (GHND; GH responses to PD+GHRH and to clonidine > or =20 and >7 microg/L, respectively; mean integrated nighttime GH concentrations <3 microg/L), and 18 children were short normal children [normal controls (NC)]. All children received a constant infusion of SS at the dose of 3 microg/Kg x h for 90 min. SSIW elicited a clear-cut GH rise in NC children (13.7+/-1.0 microg/L), but not in GH-deficient children, regardless of the underlying etiology (GHD, 1.6+/-0.4 microg/L; GHND, 2.4+/-0.3 microg/L). The GH response to SSIW was similar between GHD and GHND children. There was no overlapping of the maximum SSIW-stimulated GH peaks between NC and GHD or GHND children. In conclusion, we have demonstrated that SSIW elicits a significant GH rise in NC children, but not in GH-deficient children, regardless of the underlying etiology (GHD or GHND). This resulted in complete discrimination of NC from GHD or GHND children. Were these present findings confirmed on a larger number of children, SSIW, because of its testing efficaciousness and safety, procedural simplicity, and economy holds promise of being a useful diagnostic tool for GH-dependent growth disorders.

Adrenergic alpha-Agonists↗
PubMed1999

Six-week treatment with hexarelin in young dogs: evaluation of the GH responsiveness to acute hexarelin or GHRH administration, and of the orexigenic effect of hexarelin.

In this study we evaluated, in six young (5-7 year-old) beagle dogs, the effects of a 6-week administration of hexarelin (250 microg/kg s. c. twice daily) on the GH response to an acute challenge with hexarelin or GHRH (2 microg/kg i.v.), delivered before and after 3 and 6 weeks of treatment. The GH peak response to acute hexarelin or GHRH initially increased, with a maximum observed at the 3rd week, and then decreased to basal values (GHRH) or less (hexarelin) at the 6th week. These data would indicate that hexarelin initially primed the pituitary to acute administration of further hexarelin or of GHRH, followed by downregulation of the GH response to hexarelin and preservation of the response to GHRH. We then studied the rebound increase in GH secretion after withdrawal of an infusion of somatostatin (4 microg/kg per h for 1.5 h), a likely stimulus of endogenous GHRH function. The pattern obtained was similar to, though not superimposable upon, that ensuing after acute hexarelin or GHRH administration. Parallel evaluation of the acute orexigenic effect of hexarelin evinced a different time-course of the behavioural response, namely an acute feeding response to hexarelin that was abolished at the 3rd week and returned to normal at the 6th week. The differing timing of the neuroendocrine or behavioural response to hexarelin would suggest the existence of different subtypes of central nervous system GH-releasing peptide receptors.

Animals↗
PubMed1999

Leptin regulates GH secretion in the rat by acting on GHRH and somatostatinergic functions.

Leptin is a hormonal product of adipose tissue whose expression reflects the body state of nutritional reserves. Previous experiments have demonstrated that leptin is one of the metabolic signals capable of regulating GH secretion. The aim of the present study was to evaluate whether CNS-mediated mechanisms underlie the GH-releasing activity of leptin. Freely moving mature male rats were injected i.c.v with leptin or isovolumetric amounts of diluent once daily for 3 days and were killed 2 h after the last administration. Central injection of leptin increased pituitary GH mRNA levels by 53. 2% and hypothalamic GHRH mRNA by 61.8%, and reduced somatostatin mRNA levels by 41.5%. To evaluate the direct effect of leptin on the pituitary, it was added alone or in combination with GHRH to primary cultures of anterior pituitary cells. Addition of leptin (10(-11)-10(-7) M) did not alter basal GH release nor the GH-releasing activity of GHRH. These results demonstrate that leptin is a metabolic signal that regulates GH secretion in the rat by acting on hypothalamic GH-regulatory hormones.

Animals↗
PubMed1999

Elimination of viruses, phages, bacteria and Cryptosporidium by a new generation Aquaguard point-of-use water treatment unit.

The elimination of human viruses, phages, bacteria and Cryptosporidium oocysts by a new generation commercial Aquaguard purifier for the domestic treatment of drinking water, has been evaluated. The unit basically consists of a candle prefilter, activated carbon filter and ultraviolet irradiation compartment. Drinking water seeded with selected laboratory test strains of resistant micro-organisms was passed through the unit. Similar tests were carried out with sewage-contaminated river water and secondary treated waste water containing naturally occurring organisms. Test procedures were based on internationally accepted principles for the evaluation of point-of-use water treatment units, including a standard test protocol of the United States Environmental Protection Agency. Reduction in numbers of seeded test organisms at several log levels higher than those expected in water for which the unit is intended, was determined by the cultivation of viable organisms. In the case of seeded viruses and Cryptosporidium parvum oocysts the qualitative absence of nucleic acid was determined by the reverse transcriptase polymerase chain reaction (RT-PCR). At the design flow rate of one litre per minute, numbers of polio, hepatitis A, adeno types 2 and 41, rota SA11, human rota and astro viruses, as well as somatic and MS2 coliphages, and Escherichia coli, Streptococcus faecalis, Clostridium perfringens, total coliform bacteria, enterococci, heterotrophic bacteria and C. parvum oocysts, were reduced by more than 99.999% in all waters tested. This efficiency conforms to specifications for such units. The quality of the treated water was well within microbiological limits of international specifications for drinking water.

Animals↗
PubMed1998

Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release.

Growth hormone-releasing peptides (GHRPs) are a class of small peptides that stimulate growth hormone (GH) release in several animal species, including the human. Moreover, GHRPs injected into the brain ventricles stimulate feeding in the rat. The aim of this study was to evaluate the GH-releasing properties of a series of novel GHRP analogs and the possible existence of functional correlations between the GH-releasing activity and the effects on feeding behavior. Two well-known hexapeptides, GHRP-6 and hexarelin, given s.c., dose dependently stimulated both GH release and feeding behavior in satiated rats. However, in a series of tri-, penta- and hexapeptide analogs of hexarelin, some compounds were active either on GH release or on eating behavior. Interestingly, even minor structural modifications resulted in major changes of the pharmacological profile. We conclude that GHRPs have orexigenic properties after systemic administration which are largely independent from the effects they exert on GH release.

Animals↗
PubMed1998

Protectant activity of hexarelin or growth hormone against postischemic ventricular dysfunction in hearts from aged rats.

The ability of hexarelin, a recently synthesized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against postischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats. Heart preparations from control (saline-treated) senescent rats, subjected to moderate ischemia, showed at reperfusion: (a) a low recovery of postischemic left ventricular developed pressure (LVDP; 37% of the preischemic values; from 90 +/- 5.7 to 33.5 +/- 3.8 mm Hg; p < 0.01; n = 10) coupled to a substantial increase in coronary perfusion pressure (CPP; 71% over baseline; from 68.3 +/- 5.2 to 116.8 +/- 4.6 mm Hg; p < 0.01; n = 10); (b) a marked increase of creatine kinase (CK) released in the perfusates (6.6-fold increase over preischemic values; from 45 +/- 4 to 298 +/- 25 mU/min/g wet tissue; p < 0.001; n = 10). In vivo administration of hexarelin (80 microg/kg, b.i.d., s.c.) for 21 days resulted in a striking heart protection against reperfusion stunning. In fact, the recovery of LVDP at reperfusion was almost complete (90% of the preischemic values; from 93 +/- 5.8 to 83.7 +/- 5.9 mm Hg; p > 0.05; n = 9), and the increase in coronary resistance was minimal (from 67 +/- 5.8 to 79.7 +/- 6.9 mm Hg; p > 0.05; n = 9). Furthermore, the concentration of CK in the perfusates was increased only twofold (from 45.8 +/- 5.5 to 90 +/- 7.2 mU/min/g wet tissue; p < 0.05; n = 9), with a gradual return toward basal values at the end of reperfusion. The protectant activity of hexarelin was divorced from any detectable alteration of the somatotropic function, as assessed by pituitary GH messenger RNA (mRNA) and plasma insulin-like growth factor I levels. In vivo administration of GH (400 microg/kg b.i.d., s.c.) for the same time lapse resulted in only a partial protectant activity: 55% of LVDP recovery (from 91.5 +/- 6.2 to 50 +/- 3.5 mm Hg; p < 0.01; n = 6); 65% increase of coronary resistance (from 68 +/- 4.3 to 112.2 +/- 5.2 mm Hg; p < 0.01; n = 6); 5.3-fold increase of CK concentrations in heart perfusates on reperfusion (from 43.8 +/- 3.8 to 232 +/- 16 mU/min/g wet tissue; p < 0.001; n = 6). Evaluation of the rate of release of 6-keto-prostaglandin F1alpha (PGF1alpha), the stable metabolite of prostacyclin, in heart perfusates, and assessment of the vasopressor activity of angiotensin II on the coronary vasculature, did not show any change in these parameters among the three experimental groups. Collectively these data indicate that hexarelin displays a strong heart-protectant activity against myocardial stunning in senescent rats. The protection afforded by the peptide is likely due to a direct cardiotropic action and is far greater than that of GH. Neither compound appears able to interfere with the endothelium-dependent relaxant mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Intra- and postoperative myocardial ischemia without significant coronary artery stenosis.

A 73-year-old man without a history of coronary artery disease had two episodes of significant ST-segment elevation indicative of inferior myocardial ischemia during the resection of an abdominal aortic aneurysm. During the further course, sudden ST-segment elevations occurred and resolved spontaneously without preceding hemodynamic instability. The patient sustained two episodes of cardiac arrest due to ventricular fibrillation and intermittent third-degree atrioventricular block with ventricular asystole. On cardiac catheterization, coronary arteries had a right dominant pattern. The right coronary artery was entirely patent on multiple injections. Thus, right coronary artery spasm is the only possible explanation for these observations.

Aged↗
PubMed1998

Unexpected activation of pituitary-adrenal axis in healthy young and elderly subjects during somatostatin infusion.

In this study we explored, in man, the effect of acute attenuation of growth hormone (GH) release induced by somatostatin (SRIH) on ACTH and cortisol plasma levels. Sixteen young (8 women, aged 23-32 years, and 8 men, aged 18-27 years) and 14 elderly (8 women, aged 65-82 years, and 6 men, aged 65-70 years) healthy subjects volunteered to participate in this investigation. Each subject was tested on two separate occasions by: (1) a 90-min i.v. infusion of SRIH given in 50 ml 0.9% saline delivered at a rate of 9 microg/kg/h, and (2) a 90-min i.v. infusion of isovolumetric amounts of 0.9% saline. Plasma GH, ACTH, cortisol and glucose concentrations were determined prior and up to 180 min after SRIH or saline infusion. SRIH induced a significant (p < 0.05) decrease in plasma GH levels from basal values of 0.6 +/- 0.15 and 0.5 +/- 0.15 microg/l to nadir values 0.25 +/- 0.1 and 0.2 +/- 0.1 microg/l in young and elderly subjects, respectively. The administration of SRIH was associated with a clear-cut increase in plasma ACTH levels both in young (peak, 10.6 +/- 1.6 pmol/l; AUC, 558.6 +/- 147.5 pmol/l/h) and in elderly (peak, 21.3 +/- 5.6 pmol/l; AUC, 841.9 +/- 153.8 pmol/l/h) subjects with a significant (p < 0.01) difference as compared to saline infusion. Consistent with these results, SRIH infusion resulted in an unequivocal rise in plasma cortisol levels both in young (peak, 394.8 +/- 36.4 nmol/l; AUC, 18,591.62 +/- 1,372.45 nmol/l/h) and in elderly (peak, 585.6 +/- 51.5 nmol/l; AUC, 24,871.05 +/- 1,837.03 nmol/l/h) subjects. The ACTH and cortisol responses to SRIH were significantly (p < 0.05 and p < 0.01) higher in elderly than in young subjects. No sex-related differences occurred in the SRIH-induced activation of hypothalamic-pituitary-adrenocortical (HPA) axis. We conclude that (1) infusion of SRIH, at a dose that inhibited basal GH secretion, was associated with an activation of HPA axis, and (2) this response was higher in elderly individuals compared with younger adults. The reason for this novel and unexpected SRIH effect is presently unclear; however, the latter may be mediated, at least in part, by some central nervous system ACTH-releasing mechanisms activated by SRIH-induced decrease in GH secretion.

Adolescent↗
PubMed1998

Growth hormone responses to growth hormone-releasing hormone and hexarelin in fed and fasted dogs: effect of somatostatin infusion or pretreatment with pirenzepine.

Using unanesthetized young male and female beagle dogs, before and after a 2-day fast, we studied the effect of an i.v. infusion of 0.9% saline (5 ml/h), somatostatin (SS, 4 or 8 micrograms/kg/h), or pretreatment with pirenzepine (PZ, 0.6 mg/kg i.v.), a muscarinic cholinergic antagonist which allegedly releases SS, on the GH release evoked by acute administration of GHRH (2 micrograms/kg i.v.), hexarelin (HEXA), a member of the GH-releasing peptide family (250 micrograms/kg i.v.) or GHRH plus HEXA. In fasted dogs, GHRH delivered during saline infusion induced a clear-cut rise in plasma GH levels, significantly higher than that which it induced in fed dogs. In contrast, HEXA, although very effective in causing the release of GH, only slightly increased GH secretion in fasted dogs over that which it induced in fed dogs. Co-administration of GHRH plus HEXA into fed dogs induced a synergic GH response that further increased with fasting. The action of GHRH in fed dogs was abolished by the lower dose of SS, whereas SS at either dose was ineffective in suppressing the GH-releasing effect during fasting. Infusion of the lower dose of SS failed to counter the action of HEXA, either before or during fasting, whilst the higher SS dose partially reduced it in both conditions. In contrast to SS, PZ reduced the GH-releasing effect of GHRH and HEXA, both in the fed state and, though to a lesser extent, during fasting. Pirenzepine only slightly reduced the robust GH rise elicited by GHRH plus HEXA in fed dogs. The suppressive effect of PZ on the GH response to combined administration of the peptides was lowest in fasted dogs. These data show that: (1) fasting augmented the GH response to GHRH and (to a lesser degree) to HEXA; (2) SS inhibited the GH response to GHRH in the fed state, but not in the fasted state; (3) only the higher dose of SS partially reduced the GH stimulation by HEXA in either the fed or the fasted state; (4) PZ lowered the GH response to GHRH and to HEXA in both the fed and (to a lesser degree) the fasted state; (5) PZ did not modify the GH release due to the combined administration of GHRH and HEXA. It is suggested that: (1) during fasting the greatly enhanced GH response to GHRH alone or GHRH plus HEXA probably reflects an augmented GHRH secretion; (2) somatotrope refractoriness to SS may contribute to the enhanced GH secretion in states of calorie deprivation; (3) in contrast to a general belief, muscarinic cholinergic antagonists, e.g. PZ, do not act exclusively via release of SS, but probably also through inhibition of GHRH function.

Analysis of Variance↗