Exercise in hypertrophic cardiomyopathy is associated with sympatho-adrenal imbalance.
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Cardiomyopathy, Hypertrophic↗
Biomedical subjects
H Ong
Publications and source records attributed to H Ong.
Measurement of phosphorus content in normal and osteomalacic rabbit bone by solid-state 3D radial imaging.
In osteomalacia decreased mineralization reduces the stiffness and static strength of bone. We hypothesized that hypomineralization in osteomalacic bone could be quantified by solid-state (31)P magnetic resonance imaging (SS-MRI). Hypomineralization was measured with a 3D radial imaging technique at 162 MHz (9.4T) in rabbit cortical bone of hypophosphatemic (HY) and normophosphatemic (NO) animals. The results were compared with those obtained by quantitative micro-CT (micro-CT) and (31)P solution NMR. 3D images of 277 microm isotropic voxel size were obtained in 1.7 hr with SNR approximately 9. Mineral content was lower in the HY relative to the NO group (SS-MRI: 9.48 +/- 0.4 vs. 11.15 +/- 0.31 phosphorus wet wt %, P < 0.0001; micro-CT: 1114.6 +/- 28.3 vs. 1175.7 +/- 23.5 mg mineral/cm(3); P = 0.003). T(1) was shorter in the HY group (47.2 +/- 3.5 vs. 54.1 +/- 2.7 s, P = 0.004), which suggests that relaxation occurs via a dipole-dipole (DD) mechanism involving exchangeable water protons, which are more prevalent in bone from osteomalacic animals.
Anatomy, Cross-Sectional↗
Molecularly cloned SHIV-1157ipd3N4: a highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade C Env.
Human immunodeficiency virus type 1 (HIV-1) clade C causes >50% of all HIV infections worldwide, and an estimated 90% of all transmissions occur mucosally with R5 strains. A pathogenic R5 simian-human immunodeficiency virus (SHIV) encoding HIV clade C env is highly desirable to evaluate candidate AIDS vaccines in nonhuman primates. To this end, we generated SHIV-1157i, a molecular clone from a Zambian infant isolate that carries HIV clade C env. SHIV-1157i was adapted by serial passage in five monkeys, three of which developed peripheral CD4(+) T-cell depletion. After the first inoculated monkey developed AIDS at week 137 postinoculation, transfer of its infected blood to a naïve animal induced memory T-cell depletion and thrombocytopenia within 3 months in the recipient. In parallel, genomic DNA from the blood donor was amplified to generate the late proviral clone SHIV-1157ipd3. To increase the replicative capacity of SHIV-1157ipd3, an extra NF-kappaB binding site was engineered into its 3' long terminal repeat, giving rise to SHIV-1157ipd3N4. This virus was exclusively R5 tropic and replicated more potently in rhesus peripheral blood mononuclear cells than SHIV-1157ipd3 in the presence of tumor necrosis factor alpha. Rhesus macaques of Indian and Chinese origin were next inoculated intrarectally with SHIV-1157ipd3N4; this virus replicated vigorously in both sets of monkeys. We conclude that SHIV-1157ipd3N4 is a highly replication-competent, mucosally transmissible R5 SHIV that represents a valuable tool to test candidate AIDS vaccines targeting HIV-1 clade C Env.
Administration, Rectal↗
Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy.
BACKGROUND: Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy. METHODS AND RESULTS: We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro. Specific COX-2 but not COX-1 inhibitors prevented intravitreal neovascularization, whereas prostaglandin E2, mainly via its prostaglandin E receptor 3 (EP3), exacerbated neovascularization. COX-2 inhibition induced an upregulation of thrombospondin-1 and its CD36 receptor, consistent with the observed antiangiogenic effects of COX-2 inhibition; EP3 stimulation reversed effects of COX-2 inhibitors on thrombospondin-1 and CD36. CONCLUSIONS: These findings point to an important role for COX-2 in ischemic proliferative retinopathy, as in diabetes.
Adult↗
CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart.
Growth hormone-releasing peptides (GHRPs) are known as potent growth hormone secretagogues whose actions are mediated by the ghrelin receptor, a G protein-coupled receptor cloned from pituitary libraries. Hexarelin, a hexapeptide of the GHRP family, has reported cardiovascular activity. To identify the molecular target mediating this activity, rat cardiac membranes were labeled with a radioactive photoactivatable derivative of hexarelin and purified using lectin affinity chromatography and preparative gel electrophoresis. A binding protein of M(r) 84 000 was identified. The N-terminal sequence determination of the deglycosylated protein was identical to rat CD36, a multifunctional glycoprotein, which was expressed in cardiomyocytes and microvascular endothelial cells. Activation of CD36 in perfused hearts by hexarelin was shown to elicit an increase in coronary perfusion pressure in a dose-dependent manner. This effect was lacking in hearts from CD36-null mice and hearts from spontaneous hypertensive rats genetically deficient in CD36. The coronary vasoconstrictive response correlated with expression of CD36 as assessed by immunoblotting and covalent binding with hexarelin. These data suggest that CD36 may mediate the coronary vasospasm seen in hypercholesterolemia and atherosclerosis.
Animals↗
Permeability of the peptidic GH secretagogues hexarelin and EP 51389, across rat jejunum.
The intestinal permeability of hexarelin and EP 51389, two growth hormone releasing hexa- and tri- peptide analogues, was assessed in vitro with side-by-side diffusion chambers in the apical-to-basolateral (AP-to-BL) and in the basolateral-to-apical (BL-to-AP) direction using excised rat jejunal segments. The effect of EP 51389 on P-glycoprotein (P-gp) was evaluated by rhodamine 123 accumulation on monolayers of CH(R)C5 cells with increasing concentrations of EP 51389. Hexarelin and EP 51389 permeability were found to be < 1%. Permeability coefficients (P(app)) were 18.87 +/- 2.86 (x10(-7) cm/s) and 5.87 +/- 0.45 (x10(-7) cm/s) for hexarelin and EP 51389, respectively. Bidirectional studies revealed that hexarelin transport was similar in both directions. EDTA did not influence hexarelin permeability. Permeability was predominantly secretory for EP 51389 as P(app) in the BL-to-AP direction [32.56 +/- 6.11 (x10(-7) cm/s)] was greater than AP-to-BL. Confirming involvement of a secretory transport system, chlorpromazine inhibited EP 51389 transport across the jejunum. EP 51389 inhibited P-gp in a dose dependent manner resulting in the intracellular accumulation of rhodamine in CH(R)C5 cells. These results suggest that: 1) the intestinal permeability of hexarelin and EP 51389 is poor; 2) the passage of hexarelin is mainly via a transcellular passive pathway since the contribution of paracellular permeability to the overall permeability is rather low; 3) P-gp may act as a potential barrier for the intestinal absorption of EP 51389.
Animals↗
Increased incidence of sepsis and altered monocyte functions in severely injured type A- glucose-6-phosphate dehydrogenase-deficient African American trauma patients.
OBJECTIVE: To determine whether trauma patients with the common, type A- glucose-6-phosphate dehydrogenase (G6PD) deficiency have an aggravated inflammatory response, increased incidence of septic complications, and/or more profound alterations in leukocyte functions compared with nondeficient trauma patients. SETTINGS: Intensive and surgical care units of a trauma center and flow cytometry and experimental laboratories at a teaching university hospital. DESIGN: Prospective cohort clinical study with measurements on days 2 and 5 postinjury. Monocyte and neutrophil oxidant content, apoptosis, and CD11b expression and plasma cytokine levels were compared between G6PD-deficient and nondeficient patients. PATIENTS: A total of 467 male African American trauma patients were screened for the deficiency. Forty-four type A-202/376 G6PD-deficient patients were identified and enrolled in the study; 43 nondeficient patients were also enrolled and were matched by age, clinical criteria of injury severity, and type of trauma. MAIN RESULTS: After severe injury (Injury Severity Score, > or =16), 50% of the deficient and 6.2% of nondeficient patients developed sepsis with positive bacterial blood cultures. In deficient patients, the frequency of bronchial (75%) and wound infections (25%) was also increased compared with nondeficient patients (32% and 0%). The durations of systemic inflammatory response syndrome, Sepsis Syndrome, and days on antibiotics were three times longer in deficient than in nondeficient individuals. However, adult respiratory distress syndrome occurred in 37% of both groups. Anemia was more severe in the deficient than nondeficient patients from day 10 posttrauma. On day 5, the peroxide content was doubled, apoptosis was decreased, and CD11b expression was increased in monocytes from deficient patients compared with cells from nondeficient patients. On day 5, the plasma interleukin (IL)-10 concentration was significantly lower in deficient than nondeficient patients, whereas tumor necrosis factor-alpha, IL-6, and IL-8 levels were similar. After moderate injuries (Injury Severity Score, 9-16), the deficiency was not associated with adverse clinical effects, and the trauma-induced changes in leukocyte function were similar in deficient and nondeficient patients. CONCLUSIONS: The common type A- G6PD deficiency predisposes septic complications and anemia in trauma patients after severe injuries as defined by an Injury Severity Score of > or =16. This adverse clinical course is accompanied by altered monocyte functions manifested as augmented oxidative stress, a decreased apoptotic response, increased cell adhesion properties, and a diminished IL-10 response.
Adult↗
Immunofluorometric assay of human kallikrein 10 and its identification in biological fluids and tissues.
BACKGROUND: The human kallikrein 10 gene [KLK10, also known as normal epithelial cell-specific 1 gene (NES1)] is a member of the human kallikrein gene family. The KLK10 gene encodes for a secreted serine protease (hK10). We hypothesize that hK10 is secreted into various biological fluids and that its concentration changes in some disease states. The aim of this study was to develop a sensitive and specific immunoassay for hK10. METHODS: Recombinant hK10 protein was produced and purified using a Pichia pastoris yeast expression system. The protein was used as an immunogen to generate mouse and rabbit polyclonal anti-hK10 antisera. A sandwich-type immunofluorometric assay was then developed using these antibodies. RESULTS: The hK10 immunoassay has a detection limit of 0.05 microg/L. The assay is specific for hK10 and has no detectable cross-reactivity with other homologous kallikrein proteins, such as prostate-specific antigen (hK3), human glandular kallikrein 2 (hK2), and human kallikrein 6 (hK6). The assay was linear from 0 to 20 microg/L with within- and between-run CVs <10%. hK10 is expressed in many tissues, including the salivary glands, skin, and colon and is also detectable in biological fluids, including breast milk, seminal plasma, cerebrospinal fluid, amniotic fluid, and serum. CONCLUSIONS: We report development of the first immunofluorometric assay for hK10 and describe the distribution of hK10 in biological fluids and tissue extracts. This assay can be used to examine the value of hK10 as a disease biomarker.
Amino Acid Sequence↗
Kinetics and disposition of hexarelin, a peptidic growth hormone secretagogue, in rats.
To document the disposition of hexarelin, a peptidyl growth hormone secretagogue, male Sprague-Dawley rats received a 5-microg/kg bolus i.v. dose or three single s.c. doses of 5, 10, and 50 microg/kg. To assess hexarelin tissue distribution and excretion, rats were given 1 microg/kg of [(3)H]hexarelin (9.4 Ci/mmol). Metabolism of [(3)H]hexarelin was assessed in bile duct-exteriorized rats given 50 microg/kg where radiolabeled hexarelin biliary and urinary excretion was quantified. After its i.v. injection, hexarelin displayed a half-life of 75.9 +/- 9.3 min, a systemic clearance of 7.6 +/- 0.7 ml/min/kg, and a volume of distribution at steady state of 744 +/- 81 ml/kg. After s.c. administration, the area under the curve (477-3826 pmol.min/ml) estimated with increasing doses confirmed the absence of hexarelin accumulation. Clearance/F (12-15 ml/min/kg) and volume of distribution/F (1208-1222 ml/kg) were dose independent. Hexarelin bioavailability given s.c. was 64%. The highest radioactivity levels were detected in the kidney, liver, and duodenum. The pattern of hexarelin excretion was similar after i.v. or s.c. administrations. Total radioactivity in bile, urine, and feces corresponded to 60, 22, and 10% of the dose, respectively. Of the radioactivity excreted in bile and urine, 90 and 71% was unchanged hexarelin, respectively. These results suggest that: 1) the kinetics of hexarelin appear to be first order up to 50 microg/kg; 2) hexarelin is rapidly absorbed after s.c. administration; 3) biliary excretion is the primary route of hexarelin elimination; and 4) the high recovery of unchanged peptide in bile and urine demonstrates hexarelin stability toward proteolytic enzymes.
Animals↗
Identification and characterization of a new growth hormone-releasing peptide receptor in the heart.
Hexarelin, a synthetic hexapeptide of the growth hormone-releasing peptide (GHRP) family with strong growth hormone (GH)-releasing activity, features protecting activity against postischemic ventricular dysfunction in hearts from GH-deficient and senescent rats. To document whether hexarelin action is mediated through specific cardiac receptors, perfusion of Langendorff rat hearts with hexarelin and binding studies were carried out. In the Langendorff rat heart system, hexarelin induced a dose-dependent increase in coronary perfusion pressure. Nifedipine, chelerythrine, and bisindolylmaleimide partially inhibited the vasoconstriction induced by hexarelin, suggesting that this effect was mediated at least in part by L-type Ca(2+) channels and protein kinase C. In contrast, diclofenac and 1-(7-carboxyheptyl)imidazole were without effect, suggesting that prostaglandins and thromboxanes were not involved in the coronary vasoconstriction induced by hexarelin. To characterize the hexarelin binding sites in the rat heart, [(125)I]Tyr-Bpa-Ala-hexarelin was used as photoactivatable radioligand in saturation and competitive binding studies. We specifically labeled a hexarelin receptor with an M(r) of 84 000 in rat cardiac membranes. Saturation binding curves revealed a single class of binding sites with a K(d) of 14.5 nmol/L and a density of 91 fmol/mg of protein. Competition binding studies gave an IC(50) of 2.9 micromol/L for hexarelin; MK-0677 and EP51389, both potent GH secretagogues, did not displace the binding of the photoactivatable derivative from rat cardiac membranes. Interestingly, both compounds were devoid of any vasoconstrictive activity. These results suggest the existence of a new class of hexarelin receptor in the heart, whose role in the regulation of the coronary vascular tone is yet to be determined.
Animals↗
Cardiac effects of hexarelin in hypopituitary adults.
Growth hormone (GH)-releasing peptides possess specific pituitary, hypothalamic, and myocardial receptors. Seven adult male patients with GH deficiency (GHD) (age, mean+/-S.E.M.: 42.0+/-4.0 year) were studied by equilibrium radionuclide angiocardiography after i.v. administration of hexarelin, a peptide GH secretagogue. Data for these patients were compared with those for nine adult male controls (37.0+/-2.7 year). The GH response to hexarelin was negligible in patients with GHD compared to control subjects (CS) (peak: 1.9+/-0.9 vs. 45.7+/-3.6 microg/l, P<0.001). Basal left ventricular ejection fraction (LVEF) in patients with GHD was lower than that in CS (50+/-1% vs. 63+/-2%, P<0.001). Hexarelin administration increased LVEF both in patients with GHD and in CS (peak: 57+/-2 vs. 70+/-2, respectively, P<0.05 vs. baseline) without changing catecholamine levels, mean blood pressure (MBP), or cardiac output in either group. In conclusion, the acute administration of hexarelin exerts a short-lasting positive inotropic effect in humans, probably GH-independent and mediated by specific myocardial receptors for GH secretagogues.
Adult↗
T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules.
Despite being a major group of intracellular pathogens, the role of class I-restricted T cells in the clearance of Gram-negative bacteria is not resolved. Using a murine typhoid model, a role for class I-restricted T cells in the immune response to the Gram-negative pathogen Salmonella typhimurium is revealed. Class I-deficient beta2-microglobulin-/- mice show increased susceptibility to infection with S. typhimurium. Following infection, CD8+ CTLs specific for Salmonella-infected targets can be readily detected. The Salmonella-specific CTLs recognize infected H-2-mismatched targets, suggesting the involvement of shared class Ib molecules. Studies using transfectants expressing defined class Ia and class Ib molecules indicate the involvement of the class Ib molecule, Qa-1. Ab-blocking studies and the measurement of bacteria-specific CTL frequencies identified Qa-1 as a dominant restricting element. The Qa-1-restricted CTL recognition depends on TAP and proteasome functions. Surprisingly, Qa-1-restricted CTLs recognized cells infected with other closely related Gram-negative bacteria. Taken together, these observations indicate that Salmonella-specific CTLs recognize a cross-reactive epitope presented by Qa-1 molecules and, as such, may be novel targets for vaccine development.
Animals↗
Single H2Kb, H2Db and double H2KbDb knockout mice: peripheral CD8+ T cell repertoire and anti-lymphocytic choriomeningitis virus cytolytic responses.
Single H2Kb, H2Db and double H2KbDb homozygous knockout (KO) mice were generated and their peripheral CD8+ T cell repertoires compared to that of C57BL/6 (B6) mice. Limited (10-20%, H2Db), substantial (30-50%, H2Kb) and profound (90%, H2KbDb) reduction of peripheral CD8+ T cells was observed in KO mice, without Vbeta diversity alteration. Classical class Ia molecules therefore ensure most but not all of the peripheral CD8+ T cell repertoire education. As expected, H2Kb but also H2Db KO mice developed choriomeningitis following intracranial infection by lymphocytic choriomeningitis virus with the same kinetics, lethality and CD8+ cell implication as wild-type B6 mice. By contrast, H2KbDb (class Ia-Ib+) KO mice survived. Choriomeningitis of H2Db KO mice was linked to the development of a subdominant (in normal B6 mice) H2Kb-restricted cytotoxic T lymphocyte response. Mice expressing a restricted set of histocompatibility class I molecules should represent useful tools to evaluate the immunological potentials of individual MHC class I molecules.
Animals↗
Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans.
Reduced cardiac mass and performances are present in GH deficiency and are counteracted by rhGH replacement. GH and IGF-I possess specific myocardial receptors and have been reported able to exert an acute inotropic effect. Synthetic GH secretagogues (GHS) possess specific pituitary and hypothalamic but even myocardial receptors. In 7 male volunteers, we studied cardiac performance by radionuclide angiocardiography after iv administration of rhGH or hexarelin (HEX), a peptidyl GHS. The administration of rhGH or HEX increased circulating GH levels to the same extent (AUC: 1594.6+/-88.1 vs 1739.3+/-262.2 microg/l/min for 90 min) while aldosterone and catecholamine levels did not change; HEX, but not rhGH, significantly increased cortisol levels. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP) and heart rate (HR) were unaffected by rhGH (62.4+/-2.1 vs 62.1+/-2.3%, 90.6+/-3.4 vs 92.0+/-2.5 mm Hg, 62.3+/-1.8 vs 66.7+/-2.7 bpm). HEX increased LVEF (70.7+/-3.0 vs 64.0+/-1.5%, p<0.03) without significant changes in MBP and HR (92.8+/-4.7 vs 92.4+/-3.2 mm Hg, 63.1+/-2.1 vs 67.0+/-2.9 bpm). LVEF significantly raised at 15 min, peaked at 30 min and lasted up to 60 min after HEX. These findings suggest that in man, the acute administration of Hexarelin exerts a short-lasting, positive inotropic effect. This effect seems GH-independent and might be mediated by specific GHS myocardial receptors.
Adult↗
Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits.
1 To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73+/-0.43 to 1.48+/-0.13 ml min-1 kg-1 (P<0. 05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC prevented the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre-treatment with 3MC prevents the hypoxia-induced depression of the P450.
Animals↗
Tumor defense by murine cytotoxic T cells specific for peptide bound to nonclassical MHC class I.
Cytotoxic T Cells (CTLs) can exhibit considerable antitumor activity. Thus far, the characterized tumor peptide antigens recognized by CTLs are all presented by classical MHC class Ia molecules [human lymphocyte antigen A (HLA-A), HLA-B, and HLA-C in humans and H-2K, H-2D, and H-2L in mice]. Here we show that CTLs recognized peptides presented by nonclassical MHC class Ib molecule Qa-1b expressed by tumor cells. These CTLs conferred in vivo protection by delaying the growth of Qa-1b-expressing B78H1 melanoma cells pulsed with Qa-1b-binding peptides Cw4L or B35L and injected s.c. in C57BL/6 mice. A hierarchy of the peptides was found with regard to their ability to trigger CTLs; Cw4L stimulated a strong CTL response. The closely related and cross-reactive peptide B35L induced a weaker CTL response but was still efficient in sensitizing the target cells. Finally, Qa-1b-expressing melanoma cells without exogenous peptides were not immunogenic but possibly expressed endogenous cross-reactive antigenic peptides. The data are compatible with earlier findings that CTL activation requires relatively strong peptide antigens, whereas subsequent effector functions are also mediated by weak peptide analogues. In conclusion, CTLs mediated tumor immunity through the recognition of peptides presented by nonclassical MHC class Ib molecules. The identification of similar CTLs in humans may facilitate the vaccination of cancer patients because MHC class Ib/peptide complexes are much less polymorphic than MHC class Ia/peptide complexes.
Animals↗
Regulatory role of T cells in a murine model of lymphoproliferative disease.
As NZB mice age, approximately 90% of the 12-month-old mice possess an expansion of malignant B-1 (CD5+ B cells) cells with many similarities to the human lymphoproliferative disease, chronic lymphocytic leukemia. Malignant B-1 cells derived from NZB mice produce significantly higher levels of IL-10 mRNA and protein than normal B-1 or B cells. IL-10 may act as an autocrine growth factor for the expansion of B-1 cells. In this report, the infrequent animals which survived 18 months of age or longer were studied and compared to NZB mice at 12-14 months of age. Analysis of lymphoid subpopulations in the spleen and peritoneal cavity indicated that long-lived NZB mice had an expansion of CD8+ T cells rather than the typical B-1 expansion observed in the majority of NZB animals at 12 months of age. We established a CD8+ T cell clone from long-lived NZB mice which was cytotoxic for malignant B-1 cells of NZB origin both in vivo and in vitro. Analysis of the regulatory mechanisms preventing the development of genetically programmed age-dependent CLL in the murine system may elucidate possible avenues for therapeutic intervention in CLL.
Animals↗
Binding sites for growth hormone-releasing peptide.
Growth hormone-releasing peptides (GHRPs) are known to release growth hormone (GH) in vivo and in vitro by a direct action on receptors in anterior pituitary cells. Measurement of second messengers released following somatotroph stimulation suggests the existence of more than one GHRP receptor subtype in the hypothalamic-pituitary system. Furthermore, hexarelin, a hexapeptide of the GHRP family and a potent GH secretagogue, is reported to increase left ventricular ejection fraction, suggesting the expression of specific myocardial GHRP binding sites. In order to confirm such a hypothesis, a photoactivatable derivative of hexarelin, Tyr-p-benzoyl phenylalanine-Ala-hexarelin, was developed. A putative GHRP receptor with an apparent relative molecular mass of 57,000 was specifically labelled and characterized in human, bovine and porcine anterior pituitary membranes using this hexarelin derivative. The existence of myocardial binding sites was also demonstrated using the same approach. The differential binding affinity of GHRP analogues to cardiac tissue raises the possibility of the existence of distinct GHRP receptor subtypes in the pituitary and the cardiovascular system, for which physiological roles have yet to be determined.
Animals↗