Search PubMed⌕ Search

Biomedical subjects

R Muff

Publications and source records attributed to R Muff.

50 records · Page 3Linked to original sources
PubMed1989

Distinct hemodynamic and renal effects of calcitonin gene-related peptide and calcitonin in men.

Cardiovascular and renal actions of human calcitonin gene-related peptide II (or beta) (CGRP) and of human calcitonin (CT) infused intravenously for 1 h each (79 and 263 pmol.kg-1.h-1) have been compared in normal men (n = 10 for CGRP, n = 6 for CT and vehicle alone). CGRP lowered diastolic blood pressure by 26% and increased the heart rate by 35% and raised plasma levels of norepinephrine, epinephrine, and dopamine and renin activity (P less than 0.01). The fractional excretion rates (FE) of sodium and chloride were doubled (P less than 0.05-0.01) in the presence of an unaltered glomerular filtration rate. CT, on the other hand, did not affect the diastolic blood pressure, but the stimulation of diuresis and of the FE of sodium and chloride was more pronounced with CT than with CGRP (P less than 0.01). Moreover, CT lowered serum calcium levels and stimulated urinary adenosine 3',5'-cyclic monophosphate and phosphate excretion (P less than 0.01). In conclusion, the cardiovascular effects of CGRP are contrasted by weaker renal tubular actions of the neuropeptide in relation to CT.

Adult↗
PubMed1989

Trypsinization of bovine parathyroid cells abolishes Ca2+-regulated parathyroid hormone secretion.

The secretion of parathyroid hormone (PTH) is inversely related to the extracellular Ca2+ concentration (Ca2e+). To test the hypothesis that a Ca2+ sensor on the surface of parathyroid cells is involved in Ca2+-regulated PTH secretion, limited trypsinization of bovine parathyroid cells was carried out. Treatment with trypsin (1.1-10 mg/ml) inhibited, in a dose-dependent manner, PTH secretion stimulated by lowering Ca2e+ from 2.0 to 0.5 mmol/l. In control cells, activation of protein kinase C with 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced PTH secretion at 2.0 mmol Ca2e+/l but not at 0.5 mmol Ca2e+/l. In trypsinized cells, however, TPA enhanced PTH secretion at both 0.5 and 2.0 mmol Ca2e+/l. Isoproterenol-stimulated PTH secretion was maintained in trypsinized cells, but reduced cyclic AMP production revealed that some beta-adrenergic receptors were destroyed. The cytosolic free Ca2+ concentration (Ca2i+), as measured with fura-2, was raised within seconds in response to increasing Ca2e+ from 0.5 to 2.0 mmol/l and was then lowered within 1 min to a sustained plateau; the changes were the same in trypsinized and control cells. In conclusion, trypsinization of parathyroid cells abolished Ca2+-regulated PTH secretion without affecting Ca2i+.

Animals↗
PubMed1988

Regulation of hormone secretion and cytosolic Ca2+ by extracellular Ca2+ in parathyroid cells and C-cells: role of voltage-sensitive Ca2+ channels.

The two dihydropyridine enantiomers, (+)202-791 and (-)202-791, that act as voltage-sensitive Ca2+ channel agonist and antagonist, respectively, were examined for effects on cytosolic Ca2+ concentrations ([Ca2+]i) and on hormones secretion in dispersed bovine parathyroid cells and a rat medullary thyroid carcinoma (rMTC) cell line. In both cell types, small increases in the concentration of extracellular Ca2+ evoked transient followed by sustained increases in [Ca2+]i, as measured with fura-2. Increases in [Ca2+]i obtained by raised extracellular Ca2+ were associated with a stimulation of secretion of calcitonin (CT) and calcitonin gene-related peptide (CGRP) in rMTC cells, but an inhibition of secretion of parathyroid hormone (PTH) in parathyroid cells. The Ca2+ channel agonist (+)202-791 stimulated whereas the antagonist (-)202-791 inhibited both transient and sustained increases in [Ca2+]i induced by extracellular Ca2+ in rMTC cells. Secretion of CT and CGRP was correspondingly enhanced and depressed by (+)202-791 and (-)202-791, respectively. In contrast, neither the agonist nor the antagonist affected [Ca2+]i and PTH secretion in parathyroid cells. Depolarizing concentrations of extracellular K+ increased [Ca2+]i and hormone secretion in rMTC cells and both these responses were potentiated or inhibited by the Ca2+ channel agonist or antagonist, respectively. The results suggest a major role of voltage-sensitive Ca2+ influx in the regulation of cytosolic Ca2+ and hormones secretion in rMTC cells. Parathyroid cells, on the other hand, appear to lack voltage-sensitive Ca2+ influx pathways and regulate PTH secretion by some alternative mechanism.

Animals↗
PubMed1988

Calcitonin gene-related peptide is a stimulator of renin secretion.

Calcitonin gene-related peptide (CGRP) was found to stimulate renin secretion in vivo in normal human volunteers. Moreover, CGRP stimulated the release of renin in vitro from isolated rat renal juxtaglomerular cells (half-maximal effective concentration [EC50] 100 nM) concomitant with stimulation of cAMP production (EC50 60 nM). Immunoreactive CGRP was recognized in rat renal cortical nerve fibers, and intact rat CGRP was identified in extracts of the rat renal cortex. Because CGRP containing sensory nerve fibers are seen in the region of the juxtaglomerular apparatus, it would seem that the release of CGRP from these afferent nerves may be involved in the physiological control of renin secretion.

Animals↗
PubMed1988

Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of Paget's disease.

Nine patients with Paget's disease were treated with 200 U (15 nmol) synthetic salmon calcitonin (sCT) intranasally (in)/day for 12 months. Five of them had received im or in sCT therapy for 1-4 yr up to 0.5-5 yr before this study. Low titer antibodies to sCT were detected in the serum of three of these five patients, but not in the four patients who had not received prior sCT therapy. After 2 months of in sCT administration, four of the former group, but none of the latter group, had antibodies to sCT. After 12 months of treatment, antibodies to sCT were found in all patients who had received sCT earlier and in three of the four patients who had not. The half-maximal inhibition of [125I]sCT binding ranged from 44-284 pmol/L sCT. In a cultured human breast cancer cell line (T47D) cAMP production was stimulated by sCT (EC50, 70 pmol/L). cAMP production stimulated by sCT (5 pmol/L) was reduced to 6-20% of the control value in the presence of serum from patients which inhibited [125I]sCT binding by more than 50% in a dilution of 1:50 or greater. In patients with lower titer antibodies cAMP production was not inhibited. Serum alkaline phosphatase activity was transiently lowered to 79 +/- 6% (+/- SE) of basal levels in the patients who had earlier received sCT (P greater than 0.1), while sustained reduction to between 66 +/- 2% and 84 +/- 6% of basal levels (P less than 0.05) occurred in the patients who had not been treated with sCT previously. In conclusion, reexposure to sCT of five patients with Paget's disease caused secondary antibody responses and clinical resistance.

Administration, Intranasal↗
PubMed1988

Calcitonin gene-related peptide and calcitonin secretion from a human medullary thyroid carcinoma cell line: effects of ionomycin, phorbol ester and forskolin.

Calcitonin gene-related peptide (CGRP) and calcitonin are secreted together from medullary thyroid carcinoma (MTC) cells. Interactions of cytosolic free calcium concentration (Cai2+) and the protein kinase C and A pathways on the secretion of immunoreactive CGRP and calcitonin have been investigated in a human MTC cell line. Ionomycin (10 mumol/l) raised the concentration of Cai2+, concomitant with a transient stimulation of the secretion of CGRP and calcitonin. 12-O-tetradecanoylphorbol-13-acetate (TPA; 16 nmol/l) did not affect the concentration of Cai2+, but caused a gradual rise of the secretion of CGRP and calcitonin. Combined addition of 10 mumol ionomycin/l and 16 nmol TPA/l resulted in additive stimulation of CGRP and calcitonin secretory responses. Forskolin (10 mumol/l) alone did not change the concentration of Cai2+, marginally enhanced (P greater than 0.1) the release of CGRP and calcitonin and increased by 23-fold the cellular levels of cyclic AMP (cAMP). Ionomycin and TPA did not change cellular cAMP. Forskolin synergistically enhanced (P less than 0.01) the ionomycin-induced early phase as well as the TPA-induced late phase of the CGRP and calcitonin secretory responses. In conclusion, increased concentrations of Cai2+ together with protein kinase C and A activation mediate the secretion of CGRP and calcitonin in MTC cells.

Calcitonin↗
PubMed1987

Role of cytosolic free calcium concentration in the secretion of calcitonin gene-related peptide and calcitonin from medullary thyroid carcinoma cells.

Calcitonin gene-related peptide (CGRP) and calcitonin (CT) are secreted by medullary thyroid carcinoma (MTC). Relationships between extracellular calcium ([Ca2+]e), cytosolic free calcium ([Ca2+]i) (as measured with fura-2), and secretion of immunoreactive CGRP and CT have been investigated in rat and human MTC cell lines. Rat MTC 6-23 cells responded to a rise in [Ca2+]e from 0.5 to 3.0 mM with a transient increase of [Ca2+]i, and the secretion of CGRP and CT was raised from 19 +/- 2 (mean +/- SE) to 122 +/- 28 pg rat CGRP/mg protein . min and from 33 +/- 8 to 155 +/- 42 pg rat CT/mg protein . min (P less than 0.01). In the human MTC (TT) cell line, a rise of [Ca2+]e from 0.5 to 3.0 mM did not affect [Ca2+]i, and the secretion of CGRP and CT remained unchanged at 7.0 +/- 1.1 ng CGRP/mg protein . min and 1.0 +/- 0.1 ng CT/mg protein . min. However, when the plasma membrane was bypassed by electropermeabilization, the release of CGRP and CT was stimulated by calcium with an ED50 of 0.5 microM and 0.3 microM, respectively. With ionomycin, the secretion of CGRP and CT was also stimulated up to 17-fold in [Ca2+]i-dependent manner. The results indicate a role of [Ca2+]i in the secretion of CGRP and CT and provide evidence for a defect in Ca2+ signal transduction in the human MTC cell line.

Animals↗
PubMed1986

Parathyroid hormone secretion does not respond to changes of free calcium in electropermeabilized bovine parathyroid cells, but is stimulated with phorbol ester and cyclic AMP.

The secretion of parathyroid hormone (PTH) is suppressed in bovine parathyroid cells by raised extracellular [Ca2+], and 12-0-tetradecanoyl-phorbol-13-acetate (TPA) stimulates the release of PTH from cells suppressed by high extracellular [Ca2+]. Extracellular and cytosolic free [Ca2+] are proportionally related in intact cells. To assess the role of cytosolic free [Ca2+] on PTH secretion, bovine parathyroid cells were rendered permeable by brief exposure to an intense electric field. PTH secretion was comparable at 40 nM, 500 nM, 5 microM, 28 microM, 0.5 mM and 2 mM [Ca2+] (release of total cellular PTH 3.7 +/- 0.5%, 3.9 +/- 0.4%, 3.4% +/- 0.3%, 3.9 +/- 0.4%, 3.1 +/- 0.3%, 3.5 +/- 0.7%, respectively), but the secretion was stimulated twofold (P less than 0.05 vs. control) in a dose and ATP dependent manner with TPA (100 nM) and cyclic AMP (1 mM). As a result, free [Ca2+] in the range of those observed in intact cells during regulation of PTH secretion by changes of extracellular [Ca2+] did not affect the release of PTH in permeabilized cells. The [Ca2+] independent stimulation of PTH release by TPA and cyclic AMP indicates that changes of cytosolic free [Ca2+] may represent a secondary event not related to the regulation of PTH secretion.

Adenosine Triphosphate↗
PubMed1986

Stimulation of parathyroid hormone secretion by phorbol esters is associated with a decrease of cytosolic calcium.

Unlike in other endocrine systems calcium inhibits parathyroid hormone (PTH) secretion and this inhibition is paralleled by a rise of cytosolic calcium concentration ([Ca]i). Because of evidence that diglyceride levels and protein kinase C activity are also decreased by high extracellular calcium we have investigated the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, on [Ca]i and PTH secretion using dispersed bovine parathyroid cells. At 1.5 mM medium calcium TPA enhanced PTH secretion and caused reduction of [Ca]i from 639 +/- 36 nM (SE) to 335 +/- 21 nM (P less than 0.001); at 0.5 mM calcium TPA was ineffective. Moreover, TPA suppressed the rise of [Ca]i evoked by high extracellular calcium. Thus TPA presumably stimulates PTH secretion via activation of protein kinase C, and the lowering of [Ca]i may TPA presumably stimulates PTH secretion via activation of protein kinase C, and the lowering of [Ca]i may be a secondary event related to diglyceride availability.

Animals↗
PubMed1986

Specific receptor and cardiovascular effects of calcitonin gene-related peptide.

Specific binding sites for calcitonin gene-related peptide (CGRP) were demonstrated in the rat heart and spleen. Autoradiography revealed rat [125I]iodo CGRP binding associated with the intima and media of the aorta, the coronary arteries and the heart valves, and the red pulp of the spleen. Half-maximal inhibition of rat [125I]iodo-CGRP binding to membranes of the rat atria and the spleen was obtained with, respectively, 5 and 0.35 nM unlabeled rat CGRP; these values correspond to EC50 values of 3 and 0.14 nM for activation of adenylate cyclase by CGRP. In the isolated, spontaneously beating right atrium, the EC50 values of stimulation of the force and rate of contraction by rat CGRP were 120 and 70 nM, respectively. Rat CGRP caused relaxation of splenic strips, precontracted with noradrenaline; the EC50 was 50 nM. The beta-adrenergic blocking agent metoprolol, while obliterating the increase in the force and rate of contraction evoked by noradrenaline in the right atrium, did not significantly change the action of CGRP. Similarly, preserved action of CGRP in the presence of indomethacin as well as mepyramine and cimetidine argues against a role of prostaglandins or histamine in the functional responses of CGRP. Much like CGRP, capsaicin, which releases mediators from sensory neurons, caused stimulation of the force and rate of contraction of the isolated right rat atrium. After tachyphylaxis to CGRP, the response to noradrenaline was intact, while the positive chronotropic and inotropic effects of capsaicin were suppressed. The results indicate that the cardiac effects of capsaicin may be due to the release of endogenous CGRP through a local mode of action.

Animals↗
PubMed1986

Reduced parathyroid hormone response to peroral phosphate in osteoporotic patients.

To determine whether PTH secretion can be stimulated in osteoporosis by peroral phosphate (1.5 g phosphorus), we have compared serum PTH and urinary cyclic AMP responses in 8 osteoporotic patients with vertebral compression fractures to those of 7 age-matched control subjects. While there was no statistically significant difference in the rise of serum phosphate and urinary phosphate excretion and in the fall of serumionized calcium concentrations, serum PTH and urinary cyclic AMP were increased in control subjects, but not in osteoporotic patients (osteoporotics vs. control group: PTH, p less than 0.01; cyclic AMP/glomerular filtrate, p less than 0.05). Moreover, plasma levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were the same in the 2 groups of subjects. Serum levels of the carboxyl-terminal flanking peptide (PDN-21) encoded by the calcitonin gene and cosecreted with calcitonin were similar in normal and osteoporotic subjects before and 3 min after 1-min intravenous calcium infusions (2 mg/kg body weight), and of calcitonin after the calcium infusions. We conclude that calcitonin and PDN-21 responses to intravenous calcium are the same in normal and osteoporotic subjects, whereas stimulation of PTH secretion by peroral phosphate is impaired in some osteoporotic patients.

Administration, Oral↗
PubMed1983

Potassium stimulates parathyroid hormone release in the absence of extracellular calcium.

Potassium-stimulated release of many hormones requires the presence of extracellular calcium. At variance with this mechanism, potassium-evoked parathyroid hormone (PTH) release from perifused dispersed bovine parathyroid cells also occurred in calcium-free medium containing 1 mM EGTA. Tetraethylammonium, which presumably suppresses the efflux of potassium from parathyroid cells, also stimulated PTH secretion. Removal of sodium did not suppress potassium-stimulated PTH secretion, but inhibited the release of the hormone evoked by calcium removal and by isoproterenol. Ouabain, on the other hand, suppressed the release of PTH evoked by calcium removal and by potassium, but not by isoproterenol. Unlike high potassium and removal of calcium, isoproterenol caused a parallel increase in cAMP release. In conclusion, PTH secretion is reversibly stimulated by potassium in the absence of extracellular calcium. Our findings suggest that potassium stimulates PTH secretion by a unique mechanism the nature of which remains to be elucidated.

Animals↗
PubMedDate not supplied

Dissociation of cAMP accumulation and phosphate uptake in opossum kidney (OK) cells with parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP).

Bovine parathyroid hormone (PTH) 1-34 [bPTH(1-34)] and human PTH related protein [hPTHrP(1-34)] stimulated cAMP accumulation in opossum kidney (OK) cells with Km of 5 x 10(-9) M, but inhibition of phosphate uptake was obtained with 17-fold lower Km of 3 x 10(-10) M. Phosphate uptake was partially inhibited with [Nle8.18Tyr34]bPTH(3-34)NH2 without concomitant cAMP stimulation. With hPTHrP(7-34)NH2, cAMP accumulation was increased in parallel to inhibition of phosphate uptake. [D-Trp12Tyr34]bPTH(7-34)NH2 and [Tyr34]hPTH(7-34)NH2 had no agonist activity on cellular cAMP and inhibition of phosphate uptake. bPTH(1-34)-stimulated cAMP accumulation was antagonized by [Nle8.18Tyr34]bPTH(3-34)NH2, [D-Trp12Tyr34]bPTH(7-34)NH2, hPTHrP(7-34)NH2 and [Tyr34]hPTH(7-34)NH2 with Ki of 1.4 x 10(-7), 2 x 10(-7), 4.7 x 10(-7) and 3.7 x 10(-6) M, respectively. But [Nle8.18Tyr34]bPTH(3-34)NH2 and [D-Trp12Tyr34]bPTH(7-34)NH2 reversed the inhibition of phosphate uptake only marginally, and hPTHrP(7-34)NH2 and [Tyr34]hPTH(7-34)NH2 were inactive. With hPTHrP(1-34) the Ki for cAMP accumulation of [Nle8,18Tyr34]bPTH(3-34)NH2 and hPTHrP(7-34)NH2 were 1.9 x 10(-7) and 7.2 x 10(-7) M, and inhibition of phosphate uptake was partially reversed with [Nle8,18Tyr34]bPTH(3-34)NH2, but not with hPTHrP(7-34)NH2. The present results indicate that truncated hPTHrP(7-34)NH2, unlike [Tyr34]hPTH(7-34)NH2 and [D-Trp12Tyr34]bPTH(7-34)NH2, elevates cellular cAMP and inhibits phosphate uptake. bPTH(1-34)- and hPTHrP(1-34)-evoked cAMP accumulation is suppressed by PTH and PTHrP fragments while inhibition of phosphate uptake remains largely unaltered.

Amino Acid Sequence↗