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Biomedical subjects

W Rascher

Publications and source records attributed to W Rascher.

17 recordsLinked to original sources
PubMed1992

Novel generation of hormone receptor specificity by amino terminal processing of peptide YY.

The physiological significance of multiple Y receptors has not been determined since until recently only one form of endogenous agonists was known, namely PYY1-36 and NPY1-36. Recently, a new molecular form of PYY was characterized as des(Tyr-Pro)PYY (PYY3-36 or PYY-II). Its ability to interact at various Y receptors was not characterized. Analytical chromatography of fresh canine colon extracts shows two peaks of immunoreactivity eluting in the positions of PYY-II and PYY1-36 (PYY). PYY-II was about 40% of the total PYY immunoreactivity indicating that it is one of the major forms of PYY expressing its biological activity. It is shown that PYY-II will not displace label from the Y1 receptors found on a human neuroblastoma cell line. It is further shown that PYY-II is as potent as PYY for the inhibition of pancreatic secretion, which must occur through Y2 receptors. The enzymatic removal of Tyr-Pro from PYY to form PYY-II must therefore regulate the relative expression of a non-selective agonist (PYY) to a highly selective Y2 agonist (PYY-II). Amino terminal processing of PYY represents a novel type of regulation of peptide hormone specificity. It has important biological implications for PYY and potential relevance for other peptide hormone receptor systems.

Animals↗
PubMed1992

Atrial natriuretic peptide and cyclic 3'5'-guanosine monophosphate as indicators of fluid volume overload in children with chronic renal failure.

Plasma atrial natriuretic peptide (ANP) and cyclic 3'5'-guanosine monophosphate (cGMP) were investigated as indicators of fluid volume overload in children and adolescents with chronic renal failure. Plasma ANP and cGMP were measured in both paediatric patients with chronic renal failure (n = 17, mean serum creatinine 371 +/- 242 mumol/l) and those with end-stage renal disease on haemodialysis (n = 18). cGMP was higher in children with chronic renal failure than in 45 healthy controls (1.0 +/- 0.4 vs 2.1 +/- 0.8 nmol/l, P less than 0.01), whereas plasma ANP was similar (26.9 +/- 9.7 vs 34.0 +/- 12.3 pmol/l). Both ANP and cGMP were markedly elevated in children with end-stage renal disease before haemodialysis and fell significantly during dialysis. During dialysis body weight decreased by 1.6 +/- 0.7 kg, corresponding to 4.5 +/- 2.1% of body weight. Plasma ANP correlated positively with plasma cGMP in haemodialysed patients (r = 0.43, P less than 0.05). Reduction in body weight and in mean arterial pressure correlated more closely with plasma ANP than with cGMP. Therefore, elevation of plasma ANP appears to indicate volume overload in children undergoing haemodialysis, but whether it can be used also in children with chronic renal failure requires further investigation.

Adolescent↗
PubMed1992

Neuropeptide Y (NPY) receptors in HEL cells: comparison of binding and functional parameters for full and partial agonists and a non-peptide antagonist.

1. We have compared the binding and Ca2+ mobilizing properties of various full agonists, partial agonists and a non-peptide antagonist at the neuropeptide Y (NPY) receptor of human erythroleukemia (HEL) cells. 2. [125I]-NPY binding to intact HEL cells was rapid, saturable, of high affinity and with a specificity typical for the Y1-like subtype: NPY, peptide YY (PYY) and [Pro34]-NPY competed for [125I]-NPY binding with high affinity whereas NPY13-36 and NPY18-36 had only low affinity. 3. NPY, PYY and [Pro34]-NPY potently increased intracellular Ca2+ in HEL cells and had equal efficacy. NPY13-36, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP) increased intracellular Ca2+ only poorly. 4. Whereas VIP and PP did not significantly affect NPY-stimulated Ca2+ mobilization, NPY13-36 inhibited NPY-stimulated Ca2+ increases and shifted the NPY concentration-response curve to the right without altering its maximal effect. 5. The agonist (pEC50) potencies of the various peptides corresponded well with the affinities of these compounds in the binding assay (pKi), whereas the antagonist potencies (pKb) of the peptide partial agonists and the pA2 value of the non-peptide NPY antagonist (He 90481), calculated from functional data, were lower than the respective affinities determined in the binding studies. 6. A plot of the fractional Ca2+ response vs the fractional receptor occupancy did not reveal any non-linear receptor-effector coupling for NPY or [Pro34]-NPY; a small receptor reserve might exist for PYY. 7. We conclude that the binding and functional properties of HEL cell NPY receptors are very similar. NPY, PYY and [Pro34]NPY are full agonists at these receptors, whereas NPY13-36 is a partial agonist.

Calcium↗
PubMed1992

NPY-stimulated Ca2+ mobilization in SK-N-MC cells is enhanced after isoproterenol treatment.

Neuropeptide Y (NPY) receptors in the SK-N-MC human neuroblastoma cell line couple to mobilization of intracellular Ca2+ and inhibition of adenylylcyclase. Pretreatment of SK-N-MC cells with isoproterenol enhanced the NPY-stimulated Ca2+ mobilization, mainly by increasing the maximal response to NPY. The enhancement was time-(maximal after 24 h) and concentration-dependent (maximal at 10 microM isoproterenol), blocked by the beta-adrenergic antagonist propranolol, and mimicked by forskolin. Concomitant treatment with cycloheximide prevented the enhancing effect of isoproterenol, suggesting the involvement of protein synthesis. Isoproterenol treatment did not alter the number or affinity of 125I-labeled NPY binding sites, the amount of pertussis toxin substrates, or NPY-mediated inhibition of cAMP accumulation. Similarly, isoproterenol treatment had no effect on basal intracellular Ca2+ and on Ca2+ increases elicited by carbachol, caffeine, or ionomycin. We conclude that isoproterenol treatment can sensitize NPY receptor responsiveness in a way that is specific for Ca2+ mobilization mechanisms used by this hormone.

Adenylyl Cyclases↗
PubMed1979

Catecholamine turnover changes in hypothalamus and dorsal midline area of the caudal medulla oblongata of spontaneously hypertensive rats.

The central noradrenaline (NA) and adrenaline (A) turnover in 15--16-week-old stroke prone, spontaneously hypertensive (sp-SH) female rats in an advanced stage of hypertension was found to differ from that of normotensive Wistar-Kyoto (WKy) control rats. The catecholamine (CA) levels were measured after inhibition of dopamine-beta-hydroxylase (DBH) or phenylethanolamine-N-methyltransferase (PNMT). in the hypertensive rats the dopamine (DA) and NA levels and the NA turnover were reduced in the hypothalamus, while in the dorsal part of the caudal medulla oblongata NA levels and A turnover were reduced. Changes in hypothalamic DA and NA mechanisms and in A mechanisms in medulla oblongata may therefore be of importance in the blood pressure regulation of sp-SH rats.

Animals↗
PubMed1979

Effects of an orally active converting-enzyme inhibitor, SQ 14225, on pressor responses to angiotensin administered into the brain ventricles of spontaneously hypertensive rats.

1. Two hours after oral feeding of normotensive Wistar Kyoto rats with the converting-enzyme inhibitor SQ 14225 (1 and 10 mg/kg), an increase of angiotensin I plasma concentrations from 892 +/- 113 to 1660 +/- 167 and 2951 +/- 405 pg/ml was observed. 2. Administration of SQ 14225 with the drinking fluid overnight suppressed the pressor responses to intravenous angiotensin I, although the blood pressure increase after intravenous angiotensin II was not altered in normotensive and spontaneously hypertensive rats. No change of pressor effects after injections of angiotensin I and II into the brain ventricles was observed after oral SQ 14225. 3. Intracerebroventricular infusions of SQ 14225 in spontaneously hypertensive rats abolished the central pressor responses to angiotensin I. 4. The results show that SQ 14225 effectively blocked the conversion of endogenous and exogenous angiotensin I into angiotensin II in plasma, and the conversion of exogenous angiotensin I in brain. Under the conditions studied, SQ 14225 does not cross the blood-cerebrospinal fluid barrier in spontaneously hypertensive rats.

Administration, Oral↗
PubMed1979

Vascular reactivity in the pathogenesis of spontaneous hypertension.

1. Alterations in vascular reactivity were assessed in isolated artificially perfused kidneys from stroke-prone spontaneously hypertensive (spSH) rats at different stages of hypertension and after neonatal sympathectomy with 6-hydroxydopamine (6-OHDA). 2. During the pre-hypertensive stage, and the early and chronic stages of hypertension, the responses to noradrenaline, vasopressin, serotonin and angiotensin II were enhanced in renal vascular beds from spSH animals compared with age- and sex-matched Wistar-Kyoto (WK) rats; dose-response curves were shifted to the left, had steeper slopes, greater maximal responses and decreased thresholds. 3. With increasing severity and duration of hypertension, renal vascular resistance at maximal vasodilatation increased, the slopes of the dose-response curves were steeper and maximal responses were greater. 4. Neonatal sympathectomy with 6-OHDA greatly attenuated but did not prevent the eventual development of hypertension; furthermore, this treatment had no effect on the enhanced resistance or reactivity in renal vascular beds from spSH rats. 5. The appearance of enhanced resistance and reactivity in the early stages of hypertension and the inability to prevent these vascular changes by neonatal sympathectomy suggest that these alterations are a primary pathogenic mechanism in spSH rats.

Angiotensin II↗
PubMed1979

A novel orally active converting-enzyme inhibitor YS 980: effects on blood pressure in spontaneously hypertensive rats.

1. The effects of long-term treatment with the angiotensin I converting-enzyme inhibitor YS 980 were examined in stroke-prone spontaneously hypertensive (sp-SH) rats. Development of hypertension was markedly blunted in the YS 980-treated animals. 2. Effective converting-enzyme inhibition was confirmed by significant increases in plasma angiotensin I (ANG I) and plasma renin concentration, inhibition of the pressor responses to intravenous ANG I and potentiation of the depressor responses to intravenous bradykinin. 3. Urinary free aldosterone excretion was decreased but no changes in urinary sodium and potassium excretion were observed. 4. The pressor responses to intravenous leucine-enkephalin were reduced. 5. The pressor responses to injection of ANG I and bradykinin into the lateral brain ventricle were unaltered. 6. We conclude that the antihypertensive action of YS 980 in sp-SH rats cannot be explained by the inhibition of the plasma renin-angiotensin system alone. Effects on other peptide systems must be considered.

3-Mercaptopropionic Acid↗
PubMed1979

Effect of neonatal sympathectomy by 6-hydroxydopamine on volume and resistance regulation in stroke-prone spontaneously hypertensive rats.

1. Neonatal sympathectomy with 6 hydroxy-dopamine (6-OHDA) was used as a tool to assess the significance of an increased sympathetic vascular tone for the development of high blood pressure in stroke-prone spontaneously hypertensive rats. After administration of 6-OHDA the rise in blood pressure was blunted for the following 9 weeks until innervation was re-established. 6-OHDA-treated rats retained more sodium and had larger plasma and blood volumes than sham-treated rats. 2. Catecholamines in plasma were increased 2-10-fold immediately after sympathectomy, but their concentrations were subnormal on day 7. Eight weeks after sympathectomy plasma noradrenaline and dopamine were not elevated, but plasma adrenaline has increased twofold. 3. The reactivity of resistance vessels to noradrenaline was markedly enhanced and the neuronal uptake and metabolism of noradrenaline were still reduced 8 weeks after neonatal sympathectomy. 4. These results confirm the significance of an intact sympathetic nervous system for the development in these rats. Sodium retention and increased plasma and blood volume may be considered as a compensatory mechanism for the vasodilatation resulting from decreased vasomotor tone.

Animals↗
PubMed1979

Modulation of sympathetic vascular tone by prostaglandins in corticosterone-induced hypertension in rats.

1. In corticosterone-induced hypertension in rats the activity of the peripheral sympathetic nervous system and its modulation by prostaglandins was studied. 2. Plasma concentrations of noradrenaline were reduced if compared with those in normotensive control rats. 3. The sensitivity of the isolated perfused hind-limb preparation to noradrenaline was enhanced before blood pressure rose and increased further with the development of hypertension. 4. Arachidonic acid, prostacyclin (prostaglandin I2), but not 6-keto-prostaglandin F1 alpha, reversed the supersensitivity to noradrenaline. 5. These results suggest that corticosterone induces a supersensitivity to noradrenaline by inhibiting the biosynthesis of prostaglandins. Changes in the sensitivity of the vascular smooth muscle may play a role in the development of glucocorticoid hypertension.

Animals↗
PubMed1978

Reversal of renal hypertension: effects on renin, salt and water balance.

The effect of removal of one renal artery stenosis on renal sodium and fluid excretion and on the activity of the renin-angiotensin system (RAS) has been investigated in three types of renal hypertension of rats. Blood pressure fell in all experimental models after declamping, independently of changes in urinary sodium and water excretion or plasma angiotensin II (ANG II). Plasma concentrations of ANG II did not rise in response to salt and fluid loss induced by declamping when the contralateral kidney had been removed or when it was depleted from renin. A high renin content of the declamped kidney prevented major salt and fluid loss, whereas renin depletion of this kidney was accompanied by an exaggerated natriuresis and diuresis. Besides this tubular modulation of renal salt and water handling by the local RAS, glomerular filtration rate could be reduced by a stimulated activity of this system in plasma, indicated by a close relationship between serum urea and plasma ANG II levels.

Angiotensin II↗
PubMed1978

Inhibition of the renin-angiotensin-system in Brattleboro rats with hereditary hypothalamic diabetes insipidus.

Brattleboro rats homozygous for hypothalamic hereditary diabetes insipidus (DI rats) were used to investigate the following questions: a) Do exogenous and endogenous angiotensin II (AII) have an antidiuretic effect in diabetes insipidus? b) Does AII mediate the antidiuresis induced by furosemide? The following results were obtained: 1. AII (5 mg/kg s.c. in oil) and furosemide (50 mg/kg i.p.) decreased urine flow and increased urinary sodium excretion. Furosemide led to a two-fold increase of AII plasma concentrations and a decrease of plasma sodium levels. 2. SQ 14 225 (2 x 2.5 mg/kg p.o.), an angiotensin I-converting enzyme inhibitor, led to an increase of urine flow and to a slightly elevated urinary sodium excretion. 3. When the formation of AII was blocked by SQ 14 225 (2 x 2.5 mg/kg p.o.), AII plasma concentrations were 2.5-fold decreased, but furosemide still reduced urine flow. We conclude that plasma AII might have an antidiuretic action in DI rats. However, AII does not mediate the antidiuresis induced by furosemide.

Angiotensin II↗
PubMed1978

Effects of beta-adrenergic blocking agents on peripheral vascular resistance.

The effects of the beta-adrenergic blocking agents propranolol, pindolol, atenolol, bunitrolol, and methypranol on the vascular resistance of isolated perfused hindlimbs of rats were investigated. At concentrations of 0.01 microgram/ml in the perfusate dl-propranolol and pindolol significantly increased vascular resistance by blockade of beta2-receptor mediated vasodilatation, whereas atenolol, bunitrolol and methypranol had no effect on peripheral resistance at this concentration. With increasing concentrations up to 10 microgram/ml all drugs, with the exception of atenolol, caused vasodilatation. We conclude that the specificity of beta-blocking agents can be established in the isolated perfused hindlimb vasculature of rats through its effect on vascular resistance. The lack of inhibition of vascular beta2-receptors at low concentrations of atenolol and also bunitrolol and methypranol show relative selectivity for beta1-receptors. The differential effects of beta-adrenergic agents on vascular resistance may have significance for the clinical use of the drugs.

Adrenergic beta-Antagonists↗
PubMed1976

Measurement of two plasma triglyceride lipases by an immunochemical method: studies in patients with hypertriglyceridemia.

Postheparin plasma lipolytic activity consists of two hydrolytic activities, hepatic triglyceride lipase and lipoprotein lipase. These two enzymes were separated and partially purified by means of ammonium sulfate precipitation and affinity chromatography using Sepharose with covalently linked heparin and concanavalin A, respectively. Antibodies were produced against hepatic triglyceride lipase and they did not cross react with lipoprotein lipase. Optimal conditions for selective precipitation of hepatic lipase and specific measurement of these two lipases were investigated. This method was applied to the study of 15 patients with hypertriglyceridemia and 8 patients with familial lecithin-cholesterol-acyltransferase deficiency of whom 6 also had a marked elevated plasma triglyceride concentration. All patients had normal values of hepatic plasma lipase. All 8 patients with Type I and 2 of 4 patients with Type V hyperlipoproteinemia had lipoprotein lipase activities that were markedly reduced. The patients with Type III hyperlipoproteinemia and all 8 patients with lecithin-cholesterol-acyltransferase deficiency also had normal lipoprotein lipase values. These studies emphasize the necessity for differentiating between triglyceride lipase activity of hepatic and extrahepatic origin in evaluating patients with impaired triglyceride metabolism.

Acyltransferases↗