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Biomedical subjects

A Pfeiffer

Publications and source records attributed to A Pfeiffer.

At least 163 records · Page 9Linked to original sources
PubMed1986

Influence of bile salts and lipids on intestinal absorption of griseofulvin in man.

The influence of bile salts and lipids on the intestinal absorption of griseofulvin has been studied in 11 healthy male volunteers by the intestinal perfusion technique. The drug in a nutrient solution (Realmentyl) was perfused into the second part of duodenum at 5 ml/min. Intestinal samples were taken continuously at 1 ml/min, 20 cm (at the angle of Treitz) and 45 cm distal to the perfusion point. To study the effect of lipids on griseofulvin absorption, the drug was perfused with solutions A and B, of which B contained a total lipid and caloric load three times that of A. The influence of bile salts on griseofulvin absorption was examined by perfusing the drug on Day 1 with bile salts and again on the following day after bile salt depletion. Bile salts and a varying quantity of lipid perfusate had no significant influence on the duodeno-jejunal griseofulvin absorption rate per cm of intestine. Lipids, however, may still play a role in griseofulvin absorption along the entire intestine.

Adult↗
PubMed1986

Effects of a kappa-opioid agonist on adrenocorticotropic and diuretic function in man.

Although kappa-opiate receptors represent an important fraction of the total opiate receptor capacity in human brain their endocrine function is unknown. We determined the effects of a kappa-opiate receptor agonist on the secretion of vasopressin, ACTH and cortisol and on diuresis. The racemic benzomorphan kappa agonist MR 2033 or its opiate active (-)-isomer, MR 2034, inhibited the release of cortisol and ACTH in 12 trials in a naloxone reversible manner; plasma levels of vasopressin were not altered. The (+)-isomer, MR 2035, did not affect the secretion of cortisol or ACTH. Surprisingly, in five other subjects large increases were observed in vasopressin, ACTH and cortisol following the kappa-agonist, which were probably elicited indirectly by aversive effects of the opioid. The subjects in whom vasopressin release was not altered by MR 2033 and MR 2034 displayed large decreases in urine osmolality which were not antagonized by naloxone. The opiate inactive (+)-isomer, MR 2035, caused no diuretic response. Subjects in whom vasopressin release was stimulated did not show decreases in urine osmolality indicating that vasopressin is capable of antagonizing the diuretic action of the kappa-agonist. Our data show that a kappa-agonist inhibits secretion of cortisol and ACTH by acting at stereospecific opiate receptors and elicits diuresis by acting at stereospecific, but naloxone-insensitive non-classical opioid receptors. These data support the concept that different types of kappa-receptors can be distinguished in man.

Adrenocorticotropic Hormone↗
PubMed1986

Anterior pituitary hormone responses to a kappa-opioid agonist in man.

The present study was designed to investigate pituitary hormone responses to a kappa-opiate receptor agonist in man. Normal men were given the racemic benzomorphan kappa-agonist MR 2033 or its levorotatory isomer MR 2034 iv. Plasma levels of PRL and GH markedly increased after injection of 3.5 micrograms/kg MR 2033 or 1.9 or 3.8 micrograms/kg MR 2034. These effects of MR 2033 were blocked by the opiate antagonist naloxone (10 mg), thereby demonstrating their mediation by opiate receptors. The kappa-agonist did not change plasma levels of LH and FSH. The secretion of TSH was significantly suppressed by MR 2033 and MR 2034, but this action was not antagonized by pretreatment with naloxone. The suppression of plasma TSH was, however, stereospecific since the (+)-isomer, MR 2035, did not affect TSH secretion. These data indicate that kappa-opiate receptors are located on neuronal pathways regulating GH, TSH, and PRL secretion. The pattern of pituitary responses elicited by the kappa-agonist differs from that of mu-opioid agonists, indicating differential endocrine functions for the endogenous agonists.

Adult↗
PubMed1985

Central kappa- and mu-opiate receptors mediate ACTH-release in rats.

The control of ACTH secretion by opiates seems to involve stimulatory and inhibitory pathways, since opiate agonists and antagonists are capable of releasing ACTH in conscious rats. To elucidate the role of different opiate receptors in the control of ACTH release, rats were treated with receptor-selective opiate agonists and antagonists. The mu-opiate agonists, morphine and (D-Ala2, MePhe4, Gly5-ol)enkephalin, and the benzomorphan kappa-opiate agonists, MR 2034 and MRZ 2549, both stimulated ACTH release after central or peripheral injection. The effects of morphine, but not those of MR 2034, were blocked by a low dose of naloxone (50 micrograms/kg) and by the mu-receptor antagonist, beta-funaltrexamine. A 20 times higher dose of naloxone also blocked the effects of the kappa-agonist. Our data suggest that both mu- and kappa-opiate receptors are involved in the stimulation of ACTH release in rats.

Adrenocorticotropic Hormone↗
PubMed1984

An increase in opiate receptor-sites is associated with enhanced cardiovascular depressant, but not respiratory depressant action of morphine.

Rats were treated for 4 weeks with a constant infusion of 2 mg/kg/h of the opiate antagonist naloxone. This treatment increased mu-, delta- and kappa-binding sites by 60-180% in several brain regions, suggesting effective blockade of the 3 types of opiate sites. The significance of changes in opiate binding sites for opiate receptor mediated physiological responses were examined using cardiovascular and respiratory responses to morphine (assessed after elimination of naloxone) as physiological parameters. Chronically naloxone-treated rats showed no alteration in respiratory responses to morphine, whereas there was a marked supersensitivity to depressor and bradycardic effects and a loss of pressor and tachycardic effects of morphine. These data are the first indication that cardiovascular effects of opiates vary with changes in central opiate receptor levels. Our observations, moreover, show that there are complex relationships between receptor number and receptor-mediated effects of opiates.

Animals↗
PubMed1984

Thallium-201 scintigraphy in complete left bundle branch block.

Nineteen symptomatic patients with left bundle branch block (LBBB) were examined by thallium-201 (TI-201) exercise scintigraphy and selective coronary arteriography. All elicited significant anteroseptal perfusion defects in the exercise scintigrams, but in only 4 was coronary artery disease (CAD) involving the left anterior descending coronary artery present. To further elucidate the effect of LBBB on septal TI-201 uptake in the absence of CAD, TI-201 scintigrams combined with regional myocardial blood flow measurements using radioactive microspheres were carried out in 7 dogs during right atrial and right ventricular pacing (LBBB in the ECG) at similar heart rates. During right atrial pacing, TI-201 uptake was homogeneous in the entire left ventricle, as were tissue flows. During right ventricular pacing, TI-201 activity was reduced to 69% of maximal TI-201 activity within the septum, whereas it averaged 90% in the lateral wall (p less than 0.05) in 6 dogs. Correspondingly, regional myocardial blood flow was lower within the septum as compared with that in the lateral wall, averaging 89 and 120 ml/min/100 g, respectively (p less than 0.005). In 1 dog, normal TI-201 distribution and tissue flows were found in both studies. Thus, symptomatic patients with LBBB may elicit abnormal TI-201 exercise scintigrams, suggesting anteroseptal ischemia despite normal coronary arteries. The electrical induction of LBBB in dogs results, in most instances, in a comparable reduction in septal TI-201 uptake associated with diminished septal blood flow. Therefore, exercise-induced septal perfusion defects in the presence of LBBB do not necessarily indicate CAD even in symptomatic patients, but may reflect functional ischemia due to asynchronous septal contraction.

Adult↗
PubMed1984

Endocrine actions of opioids.

The widespread occurrence of opioid peptides and their receptors in brain and periphery correlates with a variety of actions elicited by opioid agonists and antagonists on hormone secretion. Opioid actions on pituitary and pancreatic peptides are summarized in Table 1. In rats opioids stimulate ACTH and corticosterone secretion while an inhibition of ACTH and cortisol levels was observed in man. In both species, naloxone, an opiate antagonist, stimulates the release of ACTH suggesting a tonic suppression by endogenous opioids. In rats, a different stimulatory pathway must be assumed through which opiates can stimulate secretion of ACTH. Both types of action are probably mediated within the hypothalamus. LH is decreased by opioid agonists in many adult species while opiate antagonists elicit stimulatory effects, both apparently by modulating LHRH release. A tonic, and in females, a cyclic opioid control appears to participate in the regulation of gonadotropin secretion. Exogenous opiates potently stimulate PRL and GH secretion in many species. Opiate antagonists did not affect PRL or GH levels indicating absence of opioid control under basal conditions, while a decrease of both hormones by antagonists was seen after stimulation in particular situations. In rats, opiate antagonists decreased basal and stress-induced secretion of PRL. Data regarding TSH are quite contradictory. Both inhibitory and stimulatory effects have been described. Oxytocin and vasopressin release were inhibited by opioids at the posterior pituitary level. There is good evidence for an opioid inhibition of suckling-induced oxytocin release. Opioids also seem to play a role in the regulation of vasopressin under some conditions of water balance. The pancreatic hormones insulin and glucagon are elevated by opioids apparently by an action at the islet cells. Somatostatin, on the contrary, was inhibited. An effect of naloxone on pancreatic hormone release was observed after meals which contain opiate active substance. Whether opioids play a physiologic role in glucose homeostasis remains to be elucidated.

Adrenocorticotropic Hormone↗
PubMed1984

Duodenal total and ionised calcium secretion in normal subjects, chronic alcoholics, and patients with various stages of chronic alcoholic pancreatitis.

Previous studies have shown increased secretion of total calcium in the duodenal juice of patients with chronic alcoholic pancreatitis compared with healthy subjects. In order to get more detailed information on calcium secretion and pancreatic stone formation in chronic alcoholic pancreatitis, ionised and total calcium concentrations were determined in the duodenal juice of normal subjects, chronic alcoholics, and patients with various stages of chronic alcoholic pancreatitis. Total calcium secretion was in agreement with previously published data. Chronic alcoholics presented a significant increase of ionised calcium. In the course of pancreatitis all calcium fractions increased progressively revealing highest concentrations in patients with severe exocrine insufficiency. In non-calcified and calcified pancreatitis all calcium fractions were identical. It is suggested that the increase of ionised calcium originates from serum ionised calcium passing by diffusion into the damaged pancreatic duct system.

Adult↗
PubMed1984

Effect of caerulein on total and ionized calcium secretion in the duodenal juice of man.

Previous studies have demonstrated an increase of total calcium secretion in the duodenal juice of healthy subjects after cholecystokinin (CCK) administration superimposed on a continuous secretion infusion. In order to get more detailed information on the physiology of calcium secretion and its dependance on hormonal stimulation, ionized and total calcium were determined in the duodenal juice of 9 volunteers under constant stimulation with secretin and graded caerulein doses; bound calcium was calculated as the difference of total and ionized calcium. The results of total calcium were in good agreement with previously published data. We found that total calcium secretion is mainly determined by bound calcium and bound calcium is mainly secreted together with bile products. Since ionized calcium concentration was independent of caerulein administration it is suggested that its concentration in gallbladder bile must be in good accordance with that of hepatic bile and pancreatic juice together.

Adult↗
PubMed1983

Chromatography and partial purification of solubilized opiate receptors.

Sheep brain membrane opiate receptors were solubilized using two different approaches: (A) Chaps was used to solubilize [3H]buprenorphine labeled membranes. Macromolecular labeled material had a stokes radius of approximately 90 A. Treatment with phospholipase A2, but not phospholipase C, decreased the stokes radius to 50 A indicating the presence and eventual structural role of phospholipids in the solubilized opiate receptor complex. (B) Digitonin-NaCl was used for solubilization of receptors which were then labeled with [3H]diprenorphine. This complex could be chromatographed on hydroxylapatite, DEAE-sepharose and phenylboronate gels successively permitting an approximately 100-fold purification over the solubilized starting material.

Animals↗
PubMed1983

Mu-receptors mediate opioid cardiovascular effects at anterior hypothalamic sites through sympatho-adrenomedullary and parasympathetic pathways.

Intracerebroventricular injections of selective opioid agonists were used to investigate the role of opiate receptor subtypes in cardiovascular function in awake rats. The mu-agonist (D-Ala2,MePhe4,Gly5-ol)enkephalin (1 nmol) caused a prolonged increase in blood pressure and an initial decrease followed by a delayed increase in heart rate. These effects were antagonized by the selective mu-antagonist beta-funaltrexamine. A selective delta-agonist (dimeric tetrapeptide enkephalin) was devoid of cardiovascular effects at 10 nmol, whereas a benzomorphan kappa-agonist MRZ caused a pressor response which was not antagonized by beta-funaltrexamine. The mechanisms by which opioids elicit cardiovascular effects were analyzed in detail by using microinjections into the anterior hypothalamic area. Low doses of enkephalin produced increases in heart rate and blood pressure. Associated elevations of plasma norepinephrine and epinephrine, but not vasopressin, suggested a stimulation of sympatho-adrenomedullary pathways. Higher doses caused increases in blood pressure but decreases in heart rate. Peripheral vagal blockade with atropine methyl nitrate caused a large sudden rise in heart rate, indicating that an increased vagal outflow counteracted the sympathetic activation. Adrenal demedullated rats displayed no tachycardia after anterior hypothalamic injection of low doses of enkephalin, whereas high dose caused pronounced bradycardia. Additional treatment of demedullated rats with the sympathetic blocker bretylium led to severe hypotension in addition to bradycardia. These data provide evidence that mu-opiate receptors primarily mediate cardiovascular effects of opiates in awake rats. At low doses, a sympathetic adrenomedullary activation occurs, whereas higher doses additionally activate parasympathetic efferents, both possibly from anterior hypothalamic sites.

Adrenal Medulla↗
PubMed1983

Cardiovascular and respiratory effects of mu-, delta- and kappa-opiate agonists microinjected into the anterior hypothalamic brain area of awake rats.

Relatively selective mu-, delta- and kappa-opiate agonists were microinjected into anterior hypothalamic and septal brain regions of the unanesthetized rat in order to investigate the potential role of specific opiate receptors in central cardiovascular regulation. Low doses (0.2-3 nmol) of both [D-Ala2,MePhe4,Gly-(ol)5] enkephalin (DAGO, mu-agonist) and [D-Ala2,D-Leu5]enkephalin (DADL, delta-agonist) caused dose-dependent increases in blood pressure and heart rate which were naloxone reversible. Higher doses (7.5-30 nmol) of DAGO and DADL produced pressor responses but had little effect on heart rate. The kappa-agonist MR 2034 had no effect on cardiovascular parameters at these doses. DAGO but not MR 2034 also depressed respiration at the higher doses resulting in hypoxia, hypercapnia and acidosis while DADL only slightly depressed respiration. DAGO was approximately 10-fold more potent than DADL in eliciting cardiovascular and respiratory responses. These findings implicate mu-receptors in mediating the cardiovascular and respiratory effects of opiates at anterior hypothalamic sites.

Animals↗
PubMed1982

Opiate receptor binding sites in human brain.

Subclasses of opiate receptor binding sites in human brain membranes were investigated by means of competitive binding techniques. The experimental data were analyzed by use of a computerized non-linear regression curve fitting program. mu-, delta-and chi-types of opiate binding were found in 5 different regions of the brain. A more extensive analysis of the regional distribution of subclasses of opiate binding sites was performed using a simple sequential inhibition technique. This method was shown to yield results which are comparable to those obtained by computer analysis of multiple tracer displacement curves. Chi-and mu-sites represented the major component of binding in most brain areas whereas delta-sites were fewer in number. The 3 types of binding showed different distribution patterns, suggesting that they are independent from each other. The distribution pattern observed in human brain resembled the one observed in rat brain, although chi-sites appear to represent a more important, and delta-sites appear to represent a less important, fraction of binding in human as compared to rat brain.

Adolescent↗
PubMed1982

Mixed type inhibition of [D-Ala2, D-Leu5]enkephalin binding to mu-opiate binding sites by mu-, but not by kappa-opiate ligands.

The interaction of the delta-opiate agonist [D-Ala2,D]Leu5]enkephalin (DADL) with the mu-opiate ligands dihydromorphine (DHM) and naloxone and the kappa-opiate ligand ethylketocyclazocine (EK) was studied in rat diencephalic membranes which contain mainly mu-opiate binding sites. Saturation binding experiments performed with tritiated DADL in the presence of DHM and naloxone were indicative of mixed type inhibition whereas EK behaved as a competitive inhibitor. This result indicates differences in the interaction of mu-, delta- and kappa-ligands with mu-opiate binding sites.

Animals↗
PubMed1982

Enhancement of delta- but not mu-opiate agonist binding by calcium.

Present evidence for distinction of 2 types of opiate receptor sites in rat brain homogenates originates from different relative affinities of morphine-like alkaloids and enkephalins to delta- or enkephalin and mu- or morphine-receptor sites. We now report that Ca2+ in a physiological dose range (0.5-3 mM) enhances the binding of 3H-enkephalin in hypotonically treated rat brain membranes, whereas specific binding of 3H-morphine-like alkaloids is not affected. Furthermore, the potency of [D-Ala2,D-Leu5]-enkephalin to inhibit [3H]-diprenorphine and [3H]-ethylketazocine binding increased in the presence of Ca2+, whereas an increase in potency of [D-Ala2,D-Leu5]-enkephalin to inhibit binding of mu-receptor ligands was not observed. Kinetic analysis revealed that Ca2+ decreased the rate of dissociation of [D-Ala2,D-Leu5]-enkephalin without affecting the rate of association, thereby increasing the affinity. However, in saturation binding studies, performed in diencephalic membranes, in which [D-Ala2,D-Leu5]-enkephalin binds predominantly to mu-receptors, Ca2+ also increased the binding affinity of [3H]- [D-Ala2,D-Leu5]-enkephalin. Double reciprocal analysis suggested a mixed competitive-noncompetitive type of inhibition of [D-Ala2,D-Leu5]-enkephalin binding by dihydromorphine. Thus, the interaction of delta- and mu-opiate ligands with mu-receptors may involve topographically different, but closely related binding sites, located on a single receptor molecule.

Animals↗