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Biomedical subjects

K Folkers

Publications and source records attributed to K Folkers.

At least 109 records · Page 6Linked to original sources
PubMed1984

Micro-analysis for coenzyme Q10 in endomyocardial biopsies of cardiac patients and data on bovine and canine hearts.

A micro-analysis was designed for determining the levels of coenzyme Q10 (CoQ10) in specimens of ca. 500 nanograms of myocardial tissues. The prime steps included acetone extraction, purification by thin-layer chromatography, and HPLC. CoQ11 was the internal standard. This methodology was successful for human endomyocardial biopsies from cardiac patients before and after therapy with CoQ10 and has now been used for canine and bovine tissues. The mean canine CoQ10 level from six specimens from the left ventricle (l.v.) of a single animal is 0.99 +/- 0.06 micrograms/mg/d.w. The mean levels of the tissues from nine animals is 1.04 +/- 0.17 (l.v.) and 1.11 +/- 0.16 (r.v.). The mean bovine level from seven animals was 0.48 +/- 0.12 (l.v.) and 0.68 +/- 0.06 (r.v.).

Animals↗
PubMed1984

Antagonists of the luteinizing hormone releasing hormone (LHRH) with emphasis on the TRP7 of the salmon and chicken II LHRH's.

The sequences of four naturally occurring luteinizing hormone releasing hormones (LHRH's) differ only in positions 5, 7 and 8. Salmon and chicken II LHRH's have Trp7; porcine/ovine (P/O) and chicken I LHRH's have Leu7. The receptor for P/O LHRH might effectively bind certain antagonists with Trp7. Thirteen antagonists having Trp7 and eight antagonists with other substitutions in position 7 were synthesized. One of the thirteen antagonists with the natural Trp7, [N-Ac-D-2-Nal1,D-pClPhe2,D-3-Pal3,D-Arg6,Trp7,D- Ala10]-LHRH, not only maintained activity, but had increased potency (ca. 58%; 90% antiovulatory activity/250 ng; rats) in comparison with the companion analog with the natural Leu7 of P/O LHRH. The other twelve Trp7-antagonists had lower potency.

Amino Acid Sequence↗
PubMed1984

A pioneer synthesis of conjugates of a thymic peptide hormone and polyamines.

To synthesize peptidic derivatives of polyamines, sequential reactions were designed for the polyfunctional peptides and polyfunctional amines which utilize specific protection and deprotection. Utilizing these reactions, a thymic nonapeptide, a lymphocyte-differentiating hormone, was coupled with spermidine and spermine to yield, respectively: Glp-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn-NH(CH2)3NH(CH2)4NH2; Glp-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn-NH(CH2)3NH-(CH2)4NH(CH2) 3NH2. Both conjugates inhibited rather than stimulated incorporation of [3H]-thymidine into DNA at levels 20-fold that of spermine. This activity is less than that based on the percent of the spermine moeity (ca. 20%) in the conjugate.

Animals↗
PubMed1984

Interaction of substance P antagonists with substance P receptors on dispersed pancreatic acini.

In the present study we examined the abilities of three analogs of substance P, [D-Pro2-, D-Phe7-, D-Trp9]-substance P, [D-Pro2-, D- Trp7 ,9]-substance P and [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P to alter substance P-induced changes in pancreatic acinar cell function and to occupy substance P receptors. At 30 microM, each analog of substance P lacked agonist activity and inhibited amylase secretion stimulated by substance P receptor agonists. The inhibition was reversible and specific for peptides that interact with substance P receptors (physalaemin, substance P, eledoisin, kassinin ). The analogs of substance P did not inhibit the actions of cholecystokinin, caerulein, gastrin, carbamylcholine, secretin, vasoactive intestinal peptide, PHI, ionophore A23187 or 8Br -cAMP. At high concentrations, [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P, but not [D-Pro2-, D- Trp7 ,9]-substance P or [D-Pro2-, D-Phe7-, D-Trp9]-substance P, caused a small but significant inhibition of bombesin-stimulated amylase release. For each analog of substance P, the inhibition was competitive in nature in that there was a rightward shift of the dose-response curve for physalaemin-stimulated amylase secretion with no change in efficacy. From Schild plots of the ability of [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P to inhibit either substance p- or physalaemin-stimulated amylase release, the slopes were not different from unity. For each analog of substance P, there was a close correlation between its ability to inhibit substance P- or physalaemin-stimulated amylase release and its ability to inhibit binding of 125I-labeled substance P or 125I-labeled physalaemin. [D-Arg1-, D-Pro2-, D- Trp7 ,9-, Leu11 ]-substance P was 2-fold more potent than [D-Pro2-, D- Trp7 ,9]-substance P which was 4-fold more potent than [D-Pro2-, D-Phe7-, D-Trp9]-substance P, (i.e., pA2 6.1, 5.9, and 5.2, respectively). For each analog, the dose-response curve for its ability to inhibit physalaemin-stimulated amylase release was superimpossible on the dose-response curve for its ability to inhibit binding of 125I-labeled physalaemin. These results indicate that each of these analogs of substance P is a specific competitive inhibitor of the action of the substance P on dispersed acini from guinea-pig pancreas, and that their abilities to inhibit substance P-induced changes in acinar cell function can be accounted for by their abilities to occupy the substance P receptor.

Amylases↗
PubMed1984

Long-term administration of a substance P antagonist, (D-Pro2, D-Trp7,9)-SP, abolishes the response to ocular trauma.

The long-term effect of ocular administration of a substance P (SP) antagonist, (D-Pro2, D-Trp7,9)-SP, was studied in the rabbit. After 2-3 months of topical administration of the antagonist twice daily, a mild trauma was applied in the form of infrared irradiation of the iris. The control eye responded with disruption of the blood-aqueous barrier, the eye treated with the antagonist did not. Two days after termination of treatment, the response to ocular injury was still reduced. Another 2 days later, ocular injury evoked a normal response, which shows that the protection was reversible. No adverse reaction to the SP antagonist was noted.

Animals↗
PubMed1984

Synthesis and biological activities of neurokinin alpha and beta.

Two novel neuropeptides, neurokinin alpha and beta isolated from porcine spinal cord, were announced. We have synthesized neurokinin alpha as Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2, which were 98-99% pure by HPLC. Assays on the isolated guinea pig ilium showed neurokinin alpha to have 81% and neurokinin beta to have 65% of the activity of Substance P. Knowledge of these three related peptides having a common activity opens new considerations of their intrinsic physiological roles in neurotransmission versus pharmacological activities, and reappraisal of the diverse activities of Substance P including that in the inflammatory response of the eye.

Amino Acid Sequence↗
PubMed1984

Quantitative determination of coenzyme Q10 in human blood for clinical studies.

A quantitative method for the determination of coenzyme Q10 (CoQ10) in human blood has been devised which allows recovery of essentially 100% of the CoQ10. The use of whole blood rather than plasma includes the CoQ10 in white cells. The method utilizes TLC instead of saponification to fractionate lipid impurities, because CoQ10 is sensitive to saponification, and utilizes CoQ11 as an internal standard which is advantageous over CoQ9 and a synthetic quinone. The final step of HPLC frequently reveals a peak with a retention time like that of CoQ9 which, being less than that of CoQ10, can be near other peaks of impurities.

Chromatography, High Pressure Liquid↗
PubMed1984

Enzymology of the response of the carpal tunnel syndrome to riboflavin and to combined riboflavin and pyridoxine.

Differential enzymic analyses of the erythrocyte glutamic-oxaloacetic transaminase and the erythrocyte glutathione reductase of a patient with a 3-yr history of the carpal tunnel syndrome (CTS) revealed high deficiencies of both vitamin B-6 and riboflavin as based on approximately equal to 30% levels of the specific activities of these enzymes. Riboflavin for 5 months caused nearly complete disappearance of the CTS and caused no change in the specific activity of erythrocyte glutamic-oxaloacetic transaminase. Combined riboflavin and pyridoxine treatment increased (P less than 0.001) the specific activities of erythrocyte glutathione reductase and erythrocyte glutamic-oxaloacetic transaminase to normal levels with total disappearance of the CTS. Objectively, the strength of pinch of both hands increased (P less than 0.001) on treatment with riboflavin and further increased (P less than 0.001) on the combined treatment. For the first time, a significant riboflavin deficiency has been found to be related to CTS. Riboflavin therapy was effective biochemically, subjectively, and objectively, and riboflavin and pyridoxine were even more effective when concomitantly administered.

Aspartate Aminotransferases↗
PubMed1984

Improved synthesis and resolution of beta-(3-pyridyl)-DL-alpha-alanine.

beta-Benzamido-alpha-(3-pyridyl)-DL-alpha-alanine hydrochloride was synthesized from 3-pyridinecarboxyaldehyde via the azlactone which was hydrolyzed to the acrylic acid before hydrogenation. The methyl ester was effectively resolved with subtilisin. The optical purity of the D-isomer was established, since the D-isomer was used in synthesis of antagonists of the luteinizing hormone releasing hormone.

Alanine↗
PubMed1984

Biological evaluation of substance P antagonists.

Five undeca- and six C-terminal heptapeptide substance P (SP) analogues were tested for their capacity to block the contractile effect of SP on the guinea-pig isolated taenia coli. They had one feature in common, namely substitutions in positions 7 and 9 in the SP molecule. In the majority of analogues D-tryptophan was used for these substitutions. All analogues tested were found to be competitive antagonists to exogenous SP and to be capable of blocking the electrically induced non-cholinergic, non-adrenergic neuronal contraction of the taenia. Of the undecapeptides, (D-Arg1, D-Pro2, D-Trp7,9, Leu11) SP and (D-Arg1, D-Trp7,9, Leu11) SP (Spantide) had the highest pA2 value, 7.1-7.2, and the lowest IC50 value, 10(-6) M. The pA2 values of the heptapeptides were generally lower. Three of the most potent antagonists were tested for specificity and found to block the smooth muscle contraction induced by SP, physalaemin, eledoisin and bombesin but not that induced by bradykinin, carbachol, 5-hydroxytryptamine, histamine, prostaglandins and vasopressin. The SP antagonists were also tested for spasmogenic effect on the taenia and for their capacity to release histamine from rat isolated peritoneal mast cells. The spasmogenic activity displayed by most of the SP antagonists tested is likely to be related to their ability to release histamine since the contractile response was reduced by mepyramine, a histamine H1-receptor antagonist. (D-Arg1, D-Trp7,9, Leu11) SP was notable for combining a high antagonistic potency with a weak spasmogenic effect (and poor histamine releasing effect).

Animals↗
PubMed1984

The biochemistry of vitamin B6 is basic to the cause of the Chinese restaurant syndrome.

The concept of this basic research was that monosodium L-glutamate could reveal a deficiency of vitamin B6 by the neurological reactions known as the Chinese Restaurant Syndrome. An other amino acid, tryptophan, administered to subjects, is known to reveal a deficiency of vitamin B6 by the excretory xanthurenic acid, etc. The presence and degree of a deficiency of vitamin B6 in 155 students on no supplemental B6 was determined by the differential assay of aspartate transaminase of erythrocytes which also allows each subject to be a control. Twenty-seven of 155 students had extraordinarily low basal specific activities of the transaminase, less than 0.26 mumol pyruvate/(h X 10(8) erythrocytes). These 27 were challenged with glutamate and a placebo. Twelve of 27 revealed the Chinese Restaurant Syndrome, and 15 did not. By double blind trials, the 12 "responders" were treated with pyridoxine and a placebo for twelve weeks, and then were rechallenged with glutamate and a placebo. Decoding showed 3 of 12 received placebo to pyridoxine and then revealed the symptoms of the syndrome again to glutamate; 9 of 12 received pyridoxine and then 8 of 9 failed to respond to glutamate. These results show, p less than 0.01, that the symptoms of the Chinese Restaurant Syndrome to oral glutamate fail to reoccur after treatment which pyridoxine, and that the biochemistry of vitamin B6 is basic to the cause of the Chinese Restaurant Syndrome.

Aspartate Aminotransferases↗
PubMed1983

Antagonists of the luteinizing hormone releasing hormone with pyridyl-alanines which completely inhibit ovulation at nanogram dosage.

[N-Ac-D-2-Nal1,pCl-D-Phe2,D-3-Pal3,D-Arg6,D-Ala10]-LHRH caused 100% and 57% inhibition of ovulation in rats, s.c., at 500 and 250 ng, respectively, and 56%, per os at 500 micrograms. [N-Ac-3,4-diC1-D-Phe1,pC1-D-Phe2,D-3-Pal3,D-Arg6,D-Ala10]-LHRH inhibited ovulation, s.c., 82% at 500 ng, and 63%, per os at 500 micrograms. These analogs are the most effective reported inhibitors of ovulation. The new introduction of pyridyl-alanines can be superior substituents. For pairs of analogs, relationships are: D-3-Pal (beta-(3-pyridyl)-D-alpha-alanine) in position 3 is superior to D-Trp3, D-2-Pal3 and D-4-Pal3. D-Arg6 was superior to D-3-Pal6 and D-4-Pal6 was superior by 2-fold to D-Arg6. D-Ala10 was superior to Gly10 and D-Abu10.

Alanine↗
PubMed1983

Cigarette smoke-induced airway oedema due to activation of capsaicin-sensitive vagal afferents and substance P release.

Exposure of rats to smoke from one cigarette caused local oedema due to a marked increased in vascular permeability from the epiglottis down to bronchioli, as indicated by extravasation of Evans blue in the airway mucosa. The cigarette smoke-induced extravasation of Evans blue was still present after removal of the tar and nicotine content of the smoke, suggesting that chemical irritants in the vapour phase were the main mediators of the vascular permeability response. Local or systemic pretreatment with capsaicin or [D-Arg1, D-Pro2, D-Trp7,9, Leu11] SP, a substance P antagonist, abolished or significantly reduced the airway oedema induced by cigarette smoke or vagal nerve stimulation. No reduction of the cigarette smoke or vagally induced tracheal oedema was seen upon pretreatment with mepyramine plus cimetidine, fentanyl, disodiumchromoglycate, methylprednisolone or terbutaline. The results thus indicate that the cigarette smoke or vagally induced tracheal oedema is most likely to be due to substance P release from local capsaicin-sensitive afferent neurons in the airway mucosa. Local administration of substance P antagonists may be considered as a pharmacological means of inhibiting local mucosal oedema in the airways caused by airway irritants such as cigarette smoke.

Afferent Pathways↗
PubMed1983

A substance P antagonist inhibits vagally induced increase in vascular permeability and bronchial smooth muscle contraction in the guinea pig.

Electrical stimulation of the cervical vagus nerve in anesthetized guinea pigs induced a rapid increase in respiratory insufflation pressure, suggesting increased airway resistance. After intravenous administration of a substance P (SP) antagonist, [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP, the insufflation pressure response to vagal stimulation was reduced by 78% while the cardiovascular effects were unchanged. Histamine receptor-blocking agents were used to inhibit the effects of histamine release induced by the SP-antagonist. [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP also reduced the increase in insufflation pressure caused by intravenous SP or capsaicin. The long-lasting noncholinergic contraction of the main and hilus bronchi induced by field stimulation in vitro, as well as the contractile effects of SP and capsaicin, were also blocked by the SP antagonist. The cholinergic contractions and the noncholinergic tracheal relaxation on field stimulation in vitro were, however, not blocked by the antagonist. Vagal stimulation in vivo also increased vascular permeability in the respiratory tract and esophagus, causing a subepithelial edema as indicated by Evans blue extravasation. Previous treatment with [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP inhibited the permeability increase induced by both vagus nerve stimulation and exogenous SP. SP release from vagal sensory nerves was indirectly shown by reduction in the bronchial levels of SP after nerve stimulation in vivo. The data suggest that a major portion of the vagally or capsaicin-induced increase in smooth muscle tone is caused by SP release from sensory neurons. In addition, activation of vagal SP-containing sensory nerves induces local edema. Tracheobronchial afferent SP-containing C fibers may thus exert local control of smooth muscle tone and vascular permeability in normal and pathophysiological conditions.

Amino Acid Sequence↗
PubMed1983

The pharmacological profile of a substance P (SP) antagonist. Evidence for the existence of subpopulations of SP receptors.

The purpose of this study was to evaluate the pharmacological properties of a substance P (SP) analogue [D-Arg, D-Pro, D-Trp, Leu]SP as an SP antagonist. This analogue, blocked the SP-induced contractions of the isolated guinea-pig ileum and the rat urinary bladder and it exhibited no spasmogenic activity on these preparations. The affinity constant (pA2) for [D-Arg, D-Pro, D-Trp, Leu]SP versus SP was 6.31 on the guinea-pig ileum preparation and 5.30 on the rat urinary bladder preparation. The slopes of the regression lines of the Schild plots were close to unity. These data indicate that [D-Arg, D-Pro, D-Trp, Leu]SP blocks SP receptors in a simple competitive manner and suggest that there are at least two subpopulations of SP receptors. The contractions caused by the closely related tachykinins eledoisin and physalaemin were also blocked by the SP analogue. However, the slopes of the regression lines were significantly different from unity. Moreover, when tested on the hamster urinary bladder, which contracts at low concentrations of eledoisin but is rather insensitive to physalaemin and SP, [D-Arg, D-Pro, D-Trp, Leu]SP did not block the contractile actions of eledoisin or of physalaemin and SP. Compared to SP eledoisin and physalaemin may bind to SP receptors in a different manner. Eledoisin also seems to interact with receptors different from the SP receptors.

Animals↗