Biomedical subjects

F Lembeck

Publications and source records attributed to F Lembeck.

At least 91 records · Page 5Linked to original sources

PubMed1984

A study of the mode and site of action of capsaicin in guinea-pig heart and rat uterus.

Capsaicin (CAP) has been shown to exert a selective neurotoxic effect on peptidergic primary afferent neurons. The effect of CAP on the isolated guinea-pig left auricle and papillary muscle preparations and on the isolated rat uterus was used to elucidate its mode and site of action with regard to cellular Ca2+ utilization. In the electrically driven left auricle CAP first increased and then decreased the size of the contractions while in the electrically driven papillary muscle CAP caused only a decrease in the contractions. Electrophysiological measurements showed that the initial increase in contraction size coincided with a decrease in the upstroke velocity of the action potential. This membrane-stabilizing effect of CAP seemed also responsible for the decrease in contractile activity. The positive inotropic effect of CAP on the left auricle was concentration-dependent (0.03-6.5 microM). The positive inotropic effect of 0.33 microM CAP was reproducible at intervals of 15 min, whereas tachyphylaxis developed at shorter intervals or higher concentrations of CAP. The percent increase in the size of contractions by 0.33 microM CAP was smaller when [Ca2+]e was doubled but larger when 2.2 microM verapamil or 0.1 mM La3+ was present. The increase in contractions by 0.4-400 microM isoproterenol was greatly reduced by 0.33 microM CAP in a noncompetitive manner. The positive inotropic effect of 2.9 microM glucagon was also inhibited by 0.33 microM CAP. In the isolated anoestrous rat uterus 0.03-3.3 microM CAP caused a transient inhibition of the spontaneous contractions similarly to the effect of 2.2 microM verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Prostaglandin release and nociceptor stimulation by peptides.

The effects of substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin octapeptide, eledoisin and bombesin on release and metabolism of incorporated (1-14C)-arachidonic acid was investigated in the isolated rabbit ear. The influence of eledoisin and bombesin on release of prostaglandins was compared with that of bradykinin (Sametz and Juan 1982). Only eledoisin and bombesin stimulated the release of prostaglandins I2 and E2 but with a lesser potency than bradykinin. Only eledoisin in a high dose stimulated nociceptors per se whereas bombesin did not. Eledoisin and bombesin in a low dose enhanced nocicpetion induced by acetylcholine in the rabbit ear; this enhancement of the algesic effect of acetylcholine was abolished by indometacin which indicates a sensitization of nociceptors by released prostaglandins. Although effects of eledoisin and bombesin are mediated at least in part by released prostaglandins, the nociceptor-stimulating and prostaglandin-releasing potency of bradykinin remaines unique among all peptides tested so far.

Animals↗

PubMed1984

Pain relief by somatostatin in attacks of cluster headache.

The pain relieving effect of somatostatin treatment during 72 attacks of cluster headache in 8 male patients was compared to treatment with ergotamine or placebo in a double-blind study. Infusion of somatostatin (25 micrograms/min for 20 min i.v.) reduced the maximal pain intensity and the duration of pain significantly compared to placebo treatment, and to a degree comparable to ergotamine tartrate treatment (250 micrograms i.m.). The results obtained provide new information concerning the possible mechanism of cluster headache attacks and suggest a new therapeutic approach.

Adult↗

PubMed1984

Intestinal peristalsis associated with release of immunoreactive substance P.

The release of immunoreactive substance P into the vascular bed of the isolated small intestine of the guinea-pig was investigated. Raising the intraluminal pressure to 5 mbar for 5 min initiated peristalsis and stimulated the release of substance P. The substance P releasing effect of pressure stimulation was reduced by 46% when hexamethonium (240 microM) was added to the perfusion solution. The ganglion stimulant drug dimethylphenylpiperazinium (32 microM) also stimulated the release of substance P; its effect was completely prevented by hexamethonium (240 microM). Intraarterial infusion of capsaicin (22 microM), a neurotoxin known to act on sensory substance P-containing neurones, stimulated the release of substance P and caused intestinal contractions. The motor effect of capsaicin in the gut can thus be explained by release of substance P from sensory nerve endings in the gut. Systemic pretreatment of the guinea-pigs with capsaicin abolished the release of substance P due to capsaicin, whereas that evoked by elevated intraluminal pressure or dimethylphenylpiperazinium was not reduced. This means that substance P released in the course of peristalsis or by dimethylphenylpiperazinium originates from neurones intrinsic to the intestine. These findings indicate that intestinal peristalsis is associated with the release of substance P from enteric neurones. Substance P is likely to be a neurotransmitter involved in the coordination of the peristaltic reflex.

Animals↗

PubMed1984

Distribution of spinal cord nerve endings containing various neurotransmitters on a continuous density gradient.

Homogenates of rat dorsal or ventral spinal cord were subjected to centrifugation on a continuous density gradient. The gradient was generated according to a new method with the aid of a microprocessor-controlled HPLC pump. The distribution of substance P-like immunoreactivity (SPI) and somatostatin-like immunoreactivity (SRIFI) across the gradient showed two peaks. The SPI peak seen at lower density was found only in dorsal spinal cord tissue. No peak of SPI was seen at this position in homogenates prepared from the spinal cords of capsaicin-pretreated rats. The second peak of SPI, found at a higher density, was accompanied by peaks in the levels of endogenous 5-hydroxytryptamine (5-HT), [14C]glycine, and [3H]norepinephrine uptake. This peak was seen at the same density in the dorsal and the ventral spinal cord. Tissue derived from capsaicin-pretreated rats exhibited one peak of SPI, accompanied by a maximum of [14C]glycine uptake. The uptake of [3H]gamma-aminobutyric acid ( [3H]GABA) was found to have a maximum at a somewhat lower density than that of [14C]glycine. It is concluded that the peak of SPI found at lower density in the dorsal spinal cord is associated with nerve endings belonging to capsaicin-sensitive primary afferents, while other endings, including those also containing 5-HT, are probably associated with the peak of SPI found at higher density.

Animals↗

PubMed1984

Release of dynorphin, somatostatin and substance P from the vascularly perfused small intestine of the guinea-pig during peristalsis.

The release of dynorphin-(1-17), somatostatin and substance P into the venous effluate of the isolated and vascularly perfused guinea-pig small intestine was measured during rest and peristaltic activity. The peptides were determined by specific radioimmunoassays. Increasing the intraluminal pressure by 5 mbar increased the release of dynorphin-(1-17), somatostatin and substance P. A substantial increase in the release of substance P was only seen in the presence of naloxone (1.5 microM) indicating an inhibitory influence of opioid peptide-containing neurones on the release of substance P. The pressure-induced release of substance P and dynorphin-(1-17) was completely prevented by tetrodotoxin (1.3 microM), which suggests a neural origin of these two peptides. The pressure-induced release of somatostatin was only partially inhibited by tetrodotoxin (1.3 microM) suggesting that somatostatin may also be released from non-neuronal sources, i.e. endocrine mucosal cells. Dimethylphenylpiperazinium (32 microM) increased the release of somatostatin and substance P and this effect was inhibited by tetrodotoxin (1.3 microM). Cholecystokinin-octapeptide (38 nM) induced a large increase in the release of somatostatin but only a minute increase in the release of substance P; these effects of cholecystokinin-octapeptide were not blocked by tetrodotoxin (1.3 microM). Noradrenaline (59 microM) inhibited the pressure-induced release of substance P but not that induced by dimethylphenylpiperazinium (32 microM). Neither the pressure-induced nor the dimethylphenylpiperazinium-evoked release of somatostatin was significantly diminished by noradrenaline. These results indicate that dynorphin-(1-17), somatostatin and substance P may be transmitters involved in the coordination of the peristaltic reflex. Part of the inhibitory effects of opioid peptides and noradrenaline on intestinal motility may be brought about by inhibition of the release of substance P.

Animals↗

PubMed1984

Systemic capsaicin treatment impairs the micturition reflex in the rat.

Filling the urinary bladder via a urethral cannula and preventing its voiding in anaesthetized rats led to rhythmic contractions of the detrusor muscle, which lasted for more than 1 h. This rhythmic activity ceased about 30 min after a s.c. injection of 50 mg kg-1 capsaicin. The contractile response of the detrusor to topically applied capsaicin was lost after systemic administration of the toxin, whereas no change in the sensitivity to acetylcholine was observed. Urinary bladders of normal rats had a capacity of about 1 ml. Bladders of rats treated with capsaicin as neonates held a volume of more than 5 ml without contracting. Such bladders were insensitive to topically applied capsaicin but they contracted to acetylcholine as strongly as the bladders of control rats. During an observation period of 3 days control rats gained weight at night and lost weight by day. Rats treated with capsaicin as neonates showed little fluctuation in body weight. Such rats hardly excreted any urine by day although at night they excreted as much as controls. A water load of 5 ml 100 g-1 was excreted by control rats within 3 h. Rats treated with capsaicin as neonates excreted only half as much. In addition, 50% of the water load was excreted far later by capsaicin treated rats than by controls. Few changes were observed in rats treated with capsaicin as adults. It is concluded that all primary afferent fibres mediating the sensation of a full bladder are capsaicin-sensitive. An additional effect of capsaicin on renal mechanisms cannot be excluded.

Animals↗

PubMed1984

Comparison of nonivamide and capsaicin with regard to their pharmacokinetics and effects on sensory neurons.

Nonanoyl vanillylamide (nonivamide NVA) was compared with trans-8-methyl-N-vanillyl-nonenamide (capsaicin, CAP) with regard to their pharmacokinetic properties, their potency in stimulating primary afferent neurons and depleting them of substance P and somatostatin in rats. Following the injection of 50 mg kg-1 the time course of the presence of NVA in brain and blood was similar to that of CAP. The concentration of NVA in brain was higher than in blood; the reverse was true for CAP. The ability of NVA and CAP to stimulate afferent neurons was measured by the reflex depressor response following i.v. injection and by the number of wiping movements following instillation of the substances into the eye. In both tests, the potency of NVA was about half of that of CAP. Treatment of newborn rats by s.c. injections of 50 mg kg-1 NVA or CAP seemed to cause a larger depletion of substance P and somatostatin in the sciatic nerve and the spinal cord than treatment of adult rats. Depletion by CAP was generally larger than that by NVA although depletion experiments are hardly suitable for quantification. The depletion of substance P by CAP and NVA could be correlated with the extent to which ocular chemosensitivity and neurogenic plasma extravasations were attenuated. The methods used are discussed in view of their possible use in screening further capsaicin analogues.

Animals↗

PubMed1983

Phenyldiguanide and capsaicin stimulate functionally different populations of afferent C-fibers.

Effects of phenyldiguanide (PDG) and capsaicin (CAP) were compared. (1) The reflex fall in blood pressure following PDG i.v. was only partially but that following CAP i.v. completely inhibited in capsaicin-desensitized rats. (2) Bilateral vagotomy in rats abolished cardiovascular reflexes by PDG i.v., but not those by CAP i.v. (3) Instillation of PDG into the rat trachea did not cause neurogenic plasma extravasation whereas CAP does. (4) Bronchial tone of guinea-pigs remained unchanged after PDG i.v. whereas it was increased by CAP i.v. It is concluded that PDG activates vagal afferent fibers which are distinct from the substance P-containing afferent fibers stimulated by CAP.

Animals↗

PubMed1983

Capsaicin-induced substance P release and sensory control of vascular permeability in the guinea-pig ureter.

Substance P-immunoreactivity (SP-IR) in the guinea-pig ureter was found to be totally depleted after systemic capsaicin pretreatment. Removal of the inferior mesenteric ganglion (IMG) led to a total depletion of SP-IR from the rostral third of the ureter and to a partial depletion from the caudal third. Electrical stimulation of the IMG caused Evans blue extravasation mainly in the rostral third of both ureters, whereas stimulation of the right pelvic nerve caused Evans blue extravasation in the caudal third of the ureters on both sides. The responses to nerve stimulation were absent in capsaicin-pretreated animals. Furthermore, capsaicin caused release of SP-IR from ureter slices in vitro, this release was not inhibited by tetrodotoxin. Potassium (60 and 120 mM) also released SP-IR. It is concluded that SP-IR in the ureter is contained in capsaicin-sensitive sensory neurons reaching the ureter via both parasympathetic (caudal part) and sympathetic nerves (rostral part). Activation of these neurons by capsaicin leads to a peripheral release of SP-IR which most likely increases vascular permeability.

Animals↗

PubMed1983

Sympathetic control of substance P releasing enteric neurones in the guinea pig ileum.

The contractile response of the isolated guinea-pig ileum to cholecystokinin octapeptide (CCK-8) that remained in the presence of atropine was greatly inhibited by the substance P antagonist D-Pro2,D-Trp7,9-substance P. This indicates that the atropine-resistant contraction to CCK-8 is mediated by the release of substance P from enteric neurones. Activation of alpha-adrenergic receptors by noradrenaline, clonidine or mesenteric sympathetic nerve stimulation inhibited the atropine-resistant contraction to CCK-8 but did not affect the contractile effect of substance P. It is concluded that alpha-adrenergic receptors exert an inhibitory influence on the release of substance P from enteric neurones.

Adrenergic alpha-Agonists↗

PubMed1983

[D-Met2, Pro5]enkephalinamide and dynorphin-(1-13) inhibit the cholinergic contraction induced in the guinea-pig ileum by substance P.

In the isolated guinea-pig ileum, the sustained phase of the longitudinal contractile response to substance P is, unlike the initial peak response, mediated by stimulation of cholinergic neurons. This cholinergically mediated response to substance P was inhibited by the specific substance P antagonist, [D-Pro2,D-Trp7,9]substance P, which suggests that substance P stimulates enteric cholinergic neurons through a specific site of action. [D-Met2,Pro5]enkephalinamide and dynorphin-(1-13) also decreased whereas naloxone increased the sustained response to substance P. The results indicate that the enteric cholinergic neurons, which are stimulated by substance P, are also under the control of enkephalin and/or dynorphin neurons.

Animals↗

PubMed1983

The effect of capsaicin application to a peripheral nerve on impulse conduction in functionally identified afferent nerve fibres.

Capsaicin applied locally to a coccygeal or saphenous nerve of rats was shown to block impulse conduction in unmyelinated afferent nerve fibres. Shortly after application of capsaicin (1% dissolved in 10% Tween 80 in paraffin oil) conduction of C-fibre--but not A-fibre--compound action potentials across the application site was markedly diminished. No recovery occurred during the period of observation, i.e. up to 2 h afterwards. C-Fibre compound action potentials stimulated and recorded proximal to the application site seemed to be unaffected. Solvent application had no effect. Recording from single units revealed that nociceptive C-fibres responding to strong mechanical and heat stimulation (MH units, polymodal nociceptors) were blocked. In contrast, unmyelinated cold fibres were not affected. The selective block of MH units indicates different membrane properties of unmyelinated MH and cold units not only at the receptive nerve endings, but also at the axons, to which capsaicin was applied.

Action Potentials↗

PubMed1983

Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis.

Capsaicin (20-80 mg/kg, s.c.) reduced the inflammatory response to inoculation with Mycobacterium butyricum in the rat. The effect was apparent within 24 h, was partial, persisted for well over 20 days, and occurred irrespective of whether capsaicin was administered before or after the onset of inflammation, or at the time when the pathology reached peak. Capsaicin also attenuated the increase in substance P content in sciatic nerve, saphenous nerve, dorsal root ganglia, dorsal roots, and dorsal spinal cord (L4, L5) which occurs in rats with adjuvant arthritis. The data are consistent with a possible role of substance P in the peripheral manifestations of adjuvant arthritis.

Animals↗

PubMed1983

Capsaicin-induced reflex fall in rat blood pressure is mediated by afferent substance P-containing neurones via a reflex centre in the brain stem.

Injection of 0.03 micrograms capsaicin into one femoral artery elicited a fall in blood pressure in the rat. This effect was completely and reversibly abolished following intrathecal injection of 1 nmol of the specific substance P antagonist, [D-Pro2,D-Trp7,9] substance P. The capsaicin-evoked depressor reflex is therefore exclusively mediated by substance P-containing primary afferent fibres. Using spinal rats or decerebration experiments, the centre of the capsaicin-evoked reflex fall in blood pressure could be localized in the brain stem.

Animals↗

PubMed1983

Vascular protein linkage in various tissue induced by substance P, capsaicin, bradykinin, serotonin, histamine and by antigen challenge.

Plasma extravasation was induced in rats or guinea-pigs by intravenous injections of (1) substance P (SP), (2) the C-terminal SP-hexapeptide SP(6--11), (3) serotonin (5-HT), (4) histamine, (5) bradykinin, (6) capsaicin and (7) by antigen challenge. Plasma extravasation induced by SP, SP(6--11), by 5-HT and by capsaicin was, with few exceptions, observed in the same tissues. The effect of SP was not blocked by H1 and H2 histamine receptor antagonists. The effect of i.v. capsaicin was absent in capsaicin desensitized animals. Plasma extravasation upon i.v. SP, SP(6--11), 5-HT and capsaicin was seen in the skin and in all organs containing mucous membranes except the intestinal mucosa. Plasma extravasation by histamine, bradykinin, and antigen challenge of sensitized guinea-pig was, in addition, also observed in the stomach and intestine. Plasma extravasation and bronchoconstriction by antigen challenge with 20 micrograms/kg ovalbumin was completely blocked by combined H1 and H2 histamine receptor blockade. Both responses were reduced to about the half capsaicin desensitized guinea-pigs, although the reduction of the permeability response was statistically not significant in all organs. In conclusion, several substances including anaphylaxis induce protein leakage in many tissues with differing selective distribution patterns. Anaphylactic histamine release leads to protein leakage partly via activation of sensory neurons. SP is a likely mediator of neurogenic protein leakage in many organs.

Animals↗

PubMed1983

Reflex fall in blood pressure mediated by capsaicin-sensitive afferent fibers of the rat splanchnic nerve.

1. Capsaicin treated rats, in which the function of substance P-containing primary sensory neurons was impaired, were used to investigate the function of afferent fibers within the splanchnic nerve. The effects of electrical stimulation of the splanchnic nerve either distal or proximal to the site of its transsection on blood pressure and heart rate were investigated. 2. Distal splanchnic nerve stimulation evoked an equal rise in blood pressure in capsaicin treated rats and in their controls. Distal splanchnic nerve stimulation did not cause plasma extravasation in the adrenal medulla, an effect which is produced by antidromic stimulation of cutaneous sensory nerves. Peripheral effects of stimulation of primary afferent fibers within the splanchnic nerve cannot be assumed from these experiments. 3. Proximal stimulation of the splanchnic nerve evoked a reflex fall in blood pressure but no bradycardia. The fall in blood pressure was absent in capsaicin treated rats, which indicates that this effect is mediated by primary afferent fibers. Since the reflex fall in blood pressure was abolished by adrenergic blockade with guanethidine, it can be explained by vasodilatation resulting from reduction of sympathetic vasoconstrictor tone.

Animals↗

PubMed1983

Release of histamine by neuropeptides from the perfused rat hindquarter.

The release of histamine and serotonin by neuropeptides and capsaicin was measured in the isolated perfused rat hindquarter preparation. Substance P and two antagonistic peptides, [D-Pro2, D-Phe7, D-Trp9]-SP and [D-Pro2, D-Trp7,9)]-SP, release histamine, the SP(4-11) and SP(6-11) analogues did not. VIP and somatostatin released histamine and also serotonin. No amines were released by bombesin. Thus, all amine releasing peptides possessed at least two basic charges. However, the histamine releasing activity of the neuropeptides tested did not correlate with their reported ability to cause vasodilation and plasma extravasation. The SP(4-11) and SP(6-11) analogues which did not release histamine caused plasma extravasation. It is concluded that SP causes plasma extravasation by a direct action on blood vessels. Capsaicin released only serotonin but no histamine either in untreated rats and such desensitized with capsaicin as neonates. In rats desensitized with capsaicin 4 days prior to the experiment the substance P induced histamine release was as high as in untreated controls; it was, however, absent in rats desensitized with capsaicin as neonates. It is assumed that the sensitivity of mast cells to substance P is lost after degeneration of substance P containing primary sensory fibers.

Animals↗