Biomedical subjects

I T Lippe

Publications and source records attributed to I T Lippe.

50 records · Page 3Linked to original sources

PubMed1987

Evaluation of a new and potent cholecystokinin antagonist on motor responses of the guinea-pig intestine.

The potency and selectivity of D,L-4-(3,4-dichloro-benzoyl-amino)-5-(dipentyl-amino)-5-oxo-pen tan oic acid (CR 1409) as a cholecystokinin (CCK) antagonist was investigated on motor responses of the longitudinal and circular muscles of the guinea-pig isolated ileum. CR 1409 was further used to examine whether nerve-mediated motor responses to electrical field stimulation or distension of the gut wall may involve the release of CCK-like peptides. CR 1409 (0.06-2.1 microM) antagonized longitudinal muscle responses to ceruletide (caerulein, a CCK-related decapeptide) in a concentration dependent and competitive manner (pA2 7.77); responses to CCK-octapeptide (CCK-8) were antagonized with a similar potency. Contractions of the circular muscle evoked by ceruletide were also blocked by CR 1409 (0.2-0.4 microM). Longitudinal muscle contractions in response to dimethylphenylpiperazinium, bethanechol, histamine, substance P, or 5-hydroxytryptamine (5-HT), and circular muscle contractions evoked by acetylcholine, 5-HT, substance P, or substance K were not altered by CR 1409 (0.4 microM). Longitudinal muscle contractions induced by electrical field stimulation (with pulses delivered at 0.05 and 1 Hz in the absence, and at 5 Hz in the presence of atropine) were not or only slightly reduced by CR 1409 (0.4 microM). Longitudinal contractions due to activation of extrinsic nerves by capsaicin remained unaltered in the presence of CR 1409 (0.4 microM). Reflex contractions of the circular muscle, induced by balloon distension and recorded orally to the site of distension, and peristaltic activity elicited by intraluminal infusion of Tyrode solution remained unaffected by CR 1409 (0.4 microM). 5 These findings indicate that CR 1409 is a potent and selective antagonist of CCK-like peptides in the guinea-pig ileum. The results do not provide any evidence that CCK-like peptides, released from extrinsic or intrinsic neurones, are involved in nerve-mediated contractions of intestinal muscle and in the peristaltic reflex.

Animals↗

PubMed1987

Involvement of capsaicin-sensitive sensory neurons in gastrointestinal function.

There is both morphological and functional evidence that capsaicin-sensitive sensory neurons innervate the digestive tract. The possible function of these neurons in gastric ulceration and gastrointestinal motility was investigated in rats which had been systemically pretreated with capsaicin (50-125 mg/kg). It was found that capsaicin-sensitive afferent neurons do not participate in the physiologic control of gastrointestinal propulsion. However, the inhibition of gastrointestinal transit due to surgical trauma or peritoneal irritation with iodine was reduced in capsaicin-treated rats. It was concluded that capsaicin-sensitive sensory neurons may be involved in sympathetic reflex inhibition of gastrointestinal propulsion. Gastric ulceration induced by the intraperitoneal injection of indomethacin or intragastric administration of ethanol was greatly aggravated in capsaicin-treated rats. Since an involvement of the autonomic nervous system as well as of histamine and prostaglandins in this effect of capsaicin treatment could be ruled out, further support was lent to the previously proposed hypothesis that sensory nerve endings can protect the gastric mucosa against ulceration by the local release of vasodilator substances.

Afferent Pathways↗

PubMed1986

Effect of pancreatic polypeptide on the motility of the guinea-pig small intestine in vitro.

The effect of porcine pancreatic polypeptide (PP) on the motor activity of the longitudinal and circular muscles of the guinea-pig isolated small intestine was investigated. PP (0.2-20 nM) inhibited cholinergic contractions of the longitudinal muscle in response to electrical field stimulation, the maximal effect being a 30% reduction of the contraction amplitude. Carbachol-induced contractions of the longitudinal muscle were not affected by PP (10 nM). PP (0.3-30 nM) also inhibited reflex contractions of the circular muscle elicited by balloon distension and recorded orally to the site of distension; the maximal effect was a 80% reduction of the reflex contraction. In contrast, carbachol-induced contractions of the circular muscle remained unaltered by PP (10 nM). It was further found that PP (10 and 100 nM) enhanced the threshold intraluminal pressure at which peristaltic waves were triggered. All these effects of PP appeared to be transient. Taken together, these data indicate that PP does not act on intestinal smooth muscle but can modulate the activity of certain enteric neurones which are involved in the regulation of intestinal motility.

Animals↗

PubMed1986

Inhibition of gastrointestinal transit due to surgical trauma or peritoneal irritation is reduced in capsaicin-treated rats.

Treatment of newborn rats with capsaicin (0.16 mmol/kg) is known to cause a permanent degeneration of mainly unmyelinated afferent neurons. In this study, postoperative ileus and ileus produced by peritoneal irritation with iodine were investigated in adult rats treated with capsaicin as neonates. It was found that in capsaicin-treated rats both forms of ileus, measured as inhibition of gastrointestinal transit, were significantly reduced as compared with vehicle-treated control animals. Adrenoceptor blockade in untreated rats reduced the ileus in response to peritoneal irritation to approximately the same degree as treatment with capsaicin. In capsaicin-treated rats, however, adrenoceptor blockade was without effect on the irritation-induced ileus. It is concluded that ileus in response to surgery or peritoneal irritation is due, at least in part, to activation of a neural reflex. The afferent limb of this reflex may be constituted by capsaicin-sensitive nerve fibers, whereas the efferent limb seems to involve sympathetic adrenergic neurons.

Animals↗

PubMed1985

The inhibitory effect of neurotensin on the motor activity of rabbit ileum: dependence on the ionic environment.

The possible ionic mechanisms underlying the inhibitory effect of neurotensin on the spontaneous phasic contractions of the longitudinal muscle of the isolated rabbit ileum were studied by varying the ionic environment. Neurotensin (0.06-60 nM) reduced and abolished the phasic contractions in a concentration-dependent manner. The effect of neurotensin was transient, and the phasic contractions began to recover after 1-3 min although neurotensin was not washed out. The response to neurotensin was very sensitive to alterations in the ionic composition of the bath medium. The changes in the effect of neurotensin brought about by changes in [Na+], [K+], [Ca2+], and [Cl-] suggest that neurotensin hyperpolarizes the smooth muscle. In addition, the effect of combined changes in [Ca2+] and [Cl-] points to a specific role of these ions in the action of neurotensin.

Animals↗

PubMed1985

Substance P action on phosphoinositides in guinea-pig intestinal muscle: a possible transduction mechanism?

The effect of substance P on the metabolism of membrane phosphoinositides and the possible role of this effect in the contractile response to substance P was investigated in longitudinal muscle strips obtained from the guinea-pig small intestine and prelabelled with [3H] inositol. Substance P (2.2 microM) failed to change significantly the tissue content of phosphoinositides but caused an accumulation of their water-soluble hydrolysis products, inositol bisphosphate (InsP2) and inositol monophosphate (InsP). These experiments were carried out in the presence of Li+ (12 mM), since only under these conditions could an accumulation of InsP2 be observed. The rate at which InsP2 and InsP accumulated was highest during the first 0.5 min of exposure to substance P (2.2 microM) and then decreased rapidly. Thus, the rate of inositol phosphate accumulation paralleled the time course of the contractile response to substance P. The magnitude of inositol phosphate accumulation was related to the concentration of substance P (22 nM-22 microM). The substance P-induced accumulation of InsP2 and InsP was not reduced when muscle strips had been incubated in Ca2+-free medium, for a time period sufficient to deplete the intracellular Ca2+ store which can be released by substance P, or in Ca2+-free medium containing high [K+]. These findings are compatible with the concept that hydrolysis of membrane phosphoinositides is a mechanism that links substance P receptor activation to contraction but further work is needed to establish a causal relationship.

Animals↗

PubMed1984

Substance P can contract the longitudinal muscle of the guinea-pig small intestine by releasing intracellular calcium.

The contraction of the longitudinal muscle of the guinea-pig isolated ileum in response to substance P (SP) in high [K+] medium and in Ca2+-free solution which contained EGTA has been investigated in order to examine whether excitation-contraction coupling involves the release of Ca2+ from an intracellular store. In tissues contracted by K+, high concentrations of SP (greater than or equal to 0.1 microM) were still capable of causing a slight, transient contraction. Bathing the ileum in a Ca2+-free medium for 2.5 min greatly diminished the potency and efficacy of SP in contracting the longitudinal muscle but concentrations of 2.2-22 microM SP were still able to produce a response 30-40% of maximal. The responsiveness to SP was completely lost within 10 min of bathing in Ca2+-free medium but was partially restored by a brief exposure (0.5-2 min) to high concentrations of Ca2+ (9-72 mM). The restorative effect of Ca2+ depended on the concentration of Ca2+ and on the time for which the tissue was exposed to this Ca2+ concentration. The fact that high concentrations of SP were able to elicit a contraction in media containing high [K+] or no Ca2+, suggested that they may do so by releasing Ca2+ from an intracellular store which is not as sensitive to removal of extracellular Ca2+ or as easily accessible to EGTA as the extracellular space of the muscle. The location of this store is not known; it may be associated with the internal side of the cell membrane. There is apparently an overlap between the Ca2+ pool associated with the action of SP and the Ca2+ pools utilized by acetylcholine, histamine or tetraethylammonium, which accounts for the cross-desensitization observed between these agonists. It was not possible to determine whether autodesensitization to SP also results from depletion of an intracellular Ca2+ store.

Acetylcholine↗

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↗

PubMedDate not supplied

Protein kinase C may regulate the tonic component of intestinal smooth muscle contraction in response to substance P.

(1) The study investigated a possible involvement of protein kinase C (PKC) in the substance P-induced contraction of the longitudinal muscle of the guinea-pig isolated ileum. (2) The predominant effect of the PKC activator, phorbol-12,13-dibutyrate (PDB), was to change the time course of the response to substance P. While the initial peak contraction was hardly influenced by PDB, the fading of the contraction was accelerated to an extent that any tonic contraction which normally followed the initial peak response was prevented. This inhibitory effect of PDB on the tonic contraction was immediate in onset and related to its concentration (20-200 nM); responses to half-maximally (2-7 nM) or maximally effective (0.74 microM) concentrations of substance P were affected in the same manner. Tetrodotoxin (0.6 microM) did not alter the effect of PDB. Phorbol-13-monoacetate (2 microM), a phorbol ester which does not stimulate PKC, failed to change the time course of the substance P-induced contraction. (3) The tonic component of half-maximal contractile responses to histamine (0.2-0.4 microM) was also depressed by PDB (0.2 microM) whereas the tonic component of maximal responses to histamine (9 microM) was enhanced. (4) PDB (0.2 microM) reduced desensitization to substance P as judged by the reduction of the peak response to substance P (2-7 nM) following a 10-min exposure to a high concentration of the peptide (0.74 microM). (5) The PKC inhibitor, polymyxin B (0.1-0.3 mM), reduced the peak contractile response to substance P, slowed the fading of the contraction, and antagonized the inhibitory effect of PDB on the tonic contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Enhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts.

It is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dtmax) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dtmax (4196 +/- 74 mm Hg s-1) and beating rate (322 +/- 8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p less than 0.001) than those of the euthyroid hearts (3267 +/- 115 mm Hg s-1 and 260 +/- 6 beats/min at an external Ca2+ of 2.5 mM). At 2.5 mM Ca2+, the working hyperthyroid hearts again displayed enhanced contractility (5636 +/- 179 mm Hg s-1 vs 4508 +/- 172 mm Hg s-1; p less than 0.001) but the spontaneous beating rate (275 +/- 7 beats/min) was not significantly different from euthyroid (261 +/- 8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p less than 0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H2O to 120 cm H2O caused significant changes in left ventricular pressure and dP/dtmax in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H2O; hyperthyroid, 294 +/- 9 beats/min; euthyroid, 224 +/- 10 beats/min; p less than 0.001). Alteration of the preload (10 to 25 cm H2O) and afterload (75 to 105 cm H2O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dtmax but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.

Animals↗

PubMedDate not supplied

The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart.

The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and euthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dtmax) was lower in the hyperthyroid (0.81 +/- 0.07 mM) than in the euthyroid hearts (1.12 +/- 0.09 mM, p less than 0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p less than 0.01) depression in dP/dtmax after 12 min in the hyperthyroid (50 +/- 7%) than in the euthyroid heart (15 +/- 2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.

Animals↗

PubMedDate not supplied

Density distribution of guinea pig myenteric plexus nerve endings containing immunoreactive substance P.

The present study was performed to investigate how myenteric plexus nerve endings containing substance P are distributed in sucrose density gradients in relation to nerve endings capable of taking up 3H-acetylcholine or 14C-noradrenaline. The peak of substance P-immunoreactivity (ISP) was found at a density of 1.157 +/- 0.001 g X ml-1, that of 3H-radioactivity at 1.160 +/- 0.002 and that of 14C-radioactivity at 1.162 +/- 0.002 g X ml-1 (mean +/- SEM, N = 6); there was considerable overlap. In a second set of experiments, the resuspended P2-pellet was layered upon a discontinuous density gradient consisting of 0.6, 1.0, 1.2 and 1.4 M sucrose. Nine fractions were recovered. There was a 2.5-3.4-fold increase in the relative specific activity of ISP in the 1.2 M fraction (density = 1.154 g X ml-1) and the adjoining interfaces. Conventional electron microscopy showed that synaptosomal elements were present in the transmitter-enriched fractions. It is concluded that the substance P-containing nerve endings of the guinea pig myenteric plexus co-distribute (and may be co-purified with) nerve endings utilizing noradrenaline or acetylcholine on sucrose density gradients.

Acetylcholine↗

PubMedDate not supplied

Tachykinins protect against ethanol-induced gastric lesions in rats.

Subcutaneous pretreatment of rats with neurokinin (NK) A or the fragment NKA(4-10) reduced the degree of gastric lesions induced by oral administration of 96% ethanol. The protective effect of NKA(4-10) was dose-dependent. Arg-NKB, the water soluble derivative of NKB, was less effective than NKA or NKA(4-10) while [Me-Phe7]NKB, substance P (SP) and SP-methyl-ester were inactive. The NKA(4-10) antilesion effect was reversed by pretreatment with N-ethyl-maleimide, suggesting a possible involvement of sulphydryls in its action. Among the nonmammalian tachykinins, kassinin significantly reduced ethanol-induced lesions while eledoisin and physalaemin at equivalent molar doses were inactive. These results provide, for the first time, evidence that tachykinins and their derivatives exert gastroprotective activity toward ethanol-induced haemorrhagic lesions. Assuming a receptor-mediated mechanism, NK-2 sites could be involved.

Animals↗

PubMedDate not supplied

Sensory nerves, nitric oxide and NANC vasodilatation.

Primary afferent neurons, originating from the dorsal root ganglia, provide a perivascular network of fibres around the arterial system throughout the body. When stimulated, these fibres cause a nonadrenergic noncholinergic (NANC) vasodilatation by release of calcitonin gene-related peptide (CGRP). This peptide is a potent vasodilator and, in this action, cooperates with nitric oxide (NO) in a tissue-specific manner. The hyperaemic effect of intravascularly injected rat CGRP-alpha in the rat gastric mucosa is reduced by blockade of the NO synthesis, which indicates that CGRP dilates the gastric microvascular bed via NO-dependent and -independent mechanisms. This is also true for endogenous CGRP, as the gastric mucosal hyperaemia, which is caused by gastric acid challenge and involves CGRP, is likewise blocked by inhibition of the NO synthesis. The CGRP/NO-mediated vasodilatation is an important element of a neural emergency system that strengthens the resistance of the gastric mucosa in the face of pending acid injury. In the rat skin, CGRP participates in neurogenic inflammatory processes but the cutaneous vasodilator action of exogenous CGRP and the CGRP-mediated vasodilatation, evoked by antidromic stimulation of afferent nerve fibres, do not depend on the formation of NO. This L-arginine-derived autacoid, however, plays a role in the release of CGRP from afferent nerve fibres in the skin since it contributes to the CGRP-mediated vasodilator responses to chemical irritation or immunological challenge via interleukin-1 beta. These data indicate that the type of interaction between CGRP and NO in causing a NANC vasodilatation varies with the vascular bed under study. Depending on the tissue, NO may facilitate the release of CGRP from afferent nerve fibres or be a secondary vasorelaxant messenger of the peptide.

Afferent Pathways↗