Biomedical subjects

Z Khalil

Publications and source records attributed to Z Khalil.

47 records · Page 3Linked to original sources

PubMed1989

Substance P induced hydrolysis of inositol phospholipids in rat skin in an in vivo model of inflammation.

The present study was undertaken to study the ability of substance P (SP) to induce inositol phospholipid (IP) hydrolysis measured as inositol mono-phosphate (IP1) accumulation, in an in vivo blister model of neurogenic inflammation in the rat hind footpad. SP was found to induce IP1 accumulation in a concentration dependent manner. The use of SP analogues (SP5-11 and SP1-7) indicated that the response is mainly mediated by the C-terminal sequence of the peptide. The response was significantly reduced by the SP antagonist spantide, suggesting that the response is mostly due to activation of the SP receptor on small diameter vessels. Capsaicin pretreatment did not have an effect on the ability of SP to induce the response. Experiments with mepyramine suggest that the response is also partly mediated by SP induced histamine release from mast cells. This is the first study to provide direct evidence for phosphoinositide mediated SP effects in the skin.

Animals↗

PubMed1989

Sympathetic neurons modulate plasma extravasation in the rat through a non-adrenergic mechanism.

A blister model of inflammation in the rat hind footpad was used to study the possible interaction between noradrenergic sympathetic fibres and primary afferent unmyelinated fibres which contain substance P (SP), the putative mediator of neurogenic inflammation. Plasma protein extravasation (PE) was used as a measure of the response of post-capillary venules to SP perfused over the blister base. In rats treated with 6-hydroxydopamine (6-OHDA, 75 mg/kg/day for 3 days intraperitoneally) PE was reduced by 42%. However, in rats treated by local perfusion of the blister base with noradrenaline (1 mumol/L) PE was also reduced. As prostaglandins have been postulated to effect some sympathetically mediated responses, PGE1 (1 mumol/L) was perfused over the blister base and found to enhance the response to SP. The results indicate that sympathetic noradrenergic neurones may contribute to SP-induced plasma extravasation by a sensitising mechanism independent of noradrenaline.

Alprostadil↗

PubMed1988

Effect of substance P on nicotine-induced desensitization of cultured bovine adrenal chromaffin cells: possible receptor subtypes.

The neuropeptide substance P (SP) has been reassessed for its ability to modify nicotine-induced catecholamine secretion from cultured bovine, adrenal chromaffin cells. SP exhibited biphasic effects in its actions of inhibiting the nicotinic secretory response and protecting against desensitization. At low concentrations, up to 3 microM, SP partially inhibited or partially protected the nicotine response by 15-20%, and at high concentrations (30 microM), SP markedly inhibited or markedly protected the nicotinic response by 80 or 92%, respectively. The SP antagonist (D-Arg1-D-Pro2-D-Trp7,9-Leu11-SP) completely blocked both effects produced by low concentrations of SP, but not those produced by high concentrations. It is concluded that SP is more potent at protecting against desensitization than at inhibiting the nicotinic response and that SP might modulate CA release through activation of two receptor subtypes.

Adrenal Medulla↗

PubMed1988

Mammalian tachykinins modulate the nicotinic secretory response of cultured bovine adrenal chromaffin cells.

We have studied the modulatory actions of two members of the tachykinin family (neurokinin A and B) on endogenous catecholamine (CA) secretion from cultured adrenal chromaffin cells. Their ability to modulate the nicotinic response was compared to that of substance P (SP). Both neurokinin A and neurokinin B were found to have two distinct actions similar to SP, on nicotine-induced CA release: (1) an inhibitory action at low nicotine concentrations; and (2) a protective action against desensitization by high nicotine concentrations. However, on a molar basis, the efficacy of neurokinin A or B to modulate the nicotinic response (both inhibition or protection) was 30 times less than SP. We have also tested the ability of a SP antagonist (D-Arg1-D-Pro2-D-Trp7,9-Leu11-SP) to antagonize the modulatory actions of SP on the nicotinic response. The results suggest the possibility that SP's actions on the bovine adrenal chromaffin cells might be mediated through two receptor subtypes of two different affinities.

Adrenal Medulla↗

PubMed1988

VIP modulates substance P-induced plasma extravasation in vivo.

Substance P (SP), a putative mediator of neurogenic inflammation, has previously been shown to induce plasma extravasation when exogenously perfused over a blister base induced on the rat hind foot pad. Using the same animal model, we have studied the role of vasoactive intestinal polypeptide (VIP), one of the neuromodulators in primary afferent neurons, on SP-induced plasma extravasation. At all concentrations tested (2.5, 5 and 10 microM), VIP did not cause plasma extravasation by itself, however, it increased that due to 1 microM SP, in a dose-related manner. We have also studied the effect of VIP on the local blood flow in the blister base using a laser doppler-flowmeter. VIP was also found to increase the local blood flow in a dose-dependent manner. The present results provide evidence for the first time in vivo of a role for VIP in modulating a neurogenic inflammatory response induced by SP. The mechanism underlying this action is probably related to the vasodilator activity of VIP.

Animals↗

PubMed1987

Sensory fibres modulate histamine-induced catecholamine secretion from the rat adrenal medulla and sympathetic nerves.

1. We have studied the mechanism of catecholamine secretion induced by histamine from the adrenal medulla and sympathetic noradrenergic neurones in the rat, and the role of capsaicin-sensitive sensory nerves in this secretion. 2. Histamine at a dose of 1 mg/kg induced adrenaline and noradrenaline secretion by a non-neurogenic mechanism. In contrast, at a dose of 3 mg/kg it induced adrenaline and noradrenaline secretion by both non-neurogenic and neurogenic mechanisms. 3. The adrenaline released in response to histamine at 3 mg/kg was exclusively of adrenal origin whereas the noradrenaline released was of non-adrenal origin (most probably noradrenergic sympathetic nerves). As with its action on the adrenal, histamine induced noradrenaline secretion from these extra-adrenal tissues by both neurogenic and non-neurogenic mechanisms. 4. When adrenaline secretion from the adrenal gland was impaired by adrenal denervation and/or adrenalectomy, the plasma noradrenaline secretion was increased. This is most probably due to compensation from the rest of the sympathetic nervous system. This compensatory increase in noradrenaline was abolished by hexamethonium, which indicates that it was mediated by a cholinergic mechanism. 5. Pre-treatment of rats as neonates subcutaneously with capsaicin (a selective neurotoxin for certain sensory nerves) at a dose of 50 mg/kg, had no effect on the non-neurogenic secretion of catecholamine induced by histamine. In contrast, capsaicin pre-treatment abolished the neurogenic catecholamine secretion in response to histamine as well as the neurogenic compensatory increase in plasma noradrenaline levels that occurred when adrenaline secretion by the adrenal gland was impaired. 6. In the present study, by using histamine as a form of stress, we have been able to provide evidence not only (a) to confirm a role for capsaicin-sensitive sensory fibres in modulating neurogenic adrenaline secretion from the adrenal gland, but also (b) to suggest a similar role for these fibres in modulating neurogenic noradrenaline release from sympathetic noradrenergic nerves in response to histamine and in response to impairment of adrenaline secretion by the adrenal gland.

Adrenal Medulla↗

PubMed1986

The role of sensory fibres in the rat splanchnic nerve in the regulation of adrenal medullary secretion during stress.

We have studied the involvement of sensory nerves containing substance P (SP) in the modulation of stress-induced catecholamine (CA) secretion from the sympathetic nervous system and adrenal medulla. Adrenaline and noradrenaline (NA) levels were measured in blood samples withdrawn from the inferior vena cava (i.v.c.) at 5 or 15 min intervals for periods of up to 60 min, in adult rats during stress induced by insulin or cold. Insulin stress caused a biphasic elevation of plasma CA. Previous studies from our laboratory have shown that the first phase lasting 30 min is neurogenic, and the second phase from 30 to 60 min is non-neurogenic in mechanism. In control adult rats (with normal levels of SP in their splanchnic nerve), insulin stress caused a slow and progressive secretion of adrenaline into the circulation for the first 30 min (neurogenic phase). In the period 30-60 min (non-neurogenic phase) plasma adrenaline and NA levels rose at a much higher rate. In capsaicin-pre-treated rats (in which SP levels in the splanchnic nerve were depleted by 68%) insulin stress produced a steady increase in plasma adrenaline levels for up to 5 min similar to that in insulin-stressed control animals; however, by 10 min the plasma adrenaline levels had fallen to basal and remained low up to 30 min. From 30 to 60 min, plasma adrenaline and NA levels rose steeply as seen with control animals. We conclude that capsaicin pre-treatment affected the neurogenic phase but did not affect the non-neurogenic phase. Cold stress increased the plasma adrenaline levels by a neurogenic mechanism over 30 min in control rats. In contrast, in capsaicin-pre-treated, cold-stressed rats, plasma adrenaline did not increase significantly. Plasma NA levels were also significantly lowered in capsaicin-pre-treated, cold-stressed rats during the neurogenic phase but NA increases were not dependent on an intact adrenal innervation. The results using both insulin stress and cold stress suggest that capsaicin-sensitive (sensory) nerve fibres in the adrenal medulla and in sympathetic ganglia are capable of modifying the secretory responses of these tissues to stress. Results from our previous in vitro work are compatible with the view that SP may be the neuromodulator released from such sensory nerves to produce these effects. This suggests that the previously reported ability of SP to modulate nicotinic receptor function in vitro by either inhibiting the nicotinic response or protecting against nicotinic desensitization may be more than a mere pharmacological curiosity.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Medulla↗

PubMed1986

Elevation in plasma catecholamines in response to insulin stress is under both neuronal and nonneuronal control.

We have examined the contribution of neurogenic and nonneurogenic influences to the secretion of adrenal catecholamines (CA) in adult rats after iv administration of insulin. Plasma CA levels were measured in control rats and in rats after surgical or pharmacological adrenal denervation or adrenalectomy. Insulin-induced CA secretion was biphasic and proportional to the insulin dose used. The first phase was neurogenic in origin and produced a moderate increase in plasma adrenaline (A) levels, with little or no change in noradrenaline (NA) levels. This neurogenic increase in plasma A was reduced by partial denervation and abolished by surgical complete adrenal denervation, adrenalectomy, or administration of hexamethonium and atropine. The second phase occurred later and produced a dramatic increase in both plasma A and NA. This phase was initiated when the plasma glucose level fell below 75 mg/100 ml. This late release of A and NA was not altered by surgical or pharmacological adrenal denervation, showing that it was nonneuronal in origin. However, both the early and late phases were abolished by adrenalectomy, showing that adrenal secretion of CA was the origin of the increased plasma levels of NA and A. The late rise in plasma CA was also abolished by iv administration of glucose. These data suggest that the mechanism responsible for the nonneurogenic secretion of adrenal CA in response to insulin stress was sensitive to the level of hypoglycemia.

Adrenal Glands↗

PubMed1984

Neonatal capsaicin treatment prevents insulin-stress-induced adrenal catecholamine secretion in vivo: possible involvement of sensory nerves containing substance P.

We have investigated the effects of neonatal capsaicin treatment on stress-induced catecholamine release from adult rats in vivo. Catecholamines released into the inferior vena cava following insulin injection were separated by HPLC and measured by electrochemical detection. Neonatal capsaicin treatment depleted the substance P levels in the splanchnic nerve of adult rats by 70% and prevented the insulin-induced hypoglycaemia from evoking release of adrenaline. The results of this study provide the first evidence in vivo for the neuromodulatory role of sensory nerves containing substance P in the secretion of catecholamines from the adrenal medulla.

Adrenal Glands↗

PubMedDate not supplied

Mitochondrial DNA deletions parallel age-linked decline in rat sensory nerve function.

In rats, the function of sensory nerves in the hind limb declines significantly with age. Normally aging rats and rats treated neonatally with capsaicin were studied here. Quantification of vascular response and substance P in young (3 months) and old (24 months) rats showed additive effects of age and capsaicin treatment. The levels in dorsal root ganglion of a particular deletion in mitochondrial DNA (mtDNA(4834)) were about 300-fold higher in old compared to young rats. Capsaicin treatment had no significant effect on mtDNA(4834) abundance. Dorsal root ganglia of old (but not young) rats were found to contain a spectrum of multiple deletions. The abundance of mtDNA(4834) in dorsal root ganglia from individual rats correlated strongly with their decline in vascular function, even where vascular responses were systematically depressed due to prior capsaicin treatment. One possibility is that mitochondrial DNA mutations directly lead to functional decline at mitochondrial and tissue levels. Alternatively, loss of mitochondrial DNA integrity and physiological decline may be consequences of the same factor, such as oxidative stress.

Aging↗

PubMedDate not supplied

Immunological and in-vivo neurological studies on a benzoic acid-specific T cell-derived antigen-binding molecule from the serum of a toluene-sensitive patient.

T-cell-derived antigen-binding molecules (TABMs) specific for benzoic acid were isolated from the serum of a toluene-sensitive patient. The resulting purified TABMs (BA-TABMs) did not contain immunoglobulin G and were associated with the cytokine transforming growth factor-beta (TGF-beta). BA-TABMs bound to benzoic acid conjugated to human serum albumin (BA-HSA), as well as to other chemicals conjugated to human serum albumin-including dinitrophenol and oxazolone. The binding of BA-TABMs to the conjugated chemicals increased the level of detectable TGF-beta, and a similar effect was observed with the unconjugated chemicals, benzoic acid and 2,4-dinitrophenol glycine. The increase in TGF-beta was critically dependent on the ratio between BA-TABMs and the conjugated or unconjugated chemicals; the increase was optimum at intermediate concentrations and absent at low and high concentrations. The authors used an established animal model in vivo and demonstrated that TGF-beta enhanced the inflammatory response induced by the release of neuropeptides from sensory nerves; this enhancement occurred in a dose-dependent manner. The BA-TABMs also enhanced this neurogenic inflammatory response in a dose-dependent manner, and this effect was blocked by anti-TGF-beta antibody. When the authors added either BA-HSA or benzoic acid, the effect of BA-TABMs on neurogenic inflammation was further enhanced at intermediate concentrations of antigen and was unaltered or reduced at higher concentrations. TABMs specific to particular chemicals, as a result of their association with cytokines (e.g., TGF-beta), may be implicated in symptom production in chemically sensitive patients.

Adult↗