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Biomedical subjects

R D Helme

Publications and source records attributed to R D Helme.

At least 55 records · Page 3Linked to original sources
PubMed1992

Nitric oxide and sensory nerves are involved in the vasodilator response to acetylcholine but not calcitonin gene-related peptide in rat skin microvasculature.

1. The contributions of sensory nerves and nitric oxide (NO) to vasodilator responses to acetylcholine (ACh) and calcitonin gene-related peptide (CGRP) were examined in rat skin microvasculature with a laser Doppler flowmeter to monitor relative blood flow. 2. Perfusion of ACh (100 microM; for 30 min) over a blister base on the rat hind footpad elicited microvascular vasodilatation and this response was not sustained. CGRP (1 microM; 10 min perfusion) also elicited vasodilatation and this response was maintained even when CGRP was no longer in contact with the blister base. 3. The vasodilator response to ACh was significantly smaller in rats pretreated as neonates with capsaicin to destroy primary sensory afferents than it was in age-matched controls. The vasodilator response to CGRP was unaffected by capsaicin pretreatment. 4. Selective inhibitors of NO synthase, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (both at 100 microM) attenuated the vasodilator response to ACh in control rats, but had no effect on the vasodilator response to CGRP. There was a significant L-NOARG-resistant component in control rats while in capsaicin-treated rats the vasodilator response to ACh was virtually abolished by L-NOARG. The inactive stereoisomer NG-monomethyl-D-arginine (100 microM) did not affect the vasodilator response to ACh. 5. The efficacy of L-NOARG and L-NMMA as inhibitors of endothelium-dependent responses was confirmed by use of an endothelium-dependent vasodilator, the calcium ionophore A23187 (100 microM; 10 min perfusion). Vasodilatation to A23187 was strongly attenuated by both L-NOARG and L-NMMA.6. These results suggest that sensory nerves and NO are both involved in the dilatation produced by ACh in rat skin microvasculature. A component of the vasodilator response elicited by ACh involves a direct action on the microvascular endothelium with subsequent generation of NO, while an additional component is elicited via activation of sensory nerves. The vasodilator mediator(s) released by ACh from sensory nerves acts largely independently of NO.7. The vasodilator response to CGRP is independent of a prejunctional action on sensory nerves and of NO.

Acetylcholine↗
PubMed1991

Tachykinin-mediated modulation of the primary antibody response in rats: evidence for mediation by an NK-2 receptor.

Evidence for the involvement of primary afferent nerves and their associated neuropeptides in in vivo immunologic responses has been based on experiments in rats in which destruction of primary afferent nerves by the sensory neurotoxin capsaicin results in a diminished ability of the animal to mount a primary antibody response to sheep red blood cell (SRBC) antigen. This effect was shown to be reversed by substance P infusion immediately following antigenic stimulation. In this report we show that neurokinin A (NKA) is 12 times more potent than substance P in its capacity to reverse the effects of neonatal capsaicin pretreatment on the antibody response. Neurokinin A has a pD2 of 6.65 compared to 5.98 for substance P. In addition, NKA was more potent than substance P in reversing the effects of surgical lesions 2 days prior to antigenic stimulation. The effects of the D- and L-Pro9 analogues of [Glp6, Pro9]-SP6-11 on the plaque-forming cell response in capsaicin-treated rats provide further support for the hypothesis that the tachykinin receptor modulating the primary antibody response is an NK-2 receptor. These results demonstrate, for the first time, a role for NKA in in vivo immunomodulation.

Animals↗
PubMed1991

Modulation of the immune response by tachykinins.

Neuro-immunology is becoming an increasingly important discipline of immunology. This review has examined the immunomodulatory function of one group of neuropeptides, the TK, particularly SP and NKA. These peptides are localized in primary afferent nerves which have been shown to innervate several immune organs. In addition, binding sites for the TK have been demonstrated in thymus, spleen and lymph node. Several immune cell types also express neurokinin receptors including human circulating lymphocytes with binding to the Th/i class predominating, murine T and B cells, a human T lymphoblastoid cell line, human monocytes, rabbit polymorphonuclear leucocytes and guinea-pig macrophages. The apposition of nerves with immune cells and receptors for neuropeptides thus produces an environment for interaction between the nervous and immune systems. Studies in vitro and, more recently, in vivo have examined how the TK regulate immune cell responses. The TK stimulate proliferation of T cells, enhance mitogen-induced release of cytokines including IFN-gamma, TNF-alpha, IL-1 and IL-6 from mononuclear cells and macrophages, enhance immunoglobulin secretion and affect cellular chemotaxis and phagocytosis. Studies in vivo have shown a role for TK in lymphocyte recirculation of sheep lymph nodes, reversal of stress-induced thymic involution and Ig production in both rat and mouse. Many of these effects appear to be mediated via NK-2 type receptors. To date, most of the work has involved studies in vitro, but the results from these are now being validated by studies in vivo where both the immune system and neuropeptides are able to interact at many anatomical sites. The complexities of the immune and the nervous systems mean that only a small number of potential interactions has been examined. Future studies can be expected to amplify these observations, especially with respect to the understanding of inflammatory and immune diseases in humans.

Amino Acid Sequence↗
PubMed1991

Microvascular skin responses in elderly people with varicose leg ulcers.

The function of cutaneous primary afferent unmyelinated nerves (C-fibres) was assessed by measuring axon reflex vasodilatation in the skin over the arms and feet of 15 elderly patients with chronic venous ulcers using a laser Doppler flowmeter. Dilatation of skin microvasculature in response to nerve-independent stimuli was also assessed. Results were compared with those of control subjects matched for age and sex. The chronic venous ulcer group showed reduced axon reflex vasodilatation in the feet but not the arms. Response to nerve-independent vasodilators was similar in both ulcer patients and controls in arms and feet. Local impairment of C-fibre function may partly explain the increased incidence and resistance to healing of leg ulcers in old people.

Aged↗
PubMed1991

A double-blind clinical trial to compare the efficacy of an active based cream F14001 against a placebo non-active based cream for the treatment of pressure ulcers in a population of elderly subjects.

A double-blind clinical trial was conducted to compare the efficacy of an active based cream against a placebo non-active based cream in the healing of superficial pressure ulcers in a population of geriatric hospital patients and residents in community nursing homes. The active group showed a small significant beneficial effect at week four. The overall results of the trial also demonstrated a significant improvement in ulcer size over the duration of the trial period in both active and placebo groups.

Administration, Topical↗
PubMed1990

Neural pathways in chronic pain.

The evidence for changes in function of the central nervous system in cases of chronic pain is persuasive. We are not dealing with a passively wired system but one which changes structure and function and even connectivity in response to incoming sensory information. Whether these changes are capable of reversal with time and treatment remains to be shown. An optimist would suggest that physiological changes without abnormalities are indeed capable of reversal given time and appropriate neural input that matches normal non-painful afferent stimulation. That this is feasible is suggested by strategies of management with successful outcomes in patients with chronic pain, especially when pain is due to intermittent or limited ongoing stimulation of nociceptors. Clinical experience suggests, however, that deafferentation pain syndromes where pain is a consequence of damage directly to the nervous system cannot be viewed in such an optimistic light. A great deal more knowledge is required of how both the peripheral and central nervous system react to damage before we will be in a position to manage this source of chronic pain successfully.

Afferent Pathways↗
PubMed1990

Serotonin modulates substance P-induced plasma extravasation and vasodilatation in rat skin by an action through capsaicin-sensitive primary afferent nerves.

Using a blister model of inflammation in the rat hind footpad, the present study was undertaken to examine the ability of serotonin (5-HT) to modulate an inflammatory reaction manifested as plasma extravasation and vasodilatation induced by the neuropeptide substance P (SP). In addition, the role of primary afferent sensory nerve fibres in these modulatory effects was studied in capsaicin pretreated rats. Using a protocol of simultaneous perfusion of amine and peptide over the blister base, no major modulatory effect was observed. On the other hand, using a protocol of sequential perfusion, 5-HT was found to extend the plasma extravasation and vasodilatation responses to SP. 5-HT maintained the plasma extravasation response to SP after cessation of stimulation (during the post-stimulation period). On the other hand, it extended the vasodilatation response to SP during the actual stimulation period by preventing the occurrence of tachyphylaxis. These modulatory effects were absent in capsacin-pretreated rats. The present study provides evidence for the first time in vivo to suggest that serotonin can modulate an inflammatory response to SP via a mechanism that involves capsaicin-sensitive sensory fibres.

Afferent Pathways↗
PubMed1990

Modulation of a peripheral inflammatory response to substance P by locally administered opioid receptor agonists.

Using a blister model of inflammation in the rat hind footpad, the present study was undertaken to examine possible peripheral effects of specific mu (DAGO) and delta (DSLET) opioid receptor agonists on an inflammatory response induced by substance P, the putative mediator of neurogenic inflammation. When perfused over the blister base, SP induced both plasma extravasation and vasodilatation responses. These responses were significantly inhibited in the presence of either opioid receptor agonist in a naloxone reversible manner. DSLET inhibited SP responses in a dose dependent manner and was 100 times more potent than DAGO. The role of primary afferent sensory nerve terminals in these modulatory effects was investigated in rats pretreated as neonates with capsaicin. The ability of DAGO and DSLET to inhibit the inflammatory response in these rats was significantly less than that in controls. The data raises the possibility that the inhibitory effect of the opioid receptor agonists on the inflammatory response might reflect a role for opioids in modulating tachyphylaxis to SP.

Administration, Topical↗
PubMed1990

Effects of capsaicin treatment on immunoglobulin secretion in the rat: further evidence for involvement of tachykinin-containing afferent nerves.

Neonatal capsaicin treatment has previously been shown to diminish the primary antibody response of adult rats to the subcutaneously administered T-dependent antigen, sheep red blood cells, as measured using a modification of the Cunningham plaque-forming cell assay technique. We have now studied the kinetics of this response in adult normal, neonatally capsaicin-pretreated and neonatally capsaicin-pretreated substance P-infused rats, and examined the effects of the tachykinin antagonist Spantide, on the plaque-forming cell response. Capsaicin pretreatment did not affect the antigen-specific plaque-forming cell response over the first 4 days following antigen injection. At days 5, 6 and 7 of the response, there was a statistically significant decrease in the number of plaque-forming cells secreting antigen-specific IgM, an effect not observed in capsaicin-pretreated rats which were given a subcutaneous infusion of substance P at the time of antigen injection. The tachykinin antagonist Spantide inhibited the plaque-forming cell response in normal rats after in vivo infusion at the time of antigen injection by more than 70%. This effect of Spantide was dose dependent, occurred with maximal effect at 10 microM, and appeared to be independent of any histamine-mediated action. The results of this study provide further evidence for a receptor-mediated immunomodulatory role of tachykinin-containing primary afferent nerves.

Animals↗
PubMed1989

Autoradiographic localization of substance P binding sites in rat footpad skin.

The autoradiographic distribution of binding sites for 60 pM [125I]Bolton-Hunter substance P (BHSP) was investigated in slide-mounted sections of rat footpad skin. BHSP binding sites were found over dermal papillae, postcapillary venules, sweat glands and arterioles. No binding was seen over mast cells, sebaceous glands or pacinian corpuscles. Specific BHSP binding was inhibited by substance P greater than neurokinin A greater than neurokinin B, indicating binding to an NK1 (substance P-preferring) site. The NK1 binding sites over postcapillary venules and arterioles probably represent receptors mediating plasma extravasation and vasodilatation, respectively. There was no apparent change in distribution or number of BHSP binding sites after neonatal capsaicin pretreatment, indicating a probable absence of NK1 receptors on sensory terminals. No binding sites were observed for 100 pM [125I]iodohistidyl neurokinin A (INKA).

Animals↗
PubMed1989

Sequence of events in substance P-mediated plasma extravasation in rat skin.

Using a blister model of inflammation in the rat hind footpad, we have studied the temporal and quantitative contribution of mast cell mediators and prostaglandins to substance P-induced plasma extravasation. In addition substance P-related peptides (neurokinin A, SP5-11 and SP1-7) were tested for their ability to induce a plasma extravasation response and the extent of histamine involvement to the response was determined. The present results show that the plasma extravasation response to substance P consists of an early substance P-mediated response that is independent of other mediators and a late response that involves interaction between substance P, mast cell mediators and prostaglandins. An early histamine-independent response was also mediated by neurokinin A, a tachykinin that shares a common C-terminal with substance P and by a C-terminally directed analogue of substance P, namely SP5-11. On the other hand, a late histamine-dependent response was mediated by the N-terminally directed analogue, SP1-7. The present data are suggestive of a possible sequence of events that might occur during an inflammatory response to substance P and might involve independent actions of its C- and N-terminal.

Animals↗
PubMed1989

Involvement of capsaicin-sensitive afferent nerve fibres in serotonin-induced plasma extravasation and vasodilatation in rat skin.

We have investigated the ability of serotonin (5-HT) to induce an inflammatory reaction manifested as plasma extravasation and vasodilatation responses in a blister model in the rat hind footpad. The involvement of unmyelinated sensory fibres in these responses was investigated using capsaicin pretreated rats. 5-HT (0.1-10 microM), when perfused over the blister base, induced both plasma extravasation and vasodilatation responses in a dose-dependent manner. Both the plasma extravasation and the vasodilatation responses were maintained throughout a 30 min stimulation period. Neonatal capsaicin treatment resulted in a 78% and 56% reduction in the plasma extravasation and vasodilatation responses, respectively. The present results provide evidence for the involvement of capsaicin-sensitive sensory nerves in 5-HT-mediated plasma extravasation and vasodilatation responses in the rat.

Animals↗
PubMed1989

Photoperiodic variation in substance P induced plasma extravasation in the rat.

Photoperiodic variation in plasma extravasation was examined following exogenous perfusion of substance P over a vacuum-induced blister base on the rat hind footpad. The results showed a generalised suppression of plasma extravasation during the dark or active phase of the light/dark cycle which appears to be independent of the circadian fluctuations in endogenous corticosterone. These findings emphasise the need to consider photoperiodic conditions as a possible source of variability in neurogenic inflammatory responses.

Animals↗
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

Lymphomatoid granulomatosis presenting as a progressive cervical cord lesion.

A 50-year-old male presented with symptoms of a progressive spinal cord lesion over two and a half months investigations, including myelography, CT scan and magnetic resonance imaging (MRI), did not show cord compression although the MRI scan demonstrated thickening of the posterior cervical meninges. CSF examination revealed pleocytosis, increased total protein and cells suggestive of a lymphoproliferative disorder. Open lung biopsy of an asymptomatic left midzone mass was diagnostic of lymphomatoid granulomatosis. We believe this to be a case of lymphomatoid granulomatosis presenting as a progressive cervical myelopathy.

Diagnosis, Differential↗
PubMed1989

NK-1 receptor mediation of neurogenic plasma extravasation in rat skin.

1. Plasma extravasation was induced by electrical nerve stimulation and by perfusion of tachykinins over a vacuum-induced blister base on rat footpad. 2. Stimulation of the sciatic nerve (18 V, 15 Hz, 0.5 ms) for 20 min produced a significant increase in the protein content of the perfusate. The response in capsaicin pretreated rats was only 4% of the control response. This indicates that the electrically-induced plasma extravasation response was mediated by capsaicin-sensitive sensory fibres. 3. Exogenous perfusion of the mammalian tachykinins substance P, neurokinin A and neurokinin B and the non-mammalian tachykinins physalaemin, kassinin and eledoisin was used to determine the tachykinin receptor type mediating the plasma extravasation response. Dose-response curves of the tachykinins (10(-9) M-10(-4) M) gave a rank order of potency of substance P = physalaemin greater than eledoisin greater than or equal to kassinin greater than neurokinin B = neurokinin A. 4. In addition, specific agonists of neurokinin receptors were perfused. Perfusion of [Glp6, D-Pro9] SP6-11 and [Glp6, L-Pro9]SP6-11 demonstrated that the L-Pro isomer was much more potent than the D-Pro isomer. 5. The rank order of potency and the greater potency of [Glp6, L-Pro9]SP6-11 over its D-isomer indicate an NK-1 neurokinin receptor mediates plasma extravasation in rat footpad 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↗