Search PubMed⌕ Search

Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 145 records · Page 8Linked to original sources
PubMed1996

Neuropeptide changes in a case of chronic paroxysmal hemicrania--evidence for trigemino-parasympathetic activation.

Chronic paroxysmal hemicrania (CPH) is a rare headache syndrome of short-lasting attacks of pain, characterized clinically by trigemino-parasympathetic activation. The features of the headache are severe attacks of pain that generally last no more than minutes in association with autonomic activation, such as lacrimation or rhinorrhea. We report a patient fulfilling International Headache Society guidelines for the diagnosis of CPH in whom levels of calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were elevated in the cranial circulation during attacks. Moreover, successful treatment of the problem with indomethacin leads to normalization of the levels of both CGRP and VIP. Given that similar neuropeptide changes are seen in cluster headache the data suggest a shared underlying pathophysiology between CPH and cluster headache.

Adult↗
PubMed1996

Correlation between clinical characteristics and cerebrospinal fluid neuropeptide Y levels in dementia of the Alzheimer type and frontotemporal dementia.

Neuropeptide Y (NPY) has been shown to be involved in the control of several neuroendocrine functions. Moreover, in animal models, NPY produces behavioral effects that are similar to those induced by anxiolytics. We studied NPY-like immunoreactivity (NPY-LI) in cerebrospinal fluid (CSF) in two primary degenerative dementias, Alzheimer disease (AD, n = 34) and frontotemporal dementia (FTD, n = 22) and correlated the CSF NPY-LI levels with clinical characteristics, as rated with the Organic Brain Syndrome scale. There were significant correlations between NPY-LI and such clinical items as suspiciousness, anxiousness, restlessness-agitation, and irritability in both AD and FTD. AD patients, but not FTD patients, showed a significant negative correlation between NPY-LI and duration of the disease. Thus, the study found significant correlations between CSF NPY-LI and emotional symptoms and behavior in organic dementia.

Adult↗
PubMed1996

Characterization of endothelin receptors in the cerebral vasculature and their lack of effect on spreading depression.

The changes in cerebral blood flow that accompany spreading depression are well-described, as are parallel changes in cellular activity, with a wave of hyperemia followed by a prolonged oligemic phase. In this study, a cat model of the CBF changes associated with spreading depression and in vitro pharmacology were used to determine if there is a role for the powerful peptide vasoconstrictor endothelin in this response. For the pharmacological studies, the middle cerebral artery was harvested from cats postmortem. For the physiological studies, cats were anesthetized with halothane induction and alpha-chloralose (60 mg/kg, intraperitoneal loading; 20 mg/kg i.v. 2-h maintenance). CBF was monitored continuously in the parietal cortex using laser Doppler flowmetry (CBFLDF) after exposure of the dura mater. The in vitro work demonstrated that endothelin-1 (ET-1) mediates a strong and potent contraction of cerebral vessels. Both the selective ETA receptor antagonist FR139317 and the combined ETA and ETB receptor antagonist Bosentan caused a rightward shift of the concentration-response curve without attenuation of the maximum effect. The calculated pA2 values were 6.28 and 6.90, respectively. The slope did not differ from unity, suggesting that the ET-1-mediated contraction is evoked by a single population of ETA receptors, which were effectively antagonized by these compounds. Spreading depression was induced with a needle stick injury to the cortex. Local administration of the endothelin antagonists FR139317 (10 microM) and Bosentan (10 microM) did not affect resting blood flow in the cortex. Induction of spreading depression following local administration of FR139317 and Bosentan resulted in responses no different from those in control cortex. These data demonstrate that endothelin does not play a significant role in the vasoconstrictor portion of the CBF change seen in spreading depression, nor does it affect resting flow. Since it is widely held that spreading depression, or a very similar mechanism, underlies the aura phase of migraine, it may be suggested from these studies that endothelin antagonists are unlikely to be useful in migraine.

Animals↗
PubMed1996

Contractile effects of neuropeptide Y in human subcutaneous resistance arteries are mediated by Y1 receptors.

The aim of our study was to determine the neuropeptide Y (NPY) receptor subtype responsible for the NPY-induced contraction of human subcutaneous (s.c.) resistance arteries. To elucidate this, we used (a) in vitro studies of NPY agonists: NPY, peptide YY (PYY), and Pro34NPY induced equally strong and equipotent concentration-dependent contractions of human s.c. resistance arteries, whereas NPY13-36 and NPY18-36 had no contractile effects; (b) in vitro studies using the NPY Y1-receptor antagonist, BIBP3226, which in nanomolar concentrations inhibited the contractile effect of NPY, causing a rightward shift of the concentration-response curve. pEC50 for NPY alone, 8.41 +/- 0.21; NPY + BIBP3226, 10 nM, 7.79 +/- 0.21; NPY + BIBP3226, 100 nM, 7.18 +/- 0.18; NPY + BIBP3226, 1 microM, 6.32 +/- 0.05 (n = 5-8). Schild-plot analysis indicated competitive antagonism: pA2 = 8.53 +/- 0.22 and slope = 0.99 +/- 0.14; (c) with reverse transcriptase-polymerase chain reaction (RT-PCR), we detected messenger RNA (mRNA) encoding the human NPY Y1 receptor and a splice variant of the receptor in human s.c. resistance arteries. On the basis of the agonists' potency order, the antagonistic effect of BIBP3226 on the NPY-induced contraction, and the presence of mRNA encoding the NPY Y1 receptor, we conclude that the NPY-induced contraction of human s.c. resistance arteries is mediated by NPY Y1 receptors.

Arginine↗
PubMed1996

Sumatriptan-induced cerebral vasoconstriction as treatment of experimental intracranial hypertension.

BACKGROUND: Increased intracranial pressure (ICP) is a major cause of mortality in severe head injuries and pharmacologically induced cerebral vasoconstriction has been suggested as a possible treatment. In the present study a porcine model of increased ICP was utilized to study the changes in cerebral haemodynamics and energy metabolism induced by a selective 5-hydroxytryptamine1 agonist (sumatriptan). METHODS: ICP was raised by inflation of two balloons covering both parieto-occipital regions extradurally. The animals were randomized into four groups receiving sumatriptan. 0.01 mg.kg-1 (A), 0.03 mg.kg-1 (B), 0.1 mg.kg-1 (C), and 0.5 mg.kg-1 (D) intravenously over 10 min. Measurements of cerebral blood flow (CBF), arterio-venous oxygen content difference (CavO2), and jugular venous pH (vpH) were performed 5, 20, 40, 60, and 75 min after start of the infusion. ICP, mean arterial pressure, and EEG were recorded continuously. Direct effects of sumatriptan were also compared in cortical arteries and veins in vitro. RESULTS: Significant decreases in ICP were obtained in groups A, B, and C while group D exhibited a progressive increase in ICP. Significant reductions in CBF, increase in CavO2, and slowing of EEG were observed in groups B, C, and D. Sumatriptan caused moderate constriction of the arteries and a more pronounced dilatation of veins in vitro. CONCLUSION: The results indicate that a low dose of sumatriptan has the potential to reduce a raised ICP. High doses of sumatriptan cause a further increase of ICP possibly by dilatation of intracerebral veins.

Animals↗
PubMed1996

Different levels of sensory neuropeptides (calcitonin gene-related peptide and substance P) during and after exercise in man.

The aim of this study was to investigate the regulation of two sensory peptides calcitonin gene-related peptide (CGRP) and substance P, reflected as circulating levels during provocation of the sympathetic nervous system. Levels in hypertensives, diabetics (NIDDM) and controls were assayed before, during and after an exercise test (average work load carried out was 76 +/- 10 kJ). CGRP levels increased progressively during exercise (P < 0.001), with maximum level at maximum exercise. This was significant in all three groups; hypertensives P < 0.001, diabetics P < 0.01 and controls P < 0.001. No differences in circulating revels of CGRP between the three groups were found. Substance P levels were fairly constant during exercise but increased 30 min after exercise (P < 0.01) in the total group. We hypothesize that CGRP might provide a counter-regulatory mechanism to the sympathetic vasoconstrictor transmitters noradrenaline (NA) and neuropeptide Y (NPY) during sympathetic activation. Substance P did not increase during exercise. This suggests differential regulation and function of the two vasodilatory peptides.

Adult↗
PubMed1996

Effects of phosphorothioated neuropeptide Y Y1-receptor antisense oligodeoxynucleotide in conscious rats and in human vessels.

1. Metabolically stabilized (phosphorothioate) human and rat NPY Y1 receptor oligodeoxynucleotides (ODNs) complimentary to the rat or human Y1 mRNA were synthesized; [sense (rY1-SODN, 5'-AATTCAACTCTGTTCTCC-3'), antisense (hY1-ASODN, 5'-CCTGGGAAAATAATGTTG-3' and rY1-ASODN, 5'-GGAGAACAGAGTTGAATT-3') and mismatches (hY1-MMODN, 5'-CCTGAGATAA-TAAGGTTG-3' and rY1-MM 5'-GTAGATCAGAGATGAAGT-3')] and used to modulate cardiovascular function in vitro in human vessels as well as in vivo in the rat. 2. The objectives of the experiments were to assess the influence of the NPY Y1 receptor on vasomotor function human resistance arteries in vitro and to investigate the contribution of the NPY receptor system to cardiovascular haemodynamics in vivo. 3. Human subcutaneous resistance arteries removed from patients who underwent surgery for nonvascular diseases were incubated in vitro with the stabilized phosphorothioated hY1-receptor ASODN or MMODN (10(-7) TO 10(-5) M). 4. In human resistance vessels preincubated with hY1-AS (10(-7) to 10(-5) M), the contractile response to NPY was significantly reduced in a dose-dependent fashion. No effects were observed in the hY1-MMODN-incubated vessels at lower concentrations (10(-7) M to 10(-6) M). 5. The haemodynamic effects of the phosphorothioated rY1-ASODN, SODN or MMODN were investigated in conscious rats during 48 h of continuous infusions. The continuous infusion with rY1-ASODN did not change MAP while the rY1-SODN unexpectedly induced an early (10-20) increase in ambulatory MAP and the rY1-MMODN a late (24-44 h) increase. 6. Contractile responses to NPY (2, 4, 8, 16 and 32 micrograms kg-1) were significantly reduced in the rats treated with long-term infusion of rY1-ASODN (2.1 mg kg-1 h-1, i.v. infusion for 48 h) compared with animals treated with rY1-SODN and MMODN, as well as animals treated with saline and glucose. Notably, the group infused with the rY1-SODN showed an exaggerated response to tested doses of NPY. 7. We conclude that the incubation of human subcutaneous arteries with a metabolically stabilized 18 base pair hY1-ASODN and long-term infusion with a corresponding rY1-ASODN attenuate NPY-induced vasoconstriction.

Animals↗
PubMed1996

Tyrphostin inhibition of ATP-stimulated DNA synthesis, cell proliferation and fos-protein expression in vascular smooth muscle cells.

1. We and others have shown that extracellular ATP (adenosine triphosphate), released from sympathetic nerves and platelets, stimulates growth of vascular smooth muscle cells (SMC). To study the importance of tyrosine kinases for ATP-mediated proliferation in vascular smooth muscle cells we used tyrphostins, a recently developed group of highly specific inhibitors of tyrosine kinases. 2. ATP induced a powerful concentration-dependent increase in DNA synthesis measured by [3H]-thymidine incorporation in rat aorta SMC (RASMC) and an increase in total cell number after 72 h of incubation as measured by an enzymatic cell proliferation assay. Tyrphostin 25 (10(-5) M) had no effect per se on basal DNA synthesis but reduced ATP-stimulated DNA synthesis and increase in cell number in a dose-dependent manner. Higher concentrations of ATP could not reverse the inhibitory effect of tyrphostin 25. The potency of several (six) other tyrphostins was also examined and found to be slightly greater than tyrphostin 25 with equal efficacy. 3. When RASMC were incubated with 10(-5) M ATP for 2 h, nearly all of the cells (87 +/- 5%) were intensely stained with an antibody to the Fos protein while in the controls only 1 +/- 2% of the cells were weakly stained. Tyrphostin 25 greatly reduced the Fos-protein staining (14 +/- 2%). 4. ATP induced a concentration-dependent increase in 45Ca(2+)-influx and formation of inositol phosphates (IPtotal) in RASMC. These effects were not inhibited by tyrphostin 25. 5. Tyrphostin 25 did not alter ATP-induced contraction in ring segments of rat aorta. 6. In conclusion, tyrphostin 25 inhibited ATP-induced DNA synthesis, cell proliferation and Fos-protein expression, but not ATP-induced 45Ca(2+)-influx, inositolphosphate-production or vasoconstriction. This indicates that the mitogenic effect of ATP on vascular smooth muscle cells is dependent on tyrosine kinases in contrast to the contractile effect of ATP in blood vessels.

Adenosine Triphosphate↗
PubMed1996

Plasticity of contractile endothelin-B receptors in human arteries after organ culture.

1. The pharmacology and mRNA expression of endothelin (ET) receptors in human omental arteries were characterized by use of functional contractile assays and the reverse transcriptase-polymerase chain reaction (RT-PCR). 2. In freshly obtained segments of human omental arteries, ET-1 and ET-3 induced concentration-dependent contractions which were normalized to the response produced by 60 mM K+. ET-1 produced a maximum contraction (Emax) amounting to 151 +/- 17% of the K+ response. The pEC50 for this agonist was 8.64 +/- 0.17. The effect of ET-3 was less pronounced (Emax: 71 +/- 22% and pEC50: 6.69 +/- 0.17) than that of ET-1. The ET receptors involved were characterized with FR139317 (a selective ETA receptor antagonist), PD 145065 (a mixed ETA and ETB receptor antagonist) and BQ 788 (an ETB receptor antagonist). A high concentration of these antagonists (10 microM) abolished the contractile responses to ET-3, and produced a parallel rightward shift of the ET-1 concentration-response curve without changing the maximal effect. FR139317 and PD 145065 were equally effective while BQ 788 was much less effective. This is consistent with ETA receptors mediating contraction in human omental arteries. 3. Arterial segments cultured for 5 days in serum-free Dulbecco's medium at 37 degrees C under sterile and humidified conditions retained contractility although responses to 60 mM K+ were somewhat reduced. ET-3 was significantly more potent in the cultured arteries (pEC50: 8.56 +/- 0.15) and achieved a greater maximum effect (Emax: 116 +/- 19%). Responses were not antagonised by FR139317 but were competitively blocked by PD 145065 and BQ 788 with the latter antagonist being the more potent. In contrast Emax (179 +/- 17%) and pEC50 (8.66 +/- 0.23) values for ET-1 were not significantly different from those obtained with fresh arteries. PD 145065 still demonstrated a rightward shift of the ET-1-induced concentration-response curve, whereas FR139317 and BQ 788 caused non-significant shifts. These findings suggest that functional ETB receptors contribute significantly to the endothelin contractile response in cultured arteries. 4. Two-site analysis of the ET-1 induced concentration-response curve from cultured arteries suggests that ETB receptors, at the high potency component, and ETA receptors, at the low potency component, contribute both to the contractile response in relative proportion of 70% and 30%, respectively. Further analysis suggested that the ETA receptor would be capable of evoking at least 75% of the ET-1 contraction in the absence of ETB receptors, although with a lower potency as compared to fresh arteries. 5. Electrophoresis of RT-PCR products from the smooth muscle layer of freshly obtained human arteries indicated the presence of mRNA for both ETA and ETB receptors. Arteries cultured for 1 and 5 days demonstrated an increase of mRNA for the ETB receptor as compared to the ETA receptor. The identities of the PCR products were verified by restriction enzyme digestion. 6. In freshly obtained human omental arteries, the contractile effects of endothelins appear to be mediated predominantly by the ETA receptor subtype, with a negligible contribution by ETB receptors. Cultured arterial segments, however, exhibited a substantial ETB receptor mediated contractile response and an increase in ETB receptor mRNA content, consistent with an upregulation of functional ETB receptors. These in vitro data suggest plasticity in the smooth muscle cell expression of contractile ETB receptors.

Arteries↗
PubMed1996

Effect of parasympathetic and sensory transmitters on human epicardial coronary arteries and veins.

Vasomotor effects of various agonists were tested on isolated human epicardial coronary arteries and veins at resting tension and after precontraction with U46619. Acetylcholine relaxed all arteries with intact endothelium but only some endothelium-denuded arteries. Most veins did not relax to acetylcholine. Higher concentrations of acetylcholine induced powerful contractions of all arteries and veins. Preincubation with atropine significantly lowered the pD(2) values but not E(max) values for contractile responses to acetylcholine in arteries and veins (pA(2) value for atropine 9.1 arteries and 9.6 veins). Vasoactive intestinal peptide, human alpha-calcitonin gene-related peptide and substance P potently relaxed all arteries with intact endothelium and all veins. Removal of the arterial endothelium abolished relaxation to substance P in most arteries whereas responses to vasoactive intestinal peptide were unaffected, and for alpha-calcitonin gene-related peptide the pD(2) value but not the E(max) value was significantly lowered. In both arteries and veins, the antagonists alpha-calcitonin gene-related peptide (8-37) and spantide lowered significantly the potency for alpha-calcitonin gene-related peptide and substance P, respectively, without significant changes in E(max) values (pA(2) value for alpha-calcitonin gene-related peptide (8-37) 7.9 arteries and 7.9 veins, for spantide 7.6 arteries and 8.1 veins).

Acetylcholine↗
PubMed1996

alpha-Trinositol: a functional (non-receptor) neuropeptide Y antagonist in vasculature.

Neuropeptide Y is a sympathetic co-neurotransmitter released with noradrenaline upon sympathetic nerve stimulation. This study describes the ability of a synthetic inositol phosphate, alpha-trinositol(D-myo-inositol 1,2,6-triphosphate; PP 56) to antagonize vasoconstrictor responses to neuropeptide Y in-vitro as well as in-vivo. In human and guinea-pig isolated arteries alpha-trinositol potently (10 nM to 1 microM extracellular concentration) suppressed the constriction evoked by neuropeptide Y alone, the potentiation by neuropeptide Y of noradrenaline-evoked constriction, and the neuropeptide Y-induced inhibition of relaxation. Moreover, in the pithed (areflexive) rat, a non-adrenergic portion of the pressor response to preganglionic sympathetic nerve stimulation was sensitive to alpha-trinositol. As studied in the recently cloned human (vascular-type) Y1 receptor, the action of alpha-trinositol does not occur through antagonism at the neuropeptide Y recognition site nor does it induce allosteric changes of this receptor. However, we found alpha-trinositol to inhibit the rise in intracellular Ca2+ as well as inositol triphosphate concentrations induced by neuropeptide Y. It is, therefore, proposed that alpha-trinositol represents a non-receptor, but yet selective antagonist of neuropeptide Y in vasculature, opening up the possibility to investigate involvement of neuropeptide Y in sympathetic blood pressure control and in cardiovascular disorders.

Adrenergic alpha-Antagonists↗
PubMed1996

Contractile endothelin-B (ETB) receptors in human small bronchi.

Endothelins (ETs) are a family of novel regulatory peptides and various lines of evidence suggest an important role for ETs in regulating pulmonary function. Two receptors for endothelin, ETA and ETB, have been found in the human lung, and according to recent studies a non-ETA receptor seems to mediate the contraction of large sized human bronchi. Several studies have emphasized the importance of small bronchi in the pathogenesis of airway disease. In the present paper, improved methodology was used which enables in vitro studies of small human bronchi down to a diameter of 0.5-1.0 mm. Using the new methodology we have tried to further characterize this receptor. Small bronchi from the distal parts of the bronchial tree were obtained from pulmonary tissue removed from 15 patients with lung cancer. They were dissected and cut into ring segments, in which isometric tension was recorded. ET-1, ET-2 and ET-3 elicited strong concentration-dependent contractions of the human small bronchus. Basically, the three peptides were equipotent with about the same maximal response. Upon reapplication, they all showed the same tachyphylaxis pattern, reaching half the initial contraction. Comparative analysis of IRL 1620, a selective ETB receptor agonist, revealed that the effect of the ETB agonist was, in all respects, similar to the responses induced by the ETs. PD 145065, a combined ETA/ETB receptor antagonist competitively inhibited the contractions induced by IRL 1620, whereas FR139317, a selective ETA receptor antagonist, was without effect. In conclusion, the present study shows that accurate measurements can be made in vitro on small human bronchi and all present data are in favour of an ETB receptor mediating endothelin-induced contraction of human bronchi smaller than 1.0 mm.

Acetylcholine↗
PubMed1996

Characterization of neuropeptide Y receptors mediating contraction, potentiation and inhibition of relaxation.

In addition to its direct vasoconstrictive effect, neuropeptide Y (NPY) potentiates noradrenaline-(NA) induced contraction and inhibits acetylcholine-(ACh) induced relaxation: The aim of the present study was to elucidate the NPY receptor subtypes responsible for mediating these three responses. NPY, peptide YY (PYY) and pro34NPY (a NPY Y1 receptor agonist) induced equipotent and equally strong concentration-dependent contractions of guinea pig basilar arteries. NPY13-36 (a NPY Y2 receptor agonist), however, caused only weak contraction with significantly lower potency. The NPY-induced contraction was significantly inhibited by the selective NPY Y1 receptor antagonist BIBP3226 (1 microM). NPY, PYY and pro34NPY but not NPY13-36 significantly potentiated the NA-induced contraction in guinea pig mesenteric arteries. The potentiation was significantly inhibited by BIBP3226 (1 microM). In precontracted guinea pig basilar arteries, ACh induced a concentration-dependent relaxation which was significantly inhibited by NPY, PYY and NPY13-36 but not by pro34NPY. BIBP3226 had no significant effect on the NPY-induced inhibition of the relaxation. These results suggests that the NPY Y1 receptors mediate the direct contraction and the potentiation of the NA-induced contraction but not the inhibition of the ACh-induced relaxation. This effect seems to be mediated by another NPY receptor subtype, presumably by the Y2 receptor, as judged from the agonist potency order.

Acetylcholine↗
PubMed1996

Vascular alpha-2 adrenoceptor function is decreased in rats with congestive heart failure.

OBJECTIVE: Vascular alpha-2 adrenoceptor function of rats with congestive heart failure (CHF) was characterized in both in vivo and in vitro experiments. METHODS: CHF was induced in Sprague-Dawley rats by coronary artery ligation. Sham-operated rats served as normal controls. Postjunctional alpha-2 adrenergic responsiveness was assessed in vivo using the pithed rat model and in vitro in organ bath. Vascular alpha-2 adrenoceptor density was studied by receptor binding assay. RESULTS: Four to 6 weeks after this surgical procedure, plasma catecholamines were markedly increased in CHF rats. In vivo vascular responses to alpha-2 adrenoceptor agonists BHT933 and clonidine were significantly decreased in CHF rats (P < 0.001). Clonidine elicited dose-dependent responses in endothelium intact mesenteric arteries in both CHF and sham-operated rats. The dose-response curve in CHF was shifted to the right with a pD2 value of 5.5 +/- 0.2 compared with control rats 6.2 +/- 0.2 (P < 0.05). The response to clonidine was selectively blocked by an alpha-2 adrenergic antagonist rauwolscine in both groups. Endothelium denuded arteries showed an enhanced response to clonidine in both CHF and control rats. However, the response to clonidine is still decreased in CHF compared to sham-operated rats (P < 0.05). Alpha-2 adrenoreceptor density, as determined by [3H]yohimbine binding in membrane preparations from mesenteric arteries was decreased in CHF compared to sham-operated rats (Bmax 43 +/- 6 vs. 104 +/- 20 fmol/mg protein, P < 0.05). CONCLUSIONS: Vascular alpha-2 adrenoceptor function is decreased in rats with CHF.

Adrenergic alpha-Agonists↗
PubMed1995

Peptidergic innervation of guinea-pig brain vessels: comparison with immunohistochemistry and in vitro pharmacology in rostrally and caudally located arteries.

The peptidergic innervation of the guinea-pig basilar artery and the posterior, middle and anterior cerebral arteries were studied by means of immunohistochemical and image analysis techniques using whole mount preparations. An in vitro pharmacological study was performed to correlate the distribution of peptide-containing nerves and the action of neuropeptides on vessel segments from the same vascular regions. The overall distribution of perivascular nerve fibres was demonstrated using an antiserum to the general neuronal marker protein gene product 9.5 (PGP 9.5) and the percentage immunostained area of total vessel wall area occupied by PGP-containing nerves, in each of the basilar, posterior and middle cerebral arteries, was set at 100% and used to determine the relative density of specific populations of autonomic and sensory nerve fibres. In all four cerebral arteries, the majority of nerve fibres possessed neuropeptide Y (NPY) and tyrosine hydroxylase (TH) immunoreactivity, occupying 6.2-13.3% and 5.8-7.5% of the total vessel wall area, respectively. Vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin-gene-related peptide (CGRP) were detected at lower densities. The pharmacological study performed on small circular segments with an intact endothelium revealed that, in all four cerebral arteries, NPY was a more potent constrictor than noradrenaline (NA). The rank order of potency for relaxant agents was CGRP = SP > VIP > ACh in the PCA and MCA, and SP = CGRP > VIP > ACh in the BA and ACA. The correlation between immunostained nerve area and the agonist potency suggested that the denser the peptidergic nerve-supply, the lower the sensitivity to the agonist.

Animals↗
PubMed1995

Characterisation of an ATP receptor mediating mitogenesis in vascular smooth muscle cells.

Adenosine triphosphate (ATP), a co-transmitter in sympathetic nerves and released from platelets, has recently been shown to stimulate growth of vascular smooth muscle cells. It might therefore contribute to the development of vascular hypertrophy seen in hypertension and atherosclerosis. We aimed at characterising the receptor mediating this mitogenic effect in rat aorta smooth muscle cells. The potency of agonists indicates a P2 purinoceptor since ATP > or = ADP >> AMP, adenosine. The P2x-receptor subtype, which is responsible for ATP induced vasoconstriction in rat aorta, does not mediate the mitogenic effect since alpha, beta-methyleneATP had no effect and beta, gamma-methyleneATP had lower potency than ATP. The P2Y-receptor subtype was excluded since the selective agonist 2-methylthioATP had weak effect with lower potency than ATP. When we studied the involvement of other nucleotides similar effects were seen of the purines ATP, GTP and ITP; also the pyrimidine UTP had powerful mitogenic effects (Emax = 52% of ATP) with similar potency. Nucleotides with fewer phosphate groups showed a stepwise fall in mitogenic effect. This indicates involvement of a nucleotide-receptor (P2U). Ap4A were of equal potency and effect as ATP. There was strong correlation between the mitogenic effects of the nucleotides and analogues with both 45Ca(2+)-influx and inositol phosphate (IP) production, indicating that they may participate in mediating the mitogenic response. This is the first study describing the potencies for the mitogenic effects of the selective ATP-analogues and other nucleotides in vascular smooth muscle cells. The receptor characterisation indicates a nucleotide-receptor similar to the receptor which stimulates 45Ca(2+)-influx and inositol phosphate-formation in rat aorta smooth muscle cells. Substances related to ATP such as GTP, ITP, UTP and Ap4A which also can be released extracellularly in vivo stimulate mitogenesis of rat aorta smooth muscle cells through the same receptor.

Adenosine Triphosphate↗
PubMed1995

Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man.

A possible involvement of perivascular vasodilatory neuropeptides in subarachnoid haemorrhage (SAH) has been evaluated in man by measuring the levels of calcitonin gene related peptide (CGRP)-, substance P (SP)- and vasoactive intestinal peptide (VIP)-like immunoreactivity (LI) in the cranial venous outflow and in CSF in 34 patients admitted to the hospital after an acute SAH. After operation with aneurysm clipping and nimodipine treatment, blood samples were taken from the external jugular vein (EJV) or cerebrospinal fluid (CSF) and analysed for neuropeptide levels with specific radioimmuno assays (RIA) during the postoperative course. The degree of vasoconstriction in the patients was monitored with Doppler ultrasound recordings bilaterally from the middle cerebral (MCA) and internal carotid arteries (ICA) following the EJV blood sampling every second day. The mean value of all CGRP-LI measurements in EJV during the entire course of SAH (n = 20) revealed a significantly higher level as compared to controls. The highest CGRP-LI levels were found in patients with the highest velocity index values (vasospasm). The relationship Vmean MCA/Vmean ICA was used as an index of vasoconstriction. In patients with MCA aneurysms (n = 10), a significant correlation (r = 0.65, p < 0.05) was found between the vasospasm index and CGRP-LI levels. There were no changes observed in the SP- and VIP-LI levels. Alterations in cerebrovascular tone induced by changing arterial CO2 tension or lowering of blood pressure (ketanserin infusion test) did not alter the levels of the perivascular peptides in the EJV. In addition, CGRP-, SP-, VIP- and neuropeptide Y (NPY)-LI were analysed in CSF in the post-operative course after subarachnoid haemorrhage (SAH) in 14 patients. The CSF VIP-LI was lower in SAH than in control (p < 0.05). The CGRP-LI level was measurable in SAH CSF but not in CSF of controls. In individual patients with marked vasoconstriction increased levels of CGRP-LI (up to 14 pmol/L) and NPY-LI (up to 232 pmol/L) were observed. The results of this study are in support of our hypothesis that there is an involvement of the sensory peptide CGRP in a dynamic reflex aimed at counterbalancing vasoconstriction in SAH.

Adult↗