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Biomedical subjects

L Edvinsson

Publications and source records attributed to L Edvinsson.

At least 199 records · Page 11Linked to original sources
PubMed1994

Localization of endothelin immunoreactivity and demonstration of constrictory endothelin-A receptors in human coronary arteries and veins.

Strong immunoreactivity for endothelins (ETs) was observed in the endothelium of both human epicardial coronary arteries and veins. The contractile responses to ET-1, ET-2, and ET-3 were investigated in isolated circular human coronary vessel segments. ET-1, ET-2, and ET-3 induced significantly higher maximum contraction (measured in percentage of contraction induced by 60 mM potassium) and more potent responses in veins as compared with arteries. ET-1 as compared with ET-2 induced equal maximum contraction and equipotent responses both when tested in arteries and veins, whereas ET-3 induced lower maximum contraction and less potent responses in both vessel types. FR 139317, a selective ETA receptor antagonist, significantly decreased the potency of ET-1 and ET-2 responses in both human coronary arteries and veins, but the maximum effect obtained did not change significantly. The existence of ET immunoreactivity (IR) in endothelial cells from both human coronary arteries and veins indicates that ETs may be released endogenously. The effect of the selective ETA receptor antagonist FR 139317 indicates that the contraction induced by ET-1 and ET-2 in both arteries and veins is mediated by ETA receptors.

Arteries↗
PubMed1994

Relationships between plasma levels of catecholamines and neuropeptides and the survival time in patients with congestive heart failure.

OBJECTIVES: To evaluate the importance of various variables reflecting neuroendocrine activation in relation to prognosis in patients with congestive heart failure (CHF). DESIGN: Plasma levels of noradrenaline, adrenaline, neuropeptide Y, substance P, calcitonin gene-related peptide, vasopressin and atrial natriuretic peptide were measured in patients presenting with CHF and related to survival time. Survival time was calculated from the time-point of this investigation until the month when the patient died or until December 1992. The follow-up period ranged up to 60 months. Seven of the 31 patients were still alive at the end of this period. SETTING: Lund University Hospital, Sweden. SUBJECTS: Thirty-one patients with CHF due to ischaemic heart disease. Six patients had a degree of heart failure corresponding to NYHA I-II and 25 corresponding to NYHA III-IV. Ten of these 25 patients were on angiotensin converting enzyme (ACE) inhibition in addition to therapy with digoxin and diuretics. The catecholamine and neuropeptide levels were compared to those of a control group of 31 healthy subjects aged 20-80 years. INTERVENTION: There were not any specific intervention in addition to the treatment for heart failure as outlined above. MAIN OUTCOME MEASURES: Survival time until death from heart disease or until the end of the follow up period in December 1992. RESULTS: There were inverse relationships between survival time on one hand and plasma values of noradrenaline (r = -0.49; P < 0.01) and atrial natriuretic peptide (r = -0.49; P < 0.01) on the other hand. There was a significant correlation between the plasma values of noradrenaline and atrial natriuretic peptide (r = 0.50; P < 0.01). CONCLUSION: Increased plasma levels of noradrenaline and atrial natriuretic peptide are of major importance as prognostic markers in patients with CHF.

Adult↗
PubMed1994

Magnesium sulphate infusion decreases circulating calcitonin gene-related peptide (CGRP) in women with primary Raynaud's phenomenon.

The effects of two different vasodilating agents (MgSO4 infusion and the calcium antagonist nifedipine) on circulating levels of calcitonin gene-related peptide (CGRP) were studied in 12 women with pronounced primary Raynaud's phenomenon (PRP) and in 12 healthy females. There were no significant differences with regard to basal levels of circulating CGRP between women with PRP and the control group; median 15.5 (range 10-48) vs. 14 (range 10-69) pmol l-1, respectively. However, treatment with MgSO4 infusion significantly decreased circulating CGRP in women with PRP only from median 15.5 (range 10-48) to 10 (range 10-110) pmol l-1) (P < 0.05). On the other hand 14 days of treatment with nifedipine did not affect circulating CGRP in either of the investigated groups. Erythrocyte magnesium (ery-Mg) levels increased significantly after MgSO4 infusion in women with PRP (2.43 +/- 0.13 vs. 2.52 +/- 0.15 mmol l-1, P < 0.05) but not in the controls (2.51 +/- 0.24 vs. 2.57 +/- 0.28 mmol l-1, ns). In conclusion, the decrease of circulating CGRP after MgSO4 infusion in women with PRP provides further evidence that magnesium plays a significant role in the pathophysiology of PRP.

Adult↗
PubMed1994

Effects of an ET1-receptor antagonist, FR139317, on regional haemodynamic responses to endothelin-1 and [Ala11,15]Ac-endothelin-1 (6-21) in conscious rats.

1. In conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, we compared responses to the putative, selective ETB-receptor agonist, [Ala1,3,11,15]endothelin-1 (ET-1), obtained from two sources (Microchemical Laboratory, Cambridge (MLC) and Neosystem Laboratory, France (NLF)). [Ala1,3,11,15]ET-1 (0.15, 0.3, 1 and 10 nmol kg-1) from MCL caused dose-dependent pressor effects, accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances; there was an initial hyperaemic vasodilatation in the hindquarters which was not dose-dependent, and only with the highest dose was there a subsequent vasoconstriction. There was no significant initial depressor response to [Ala1,3,11,15]ET-1 from MLC at any dose. However, the peptide from NLF exerted dose-dependent depressor and hindquarters vasodilator actions, and subsequent pressor effects. The difference between the two peptide preparations remains unexplained, but it appears that the [Ala1,3,11,15]ET-1 from MLC may activate ETB-receptors mediating vasoconstriction, more effectively than those mediating vasodilatation. 2. We also assessed responses to the putative ETB-receptor agonist, [Ala11,15]Ac-ET-1 (6-21) (BQ-3020), and determined the effects of the selective ETA-receptor antagonist, FR139317, on responses to ET-1 and BQ-3020 at doses matched for their initial depressor and subsequent pressor effects (ET-1, 0.5 nmol kg-1, BQ-3020, 10 nmol kg-1), and also at doses that did not affect mean arterial blood pressure, but which were matched for their renal vasoconstrictor effects (ET-1, 7.5 pmol kg-1; BQ-3020, 0.15 nmol kg-1). 3. BQ-3020 (0.15, 0.3 and 1 nmol kg-1) had dose-dependent pressor effects accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances. BQ-3020 at a dose of 10 nmol kg-1 elicited an initial depressor response which coincided with an attenuated mesenteric vasoconstrictor effect, accompanying a marked hindquarters vasodilatation. Hence, it appears that BQ-3020 may activate both vasoconstrictor and vasodilator ETB-receptors. 4. FR139317 (0.5 mumol kg-1) caused attenuation of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of ET-1 (0.5 nmol kg-1) and of BQ-3020 (10 nmol kg-1), but the reductions of the pressor and renal vasoconstrictor effects of ET-1 were greater than those of BQ-3020. However, in the presence of FR139317, significant pressor and renal, mesenteric and hindquarters vasoconstrictor responses to ET-1 and BQ-3020 still occurred, and the initial depressor and hindquarters vasodilator responses to both peptides were unchanged. 5. ET-1 at a dose of 7.5 pmol kg-1 and BQ-3020 at a dose of 0.15 nmol kg-1 had similar renal vasoconstrictor effects. However, the response to ET-1 was almost abolished by FR139317 whereas that to BQ-3020 was unaffected. Moreover, under these conditions, the mesenteric vasoconstrictor and hindquarters vasodilator responses to ET-1 and to BQ-3020 were not changed by FR139317.6. Collectively, these results are consistent with the haemodynamic effects of ET-1 and BQ-3020 involving ETA-receptors or ETB-receptors, or ETA- and ETB-receptors, depending on the dose of agonist and the regional haemodynamic effect considered.

Animals↗
PubMed1994

Effects of selective ETB-receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle.

1. This paper describes, in quantitative terms, the in vivo effects of two selective ETB-receptor agonists (IRL 1620 and BQ 3020) on vascular resistance (tone) in the following consecutive sections of the vascular bed of sympathectomized cat skeletal muscle: large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns) and the veins. The effects on capillary pressure transcapillary fluid exchange were also recorded. 2. Both IRL 1620 and BQ 3020, infused i.a. to the muscle preparation, evoked an initial transient dilator response followed by a moderate dose-dependent constrictor response, both being preferentially confined to the small arterioles. The dilator response was associated with a transient increase, and the constrictor response with a sustained decrease, in capillary pressure, the latter causing net transcapillary fluid absorption. The capillary filtration coefficient decreased during the constrictor response, indicating constriction of terminal arterioles/precapillary sphincters. 3. The vascular responses to the ETB-receptor agonists were unaffected by blockade of endothelium-derived nitric oxide (NG-nitro-L-arginine methyl ester) and by selective ETA-receptor blockade (FR139317). However, blockade of prostacyclin production with indomethacin decreased the amplitude of the dilator response, and decreased the time required to reach a steady-state vasoconstrictor response to the ETB-receptor agonists. 4. The effect of ETB-receptor stimulation on vascular tone was also evaluated in vitro on the cat femoral artery and vein. IRL 1620 had no effect on the femoral artery but caused a weak dose-dependent relaxation in the femoral vein. This large vein relaxation response seemed to be mediated by endothelium-derived nitric oxide and not by prostacyclin. 5. It may be concluded that ETB-receptor stimulation is responsible for the dilator response, and can contribute to the constrictor response, elicited by endothelins in cat skeletal muscle in vivo.

Animals↗
PubMed1994

Characterization of the histamine receptors in the guinea-pig lung: evidence for relaxant histamine H3 receptors in the trachea.

1. The histamine receptors were characterized on isolated circular segments of trachea and pulmonary arteries from the guinea-pig. The motor responses to histamine H1-, H2- and H3-receptor agonists and antagonists were tested and the responses obtained were analysed in relation to the respiratory epithelium and the vascular endothelium. 2. Histamine induced a biphasic response in trachea and in pulmonary arteries. In low concentrations, histamine acted as a potent relaxant agent of precontracted segments and in moderate concentrations it constricted both precontracted and resting segments. When arterial segments from different parts of the pulmonary vascular tree were compared, only small interregional differences in the vasomotor response were seen. 3. Mepyramine caused a parallel shift to the right of the histamine-induced concentration-response curves for both the trachea and the pulmonary artery, indicating a contractile H1-receptor. Cimetidine did not affect the histamine-induced contraction of the trachea, but a shift to the left was evident for low concentrations of histamine in the pulmonary artery. This is consistent with a dilator H2-receptor in the pulmonary artery. The pA2-value for mepyramine in the pulmonary artery, 8.75, was not affected by the presence of cimetidine. Thioperamide, a selective H3 antagonist, shifted the concentration-response for the trachea to the left. Schild analysis for histamine and mepyramine yielded a line with a slope of 0.61, whereas the same analysis in the presence of thioperamide yielded a line with a slope of 1.05 and an approximated pA2-value of 9.57. These results indicate the presence of a relaxant H3 receptor in the trachea. In precontracted tracheal segments, application of mepyramine and cimetidine did not affect the low dose histamine relaxation. Thioperamide caused a parallel shift of the histamine concentration-response curve to the right, supporting the suggestion of a dilator H3-receptor in the trachea. The pA2-value for thioperamide, in the presence of mepyramine, was 7.79. In precontracted pulmonary arteries the histamine-induced dilatation was small. In the presence of mepyramine a rather strong histamine-induced dilatation became evident and this concentration-response curve could be shifted to the right by cimetidine, with a pA2-value of 6.49. This is compatible with a dilator H2-receptor. 4. The H1-receptor agonists, thiazolylethylamine, 2-methylhistamine and pyridylethylamine and the rather unselective H2-agonist, 4-methylhistamine, induced contraction of resting tracheal and pulmonary arterial segments. In precontracted segments of trachea, all H1 and H2 agonists studied induced a dilator response. The two rather unselective histamine receptor agonists 2-methylhistamine and 4-methylhistamine were about 100 times more potent than other H1 and H2 agonists tested. In the pulmonary artery, the H2 agonists, impromidine, dimaprit and 4-methylhistamine induced a concentration-dependent relaxation. The relaxation of the pulmonary artery, elicited by the H1 agonists,thiazolylethylamine and pyridylethylamine, was smaller, but more potent than the response induced by the H2 agonists. This may reflect the presence of a separate dilator H1-receptor.5. R-alpha-methylhistamine induced a three phased response in precontracted tracheal segments. In low concentrations, a concentration-dependent dilator response appeared. At moderate concentrations, a stage with a plateau or a small contraction was seen, followed at high concentrations by a new concentration-dependent relaxation. The first dilator phase was similar to that obtained for histamine in the same preparation.6. Removal of the epithelium or endothelium enhanced the contractile histamine response in both the trachea and the pulmonary artery as well as the dilator response in the trachea. These results support the hypothesis that the endothelial layer may serve as a barrier against the penetration of certain mediators. In the precontracted pulmonary artery, the small initial dilatation was abolished whereas the second dilatation seen in the presence of mepyramine was slightly reduced. This may reflect the influence of two separate histamine receptors, one of which is associated with the release of an endothelium dependent dilator factor or factors.7. In the guinea-pig trachea, histamine-induced contraction is mediated through H1-receptors where as dilatation probably involves an H3-receptor on the smooth muscle. The guinea-pig pulmonary artery appears to be endowed with a contractile H1 receptor on the smooth muscle cells and a dilator H1 receptor located on the endothelium. A dilator H2 receptor on the smooth muscle cells seems, at least in vitro, to be the most potent mediator of histamine-mediated pulmonary arterial dilatation.

Animals↗
PubMed1994

Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage.

INTRODUCTION--Cerebral blood vessels are innervated by sympathetic nerve fibres storing neuropeptide Y (NPY), parasympathetic nerves storing acetylcholine, vasoactive intestinal peptide (VIP) and sensory afferent fibres containing calcitonin gene-related peptide (CGRP), substance P (SP) and neurokinin A. In experimental studies on subarachnoid haemorrhage (SAH) there are indications that perivascular peptides are involved. In the present study we have in man measured the levels of NPY, VIP, SP and CGRP in brain vessels of patients that have suffered a fatal SAH and compared this with the levels encountered in subjects that died of an extracerebral cause. MATERIAL AND METHODS--Vessels from patients who have died from SAH or nonSAH were obtained during autopsy performed within 24 hrs after death. The peptides were extracted and fractionated with reversed phase liquid chromatography (HPLC). The levels of NPY, VIP, SP, and CGRP were measured with radioimmunoassay. Vasomotor responses of human cerebral arteries were performed using a sensitive in vitro system. RESULTS--Human cerebral vessels contained NPY, VIP, CGRP and SP which eluted at the same positions as the authentic peptides. The level of CGRP was significantly lower (p < 0.01) in arteries removed from SAH patients as compared to control subjects. The level of SP was not changed, if anything it tended to be increased after SAH. The levels of NPY and VIP were not significantly altered after SAH. In isolated brain vessels alpha-CGRP was a potent vasodilator of arteries precontracted with whole blood, prostaglandin F2 alpha or endothelin. It had a poor effect on vessels precontracted with 60 mM potassium. CONCLUSION--The evidence suggest that the trigemino-cerebrovascular system, storing CGRP and SP, is to a differential degree involved in the pathophysiology of SAH in man and supports the hypothesis of an exhaustion of CGRP as one important factor in the development of late spasm occurring after SAH.

Adult↗
PubMed1994

Histamine-independent modulation of the neuropeptide Y-induced pressor response by alpha-trinositol in the pithed rat.

The modulatory effects of alpha-trinositol (D-myo-inositol-1.2.6- trisphosphate; PP 56) on the systemic arterial blood pressor responses induced by neuropeptide Y, preganglionic nerve stimulation, phenylephrine and vasopressin were studied in pithed rats. Intravenous administration (within 2 min.) of alpha-trinositol reduced the neuropeptide Y-induced increase in mean arterial pressure within a defined dose range without altering the heart rate. The influence of alpha-trinositol on the neuropeptide Y-induced pressor response in the presence of non-selective as well as H1- and H2-selective histamine antagonists (diphenhydramine, mepyramine and cimetidine respectively) were investigated. The maximal increase in mean arterial pressure induced by neuropeptide Y as well as the duration of the pressor response was enhanced after nonselective (diphenhydramine) or H1-selective (mepyramine) histamine blockade. The enhancement of the neuropeptide Y-induced pressor response by the H1 specific antagonist mepyramine was significantly more pronounced compared to the H2-selective agent. The exaggerated increase in mean arterial pressure in response to neuropeptide Y after histamine blockade was inhibited by alpha-trinositol to a similar extent as without such pretreatment. We conclude that neuropeptide Y interacts with histamine in the pithed rat and that this action may partially offset the pressor actions of the peptide. The neuropeptide Y-induced pressor responses may be inhibited by alpha-trinositol within a defined dose range indicating that this non-peptide agent may act as a functional inhibitor to neuropeptide Y in vascular tissue.

Animals↗
PubMed1994

Inhibition of neuropeptide Y-induced augmentation of noradrenaline-induced vasoconstriction by D-myo-inositol 1,2,6-trisphosphate in the rat mesenteric arterial bed.

The effect of the neuropeptide Y antagonist D-myo-inositol-1,2, 6-trisphosphate (alpha-trinositol) was tested against modulatory actions mediated by neuropeptide Y in the isolated rat mesenteric arterial bed. Neuropeptide Y (1 and 10 nM) had no direct postjunctional effects, but augmented vasoconstrictor responses to noradrenaline and to sympathetic nerve stimulation to an extent which was greater with the higher concentration of neuropeptide Y. The augmenting effect of neuropeptide Y at 1 nM on vasoconstriction induced by lower doses of noradrenaline was antagonized by alpha-trinositol (1 microM), producing a shift to the right of the dose-response curve. A lower concentration of alpha-trinositol (0.1 microM) had no inhibitory effect on responses to noradrenaline. Augmentation by the higher concentration of neuropeptide Y (10 nM) of noradrenaline-induced vasoconstriction was not affected by alpha-trinositol at concentrations of up to 10 microM. alpha-Trinositol did not significantly antagonize neuropeptide Y-induced augmentation of vasoconstrictor responses to sympathetic nerve stimulation. alpha-Trinositol alone did not affect vasoconstrictor responses to noradrenaline, potassium, or to sympathetic nerve stimulation. In the raised-tone preparation (tone raised with methoxamine) in the presence of guanethidine (5 microM) to block sympathetic neuro-transmission, perivascular nerve stimulation caused vasodilatation due to activation of sensory-motor nerves. Neuropeptide Y inhibited sensory-motor nerve induced vasodilatation in a concentration-dependent manner but this was not affected by alpha-trinositol (1 microM). These results suggest that alpha-trinositol can be a useful functional antagonist of neuropeptide Y-induced augmentation of vasoconstrictor responses to noradrenaline in the rat mesenteric arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Hypercapnic vasodilatation in isolated rat basilar arteries is exerted via low pH and does not involve nitric oxide synthase stimulation or cyclic GMP production.

The relaxant effect of hypercapnia (15% CO2) was studied in isolated circular segments of rat basilar arteries with intact endothelium. The nitric oxide synthase inhibitor nitro-L-arginine (L-NOARG) and the cytosolic guanylate cyclase inhibitor methylene blue (MB), significantly reduced this relaxation by 54% and 70%, respectively. The effect of L-NOARG was completely reversed by L-arginine. Blockade of nerve excitation with tetrodotoxin (TTX) had no affect on the 15% CO2 elicited vasodilatation. Measurements of cGMP in vessel segments showed no significant increase in cGMP content in response to hypercapnia. L-NOARG and MB, but not TTX, significantly reduced the basal cGMP content in cerebral vessels. Adding 1.5% halothane to the incubation medium did not result in a significant increase in cGMP content. Lowering the pH by cumulative application of 0.12 M HCl resulted in relaxation identical to that obtained by lowering the pH with 15% CO2. In vessel segments in which the endothelium had been removed beforehand 15% CO2 induced relaxation that was not different from that seen in vessels with intact endothelium. L-NOARG had no affect in endothelium denuded vessels. The results suggest that high CO2 elicits vasodilatation of isolated rat basilar arteries by a mechanism independent of nitric oxide synthase (NOS) activity. The markedly reduced basal cGMP levels in cerebral vessels by L-NOARG and MB suggest that there exists a basal NO formation in the cerebral vessel wall.

Amino Acid Oxidoreductases↗
PubMed1994

Neuropeptide Y inhibits adenylyl cyclase activity in rabbit retina.

Neuropeptide Y is known to be present in significant amounts in the retina of most vertebrates, but its physiological actions are largely unknown. We have therefore studied its effects on the intracellular cyclic AMP accumulation in rabbit retina. Neuropeptide Y had no effect on the basal cyclic AMP level but was found to inhibit the forskolin induced cyclic AMP accumulation. There were no differences between the effects of neuropeptide Y 1-36 and neuropeptide Y 13-36 (2.4 x 10(-6) M) suggesting the presence of the Y2 subtype of neuropeptide Y receptor. D-myo-inositol-1,2,6-trisphosphate, a novel neuropeptide Y-antagonist, reduced per se the forskolin induced cyclic AMP production. The pronounced inhibitory effect of neuropeptide Y on the forskolin induced cyclic AMP production was, on the other hand, totally abolished by D-myo-inositol-1,2,6-trisphosphate. The results indicate that neuropeptide Y acts on Y2 receptors in the retina to cause an inhibition of the adenylyl cyclase activity which could be antagonized by D-myo-inositol-1,2,6-trisphosphate. Such an inhibitory action of neuropeptide Y is similar to what has been found in brain tissue, but it has not previously been reported in the retina for neuropeptide Y or any of the other retinal neuropeptides.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Effect of magnesium sulfate infusion on circulating levels of noradrenaline and neuropeptide-Y-like immunoreactivity in patients with primary Raynaud's phenomenon.

The effect of a short-term magnesium sulfate (MgSO4) infusion on venous plasma concentration of noradrenaline (NA) and neuropeptide-Y-like immunoreactivity (NPY-LI) was investigated in 12 women with primary Raynaud's phenomenon (PRP) and in 12 healthy matched controls. The Raynaud's patients did not demonstrate any significant changes in mean basal plasma NA concentration (0.29 +/- 0.15 vs 0.37 +/- 0.09 ng/mL, ns) after MgSO4 infusion. However, in the controls there was more than twice the amount of circulating noradrenaline (cNA) (0.21 +/- 0.14 vs 0.54 +/- 0.22 ng/mL, P < 0.001) after MgSO4 infusion, compared with the preinfusion value. Measurements during the cold pressor test prior to the MgSO4 infusion showed a significant increase of cNA in both the PRP group and the control group (from 0.29 +/- 0.15 to 0.33 +/- 0.16 ng/mL, P < 0.05, and from 0.21 +/- 0.14 to 0.29 +/- 0.16 ng/mL, P < 0.005, respectively). After MgSO4 infusion the levels of cNA during the cold pressor test increased significantly only in the PRP group (from 0.37 +/- 0.09 to 0.41 +/- 0.11 ng/mL, P < 0.05). Circulating NPY-LI concentrations increased significantly during MgSO4 infusion in the Raynaud's patients as well as in the controls from 105 +/- 21 to 127 +/- 23 pmol/L, P < 0.05, and from 107 +/- 17 to 132 +/- 27 pmol/L, P < 0.01, respectively. There were no detectable changes during the cold pressor tests in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Low plasma concentrations of VIP and elevated levels of other neuropeptides during exacerbations of asthma.

Neuropeptides in the lung occur in neurons, neuroendocrine and inflammatory cells. Their widespread distribution and physiological effects suggest that they may play important roles in asthma. We investigated whether, during an exacerbation of asthma, patients displayed changes in plasma levels of the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY). Venous blood from 25 adult patients attending the emergency ward with an exacerbation of asthma was sampled before and after treatment. Plasma levels of VIP-, SP-, CGRP- and NPY-like immunoreactivity (-LI) were determined by immunoassay, and the results obtained were compared with findings in 21 healthy controls. The mean plasma levels of VIP-LI were lower in patients (3.4 +/- 0.4 pmol.l-1) than in controls (10.4 +/- 0.7 pmol.l-1), whereas the levels of CGRP-LI (43.7 +/- 3.4 pmol.l-1), SP-LI (4.6 +/- 0.4 pmol.l-1) and NPY-LI levels (159 +/- 6 pmol.l-1) were higher in patients than in controls (21.1 +/- 3.4; 2.2 +/- 0.2 and 105 +/- 8 pmol.l-1, respectively). A relationship was seen between the reversibility of obstruction, expressed as improvement of peak expiratory flow upon treatment, and the neuropeptide levels, such that lower VIP-LI levels and higher CGRP-LI levels correlated with less reversibility. Plasma levels of neuropeptides, VIP-LI and CGRP-LI in particular, may therefore be employed as predictors of responsiveness to bronchodilatory therapy.

Acute Disease↗
PubMed1994

The effects of alpha-trinositol on haemodynamic variables and neuropeptide Y levels in a pilot study of hypertensives and healthy volunteers.

AIMS: The aim of this study was to examine the effects of D-myo-inositol-1,2,6-trisphosphate (alpha-trinositol) on haemodynamic variables and neuropeptide Y (NPY) levels in hypertensives and healthy volunteers. METHODS: Hypertensives (n = 13) and normotensives (n = 11) were recruited after a screening of cardiovascular risk factors of all men aged 40 living in a well defined area. The hypertensives were previously unmedicated. The effect of alpha-trinositol was studied after intravenous infusion at rest, and during and after a maximal exercise test in a double-blind crossover manner with placebo. RESULTS: Haemodynamic variables and NPY levels were recorded. NPY levels did not differ between normotensives and mild hypertensives at the start of the study. However, a significant increase was seen in hypertensives after they had risen to the sitting position. During exercise, the NPY levels increased significantly both in normotensives and hypertensives. After the exercise test, the NPY levels were significantly higher in hypertensives than in normotensives; alpha-trinositol did not modify these responses. In normotensives no significant difference in systolic blood pressure was seen during or after the exercise test whether they were on alpha-trinositol or placebo. In the hypertensives on active drug, however, the blood pressure tended to be approximately 5 mmHg lower during the exercise test as compared with the placebo group. In the hypertensives on active drug, the heart rate increased significantly more during exercise as compared with the placebo groups. In normotensives, the same tendency was seen, but it did not reach statistical significance. CONCLUSIONS: The NPY antagonist, alpha-trinositol, tends to reduce the increase in systolic blood pressure induced by maximal exercise and increases the heart rate in hypertensives but not in normotensives.

Adult↗
PubMed1993

Human neuropeptide Y Y1 receptor antisense oligodeoxynucleotide specifically inhibits neuropeptide Y-evoked vasoconstriction.

This paper describes a new approach for the development of an inhibitor of the contractile responses of neuropeptide Y in human blood vessels by the use of an antisense oligodeoxynucleotide complementary to human neuropeptide Y Y1 receptor mRNA. One micromolar of an antisense 18-base oligodeoxynucleotide (hY1-AS), corresponding to the human Y1 receptor NH2-terminus, was incubated with segments of human subcutaneous arteries and veins for 48 h at 37 degrees C. Control vessels were incubated with the corresponding sense oligodeoxynucleotide (hY1-S) or a 3-base mismatched antisense oligodeoxynucleotide (hY1-MM) or no oligodeoxynucleotide. The contractile response to neuropeptide Y was markedly attenuated in both arteries and veins after treatment with hY1-AS, but was unaffected by hY1-S or hY1-MM. The pD2 values, i.e. the potency of neuropeptide Y, did not differ in hY1-AS treated vessels, suggesting a non-competitive receptor interaction as a result of down-regulation of Y1 receptors. Responses to noradrenaline or high K+ were unaffected by hY1-AS. This study may represent a new and highly specific approach to vascular pharmacology.

Base Sequence↗
PubMed1993

D-myo-inositol 1,2,6-trisphosphate blocks neuropeptide Y-induced facilitation of noradrenaline-evoked vasoconstriction of the mesenteric bed.

Perfusion of the rat mesenteric bed with 0.1 or 10 nM neuropeptide Y potentiated the noradrenaline-induced increase in mesenteric pressure; the peptide did not modify basal perfusion pressure. While perfusion with 0.1 nM neuropeptide Y significantly increased the maximal noradrenaline-evoked vasoconstriction without modifying its EC50, 10 nM neuropeptide Y potentiated the maximal noradrenaline effect and significantly shifted its concentration-response curve to the left. Perfusion with 1-10 microM D-myo-inositol 1,2,6-trisphosphate (alpha-trinositol) reduced, in a concentration-dependent fashion, the neuropeptide Y-induced potentiation of the noradrenaline-evoked vasoconstriction without altering the potency or maximal response evoked by the catecholamine alone. Perfusion with 0.1 nM neuropeptide Y plus 1 microM alpha-trinositol completely abolished the neuropeptide Y-induced facilitation of the noradrenaline effect. alpha-Trinositol 1 microM in the presence of 10 nM neuropeptide Y caused a nonparallel rightward shift of the noradrenaline concentration-response curve as compared to that obtained in the presence of 10 nM neuropeptide Y alone. The alpha-trinositol blockade of the facilitatory action of neuropeptide Y was reversible.

Animals↗
PubMed1993

The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats.

Both clinical and physiological consideration of migraine suggests that the pathophysiology of the syndrome is intimately linked to the trigeminal innervation of the cranial vessels, the trigeminovascular system. Studies were conducted in cats and humans to examine the interaction of these systems with the effective acute antimigraine drugs dihydroergotamine and sumatriptan. In the animal studies cats were anesthetized and prepared for routine physiological monitoring as well as for blood sampling from the external jugular veins. Cerebral blood flow was monitored continuously using laser Doppler flowmetry and the effect of trigeminal ganglion stimulation on both cerebral blood flow and jugular vein peptide levels determined prior to and after administration of either sumatriptan or dihydroergotamine. Stimulation of the trigeminal ganglion led to a frequency-dependent increase in cerebral blood flow, with a mean maximum of 43 +/- 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine. Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene-related peptide (CGRP), with the level rising from 67 +/- 3 to 82 +/- 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by both sumatriptan and dihydroergotamine. Human studies were conducted as part of the overall evaluation of sumatriptan for the treatment of acute migraine. In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 +/- 8 pmol/liter) were normalized, with the headache being relieved (40 +/- 8 pmol/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗