The aim of the present study was to examine if the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) can stimulate histamine release from mast cells in the dura mater and thereby play a role in cranial vasoregulation and local neurogenic inflammation. Dura mater mast cells were compared with peritoneal mast cells in the rat. Histamine was released from dura mater mast cells by compound 48/80, SP and CGRP but from peritoneal mast cells only by compound 48/80 and SP. NPY and VIP released quite small amounts of histamine from dural mast cells. The release of SP and CGRP from rat dura mater mast cells was blocked by the receptor antagonists FK888 and CGRP8-37 respectively, suggesting receptor mediated release mechanisms. None of the stimuli released histamine from human or porcine dural mast cells, possibly because the sampling procedure injures and incapacitates the cells.

Nerve fibers containing neuropeptide Y, vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) were seen in the adventitia or at the adventitia-media border of human cerebral arteries obtained during neurosurgical procedures. Radioimmunoassay of human cerebral arteries, removed at autopsy, revealed that the levels of the four peptides did not differ among the major cerebral arteries. There was, however, a gradual decline in peptide concentrations with increasing age of the patients, as measured in the proximal part of the middle cerebral artery. Pharmacological experiments on fresh segments of cerebral (pial) arteries in vitro revealed that neuropeptide Y caused vasoconstriction per se but did not potentiate the contractile response of noradrenaline. VIP, peptide histidine methionine-27 (PHM-27), SP, neurokinin A (NKA), and human CGRP potently relaxed vessels precontracted by prostaglandin F2 alpha, the relative potency being human CGRP greater than SP greater than VIP greater than NKA greater than PHM-27. The amount of relaxation varied between 55% (SP) and 96% (human CGRP) of the prostaglandin F2 alpha-induced contraction. The peptide effects were not antagonized by propranolol, atropine, or cimetidine, suggesting an action that does not involve adrenergic, cholinergic, or histaminergic receptors.

The safety of long-acting b 2 -agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or allcause mortality and morbidity were increased with formoterol use.The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol.There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterolrandomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (.90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 mg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABAtreated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant.There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting b 2 -agonistrandomised patients. However, despite data on .68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

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1 Histamine induces relaxation of human cranial arteries. Studies have revealed that the relaxant histamine H 1 -receptor predominates in human cerebral and the H 2 -receptor in temporal arteries, while H 1 -and H 2 -receptors are of equal importance in the middle meningeal artery. The purpose of the present study was to examine the role of the endothelium and nitric oxide in histamine-induced responses and to show the presence of mRNA encoding H 1 -and H 2 -receptors in human cranial arteries. 2 Electrophoresis of polymerase chain reaction (PCR) products from human cerebral, middle meningeal and temporal arteries, demonstrated products corresponding to mRNA encoding both H 1 -and H 2 -receptors in arteries with and without endothelium. The ampli®ed PCR products were sequenced and showed 100% homology with the published sequences of these histamine receptors. 3 A sensitive in vitro system was used to study vasomotor responses to histamine. In precontracted cerebral, middle meningeal and temporal arteries with and without endothelium, histamine caused a concentration-dependent relaxation with I max values between 87% and 81% and pIC 50 values between 8.14 and 7.15. In arteries without endothelium the histamine-induced relaxation was signi®cantly less potent (I max values between 87% and 66% and pIC 50 values between 7.01 and 6.67) than in cranial arteries with an intact endothelium. 4 The addition of histamine to arteries without endothelium and pretreated with the histamine H 2 -antagonist, cimetidine (10 75 M), caused a concentration-dependent contraction of the cranial arteries with E max values between 86% and 29% and pEC 50 values between 7.53 and 6.77. This contraction was blocked by the histamine H 1 -receptor antagonist, mepyramine (10 77 M), and even turned into a relaxation with I max values between 84% and 14% and pIC 50 values between 7.42 and 5.86. 5 The nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 3610 75 M) signi®cantly inhibited the relaxant response to histamine in cerebral and temporal arteries (pIC 50 values between 7.43 and 7.13). The combined treatment with L-NAME (3610 75 M) and cimetidine (10 75 M) caused a further displacement of the concentration-response curve (pIC 50 values between 7.14 and 6.57) and decreased the maximum relaxant responses in all three cranial arteries (I max values between 62% and 39%). 6 In conclusion, this is the ®rst study which show mRNA encoding histamine H 1 -and H 2 -receptors in human cranial arteries. The results indicate that histamine-induced relaxation of human cranial arteries is partially mediated via an endothelial H 1 -receptor coupled to the production of nitric oxide and partially via a H 2 -receptor associated with the smooth muscle cells. In addition, there is evidence for a contractile H 1 -receptor in the smooth muscle cells in these arteries.