Socio-economic status and major trauma in a Scandinavian urban city: A population-based case-control study.

AIMS: Epidemiological studies of patients with major trauma, including both hospitalized and immediately deceased whom are undergoing medico-legal autopsy, are very rare. We studied the incidence and mortality of major trauma in all 10 districts in the Scandinavian city of Malmö, Sweden, and the association between socio-economic status and major trauma. METHODS: Major trauma was defined as a New Injury Severity Score > 15, or a lethal outcome due to trauma. Cases with a registration address in Malmö between 1 January 2011 and 31 December 2013 were identified from the red trauma alarm list in the hospital and the autopsy register in the Forensic Department. Statistics Sweden matched each case with four randomly selected age-, gender- and district-matched controls. Social assistance within the household, level of education, income and capital income were compared. RESULTS: We identified 117 cases (80 men and 37 women) with a median age of 48.0 years (IQR 28.5-65.0). The incidence of major trauma in Malmö was 12.7 (95% CI 10.4-15.0) per 100,000 person-years; and 69 died due to major trauma, with 8.4 (95% CI 6.4-10.4) per 1000 deaths. Lower income (p = 0.024), no income (OR 1.6; 95% CI 1.0-2.4; p = 0.037) and social assistance (OR 2.3; 95% CI 1.3-4.1; p = 0.003) were associated with major trauma. The level of education was not found to be related to major trauma (p = 0.47). CONCLUSIONS: Low income and social assistance within the household were associated with major trauma in the city of Malmö, but not the level of education; in this age-, gender- and district-matched case-control study of major trauma.

Necessity of including medico-legal autopsy data in epidemiological surveys of individuals with major trauma.

BACKGROUND: It is rare that epidemiological surveys of patients with major trauma include both those admitted to the emergency department and those sent for medico-legal autopsy. The main aim of the present population-based study of major trauma was to examine the importance of medico-legal autopsy data. METHODS: A new injury severity score (NISS)>15 or lethal outcome was used as criteria for major trauma and to identify patients at the emergency, anaesthesiology and forensic departments and/or being within the jurisdiction of the Malmö police authority and subjected to a medico-legal autopsy between 2011 and 2013. According to Swedish legislation all trauma related deaths should be reported to the police who refer these cases for medico-legal autopsy. RESULTS: Among the 174 individuals included, 92 (53%) died and 81 (47%) underwent medico-legal autopsy. One hundred twenty-six patients were primarily admitted to hospital and 48 died before admission to hospital and were sent directly for medico-legal autopsy. Forty-four in-hospital deaths occurred, of whom 33 (75%) were sent to medico-legal autopsy. In those sent directly to the department of forensic medicine the proportion of accidents was lower (p<0.001), self-inflicted injuries higher (p<0.001) and gunshot wounds higher (p=0.002) in comparison with those sent to hospital. The most prevalent drugs detected by forensic toxicology screening in the 81 fatalities were ethanol (20%), sedatives (16%), anti-depressives (15%) and illicit narcotics (9%). Forty-four cases (54%) were positive for at least one drug, and twenty-eight cases (35%) were positive for two or more drugs. Factors associated with a lower rate of medico-legal autopsies among trauma-related deaths at hospital were high age (p<0.001), lower NISS (p<0.001), a longer duration between trauma and death (p<0.001), falls (p=0.030) and trauma-related infections (p<0.001). CONCLUSION: This population based study covering clinical and forensic data shows that more than half of the individuals sustaining major trauma died. An additional 25% of the in-hospital fatalities should have undergone medico-legal autopsy according to legislation, but did not. The high proportion of positive toxicological findings among fatalities examined at medico-legal autopsy implies that toxicology screening should be routine in major trauma patients, in order to improve treatment and prevention.

Long-acting beta-agonists: a review of formoterol safety data from asthma clinical trials.

The safety of long-acting beta(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 all-cause 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 formoterol-randomised 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 microg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABA-treated 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 beta(2)-agonist-randomised 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.

Big wheel keeps on turning: apoptosome regulation and its role in chemoresistance.

Apoptosis, a form of programmed cell death, enables organisms to maintain tissue homeostasis through deletion of extraneous cells and also serves as a means to eliminate potentially harmful cells. Numerous stress signals have been shown to engage the intrinsic pathway of apoptosis, with the release from mitochondria of proapoptotic factors such as cytochrome c and the subsequent formation of a cytosolic complex between apoptotic protease-activating factor-1 (Apaf-1) and procaspase-9, known as the apoptosome. Recent studies have led to the identification of an array of factors that control the formation and activation of the apoptosome under physiological conditions. Moreover, deregulation of apoptosome function has been documented in various forms of human cancer, and may play a role in both carcinogenesis and chemoresistance. We discuss how the apoptosome is regulated in normal and disease states, and how targeting of apoptosome-dependent, post-mitochondrial stages of apoptosis may serve as a rational approach to cancer treatment.

Smac-mediated sensitization of human B-lymphoma cells to staurosporine- and lactacystin-triggered apoptosis is apoptosome-dependent.

Second mitochondrial activator of caspase (Smac)-derived peptides have previously been shown to facilitate apoptosis of various types of cancer cells. However, it remains unclear whether the effects of such Smac agonists are dependent on apoptotic protease-activating factor-1 (Apaf-1), a key component of the apoptosome. Here, we explored the role of Apaf-1 through overexpression of this protein in the B-lymphoma cell line Raji that is defective for cytosolic Apaf-1 expression. Enforced expression of Apaf-1 rendered Raji cells sensitive to staurosporine as well as to the proteasome inhibitor, lactacystin. Importantly, co-treatment with Smac peptides resulted in a threefold higher degree of apoptosis in Apaf-1-expressing Raji cells, but not in mock-transfected cells. Smac peptides also potentiated apoptosis of the DG-75 cell line following liberation of endogenous Apaf-1 from the plasma membrane, but were ineffective when added alone. Furthermore, we observed high levels of expression in several B-lymphoma cell lines of cellular inhibitor of apoptosis protein-2 (cIAP2), and immunodepletion of cIAP2 (a target of Smac) was found to sensitize Apaf-1-overexpressing Raji cells to cytochrome c-dependent caspase activation. Collectively, these results demonstrate the importance of Apaf-1 in Smac-mediated potentiation of apoptosis of B-lymphoma-derived cells.

The lipoprotein profile differs during insulin treatment alone and combination therapy with insulin and sulphonylureas in patients with Type 2 diabetes mellitus.

AIMS: To study whether changes in endogenous insulin secretion at the same glycaemic control affect the plasma concentrations of lipoproteins in patients with Type 2 diabetes mellitus. METHODS: Fifteen patients, age 59+/-2 years (mean +/- SEM), body weight 86.3+/-3.0kg, body mass index 29.6+/-0.9 kg/m2 were treated with sulphonylurea and insulin in combination or with insulin alone in a randomized, double-blind, crossover study. All patients were treated with a multiple daily injection regimen with the addition of glibenclamide 10.5 mg daily or placebo tablets. RESULTS: During combination therapy, the dose of insulin was 25% less (P < 0.002) and there was a 29% increase in plasma C-peptide concentration (P = 0.01). Plasma levels of free insulin were not changed. Plasma levels of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein (IGFBP)-1 were lowered. There were no differences in the 24-h blood glucose profiles or HbA1c (6.0+/-0.2 vs. 6.3+/-0.2%; P = 0.16). Body weight was similar. There was a significant decrease in plasma LDL cholesterol (3.04+/-0.24 vs. 3.41+/-0.21 mmol/l; P = 0.04), apolipoprotein A1 and of lipoprotein(a) but an increase in VLDL-triglycerides (1.36+/-0.31 vs. 0.96+/-0.16 mmol/l; P = 0.02) during combination therapy. The ratio between LDL cholesterol and apolipoprotein B concentrations was significantly lower during combination therapy (P < 0.01). CONCLUSIONS: Combination therapy with insulin and sulphonylureas increases portal insulin supply and thereby alters liver lipoprotein metabolism when compared with insulin therapy alone.

Sutureless small bowel anastomoses: experimental study in pigs.

OBJECTIVE: To evaluate a new technique for experimental anastomosis with fibrin glue, and to compare the results with those of stapled and one-layer sutured anastomosis. DESIGN: Open laboratory study. SETTING: Teaching hospital, Sweden. ANIMALS: Ten Swedish domestic pigs. INTERVENTIONS: Each pig had three anastomoses made in the small bowel, one by each technique. The pigs were killed on the 4th postoperative day. MAIN OUTCOME MEASURES: Blood flow, collagen concentration, anastomotic index, breaking strength, thickness of bowel wall, and histological appearance. RESULTS: Two pigs died postoperatively, leaving 8 for analysis. The blood flow at each anastomotic site studied by the microsphere technique was similar irrespective of the type of anastomosis (p = 0.3), as was anastomotic collagen concentration (p = 0.09). The anastomotic index, however, was significantly higher in the stapled than in the glued or sutured ones (p = 0.03). The glued anastomosis was the weakest, being only one fifth the strength of the stapled and one third the strength of the sutured anastomosis. There was no sign of rejection of the glue (of human origin) on histological examination. Glued and stapled anastomoses showed signs of mild inflammation, which did not reach the intensity of that around the sutured anastomoses. CONCLUSION: It is possible to make a sutureless anastomosis that does not leak with a modified stapler using fibrin glue instead of staples, but the anastomosis has considerably lower breaking strength than either stapled or sutured anastomoses.

Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide.

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.

Role of endothelium and nitric oxide in histamine-induced responses in human cranial arteries and detection of mRNA encoding H1- and H2-receptors by RT-PCR.

1. Histamine induces relaxation of human cranial arteries. Studies have revealed that the relaxant histamine H1-receptor predominates in human cerebral and the H2-receptor in temporal arteries, while H1- and H2-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 H1- and H2-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 H1- and H2-receptors in arteries with and without endothelium. The amplified 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 Imax values between 87% and 81% and pIC50 values between 8.14 and 7.15. In arteries without endothelium the histamine-induced relaxation was significantly less potent (Imax values between 87% and 66% and pIC50 values between 7.01 and 6.67) than in cranial arteries with an intact endothelium. 4. This addition of histamine to arteries without endothelium and pretreated with the histamine H2-antagonist, cimetidine (10(-5) M), caused a concentration-dependent contraction of the cranial arteries with Emax values between 86% and 29% and pEC50 values between 7.53 and 6.77. This contraction was blocked by the histamine H1-receptor antagonist, mepyramine (10(-7) M), and even turned into a relaxation with Imax values between 84% and 14% and pIC50 values between 7.42 and 5.86. 5. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-5) M) significantly inhibited the relaxant response to histamine in cerebral and temporal arteries (pIC50 values between 7.43 and 7.13). The combined treatment with L-NAME (3 x 10(-5) M) and cimetidine (10(-5) M) caused a further displacement of the concentration-response curve (pIC50 values between 7.14 and 6.57) and decreased the maximum relaxant responses in all three cranial arteries (Imax values between 62% and 39%). 6. In conclusion, this is the first study which show mRNA encoding histamine H1- and H2-receptors in human cranial arteries. The results indicate that histamine-induced relaxation of human cranial arteries is partially mediated via an endothelial H1-receptor coupled to the production of nitric oxide and partially via a H2-receptor associated with the smooth muscle cells. In addition, there is evidence for a contractile H1-receptor in the smooth muscle cells in these arteries.

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.

Modulation of vascular contractile responses to alpha 1- and alpha 2-adrenergic and neuropeptide Y receptor stimulation in rats with ischaemic heart failure.

In order to evaluate adaptational changes in vascular function in congestive heart failure (CHF), we studied the contractile responses of isolated arterial and venous blood vessels from rats suffering from CHF induced by coronary artery ligature, resulting in a myocardial infarction. The contractile responses of the basilar, femoral and renal arteries and of the iliac vein were examined in relation to adrenergic and neuropeptide Y (NPY) receptor function by the action of the alpha 1 agonist phenylephrine, the alpha 2 agonist clonidine and NPY. The contractile force was measured (in mN) and in % of K(+)-induced contraction as well as pD2 to each agonist. When stimulated by a 60 mM K(+)-buffer solution, the femoral and renal arteries from CHF rats responded with a stronger contraction (Emax; 9.4 +/- 0.6 and 9.8 +/- 0.6 mN) than the corresponding Sham vessels (Emax; 6.2 +/- 0.7 and 5.6 +/- 0.4 mN respectively, P < 0.001). On the contrary, the iliac vein of CHF responded less to K+ than the Sham iliac vein (Emax 2.5 +/- 0.2 and 3.7 +/- 0.5 mN, P < 0.01). The CHF iliac vein responded with a weaker contraction when stimulated with phenylephrine (Emax 1.9 +/- 0.4 mN) and showed a lower sensitivity (pD2 5.6 +/- 0.1) than the corresponding sham vessel (Emax 5.7 +/- 2.3 mN and pD2 6.3 +/- 0.5, P < 0.05). The CHF renal artery was less sensitive to clonidine (pD2 6.4 +/- 0.6) than the Sham renal artery (pD2 7.2 +/- 0.1, P < 0.05). The results indicate differences between CHF and Sham vessel segments according to both contractile capacity induced by K(+)-depolarization and to agonist induced contractile capacity and sensitivity. The differences are not of general nature but vary according to the vascular bed examined.

Inhibition of nisoldipine on bovine mesenteric arteries and veins and on human peripheral veins.

The inhibiting effect of the calcium channel blocker nisoldipine (CAS 63675-72-9, Baymycard, Syscor) on potassium-induced contraction on bovine mesenteric veins and arteries and human peripheral veins was investigated. Nisoldipine inhibited the contraction on bovine mesenteric veins at a significantly lower concentration (1 x 10(-10) mol/l) than nifedipine and glyceryl trinitrate (GTN) (1 x 10(-7) mol/l). When the preparations were preincubated with the drugs, nisoldipine reduced the contraction, measured as area under the curve (AUC), with 47 +/- 8% (mean +/- SEM) and nifedipine with 29 +/- 13% in veins. It was necessary to use an inconsiderably higher concentration of nisoldipine to relax bovine mesenteric arteries contracted by potassium. Preincubation of these arteries with nisoldipine (1 x 10(-7) mol/l) reduced contraction measured as AUC by 46 +/- 10% and preincubation with nifedipine (1 x 10(-7) mol/l) by 77 +/- 3%. Nisoldipine also caused a marked relaxation in human saphenous veins. The introduction of nisoldipine (1 x 10(-8) mol/l) after potassium-induced contraction caused 54 +/- 8% relaxation.

Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries.

A sparse to moderate supply of nerve fibers containing neuropeptide Y-like immunoreactivity (NPY-LI), vasoactive intestinal polypeptide (VIP-LI), substance P (SP-LI), and calcitonin gene-related peptide (CGRP-LI) was demonstrated in the walls of human middle meningeal arteries. Comparison with similar studies on human cerebral and temporal arteries indicated a similar distribution and density. The immunoreactive material in all three arterial regions was characterized by reversed-phase high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA). The major peak of NPY-LI, VIP-LI, SP-LI, and CGRP-LI in each extract eluted approximately with the same elution volume as that of the corresponding synthetic analogues. The concentration of NPY in the middle meningeal arteries was lower as compared to the temporal arteries. Low concentrations of SP-LI and CGRP-LI were found in the middle meningeal arteries as compared to the cerebral arteries. In isolated ring segments of human middle meningeal and cerebral arteries, NPY caused vasoconstriction but did not potentiate the contractile response of noradrenaline. In the temporal artery, NPY did not induce contraction but potentiated the vasoconstrictor response to noradrenaline. Vasoactive intestinal polypeptide, peptide histidine methionine-27, SP, neurokinin A, and CGRP relaxed all three types of cephalic arteries. The peptide effects were not antagonized by propranolol, atropine, or cimetidine. Comparison of the responses to VIP and SP of vessels from the different regions showed a similar pattern of reactivity. The response to SP was slightly (p less than 0.05) more potent, whereas the responses to CGRP were less potent in the middle meningeal as compared to that in cerebral (p less than 0.005) vessels.

Histamine receptors in the isolated human middle meningeal artery. A comparison with cerebral and temporal arteries.

The subtypes of histamine receptors mediating dilatation of human meningeal arteries have been tested in vitro, using "selective" antagonists, and compared with cerebral and temporal arteries previously examined. Dilatory responses were tested after preconstriction with prostaglandin F2 alpha. Both mepyramine and cimetidine caused a parallel shift to the right of the histamine concentration-response curve, suggesting the presence of both H1- and H2-receptors. Combined treatment with mepyramine and cimetidine caused further displacement of the concentration-response curve to the right. Schild analysis indicated pA2 values of 6.3 for cimetidine and 9.8 for mepyramine in situations of near complete blockade of either of the receptors. Both H1- and H2-receptors seem of importance for the histamine-induced dilatation in meningeal arteries and neither appear to dominate. The data considered in conjunction with our previous findings support the finding that experimental histamine-induced headache due to vasodilatation is intracranial of origin.

Nisoldipine--effects on the renin-angiotensin-aldosterone system and catecholamines. Studies in normotensive and hypertensive subjects.

We have studied the effects of nisoldipine, a new calcium channel antagonist, on the renin-angiotensin-aldosterone system and on plasma catecholamines in 10 healthy volunteers and in 29 patients with primary essential hypertension. Of these 29 patients, thirteen had normal renin hypertension (NRH), and sixteen had low renin hypertension (LRH). Eight healthy volunteers received placebo. Short-term (24 h) effects were measured in all subjects and long-term (up to 6 months) effects of 10-40 mg nisoldipine daily were monitored in the 29 hypertensive patients. Plasma renin activity (PRA) increased slightly, although this rise was not statistically significant, 1 h after the first dose of nisoldipine in both normotensive subjects and hypertensive patients. After 2 h PRA had returned to the pre-treatment level. No change in PRA was observed after administration of placebo. Plasma angiotensin II (AII) levels showed considerable variation after nisoldipine administration. Plasma aldosterone levels decreased despite the increase in PRA and AII concentrations. However, no concomitant reduction in urinary aldosterone excretion was observed. Plasma noradrenaline levels increased slightly 2-4 h after administration of nisoldipine, and decreased again thereafter, but no changes in plasma adrenaline levels were seen. Nisoldipine had no long-term effects on the renin-angiotensin-aldosterone system or on serum catecholamine levels.

Histamine receptors in brain vessels of guinea-pig: in-vitro pharmacology and ligand binding.

The subtype of histamine receptors in brain vessels of guinea-pig has been characterized by ligand binding and in-vitro pharmacology using selective antagonists. In the basilar artery histamine caused a concentration-related contraction with an EC50 of 1.6 +/- 0.3 microM. H1-receptor blockade with mepyramine and chlorpheniramine caused a displacement to the right of the histamine concentration-response curve with an apparent KD of 0.4 and 4.6 nM respectively, whereas H2-receptor blockade with cimetidine was without effect. Histamine did not induce any dilatory responses of vessels procontracted by 60 mM potassium-containing buffer in the presence or absence of histamine antagonists. Ligand-binding studies with [3H]mepyramine yielded a KD value of 5.5 nM in pial vessel membranes and 1.7 nM in the choroid plexus, confirming the presence of H1-receptors. Nimodipine caused a concentration-related blockade of histamine-induced contractions. Omission of Ca2+ from the extracellular medium for 30 min reduced the contractile responses to histamine in the basilar artery by 96%. Subsequent addition of Ca2+ caused concentration-related contractions which were inhibited by nimodipine. Thus, the histamine H1-receptor activation in guinea-pig basilar artery is coupled to dihydropyridine-sensitive Ca2+ channels.

Pharmacological characterization of histamine receptors in the human temporal artery.

1. The subtypes of histamine-receptors which mediate dilatation of small human temporal arteries have been characterized in vitro using 'selective' agonists and antagonists. 2. Dilatory responses were studied after preconstriction with prostaglandin F2 alpha since contraction was not seen at histamine concentrations up to 10(-4) M. Histamine caused a concentration-related relaxation of cerebral vessels with an IC50 value of 2.8 +/- 0.6 X 10(-7) M. 3. Cimetidine caused a parallel shift to the right of the histamine concentration-response curve whereas mepyramine was without observable effect. This suggests the presence of histamine H2-receptors only. However, combined treatment with mepyramine and cimetidine caused a more marked displacement of the concentration-response curve to the right. Schild analysis indicated that in situations of near complete blockade of the histamine H1-receptor subtypes, simple competitive antagonism at H2-receptors can be revealed with a pA2 value of 6.58 for cimetidine. The apparent pA2 value for mepyramine was 8.58. 4. The 'selective' H1-receptor agonists pyridylethylamine, 2-methylhistamine and thiazolylethylamine, and the H2-receptor agonists dimaprit, impromidine and 4-methylhistamine all mimicked the histamine response, but all except impromidine were less potent than histamine. The order of potency was impromidine greater than thiazolylamine greater than 4-Me-histamine greater than 2-Me-histamine greater than dimaprit greater than pyridylethylamine greater than tele-Me-histamine. 5. These results indicate that the histamine-induced dilatation in small human temporal arteries is mediated by both H1- and H2-receptors and that the latter subtype of histamine receptors predominates.

Enhanced vasoconstrictor responses to potassium, 5-hydroxytryptamine, and prostaglandin F2 alpha of isolated coronary arteries from magnesium-deficient rats. Comparison with vasomotor activity of aorta.

Wistar rats were fed a low magnesium diet for 8 or 12 weeks, resulting in reduced levels of magnesium in plasma, heart, and skeletal muscle, as compared with pair-fed control rats. The magnesium-deficient rats also had reduced tissue levels of potassium. Coronary arteries and thoracic aorta from magnesium-deficient rats and control rats were incubated in tissue baths and the contractile responses to potassium, 5-hydroxy-tryptamine, and prostaglandin F2 alpha were investigated using a sensitive in vitro system. The concentration-contraction curve, for all agents was shifted to the left in coronary arteries from magnesium-deficient rats. In aorta from magnesium-deficient rats, the pattern of change in reactivity to these agonists was not uniform: the concentration-contraction curve for 5-hydroxytryptamine was shifted to the left, the contractile response to prostaglandin F2 alpha was reduced, while there was no change in the response to potassium. The contractile response to the administration of calcium to calcium-depleted, potassium-depolarized vessels from magnesium-deficient rats was enhanced; the effect was more pronounced in coronary arteries as compared to the aorta. Hence, the vasomotor reactivity of coronary arteries appears to be more sensitive than is the aorta during magnesium-deficient conditions.