Infusion Of Histamine Research Articles

Endogenous nitric oxide modulates responses of tissue and airway resistance to vagal stimulation in piglets.

The role of endogenous nitric oxide (NO) in modulating the excitatory response of distal airways to vagal stimulation is unknown. In decerebrate, ventilated, open-chest piglets aged 3-10 days, lung resistance (RL) was partitioned into tissue resistance (Rti) and airway resistance (Raw) by using alveolar capsules. Changes in RL, Rti, and Raw were evaluated during vagal stimulation at increasing frequency before and after NO synthase blockade with N(omega)-nitro-L-arginine methyl ester (L-NAME). Vagal stimulation increased RL by elevating both Rti and Raw. NO synthase blockade significantly increased baseline Rti, but not Raw, and significantly augmented the effects of vagal stimulation on both Rti and Raw. Vagal stimulation also resulted in a significant increase in cGMP levels in lung tissue before, but not after, L-NAME infusion. In seven additional piglets after RL was elevated by histamine infusion in the presence of cholinergic blockade with atropine, vagal stimulation failed to elicit any change in RL, Rti, or Raw. Therefore, endogenous NO not only plays a role in modulating baseline Rti, but it opposes the excitatory cholinergic effects on both the tissue and airway components of RL. We speculate that activation of the NO/cGMP pathway during cholinergic stimulation plays an important role in modulating peripheral as well as central contractile elements in the developing lung.

Nitric oxide in primary headaches.

The molecular mechanisms that underlie the primary headaches-migraine, cluster headache and tension-type headache-have not yet been clarified. On the basis of studies in headache induced by intravenous infusions of glyceryl trinitrate (an exogenous nitric oxide donor) and histamine (which liberates nitric oxide from vascular endothelium), it has been suggested that nitric oxide is a likely candidate responsible molecule. The present review deals with the biology of this small messenger molecule, and the updated scientific evidence that suggests a key role for this molecule in primary headaches. This evidence suggests that the release of nitric oxide from blood vessels, perivascular nerve endings or from brain tissue is an important molecular trigger mechanism in spontaneous headache pain. Pilot trials have shown efficacy of a nitric oxide synthase inhibitor in both migraine attacks and chronic tension-type headache. These observations suggest new approaches to the pharmacological treatment of headache.

Central infusion of histamine reduces fat accumulation and upregulates UCP family in leptin-resistant obese mice.

Leptin resistance has recently been confirmed not only in animal obese models but in human obesity. Evidence is rapidly emerging that suggests that activation of histamine signaling in the hypothalamus may have substantial anti-obesity and antidiabetic actions, particularly in leptin-resistant states. To address this issue, effects of central, chronic treatment with histamine on food intake, adiposity, and energy expenditure were examined using leptin-resistant obese and diabetic mice. Infusion of histamine (0.05 pmol x g body wt(-1) x day(-1)) into the lateral cerebroventricle (i.c.v.) for 7 successive days reduced food intake and body weight significantly in both diet-induced obesity (DIO) and db/db mice. Histamine treatment reduced body fat weight, ob gene expression, and serum leptin concentration more in the model mice than in pair-fed controls. The suppressive effect on fat deposition was significant in visceral fat but not in subcutaneous fat. Serum concentrations of glucose and/or insulin were reduced, and tests for glucose and insulin tolerance showed improvement of insulin sensitivity in those mice treated with histamine compared with pair-fed controls. On the other hand, gene expression of uncoupling protein (UCP)-1 in brown adipose tissue and UCP-3 expression in white adipose tissue were upregulated more in mice with i.c.v. histamine infusion than in the pair-fed controls. These upregulating effects of histamine were attenuated by targeted disruption of the H1-receptor in DIO and db/db mice. Sustained i.c.v. treatment with histamine thus makes it possible to partially restore the distorted energy intake and expenditure in leptin-resistant mice. Together, i.c.v. treatment with histamine contributes to improvement of energy balance even in leptin-resistant DIO and db/db mice.

Attenuation of Histamine-Induced Endothelial Permeability Responses after Pacing-Induced Heart Failure: Role for Endogenous Catecholamines

After congestive heart failure (CHF), lung endothelial permeability responses to a number of perturbations, including acute barotrauma, angiotensin II, and thapsigargin are blunted. Our hypothesis was that similar attenuation of permeability responses occurs in peripheral vascular beds after CHF. We compared peripheral microvascular permeability responses to the autacoid histamine in control dogs and in dogs paced to heart failure (245 bpm for approximately 36 days). Since catecholamines attenuate autacoid-induced increases in microvascular permeability in skin and muscle in normal animals, we also tested whether the known elevation in catecholamines in CHF was involved in any downregulation of permeability responses in this group. Control and paced dogs were anesthetized, intubated, and ventilated, and a hindpaw lymphatic cannulated. The reflection coefficient for total proteins (sigma) was measured at baseline and during one-hour, local intra-arterial histamine infusion. In controls, sigma fell from 0.83 +/- 0.02 to 0.73 +/- 0.04 after histamine (p < 0.05), while in the paced group sigma was no different from that at baseline (0.77 +/- 0.02). To test whether this difference was due to endogenous catecholamines, dogs were pretreated with propranolol (controls only) or the specific beta 2-antagonist ICI 118,551 prior to histamine infusion. After beta-blockade, histamine significantly reduced sigma in both control (0.83 +/- 0.01 to 0.55 +/- 0.05) and paced (0.83 +/- 0.01 to 0.57 +/- 0.07) groups (p < 0.05). We conclude that endogenous catecholamines, acting via beta 2-adrenergic receptors, attenuate the permeability response to histamine in pacing-induced heart failure.

Histamine Infusion Induces a Selective Dopaminergic Neuronal Death Along with an Inflammatory Reaction in Rat Substantia Nigra

We have evaluated the effects of a direct infusion of histamine, as mediator of inflammatory response, in substantia nigra, striatum, medial septum, and medial lemniscus. Injection of 100 and 250 nmol of histamine in substantia nigra produced a selective damage in dopaminergic neurons evidenced by the loss of tyrosine hydroxylase mRNA-expressing cells, tyrosine hydroxylase-immunolabeled-positive cell bodies, and dopamine and 3,4-dihydroxyphenylacetic acid levels. In parallel we found an acute inflammatory response manifested by a loss of glial fibrillary acidic protein-immunolabeled astrocytes and, at precisely the same area, an activation of microglia. In the striatum, only high doses (500 nmol) produced an evident terminal degeneration. The selective neurotoxicity of histamine for dopaminergic cells was demonstrated by the unaltered transcription of glutamic acid decarboxylase mRNA in substantia nigra. Moreover, intraseptal injection of 100 nmol of histamine failed to alter the pattern of choline acetyltransferase mRNA-expressing cells, and intraparenchymal injection of histamine in medial lemniscus failed to alter the pattern of serotonin-immunolabeled cells. We conclude that the substantia nigra is highly sensitive to histamine-derived neurotoxicity, where inflammatory processes mediated by histamine could be important in the pathological changes that lead to dopaminergic neuronal damage after histamine infusion.

On the Possibility of Participation of Histamine Neurons in Suppression of Luteinizing Hormone Secretion by Fasting in Rats

The effect of intracerebroventricular (ICV) infusion of histamine (HA) on the pulsatile luteinizing hormone (LH) secretion was investigated in normally fed and 48 h-fasted ovariectomized estradiol-primed (OVX E2-primed) rats. An immunohistochemical study was also conducted to examine the effect of 48h-fasting on the distribution of HA in posterior and mid portions of the hypothalamus of OVX E2-primed rats. Blood samples for LH assay were collected via atrial indwelling catheter at 6min intervals for 3h, and l0μl of HA solution (1μg/μl) were infused into the third ventricle over 60min of the second one h period of blood sampling. TCV infusion of HA caused a significant depression of mean LH concentration during the period of drug infusion in normally fed rats. The effect of HA infusion was not clear in fasted animals, although the LH release also tended to decrease during the infusion. In mmunohistochemical study, no eminent effect of fasting on the occurrence and size of HA positive particles was observed in any area of posterior and mid portions of the hypothalamus. These results indicate a possibility that HA is involved in the mechanism of the suppression of LH secretion by fasting at least in the conditions examined.

Gastric acid secretion in streptozotocin-diabetic rats – Different responses to various secretagogues

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg.kg –1, i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg.dL –1. Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg.kg –1.h –1), pentagastrin (60 μg.kg –1.h –1) or carbachol (20 μg.kg –1.h –1) or i.v. injection of YM-14673 (0.3 mg.kg –1), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.

Acid secretory changes in streptozotocin-diabetic rats: different responses to various secretagogues.

We examined gastric acid secretion in response to various stimuli in streptozotocin (STZ) induced diabetic rats and characterized the alteration of acid secretory responses in diabetic conditions. Animals were injected STZ (70 mg/kg, intraperitoneally) and used after five weeks of diabetes with blood glucose >350 mg/dl. Under urethane anesthesia, the experiment was performed in a chambered stomach or a whole stomach preparation, and the acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by intravenous infusion of either histamine (4 mg/kg/hr), pentagastrin (60 microg/kg/hr), or carbachol (20 microg/kg/hr) or by intraluminal application of peptone solution (4%), or vagal electrical stimulation (2 msec, 3 Hz, 0.5 mA). In normal rats, acid secretion was increased in response to either histamine, pentagastrin, carbachol, peptone, or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid response to histamine remained unchanged, but the responses to vagal electrical stimulation or pentagastrin and carbachol were significantly decreased or enhanced, respectively, as compared to normal rats. Likewise, the acid response to peptone was also markedly enhanced in STZ-diabetic rats, and this response was significantly blocked by atropine and YM022 (a CCKB/gastrin antagonist) as well as famotidine in both normal and diabetic rats. Both pentagastrin and carbachol increased the luminal release of histamine in normal rats, and these responses were significantly augmented in STZ-diabetic rats. The altered acid response and histamine release induced by pentagastrin in STZ diabetic rats were partially reversed by daily injection of insulin. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretion in response to various stimuli. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.

Prostaglandin E1 produces spasmolytic effects on histamine-induced bronchoconstriction in dogs.

In this study, we evaluated the spasmolytic effect of intravenous prostaglandin (PG) E1 on histamine-induced bronchoconstriction with a direct visualization method using a superfine fiberoptic bronchoscope. A university research laboratory. Mongrel dogs. The bronchial cross-sectional area (BCA) of mongrel dogs was measured by a direct visualization method using a superfine fiberoptic bronchoscope. Bronchoconstriction was elicited with histamine (H) infusion: 10 microg/kg iv bolus + 500 microg/kg/h continuous iv. The first protocol (n = 7) was designed to determine the effects of intravenous bolus of PGE1: 0 (saline), 0.01, 0.1, 1.0 and 10 microg/kg on H-induced bronchoconstriction. BCA was assessed before and 30 min after starting the H infusion and 5 min after each dose of intravenous PGE1. The second protocol was designed to determine whether continuous intravenous infusion of PGE1 reverses H-induced bronchoconstriction. In the PG group (n = 6), PGE1 was continuously infused at 0.1 microg/kg/min (20 mL/hr). In the control group (n = 6), saline was administered at a rate of 20 mL/hr iv. BCA was assessed before and 30 min after starting the H-infusion and at 5, 10, 30 and 60 min after commencing the PGE1 or saline infusion. Arterial blood was obtained simultaneously for measurement of plasma concentrations of epinephrine and norepinephrine by gas chromatography mass spectrometry. In the first protocol, PGE1 produced a dose-dependent increase in the percentage of BCA and 10 microg/kg of PGE1 almost fully reversed the H-induced bronchoconstriction. Plasma catecholamines did not change significantly. In the second protocol, continuous infusion of PGE1 produced a time-dependent reversal of H-induced bronchoconstriction (percentage of BCA increased to 80.0+/-9.0% 60 min after the start of PGE1 infusion), whereas saline infusion did not reverse the bronchoconstriction. Plasma catecholamines did not change significantly in either group. Both intravenous bolus and continuous intravenous infusion of PGE1 reversed the H-induced bronchoconstriction. PGE1 may be used safely for patients with the hyperreactive airway and might be useful as a therapeutic agent for these patients.

Relaxant effect of propofol on the airway in dogs

Propofol has been suggested to produce airway relaxant effects in vivo, although the mechanism is unclear. We have evaluated the bronchodilating effect of propofol using a direct visualization method with a superfine fibreoptic bronchoscope. We studied 21 mongrel dogs anaesthetized with pentobarbital 30 mg kg-1 i.v. and pancuronium 0.2 mg kg-1 h-1. The animals were allocated randomly to one of three groups (n = 7 in each): propofol group, atropine-propofol group and histamine-propofol group. The trachea was intubated using a tracheal tube that had a second lumen for insertion of the bronchoscope to monitor continuously bronchial cross-sectional area (BCA). BCA was measured using the NIH Image program. In the propofol group, dogs were given the following doses of propofol at 10-min intervals: 0 (saline), 0.2, 2.0 and 20 mg kg-1 i.v. In the atropine-propofol group, saline, atropine 0.2 mg kg-1 and propofol 20 mg kg-1 were given at 10-min intervals. In the histamine-propofol group, bronchoconstriction was elicited with histamine 10 micrograms kg-1 and 500 micrograms kg-1 h-1 until the end of the experiment. Thirty minutes after the start of infusion of histamine, propofol (0, 0.2, 2.0 and 20 mg kg-1) was administered. Changes in BCA were expressed as percentage of basal area. Histamine decreased BCA by 39.2 (SEM 5.4%). Propofol increased significantly basal and histamine-decreased BCA in a dose-dependent manner by 18.4 (4.5%) and 15.8 (4.9%), respectively after 20 mg kg-1 i.v. However, propofol following atropine i.v. did not increase BCA (129.9 (8.2)% after atropine vs 125.7 (8.9)% after propofol). Therefore, the relaxant effect of propofol may be a result of reduction in vagal tone.

A comparison of pulmonary arterial occlusion algorithms for estimation of pulmonary capillary pressure.

Using the arterial occlusion method, we compared five literature-based estimates of pulmonary capillary pressure (Ppc) with the corresponding double occlusion pressures (Pdo) in anesthetized dogs whose chests had been closed after sternotomy for instrumentation. Arterial occlusions were performed with a balloon-tipped pulmonary artery catheter that housed pressure transducers immediately proximal and distal to the balloon. Separation of the proximal and distal pressure waveforms during balloon inflation allowed us to precisely define the moment of occlusion. We fit a monoexponential curve to pressure data beginning 200 ms after the onset of occlusion and a biexponential curve to data beginning at the instant of occlusion, with data obtained over a range of vascular states (control, serotonin infusion, histamine infusion). In addition, we investigated the use of sampling of the raw data to estimate capillary pressure. Three of the five literature-based estimates of Ppc yielded values similar to Pdo. The optimal (least average difference from Pdo) interpolation/extrapolation time points of the curve fits varied, depending on the type of curve fitting and the state of the pulmonary vasculature. We also determined that a close approximation of Pdo may be derived from the raw data, as an alternative to exponential curve fitting.

Relaxant effect of magnesium and zinc on histamine-induced bronchoconstriction in dogs.

Magnesium sulfate (MgSO4) has been reported to produce bronchodilation in asthmatic patients. In vitro studies have suggested that divalent cations inhibit L-type voltage-sensitive calcium ion (Ca2+) channels in cardiac and smooth muscles. In this study, we evaluated the in vitro and in vivo effects of magnesium ion (Mg2+) and zinc ion (Zn2+) on the airway contracted by histamine. A university research laboratory. Tracheal smooth muscle from guinea pigs. Mongrel dogs. The tension of isolated guinea pig tracheal strips was measured isometrically with a force displacement transducer. The specimen was contracted with histamine (10 microM). Then, MgSO4 (n = 6), zinc sulfate (ZnSO4, n = 6), or sodium sulfate (Na2SO4, n = 6) was cumulatively added to the organ bath. The bronchial cross-sectional area of mongrel dogs was measured by a direct visualization method demonstrated previously. The dogs were randomly assigned to three groups: group Mg (n = 7), group Zn (n = 7), and group Na (n = 7). Bronchoconstriction was elicited with histamine (10 microg/kg plus 500 microg/kg/hr iv). Thirty minutes after the start of histamine infusion, 0 (saline), 1, 10, and 100 micromol/kg ZnSO4 or 1, 10, 100, and 1000 micromol/kg MgSO4 or Na2SO4 were administered intravenously in group Zn, Mg, or Na, respectively. The bronchial cross-sectional area was assessed before (basal) and 30 mins after the start of histamine infusion and 5 mins after each dose of ZnSO4, MgSO4, or Na2SO4. Arterial blood was also obtained to measure plasma levels of epinephrine and norepinephrine by gas chromatography-mass spectrometry. All data are expressed as mean +/- SEM. The doses of the divalent cations that reversed histamine-induced contraction by 50% were calculated by GraphPad Prism. MgSO4 and ZnSO4 (9.38+/-0.28 and 1.84+/-0.30 mM, respectively) relaxed histamine-contracted tracheal strip in a concentration-dependent manner, whereas Na2SO4 did not. Similarly, the in vivo study showed that MgSO4 and ZnSO4 dose-dependently reversed histamine-induced bronchoconstriction (potency, ZnSO4 > MgSO4), whereas Na2SO4 did not. In groups Mg and Zn, the plasma catecholamine levels also dose-dependently increased except when 1000 micromol/kg MgSO4 was administered. Because the divalent cations tested produced a spasmolytic effect on the contracted airway, infusion of divalent cations might be effective against asthmatic attack. However, high concentrations of these cations produce significant toxicity, so dosage will be an important concern in development of these agents.

The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.

We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.

Histamine-induced gastric acid secretion in horses

Abstract Objective To determine gastric secretory responses in horses treated with histamine and to determine the dose of histamine needed to elicit maximal gastric secretion. Animals 6 adult horses with an indwelling gastric cannula. Procedure Gastric contents were collected in 15-minute periods, and volume, pH, hydrogen ion concentration, hydrogen ion output, sodium concentration, and sodium output were determined. Values were determined without any treatment (baseline), after administration of pyrilamine maleate (1 mg/kg of body weight, IV, given during a 15-minute period), and during 1-hour infusions of histamine at 3 rates (7.5, 15, and 30 μg/kg/h, IV). Results Volume and hydrogen ion concentration of gastric contents and hydrogen ion output were significantly increased, compared with baseline values, during histamine infusion. Mean hydrogen ion concentration and hydrogen ion output were significantly greater during infusion of histamine at a rate of 15 or 30 μg/kg/h than at a rate of 7.5 μg/kg/h. Sodium concentration was significantly decreased, compared with baseline value, during histamine infusion, but sodium output was unchanged. Conclusions Histamine at doses of 15 and 30 μg/kg/h, IV stimulated maximal gastric secretion in horses. Histamine appeared to induce only parietal secretion. Clinical Relevance This study provides additional information related to equine gastric physiology, which may benefit further understanding of the pathogenesis of peptic ulcer disease. (Am J Vet Res 1998;59:1303–1306)

Neuronal histamine and expression of corticotropin-releasing hormone, vasopressin and oxytocin in the hypothalamus: relative importance of H1 and H2 receptors.

Centrally administered histamine (HA) stimulates the secretion of the pro-opiomelanocortin-derived peptides ACTH and beta-endorphin as well as prolactin. The effect of HA on secretion of these adenohypophysial hormones is indirect and may involve activation of hypothalamic neurons containing corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) or oxytocin (OT). We studied the effect of activating central HA receptors by central infusion of HA, HA agonists or antagonists on expression of CRH, AVP and OT mRNA in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Intracerebroventricular infusion of HA (270 nmol), the H1-receptor agonist 2-thiazolylethylamine or the H2-receptor agonist 4-methylhistamine increased the level of CRH mRNA in the PVN, and OT mRNA in the SON. In contrast, none of these compounds had any effect on expression of AVP mRNA in the PVN or SON. Administration of the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine had no effect on basal expression of CRH, AVP or OT mRNA in the PVN and/or SON except for a slight inhibitory effect of cimetidine on CRH mRNA expression in the PVN. Pretreatment with mepyramine or cimetidine before HA administration inhibited the HA-induced increase in OT mRNA levels but had no effect on the HA-induced increase in CRH mRNA levels in the PVN. We conclude that HA stimulates hypothalamic CRH and OT neurons by increasing mRNA levels, and this effect seems to be mediated via activation of both HA H1 and H2 receptors.

Carbon Monoxide, a Cyclic GMP-Related Messenger, Involved in Hypoxic Bronchodilation in vivo

Recent reports indicate the presence of two carbon monoxide (CO)-inducing enzymes, heme oxygenase (HO)-1 and -2 in airway smooth muscle. Generally HO-2 is considered to be a constitutive enzyme associated with various neuronal structures, whereas HO-1 can be induced by several factors, including hypoxia. Recent functional data indicate that exogenous CO can induce bronchodilation via a NO-independent, cyclic GMP-related mechanism. The aim of the present study was to investigate the potential role of CO as an endogenously produced airway messenger using an in vivo model of airway hypoxia. HO-1 and HO-2-like immunoreactivities were seen in airway smooth muscle along the bronchus and in the respiratory epithelium. The staining for HO-1 was relatively weak but consistent in all animals investigated. In contrast, the HO-2 staining was intense at all locations. After hypoxic stimulation, the staining for HO-1 and HO-2 was equally intense, indicating an up-regulation of the HO-1 expression. In another set up, anaesthetized, ventilated guinea-pigs were given a continuous infusion of histamine to increase total pulmonary resistance (RL). Hypoxic stimulation, induced by inhalation of 180 breaths of pure nitrogen (N2), resulted in a subsequent reduction in RL. Pretreatment with Rp-8Br-cGMPs, a cyclic GMP antagonist abolished more than 75% of this reduction, whereas L-NAME, an antagonist of NO synthesis, was without effect. Zinc protoporphyrin-IX (ZnPP), an inhibitor of HO, mimicked the effects of Rp-8Br-cGMPS. In conclusion, the present findings suggest a possible role for CO in the hypoxic regulation of airway tone.

Bronchodilatation in vivo by carbon monoxide, a cyclic GMP related messenger.

1. Recent studies suggest that gaseous carbon monoxide (CO) is involved in neurotransmission and that this molecule also is an important vasodilator in vivo. In the present study we evaluated the effect of inhaled CO on guinea-pig airway smooth muscle tone. The mechanisms involved were characterized by use of a cyclic GMP antagonist, Rp-8Br-cyclic GMPS, and a nitric oxide synthase inhibitor, L-NAME. 2. Anaesthetized, ventilated guinea-pigs were given a bolus injection of histamine (0.12 mg kg(-1), i.v.), followed by a continuous infusion of histamine (0.30 microg kg(-1) min(-1)) to increase total pulmonary resistance (RL). Subsequent exposure to 7, 15 or 30 breaths of CO (100%), resulted in a dose-dependent inhibition of the bronchoconstriction. In the highest dose tested (30 breaths), CO inhibited 80% of the histamine-induced increase in RL. 3. In separate experiments, animals receiving histamine infusions followed by 30 breaths of CO, were pretreated with Rp-8Br-cyclic GMPS (0.05 mg kg(-1)). This pretreatment abolished >60% of the CO-induced reduction in RL, but it had no effect on the bronchodilator response induced by salbutamol. In another set of experiments animals were pretreated with L-NAME (1.60 mg kg(-1)). In contrast to the Rp-8Br-cyclic GMPS pretreatment, the pretreatment with L-NAME did not affect the CO-induced reduction in RL. 4. The present findings indicate that CO causes bronchodilatation in vivo via cyclic GMP.

Effects of histamine and nitric oxide synthase inhibition on plasma levels of von Willebrand factor antigen

Endothelial cells release von Willebrand factor (vWf) either constitutively or by a regulated pathway. Based on various studies in vitro, we hypothesized that the stimulatory action of histamine on vWf release could also be induced in vivo and that it may be inhibited by endogenous production of nitric oxide (NO). Nine healthy subjects received placebo or one of two dosages of a primed constant infusion of the NOsynthase inhibitor N-monomethyl- l-arginine ( l-NMMA) in a randomized, double-blind, three-way crossover trial. Histamine was coinfused for 15 minutes at 0.16 μg/kg/min after 30 minutes of pretreatment with either placebo or l-NMMA. Thirty minutes after either the low or the high l-NMMA dose was started, which caused, respectively, a 40% decrease and a 60% decrease in exhaled end expiratory NO level ( p = 0.008), there was no increase in von Willebrand factor antigen (vWf-Ag) level ( p > 0.05). Histamine caused an 11% (95% confidence interval (CI): 0.4% to 22%; p = 0.011) increase in vWf-Ag level at 125 minutes. After pretreatment with the low and the high l-NMMA doses, vWf-Ag level increased by 18% (CI: 5% to 31%; p = 0.011) and by 29% (CI: 15% to 42%; p = 0.008), respectively. At 125 minutes, vWf-Ag level was significantly higher after either l-NMMA pretreatment when compared with the results after histamine alone ( p < 0.05). In conclusion, the infusion of histamine increased vWf-Ag level, and the inhibition of NO-synthase enhanced this effect, whereas it did not by itself elevate vWf-Ag level. Thus endogenously produced NO may dampen the regulated pathway of vWf secretion; it will be interesting to investigate whether endogenous NO production also inhibits vWf release caused by other stimulators.

Investigations into the role of nitric oxide and the large intracranial arteries in migraine headache.

Previous studies suggest that nitric oxide (NO) is involved in headaches induced by i.v. infusion of the vasodilator and NO donor glyceryl trinitrate (GTN) in healthy subjects. Extending these studies to sufferers of migraine without aura, it was found that migraineurs experienced a stronger headache than non-migraineurs. In addition, most migraineurs experienced a delayed migraine attack at variable times (mean 5.5 h) after GTN provocation. This biphasic headache response in migraineurs may be linked to hypersensitivity in the NO-cGMP pathway. Thus, compared to controls, migraineurs were found to be more sensitive to GTN-induced intracranial arterial dilatation, which is known to be mediated via liberation of NO and subsequent synthesis of cGMP Furthermore, histamine infusions in migraineurs induced headache responses and intracranial arterial responses resembling those induced by GTN in migraineurs. Histamine is known to liberate NO from the endothelium via stimulation of the H1 receptor, which is present in the large intracranial arteries in man. Because both immediate histamine-induced headache and intracranial arterial dilatation and delayed histamine-induced migraine are blocked by H1-receptor blockade, a likely common pathway for GTN and histamine-induced headaches/migraines and intracranial arterial responses may be via activation of the NO-cGMP pathway. The delay in the development of these experimental migraines may reflect activation of multiple physiological processes. The intracranial arteries of migraineurs were found supersensitive to the vasodilating effect of GTN (exogenous NO). This relates to clinical findings suggesting dilatation of the large intracranial arteries on the headache side during spontaneous migraine attacks. The function of arterial regulatory mechanisms involving NO in migraine was therefore studied. In peripheral arteries, no endothelial dysfunction of NO was found and cardiovascular and intracranial arterial sympathetic function was normal. A mild parasympathetic dysfunction may be involved and may, via denervation supersensitivity, be responsible for the observed supersensitivity to NO. Another possibility is that NO initiates a perivascular neurogenic inflammation with liberation of vasoactive peptides. NO also mediates a variety of other physiological phenomena. One of these, the pain-modulating effect observed in animals, was evaluated in a human study using GTN infusion and measurements of pain thresholds. No definite effects of GTN were demonstrated. The precise mechanisms involved in NO-triggered migraines and which part of the NO-activated cascade that is involved remain to be determined. The possibilities for pharmacological stimulation and/or inhibition of several steps of the NO-activated cascade increase rapidly and soon may be available for human studies.

Effects of aminoguanidine and L-NAME on histamine-induced blood pressure drop in the rat.

Mean arterial blood pressure changes in response to i.v. administration of histamine were monitored in the anaesthetized rat in the absence or presence of the diamine oxidase (DAO) inhibitor aminoguanidine (AMG, 10 mg kg-1). AMG prolonged the duration of the transient drop in blood pressure induced by a bolus injection of histamine (0.05 mg kg-1) by 34%. In animals pretreated with AMG, no potentiation of the decrease in pressure in response to a 10 min infusion of histamine was observed. However, when infusion was stopped, the time needed for pressure recovery was twice as long in animals treated with AMG as in controls. Blood samples were taken prior to infusion and during the recovery phase and the quantities of histamine were determined by liquid chromatography. The prolonged recovery phase observed in animals pretreated with AMG was associated with five times higher levels of histamine. The duration of histamine-induced hypotension (0.01 mg kg-1) was 50% shorter in the presence of the nitric oxide synthase inhibitor L-NAME (10 mg kg-1). We suggest that DAO, through elimination of histamine from the bloodstream, is important for the recovery from histamine-induced hypotension, and that the duration of histamine-induced pressure drop is influenced by formation of nitric oxide.