Histamine H1- and H2-receptors are differentially and spatially distributed in cerebral vessels

Receptor sites for neurotransmitters may be spatially oriented within cerebral vascular walls. The direction from which neurohumoral stimuli arise (e.g., perivascular or intravascular) and the location and type of receptor activated may therefore determine the nature of vascular response. I review a series of studies that examined cerebrovascular responses to histamine and suggest that histamine receptors are differentially and spatially organized in two profiles within the cerebral circulation. A transmural distribution is suggested from the following results: increases in permeability of the blood-brain barrier (endothelial cells) to intra-arterial infusion of histamine were mediated by H2-receptors; increases in blood flow to intra-arterial infusion of histamine occurred only after the blood-brain barrier was disrupted and were the result of stimulation of both H1- and H2-receptors. These responses probably occur within inner layers of arterial smooth muscle; dilatation of pial arterioles to local microapplication of histamine and its receptor agonists indicates that H2-receptors are the predominant type in outer layers of arterial smooth muscle. A segmental profile of histamine receptors within the cerebrovascular bed is suggested as follows: since both H1- and H2-receptors could mediate dilatation of arterioles and arteries, it may be concluded that both types of receptor are present in resistance vessels; in the capillary bed, H2-receptors are the predominant type; capacitance vessels (pial veins) did not respond to perivascular application of histamine or its agonists. These studies suggest that receptors for histamine may be sparsely populated or absent in cerebral venous smooth muscle.     

Role of histamine H1- and H2-receptors in postprandial intestinal hyperemia

Studies were conducted in anesthetized dogs to assess whether histamine H1- and/or H2-receptors play a role in post-prandial intestinal hyperemia. The vascular and metabolic responses of jejunal segments to intra-arterial infusion of histamine and luminal placement of food before and after administration of tripelennamine, an H1-receptor antagonist, metiamide, an H2-receptor antagonist, and the combination of both antagonists were compared. Administration of the antagonists had no effect of jejunal blood flow and intestinal oxygen uptake (VO2). Tripelennamine or metiamide alone attenuated while the combination of both blocked the histamine-induced increases in blood flow and VO2. Metamide alone had no effect on the food-induced increases in flow and VO2. Tripelennamine significantly attenuated the food-induced increase in flow and blocked the increase in VO2. A 30% increase in flow was reduced to 15% after tripelennamine. The effects of tripelennamine plus metiamide were statistically the same as those of tripelennamine alone. It is concluded that endogenous histamines may play a role in postprandial intestinal hyperemia, and the effect is primarily mediated by the H1-receptors.     

Regulation of H1-receptor coupling and H1-receptor mRNA by histamine in bovine tracheal smooth muscle

1. Pretreatment of bovine tracheal smooth muscle (BTSM) with histamine (1-100 microM, 1 h) induced a concentration-dependent desensitization of the contractile response to subsequently administered histamine, with a reduction of the maximum response of 72 +/- 8% (n = 5) following pre-exposure to 100 microM histamine. In contrast, concentration-response curves to the muscarinic agonist, methacholine were not affected following histamine pretreatment, indicating a homologous desensitization. Furthermore, concentration-response curves to NaF, a G-protein activator, were not altered following histamine pre-incubation. 2. The histamine H1-receptor (H1R) desensitization could be antagonized by mepyramine (an H1-receptor antagonist, 1 microM) but not by cimetidine (an H2-receptor antagonist, 10 microM), indicating that the desensitization occurred via stimulation of histamine H1-receptors, without evidence for the involvement of histamine H2-receptors. 3. Indomethacin (10 microM) did not block the H1R desensitization, suggesting no involvement of prostaglandins. Furthermore, histamine pre-incubation in calcium free medium still induced a functional uncoupling of H1R. 4. GF 109203X, a protein kinase C (PKC) inhibitor, and H-7, a non-selective kinase inhibitor, did not antagonize the homologous H1R desensitization. 5. The steady-state level of H1R mRNA, assessed by Northern blot analysis, was not affected by prolonged histamine exposure (100 microM, 0.5, 1, 2, 4, 16 and 24 h). 6. These results suggest that histamine induces desensitization of the H1R at the level of the receptor protein, which involves a mechanism independent of PKC, PKA, PKG and calcium influx, suggesting the involvement of a receptor-specific kinase.     

Histamine H2-receptor antagonism of T-593: studies on positive chronotropic responses in guinea pig atria

To assess the impact of changes in practice patterns, hospital charges (overall and component charges excluding professional fees) for 1992 were compared to 1985 data for three orthognathic surgical procedures: bilateral sagittal split osteotomy (BSSO), Le Fort I osteotomy (LFI), and a combination of both (BSSO/LFI). Data for 1992 were obtained for 59 patients (26 BSSO, 18 LFI, 15 BSSO/LFI). Secondary analysis of similar data for 1985 included 77 patients (27 BSSO, 16 LFI, 34 BSSO/LFI). Changes in clinical practice from 1985 to 1992 reduced mean length of stay (days): BSSO 3.2 to 1.2, LFI 3.7 to 1.4, BSSO/LFI 4.1 to 1.8. Mean total charges (dollars) increased: BSSO 3,086 to 5,023, LFI 3,538 to 6,784, BSSO/LFI 4,778 to 8,816. If 1992 charges are expressed in 1985 dollars, ancillary, pharmacy, and room charges all are reduced. Charges attendant to the surgical procedure (anesthesia, operating room, supply, and recovery) were just over half of total charges in 1985. By 1992, these components escalated to 80% of total charges. Most notable was the increase in supply charges. Charges for rigid fixation were a major component of increased supply charges in 1992. Surgeons minimally influence charges attendant to the operating room and postanesthesia recovery, the major components of total charges in 1992. Quality can be maintained with reduction in some charge categories, but these components total less than 25% of the patient's bill. Technology changes benefit patients, but a judgment must be made weighing benefits against increased health care costs.     

Enhancement of alcohol-induced hypoglycaemia by H2-receptor antagonists

Male Wistar rats were kept in a hypoxia chamber (9% O2) for eight hours. Control animals breathed room air in the same chamber for a similar period of time. One week later the brains of all rats were prepared for the immunohistochemical demonstration of Mn-superoxide dismutase (Mn-SOD). In comparison with the sham-exposed controls, the hypoxia-treated animals showed an increase in the number of Mn-SOD-immunoreactive neurons in several hippocampal structures. The 72 kD heat shock protein was not found to be induced one week after a moderate hypoxia.     

Therapeutic-interchange program for oral histamine H2-receptor antagonists

A therapeutic-interchange (TI) program for oral histamine H2-receptor antagonists at a hospital is described. In 1992 the pharmacy and therapeutics committee at a large teaching hospital accepted cimetidine as the preferred oral H2 antagonist. However, the program to promote cimetidine met with little success. The manufacturer of nizatidine then offered the hospital that drug at a reduced cost relative to all other members of the drug class. The committee recommended including nizatidine on the formulary; implementing a TI program so that when an order for an oral H2 antagonist was written nizatidine would be dispensed; deleting cimetidine and ranitidine tablets from the formulary; and retaining cimetidine and ranitidine oral liquid and i.v. formulations. The program was approved by the medical executive committee and was implemented in August 1994. Extensive efforts to inform the pharmacy, medical, and nursing staffs about the program were undertaken, and the pharmacy established mechanisms for monitoring compliance. Two months into the program, 97% of eligible patients were receiving nizatidine. Actual cost savings in the first four months exceeded $40,000. In July 1997 the same program was applied to famotidine, which had replaced nizatidine as the most cost-effective H2 antagonist. A successful TI program for oral H2 antagonists was achieved by gaining physician support for the program, educating providers, monitoring compliance, and responding to changes in drug costs.     

D1- versus D2-receptor modulation of visuospatial working memory in humans

The effects of pergolide, a mixed D1/D2 receptor agonist, and bromocriptine, a selective D2 receptor agonist, were assessed in a visual delay task to further investigate the "dopamine link" of working memory in humans and to look for differential D1 versus D2 receptor contributions. Two groups of 32 healthy young adults (16 female) received either 0.1 mg of pergolide or 2.5 mg of bromocriptine in a placebo-controlled cross-over design. A pretreatment with domperidone, a peripherally active D2 antagonist, was performed in both groups to reduce side effects. Interindividual differences in pharmacokinetics were controlled by the time course of serum prolactin inhibition. The working memory paradigm was a visuospatial delayed matching task; the location of a randomly generated seven-point pattern had to be memorized and compared after 2, 8, or 16 sec with a second pattern that was either identical or slightly shifted within a reference frame. The task was designed with the intention to present unique stimuli at each trial and to require minimal motor demands. Practice effects between the two pharmacological test days were minimized by training sessions that preceded the tests. The paradigm showed significant error and reaction time increases with longer delays. After comparable doses, only pergolide, but not bromocriptine, facilitated visuospatial working memory performance as demonstrated by a significant drug-by-delay interaction. These findings are in accordance with the monkey literature as well as with neuroanatomical findings, and they confirm a preferential role of prefrontal D1 receptors for working memory modulation in humans.     

Endoscopic appearances of hemorrhagic peptic ulcers and efficacy of H2-receptor antagonists

BACKGROUND/AIMS: In this retrospective study, we compared the effects of histamine H2-receptor antagonists to those of antacids and anticholinergics in patients with hemorrhagic ulcers with various endoscopic appearances of bleeding. PATIENTS AND METHODS: Patients with hemorrhagic ulcers (n = 376) were examined by emergency endoscopy and were treated with 1) antacids and anticholinergic drugs or 2) H2-receptor antagonists. RESULTS: In ulcer patients with oozing or fresh red coagulation, H2-receptor antagonists ceased further hemorrhage more effectively (65.9% of the cases) than antacids and anticholinergic drugs (46.7%). In patients with projectile bleeding, both of the treatments failed to stop hemorrhage. There were no significant differences in favorable outcome in the patients only with old black coagulation between antacid and anticholinergic drugs-treated group and H2-receptor antagonists-treated group (94.4% and 93.8%, respectively). CONCLUSIONS: The results suggest that H2-receptor antagonists are more effective than antacids and anticholinergic drugs in patents with peptic ulcer with fresh coagulation or oozing, but not with projectile bleeding or old black coagulation. The results also indicate that endoscopic appearances of peptic ulcer bleeding are good predictors for the effects of medication.     

N alpha-alkylated derivatives of 2-phenylhistamines: synthesis and in vitro activity of potent histamine H1-receptor agonists

New potent N alpha-alkylated histamine H1-receptor agonists have been prepared and functionally evaluated for partial agonist potency and selectivity. N alpha-Methyl-2-(3-trifluoromethylphenyl)histamine contracts ileal segments and aortic rings of guinea-pig with a relative potency of 174% (95% confid. lim. 161-188%) and 217% (164-287%), respectively (histamine: 100%) and is the most potent H1 receptor agonist described so far.     

Continued circulation of reassortant H1N2 influenza viruses in pigs in Japan

In 1991 and 1992, H1N2 influenza A viruses were isolated from the lungs of pigs with overt signs of respiratory disease at farms in the Chiba and Kanagawa prefectures of Japan. To determine the genetic origin of these isolates, we phylogenetically analyzed partial nucleotide sequences of their genes. The results indicate that influenza viruses possessing the N2 of human influenza virus and seven other gene segments of classical H1N1 swine influenza virus, which were first isolated in 1980, have become established in Japanese pigs.     

Histamine receptor-independent muscle relaxation elicited by a series of histamine H2-receptor agonists on the isolated guinea pig duodenum: a study into the mechanism of action

To assess the dolphin's capacity for color vision and determine the absorption maxima of the dolphin visual pigments, we have cloned and expressed the dolphin opsin genes. On the basis of sequence homology with other mammalian opsins, a dolphin rod and long-wavelength sensitive (LWS) cone opsin cDNAs were identified. Both dolphin opsin cDNAs were expressed in mammalian COS-7 cells. The resulting proteins were reconstituted with the chromophore 11-cis-retinal resulting in functional pigments with absorption maxima (lambdamax) of 488 and 524 nm for the rod and cone pigments respectively. These lambdamax values are considerably blue shifted compared to those of many terrestrial mammals. Although the dolphin possesses a gene homologous to other mammalian short-wavelength sensitive (SWS) opsins, it is not expressed in vivo and has accumulated a number of deletions, including a frame-shift mutation at nucleotide position 31. The dolphin therefore lacks the common dichromatic form of color vision typical of most terrestrial mammals.     

Comparison of structural stabilities of prostaglandin H synthase-1 and -2

There are two known isoforms of prostaglandin H synthase (PGHS), a key enzyme in the conversion of arachidonic acid to bioactive prostanoids. The "constitutive" isoform, PGHS-1, is thought to have housekeeping functions, and the "inducible" isoform, PGHS-2, has been implicated in cellular responses to cytokines. The two isoforms have high sequence conservation in the cyclooxygenase active site and quite similar crystallographic structures, but differ markedly in their interactions with many cyclooxygenase substrates and inhibitors. We have evaluated the stability of the overall folding, and of the active sites of ovine PGHS-1 and human PGHS-2 using denaturation with guanidinium hydrochloride (GdmHCl). Changes in hydrodynamic and cross-linking properties indicated a dimer --> monomer transition for both isoforms between 0.5 and 2 M GdmHCl; the monomers unfolded at higher GdmHCl levels. Changes in overall secondary and tertiary structure, measured by tryptophan fluorescence and circular dichroism, occurred in two phases for each isoform, with the transition between the phases at 0.2-0.5 M GdmHCl. Disruption of active site functions (cyclooxygenase, peroxidase, and cyclooxygenase inhibitor binding activities) began at GdmHCl levels below 0.2 M. The structural and functional changes were completely reversible up to about 2 M GdmHCl, they were more pronounced at lower protein levels, and they required lower GdmHCl levels for PGHS-2 than for PGHS-1. The results are consistent with a four-state denaturation process for both isoforms: native dimers --> inactive dimers --> compact monomers --> unfolded monomers. The first two steps are reversible for both isoforms; PGHS-2 undergoes the first and last steps more readily than PGHS-1. Thus, the structural stability of PGHS-2, both in the active site regions and in the subunits overall, is distinctly less than that of PGHS-1. These differences in structural stability may contribute to the isoforms' active site ligand selectivity.     

Synthesis and QSAR of some 3-amino-2-(substituted)aminomethyl-5,6-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones as novel H1-receptor antagonists

The plasma concentrations of two bone matrix proteins (osteocalcin, osteonectin) were monitored in 56 samples from 14 patients receiving renal transplants and the values compared with serum bone alkaline phosphatase mass concentrations and osteotropic hormone levels (parathyroid hormone, calcitriol). There were no significant changes in the concentrations of plasma osteonectin at any time after transplantation, as compared with the values before transplantation (P > 0.1). None of the plasma samples showed osteonectin levels above the reference interval. There was a weak but significant relationship between platelet counts and plasma osteonectin levels (r = +0.322; P < 0.05). Osteocalcin showed a marked decrease of the values 1 week following transplantation as compared with the values before transplantation without further change of the values 1 and 3 months after transplantation (P > 0.5) whereas 3 months after transplantation bone alkaline phosphatase levels were higher than before transplantation (P < 0.05). Multiple regression analysis (performed with data from 42 samples obtained after transplantation) revealed serum creatinine as an independent predictor of plasma osteocalcin whereas serum calcitriol was an independent predictor of serum bone alkaline phosphatase (P < 0.05). No correlation was observed between serum calcitriol/plasma parathyroid hormone on the one hand and plasma osteocalcin on the other (P > 0.05). After transplantation there was a lack of correlation between serum bone alkaline phosphatase mass concentrations and plasma osteocalcin values (P > 0.05). In conclusion, serum bone alkaline phosphatase should be preferred to bone matrix proteins for the assessment of bone metabolism in patients receiving renal transplants: (a) bone alkaline phosphatase-but not osteocalcin-is significantly correlated with calcitriol and adequately reflects increased bone formation after renal transplantation; (b) interpretation of osteocalcin values is severely hampered by their strong correlation with serum creatinine concentrations; (c) plasma osteonectin determinations are not useful for monitoring bone formation.     

H1- and H2-receptors for histamine in the ileum of the guinea pig

Clark's equation used in its inverted form (double reciprocal plots) was shown to be valid regarding the interaction of histamine with its receptors in the guinea-pig ileum. Burimamide, a typical H2-receptor antagonist potentiated the stimulating effect of small concentrations of histamine (10(-6) M) on the intestinal smooth muscle, probably, by blocking H2-receptors which may show the opposite effect. The calculated parameters of affinity (pKn) remained constant under different conditions. A linear correlation between length of the preparation and maximal contractions has been found.     

Activation of heterocyclic amines by combinations of prostaglandin H synthase-1 and -2 with N-acetyltransferase 1 and 2

Gender asymmetry in touch in U.S. populations is related to the age of the participants in some studies and to the relationships between the participants in others. In the present study, researchers observed dyads in public settings in the United States frequented by couples and recorded the occurrence of touch, the touch initiator, and the body areas touched. The researchers then approached the couples and asked them to complete questionnaires indicating their ages, their relationship, and their level of agreement on major issues. Age and relationship were predictive of the gender of touch initiators. Although levels of agreement were less predictive of touch initiation, the women indicated higher levels of agreement than the men did. The results were generally consistent with a model of sex differences in reproductive strategies.