PARTICIPATION OF Hi- AND H 3-RECEPTORS IN THE REGULATION OF GUINEA-PIG TRACHEAL TONE - INFLUENCE OF INDOMETHACIN

The tracheal tone is influenced by histaminergic receptors and by the epithelium derived relaxing factor (EpDRF) which contains metabolites of arachidonic acid. The aims of the present study were the following: 1) to investigate the role of Hi- and Нз-receptors in the tracheal tone regulation using as test substances histamine (H), the Hi-receptor antagonist mepyramine and the Нз-receptor agonist (R)a-methylhistamine [(R)a -MHA]; 2) to study the influence of the cyclooxygenase (COX) inhibitor indomethacin on the tracheal responsiveness to the examined substances. The experiments were carried out on isolated guinea-pig tracheal rings. Histamine at cumulative concentrations contracts the trachea. In the presence of mepyramine the concentration- response curves to H are shifted to the right that proves the concept of the Hi-receptor mediated tracheal contraction. In the presence of indomethacin the concentration-response curves to H are shifted to the left and the maximal contraction is significantly increased due to the inhibition of the COX pathway. (R)oc-MHA at concentrations up to lxlfH M leads to a slight tracheal contraction, which is probably Hi-receptor mediated as it is reduced in the presence of mepyramine. The ЗхКИ M concentration of (R)a-MHA relaxes the trachea probably due to its Нз-receptor agonistic activity. In the presence of indomethacin this relaxation is turned to a further contraction. After tracheal precontraction by H, (R)a-MHA concentration dependently relaxes the trachea. This spasmolytic effect is insignificantly influenced by mepyramine and is almost completely abolished in the presence of indomethacin, which shows that it is probably due to an increased production of metabolites of arachidonic acid

A community approach for pathogens and their arthropod vectors (ticks and fleas) in cats of sub-Saharan Africa

Background Arthropod-borne pathogens and their vectors are present throughout Africa. They have been well studied in livestock of sub-Saharan Africa, but poorly studied in companion animals. Given their socioeconomic importance, the African Small Companion Animal Network (AFSCAN), as part of the WSAVA Foundation, initiated a standardized multi-country surveillance study. Methods In six countries (Ghana, Kenya, Nigeria, Tanzania, Uganda, and Namibia) in both rural and urban settings, 160 infested cats were sampled to assess their ectoparasite community (ticks and fleas), as well as the micro-parasite prevalence within those ectoparasites (60 and 118 pools of ticks and fleas, respectively) and blood (276 cats, including 116 non-infested). Results Almost two thirds of all infested cats originated from Tanzania and Kenya. Despite the large macro-geographical variation, no consistent difference was found in ectoparasite diversity and numbers between East and West Africa. Far more flea-infested than tick-infested cats were found. The most dominant ectoparasite was Ctenocephalides felis. Among the ticks, the exophilic Haemaphysalis spp. were the commonest, including species that are not typically linked with companion animals (Haemaphysalis spinulosa and Haemaphysalis elliptica). The most prevalent pathogens found in the blood and fleas were Bartonella henselae and Mycoplasma haemofelis. In the ticks, the dog-associated Hepatozoon canis was most commonly found. A high degree of co-parasitism was found in all countries and habitats. Conclusions Our continent-wide standardized field study highlights the cat’s potential to serve as a reservoir of pathogens that can be transmitted to humans or livestock, especially when cats are expected to become more commonly kept in African villages and towns

Evidence for a less high acceptor substrate specificity of gastric histamine methyltransferase: methylation of imidazole compounds

The transmethylation catalysed by HMT (EC 2.1.1.8)* has been considered as absolutely specific for histamine as acceptor substrate. In this investigation Nα-MH, Nα,NαDMH, spinaceamine and synthetically prepared 4-[(2-amino-ethylmercapto)-methyl]-imidazole could be identified as further methyl-group accepting substrates (optimum substrate concentration ~ 1 mM), but the yield of extractable 14C-labelled methylation products was never greater than 21 per cent of that of histamine. The 3 per cent methylation of Nα,Nα-DMH was considerably smaller than that of 33 per cent reported in the literature. This discrepancy was resolved and found to be ascribable to an inappropriate product extraction procedure used in the former experiments. When Nα-MH and Nα,Nα-DMH were the substrates, the corresponding products were isolated by t.1.c. in four different solvent systems and identified to be Nτ,Nα-DMH and Nτ,Nα,Nα-TMH. Thus HMT catalysed in all cases a uniform methyl of the Nα-nitrogen atom of the imidazole nucleus. The investigation of a series of various substituted imidazole compounds revealed that a methylation of the ring system had to be considered, if it was not substituted in the Nτ-, 2- or Nπ-position and if it carried a 4-substituent with a strong basic aminogroup, whereas substitution in the ring 5-position seemed to be of minor importance. Furthermore H1-receptor antagonists, H2-receptor antagonists, the non-imidazole H2-receptor agonist dimaprit, as well as the enzyme inhibitors aminoguanidine, tranylcypromine, pargyline and nicolinamide, were not methylated under the catalysis of HMT. The evidence for a less high substrate specificity of HMT may influence the relevance of histamine determinations using this enzyme: caution seems necessary

Lipophilic beta-adrenoceptor antagonists and local anesthetics are effective direct activators of G-proteins

We studied the effects of various beta-adrenoceptor (beta AR) antagonists and local anesthetics (LAs), i.e. substances possessing one basic and one lipophilic domain each, on activation of regulatory heterotrimeric guanine nucleotide-binding proteins (G-proteins). In membranes of differentiated HL-60 cells, propranolol activated high-affinity GTP hydrolysis with a half-maximal effect at 0.19 mM and a maximum at 1 mM. There was a close correlation between the log Q values (logarithm of the octanol: water partition coefficient) of beta AR antagonists and the logarithm of their effectiveness at activating GTPase (EC 3.6.1.-) in HL-60 membranes. The lipophilic LA, tetracaine, was also an effective activator of GTPase in HL-60 membranes, whereas more hydrophilic LAs were less stimulatory (bupivacaine and lidocaine) or even inhibitory (procaine). Propranolol and tetracaine also stimulated binding of guanosine 5'-O-[3-thio]triphosphate (GTP[gamma S]) to HL-60 membranes, but their stimulatory effects on GTP[gamma S] binding were smaller than on GTP hydrolysis. The stimulatory effects of propranolol and tetracaine on GTPase and GTP[gamma S] binding were inhibited by pertussis toxin. Propranolol and tetracaine effectively activated GTP hydrolysis of a reconstituted mixture of bovine brain Gi/Go-proteins, but the concentrations of substances needed for GTPase activation were higher than in HL-60 membranes. Procaine showed stimulatory effects on the GTPase of Gi/Go-proteins. Our data show that beta AR antagonists and LAs activate pertussis toxin-sensitive G-proteins, presumably through interaction with the C-terminus of their alpha-subunits. Apparently, the lipophilic domain of beta AR antagonists and LAs is more important for G-protein activation than the basic domain. We discuss the possibility that activation of nucleoside diphosphate kinase by beta AR antagonists and LAs contributes to their stimulatory effects on GTP hydrolysis in HL-60 membranes

[H2-antagonistic activity of the impromidine analog, cyanoguanidine. 37. H2 antihistaminics]

In studies on structure-activity relationships among impromidine-like histamine H2-receptor agonists, the synthesis of impromidine analogous guanidines led to the corresponding intermediate cyanoguanidines. The latter are structurally related to cimetidine. For that reason they were tested for H2-antagonistic activity on the isolated guinea-pig atrium. Compound 5h proved to be significantly more potent than cimetidine. Derivatives with branched thioether moiety were devoid of affinity. The results are consistent with existing structure-activity relationships