1 SK&F 93944 (temelastine), a novel histamine HI-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. 2 SK&F 93944 was a competitive antagonist of histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of histamine on guinea-pig atrium. 3 In anaesthetized guinea-pigs SK&F 93944 displaced histamine bronchoconstriction dose-response curves at doses which had negligible effects on histamine tachycardia. 4 In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine HI-receptor agonists, 2-(2-aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2-receptor agonist, dimaprit. described HI-receptor antagonists in that it lacks a tertiary amino group and is largely unprotonated at physiological pH. This paper describes the pharmacology of SK&F 93944 in a range of in vitro and in vivo models designed to evaluate both its potency and selectivity. In addition, studies are described which show that the compound has negligible ability to cross the bloodbrain barrier in rats, and is consequently highly unlikely to elicit CNS side-effects. A Animals were artificially ventilated through a tracheal cannula using the volume of air just required to fill the lungs at an airway pressure of 12 cmH2O. A pressure transducer was inserted into the outflow limb of the system to measure airway inflation pressure as an index of resistance. Blood pressure, heart rate and airway pressure were registered continuously on an electronic recorder (Lectromed, Ml 9). Dose-response curves for histamine-induced bronchoconstriction and tachycardia were constructed in each animal prior to and following intravenous injection of a histamine HI-receptor antagonist at a series of doses. In a further series ofexperiments with SK&F 93944, carbachol was used as the agonist to elicit bronchoconstriction.Studies in anaesthetized cats Studies were carried out in cats of either sex, body weight 1.65-3.15 kg. Following induction of anaesthesia the trachea was cannulated. Systemic blood pressure was measured from a catheter in one carotid or femoral artery and monitored on a Lectromed M19 recorder. Heart rate was measured with an instantaneous rate meter triggered by the blood pressure pulse. Injections of drugs and supplementary doses ofanaesthetic were made via cannulae inserted into the femoral and/or brachial veins.Studies with selective histamine receptor agonists Cats were anaesthetized with sodium pentobarbitone, 60 mg kg-' i.p. Responses to 2-(2-aminoethyl) pyridine (2-PEA), betahistine and dimaprit were obtained in separate groups of cats, using procedures described by Owen (1975 Vascular permeability changes were measured 15 min after injection of histamine since preliminary experiments indicated this time to be optimal in the rat. At this time the rats were again anaesthetized, the abdomen opened and a I ml sample of blood taken from the vena cava. The animals were then killed and th...
The effects of histamine on blood pressure have been compared with the effects caused by four histamine‐like agonists in anaesthetized cats. It has been confirmed that the depressor responses to histamine involve both H1‐ and H2‐receptors: depressor responses also follow the administration of selective H1‐ and H2 ‐receptor agonists. 2‐Methylhistamine, in doses up to 1 × 10−7 mol/kg, lowers blood pressure by interaction with H1‐receptors. Larger doses of 2‐methylhistamine also lower blood pressure but this may involve H2‐receptors. 4‐Methylhistamine, in doses up to 1 × 10−7 mol/kg, lowers blood pressure by interaction with H2‐receptors. Larger doses of 4‐methylhistamine also lower blood pressure but this may involve H1‐receptors. 2‐(2‐Aminoethyl)pyridine and 2‐(2‐aminoethyl)thiazole both lower blood pressure by interaction with H1‐receptors only. The potential value and limitations of these compounds as tools to investigate the cardiovascular effects of histamine are discussed.
The rates of uterine and ovarian blood flow during the oestrous cycle in rats were measured using radioactive microspheres. Blood flow was highest in the ovaries and uteri during pro-oestrus and lowest during metoestrus. During pro-oestrus, mean ovarian blood flow was 676-2 +/- 183-6 (S.D.) ml/min/100 g wet tissue and mean uterine blood flow was 249-7 +/- 120-1 ml/min/100 g. During metoestrus mean ovarian blood flow was 117-4 +/- 19-8 ml/min/100 g and mean uterine blood flow was 38-5 +/- 7-4 ml/min/100 g. In ovariectomized rats, uterine blood flow was 28-7 +/- 10-5 ml/min 100 g.
The pharmacology of histamine-induced increases in microvascular permeability has been studied in rat skin. Histamine caused dose-dependent increases in microvascular permeability, assessed as increases in extravascular albumin accumulation. The responses to histamine were inhibited in a dose-dependent manner by pretreatment with mepyramine and were not changed by cimetidine. 2-(2-Aminoethyl)pyridine also increased microvascular permeability whereas impromidine did not. These results suggest that H1-receptors and not H2-receptors are involved in the permeability response to histamine in rat skin. In contrast, dimaprit increased microvascular permeability and responses to dimaprit exceeded the maximum response to histamine. The response to dimaprit proved to be independent of H2 receptors and was consistent with an indirect response due to mast cell degranulation.
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