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Biomedical subjects

M E Parsons

Publications and source records attributed to M E Parsons.

At least 91 records · Page 5Linked to original sources
PubMed1977

Dimaprit -(S-[3-(N,N-dimethylamino)prophyl]isothiourea) - a highly specific histamine H2 -receptor agonist. Part 1. Pharmacology.

S-[3-(N,N-Dimethylamino)propyl]isothiourea (dimaprit), has been shown to be a highly specific histamine H2-receptor agonist. Parallel line assays showed that in vitro at H2-receptors it had approximately 17.5% the activity of histamine on the rat uterus and 71% on the guinea-pig right atrium, with similar maximal responses; it had less than 0.0001% the activity of histamine on H1-receptors. Dimaprit stimulated gastric acid secretion in the rat, dog and cat in which it had, respectively, approximately 19,58 and 400-500% the activity of histamine. In the dog and cat the maximum secretory response to dimaprit was significantly greater than that obtained to histamine. The H2-receptor specificity of dimaprit in causing depressor and vasodilator effects was also demonstrated in the cat, in which it had 18-20% of the H2-receptor activity of histamine. Dimaprit should prove to be a very useful tool in studies examining the role of histamine in physiology and pathology. The absence of marked cardiovascular effects at doses maximal for the stimulation of gastric acid secretion, as seen in the cat studies, could lead to this compound being of value as a diagnostic agent in the measurement of maximal acid secretory capacity.

Animals↗
PubMed1977

Dimaprit, (S-[3-(N,N-dimethylamino)propyl]isothiourea). A highly specific histamine H2-receptor agonist. Part 2. Structure-activity considerations.

Dimaprit, S-[3-(N,N-dimethylamino)propyl]isothiourea, appears to be a highly specific histamine H2-receptor agonist. Further indications of specificity are obtained from chemical considerations. Dimaprit has two basic centres (pKa values respectively 8.23 and 9.23, at 40 degrees) and at pH 7.4 about 5% of the molecules will be present as the monocation analogous to histamine monocation. Chemical comparison suggests that the --N+HMe2 group corresponds to the --N+H3 of histamine, and that the isothiourea group of dimaprit (which can undergo 1,3-prototropic tautomerism) may simulate the imidazole ring of histamine and function as a proton transfer agent at H2 receptors. Simple structural analogues of dimaprit are only weakly active, indicating a high degree of chemical specificity for H2-receptor stimulation; such compounds (e.g. the lower homologue, SK & F 91487) may serve as useful chemical controls when studying the actions of dimaprit.

Histamine↗
PubMed1977

The effect of hexamethonium on gastric acid secretion in the conscious rat.

Evidence against a role for histamine in pentagastrin-stimulated acid secretion has been obtained previously using hexamethonium in gastric fistula rats. This possibility has been re-examined in conscious rats provided with gastric fistulae or Heidenhain pouches. Hexamethonium (20 mg/kg s.c.) inhibited basal acid secretion and acid secretion stimulated by histamine and pentagastrin in gastric fistula rats. The same dose of hexamethonium failed to produce a significant inhibition of acid secretion stimulated by bethanechol, pentagastrin or histamine in the presence of a low dose of bethanechol in Heidenhain pouch rats. These results provide no evidence to oppose the view that pentagastrin-stimulated acid secretion in the rat is mediated at least in part through the mobilization of gastric mucosal histamine. The inhibition of secretagogue induced acid secretion in the gastric fistula rat is mainly the result of a reduction in the basal acid output.

Animals↗
PubMed1977

Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine.

In the histamine H2-receptor antagonist metiamide (2a) isosteric replacement of thione sulfur (=S) by carbonyl oxygen (=O) or imino nitrogen (=NH) affords the urea 2c and guanidine 2d which are antagonists of decreased potency. The guanidine is very basic and at physiological pH is completely protonated. However, introduction of strongly electronegative substituents into the guanidine group reduces basicity and gives potent H2-receptor antagonists, viz. the cyanoguanidine 2b (cimetidine, "Tagamet") and nitroguanidine 2e. A correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4. The close correspondence between cyanoguanidine and thiourea in many physicochemical properties and the pharmacological equivalence of these groups in H2-receptor antagonists leads to the description of cyanoguanidine and thiourea as bioisosteres. Acid hydrolysis of the cyanoguanidine 2b yields the carbamoylguanidine 2f at ambient temperatures and the guanidine 2d at elevated temperatures. Cimetidine is slightly more active than metiamide in vivo as an inhibitor of histamine-stimulated gastric acid secretion and has clinical use in the treatment of peptic ulcer and associated gastrointestinal disorders.

Chemical Phenomena↗
PubMed1977

The effect of atropine on acid secretion stimulated by acetylcholine, histamine and gastrin in the isolated whole stomach of the rat.

1 An isolated stomach preparation from immature rats has been used to study the effect of atropine on gastric acid secretion. 2 The acid secretory response to acetylcholine was not inhibited by atropine at a concentration of 0.3 micrometer. Concentrations of atropine of 1 to 3 micrometer produced a measurable inhibition of acid secretion, and a concentration of atropine of 10 micrometer caused a complete block of acid secretion which could not be surmounted by high concentrations of acetylcholine. 3 The acid secretory response to histamine was not inhibited by concentrations of atropine of up to 1 mM. 4 Concentrations of atropine of 1 micrometer and 10 micrometer did not inhibit gastrin-stimulated acid secretion, although a significant inhibition of acid output was observed with atropine at concentrations of 0.1 mM and 1 mM. 5 These findings are discussed in relation to the role of cholinergic mechanisms in the control of gastric acid secretion.

Acetylcholine↗
PubMed1977

The effect of anaesthesia on the inhibition of pentagastrin-evoked gastric acid secretion induced by atropine in the rat.

1. In the anaesthetized, vagally intact rat, with a perfused gastric lumen, atropine produced a maximum inhibition of 60% of maximal pentagastrin-evoked gastric acid secretion. Sub-maximal pentagastrin-stimulated secretion was also inhibited by atropine.2. In the anaesthetized, vagotomized rat, with a perfused gastric lumen, atropine had no inhibitory effect on maximal pentagastrin-evoked gastric acid secretion.3. In the conscious fistula rat, atropine totally abolished both the basal gastric acid secretion and the maximal gastric acid secretion evoked by pentagastrin. In the anaesthetized chronic fistula rat, doses of atropine up to 1.6 mg.kg(-1) administered subcutaneously produced a maximum inhibition of 70% of maximal pentagastrin-evoked gastric acid secretion. Vagotomy did not affect the response to atropine.4. In the conscious Heidenhain pouch rat, doses of atropine up to 1.6 mg.kg(-1) administered subcutaneously produced a maximum inhibition of 70.9% of maximal pentagastrin-evoked gastric acid secretion. Both anaesthesia and vagotomy, alone or in combination, did not affect the response to atropine.

Anesthesia, General↗
PubMed1976

Separation of rat muscle aminopeptidases.

By means of chromatography on DEAE-Sephadex, two arylamidases (hydrolysing L-arginine 2-naphthylamide) and three dipeptidyl peptidases (hydrolysing dipeptide 2-naphthylamides) were distinguished in extracts of rat muscle. However, the arylamidase from the larger peak also hydrolysed the dipeptide 2-naphthylamides. Glycyl-L-arginine amide, an alternative substrate for dipeptidyl peptidase I, was not hydrolysed by arylamidase. L-Leucine amide was hydrolysed by an enzyme, presumed to be leucine aminopeptidase, from a separate peak, but was also hydrolysed by arylamidase. Arylamidase, dipeptidyl peptidase III and most of the leucine aminopeptidase could be extracted from the muscle with a neutral salt solution, but dipeptidyl peptidase I was extracted only in the presence of Triton X-100; dipeptidyl peptidase II showed an intermediate extraction behaviour.

Aminopeptidases↗
PubMed1976

The effect of metiamide on acid secretion stimulated by gastrin, acetylcholine and dibutyryl cyclic adenosine 3',5'-monophosphate in the isolated whole stomach of the rat.

1 An isolated stomach preparation from immature rats is described. The lumen of the stomach was perfused and the hydrogen ion activity of the perfusate recorded continuously. 2 The preparation gave dose-dependent responses to gastrin, acetylcholine and dibutyryl cyclic adenosine 3',5'-monophosphate and these responses were readily reversed on washing out the agonist. 3 The acid secretory response to gastrin was inhibited by metiamide at concentrations of 10(-5) M and 3 X 10(-5)M. 4 The acid secretory responses to acetylcholine and dibutyryl cyclic adenosine 3',5'-monophosphate were not inhibited by concentrations of metiamide up to 10(-3) M. 5 These findings are discussed in relation to the role of histamine in the control of gastric acid secretion.

Acetylcholine↗
PubMed1976

A quantitative study of metiamide, a histamine H2-antagonist, on the isolated whole rat stomach.

1. An isolated whole stomach preparation from immature rats is described. The lumen of the stomach was perfused and the hydrogen ion activity of the perfusate recorded continuously. 2. The mean basal acid secretion before stimulation was 4-19 +/- 0-31 X 10 (-8) mol min-1. Metiamide did not significantly reduce this spontaneous secretion. 3. The preparation gave dose-dependent responses to histomine (10(-5)-10(-4)M) which were readily reversed on washing. 4. The effect of metiamide on histamine-stimulated acid secretion was investigated. Metamide, at doses of 3 X 10(-6)M, and 3 X 10(-5)M, caused a parallel displacement of the histamine dose-response curve, indicating competitive antagonism. These dose-response curves were used to calculate dose ratios (DR) for metiamide. 5. A plot of log10 (DR - 1) against log 10 [antagonist] gave a pA2 value for metiamide of 5-91.

Animals↗
PubMed1976

The pharmacology of burimamide and metiamide, two histamine H2-receptor antagonists.

Burimamide and metiamide are two histamine H2-receptor antagonists. Evidence is presented that indicates the competitive nature and the specificity of the antagonism. Metiamide is about ten times more potent than burimamide and is also more effective than burimamide when given orally. Both compounds inhibit gastric secretion and the evidence is consistent with this inhibition being due to competitive antagonism of H2 receptors in the gastric mucosa. Burimamide, unlike metiamide, causes release of catecholamines even at dose levels that are just sufficient to produce H2-receptor antagonism. Burimamide, but not metiamide, has alpha-adrenoceptor blocking activity. In certain models for inflammation, particularly rat paw edema induced by compound 48/80, burimamide in combination with the H1-receptor antagonist mepyramine shows anti-inflammatory activity. This may, in part, be associated with the catecholamine-releasing properties of the compound. Metiamide is less active in this respect.

Animals↗
PubMed1975

Potential histamine H2-receptor antagonists. 2. N-alpha-Guanylhistamine.

The agonist molecule, histamine, has been used as a starting point for the design of potential H2-receptor antagonists. Converting the side-chain amino group into a guanidine yielded the first histamine H2-receptor antagonist, Nalpha-guanylhistamine. Antagonism of H2 receptors was demonstrated by the inhibition of histamine-stimulated gastric acid secretion in the rat at high dose levels (approximate ID50 800 MUmol/kg, iv) and by the inhibition of histamine-stimulated tachycardia of guinea-pig right atrium (pA2 equals 3.9). Guanylhistamine behaves as a partial agonist at histamine H2 receptors.

Animals↗
PubMed1975

Chemical differentiation of histamine H1- and H2-receptor agonists.

Histamine exists predominantly as the NT-H tautomer of the monocation (IIa) at a physiological pH of 7.4 and structure-activity studies indicate that this tautomer is likely to be the pharmacologically active species for both H1 and H2 receptors. Effective H2-receptor agonists appear to require a prototropic tautomeric system whereas H1-receptor agonists do not need to be tautomeric. This identifies a chemical difference in the receptor requirements which provides the basis for obtaining selective histamine H1-receptor agonists. Thus 2-(2-aminoethyl)thiazole and 2-(2-aminoethyl)pyridine are nontautomeric and are highly selective agonists for histamine H1 receptors (H1:H2 ca. 90:1 and 30:1, respectively). In conjunction with the selective H2-receptor agonist, 4-methylhistamine, they are of great value for studying the pharmacology of histamine receptors.

Animals↗
PubMed1975

An analysis of the depressor responses to histamine in the cat and dog: involvement of both H1- and H2-receptors.

1 The depressor responses to histamine, in anaesthetized cats and dogs, have been shown to involve both histamine H1- and H2-receptors. 2 In both species, histamine caused dose-dependent falls in blood pressure. The dose-response curve could be displaced to the right by administration of mepyramine 2.5 times 10(-6) mol/kg i.v. The displacement was maximal with a dose-ratio of less than ten. 3 Metiamide alone, up to 2 times 10(-6) mol kg-1 min-1, had no significant effect on the histamine dose-response curve. 4 When administered in the presence of mepyramine, metiamide, 4 times 10(-7) and 2 times 10(-6) mol kg-1 min-1, caused dose-dependent displacements to the right, of the histamine dose-response curve greater than could be achieved with mepyramine alone. 5 The results indicate the presence of both histamine H1- and H2-receptors in the cardiovascular system of the cat and dog. Both receptors produce a common response, i.e. a fall in blood pressure.

Animals↗