Biomedical subjects

R G Pendleton

Publications and source records attributed to R G Pendleton.

At least 37 records · Page 2Linked to original sources

PubMed1986

Leukotriene effects upon the transgastric potential difference and pepsin secretion.

The effects of leukotrienes on gastric mucosal function in vivo, and on acid and pepsin secretion in vitro were investigated. In cats, treatment with leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) caused significant decreases in the transgastric electrical potential difference (P.D.) and significant increases in pepsin secretion, which returned toward control levels over 30-90 min. No detectable changes were observed in either acid concentration or gastric secretion volume over the entire 210 min experimental period. Leukotriene B4 (LTB4) had no effect upon any of these parameters. Treatment with LTD4 in isolated rabbit gastric glands resulted in significant increases in pepsin secretion, with no changes observed in aminopyrine accumulation (acid secretion). These results indicate that exogeneous LTC4, LTD4 and LTE4 can affect certain gastric mucosal functions.

Animals↗

PubMed1985

Effects of H2-receptor antagonists upon physiological acid secretory states in animals.

The results reported in this paper indicate that representative H2-receptor antagonists are capable of maximally inhibiting gastric acid secretion in animals under the two general circumstances in which it occurs physiologically. Interdigestive or basal secretion was examined in chronic gastric fistula rats and food-stimulated secretion in vagally innervated, lesser curvature pouch dogs. The H2 antagonists studied and omeprazole, an inhibitor of the proton pump H+, K+-adenosine triphosphatase, also decreased pepsin secretion in rats, although not to the same maximal degree as acid secretion. Gastric emptying was increased by each H2 antagonist but only at high acid inhibitory doses. Omeprazole, in contrast, did not alter gastric emptying at a similar antisecretory dosage level. In dogs, a representative H2-receptor antagonist markedly inhibited food-stimulated acid secretion. These data suggest that the predominant effect of omeprazole and H2-receptor antagonists upon gastric function is to inhibit acid secretion and that H2-receptor antagonists may be capable of maximally inhibiting endogenous acid secretion in humans, as does omeprazole, if given under proper conditions.

Animals↗

PubMed1984

Studies on the H2-receptor antagonism of MK-208 in isolated rabbit gastric glands.

Using isolated rabbit gastric glands, the H2-receptor antagonist MK-208 was investigated with respect to its effects on [14C]aminopyrine uptake as an index of gastric acid secretion. In addition to shifting the histamine concentration-response curve to the right in a parallel fashion, the antagonism produced by MK-208 was reversible, contrary to that previously seen in the guinea pig atria. These observations suggest that the H2-receptors responsible for mediating gastric secretion in the rabbit and the chronotropic response in guinea pig atria are different.

Aminopyrine↗

PubMed1984

Studies on the properties of 3-N-[3-[3-(1-piperidinomethyl)phenoxy]-propyl]amino-4-amino-1,2, 5-thiadiazole-1-oxide (L-643,441) as an H2-receptor antagonist in isolated gastric glands.

The H2-receptor blocking properties of L-643,441 were compared with ranitidine in isolated rabbit gastric glands. [14C]Aminopyrine uptake was used as the indicator of gastric acid secretion. Unlike ranitidine, inhibition by L-643,441 was time-dependent, only partially reversible, and was not surmounted by increasing doses of histamine. These and other findings are similar to those found previously in guinea pig atria, providing further evidence that at the receptor level, the mechanism of action of L-643, 441 is different from standard H2-receptor antagonists such as ranitidine.

Aminopyrine↗

PubMed1984

Comparison of central gastric antisecretory effects of desmethylimipramine, doxepin and pirenzepine in rats.

Certain tricyclic drugs, some of which are primarily used clinically as antidepressants, have been shown to act as gastric antisecretory agents. The anatomical site(s) and mechanism(s) of action of these agents is, however, in most cases unclear. In this study, we found that desmethylimipramine (DMI) was approximately 28 times more potent in inhibiting gastric acid secretion when administered intracerebroventricularly (i.c.) than when administered intravenously (i.v.) in pylorus-ligated rats, which is indicative of a site of action in the central nervous system. Qualitatively similar results were obtained with pirenzepine where the i.c./i.v. potency ratio was 8. Doxepin also preferentially inhibited acid secretion when given i.c. at low but not at high doses. Atropine and chlorpromazine were equipotent antisecretory agents by both routes of administration. Doxepin and DMI but not pirenzepine were effective inhibitors of brain stem norepinephrine uptake in vitro thus making this an unlikely common mechanism to explain the central actions of these compounds.

Animals↗

PubMed1983

Effects of bethanechol, metoclopramide, and domperidone on antral contractions in cats and dogs.

The effects of bethanechol, metoclopramide, and domperidone were examined on antral contractions in anesthetized dogs and cats. Bethanechol and metoclopramide were found to increase contractility in both the dog and cat, while domperidone did not stimulate contractions in the cat but was effective in the dog. With domperidone, unlike bethanechol and metoclopramide, changes in mean blood pressure were not produced. Our results indicate that all three of the agents examined can stimulate contractions in the antrum, but the choice of animal model is critical for the proper evaluation of the compounds.

Animals↗

PubMed1983

Apparent irreversible H2-receptor blocking and prolonged gastric antisecretory activities of 3-N-(3-[3-(1-piperidinomethyl)phenoxy]propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide (L-643, 441).

L-643,441 is a highly potent histamine H2-receptor antagonist in guinea-pig atria, acting via a unique mechanism. Unlike ranitidine, the onset of action of this compound was slow and its inhibitory action persisted after repeated washing of the tissues. Preincubation of atria with ranitidine, however, protected the H2-receptor from the apparently irreversible antagonism of L-643,441. H2-receptor antagonism produced by L-643,441 was not surmountable by increasing the concentration of dimaprit. The compound did not alter the response of this tissue to isoproterenol or affect basal atrial rate under conditions in which maximal H2-receptor blockade was achieved. In dogs, L-643,441 was effective both orally and i.v. in inhibiting gastric acid secretion evoked by histamine, gastrin, 2-deoxy-D-glucose and food. Orally, it was equipotent with ranitidine against histamine-induced secretion, but the duration of action of L-643,441 was substantially longer.

Animals↗

PubMed1983

Studies on MK-208 (YM-11170) a new, slowly dissociable H2-receptor antagonist.

MK-208 [3-(((2-(aminoiminomethyl)amino)-4-thiazolyl)-methyl)thio)-N'-(a minosulfonyl) propanimidamide], also known as YM-11170, is a highly potent histamine H2-receptor antagonist in guinea-pig atria, acting via a unique binding mechanism. Unlike ranitidine, the onset of action of this compound was slow and its inhibitory action was difficult to remove from the tissues by repeated washing. Preincubation of atria with ranitidine, however, protected the H2-receptor from these prolonged inhibitory effects of MK-208. The H2-receptor antagonism produced by MK-208 was not surmountable by increasing concentrations of dimaprit. The compound did not alter the response of this tissue to isoproterenol or affect basal atrial rate under conditions where maximal H2-receptor blockade was achieved. In dogs, MK-208 was effective in inhibiting gastric acid secretion evoked by histamine, gastrin and 2-deoxy-D-glucose. Orally, it was approximately 7 times as potent as ranitidine against histamine-induced secretion, and its duration of action was substantially longer. The compound was also highly effective in inhibiting basal acid secretion in chronic gastric fistula rats.

Animals↗

PubMed1983

Effects of indomethacin, aspirin and related compounds on the transgastric potential difference in cats.

Indomethacin was effective orally (intragastrically) and intravenously at 5 mg/kg in producing decreases in the transgastric electrical potential difference of anesthetized cats. The onset of action was, however, delayed as compared with direct irritants administered intragastrically such as salicylic acid. Aspirin administered intragastrically at 50 mg/kg caused a biphasic effect, an initial rapid drop followed by partial recovery after washout and then a subsequent slow decline similar to that observed after intravenous administration of the same dose. The effects of intragastric indomethacin were prevented by the concomitant topical administration of prostaglandin E2 while those of aspirin were only attenuated. The results are consistent with a prostaglandin mechanism (depletion) for the gastric mucosal effects of indomethacin. Aspirin, on the other hand, may have a direct irritant effect on the gastric mucosa as well as acting as an inhibitor of prostaglandin synthetase (cyclooxygenase).

Animals↗

PubMed1982

Lowering of blood pressure in hypertensive rats by SKF 64139 and SKF 72223.

The effects of a centrally acting phenylethanolamine N-methyl-transferase (PNMT) inhibitor, SKF 64139, and of its analog, SKF 72223, which is devoid of PNMT inhibitory activity on blood pressure and heart rate, were investigated in spontaneously hypertensive rats (SHR) and in DOCA-salt hypertensive rats. SKF 64139 lowers blood pressure and decreases pulse rate, while SKF 72223 lowers blood pressure and transiently increases pulse rate in SH-rats and in DOCA-salt hypertensive rats. SKF 72223 has no effect on blood pressure or heart rate in normotensive Wister-Kyoto rats. These results suggest that the antihypertensive action elicited by these two tetrahydroisoquinoline (TIQ) derivatives is not due to lowering of central epinephrine (E) levels. To determine whether the cardiovascular response elicited by SKF 72223 is due to stimulation of presynaptic alpha 2-adrenoreceptors, or to blockade of alpha 1-adrenoreceptors, we have examined its effect in combination with the partial alpha 2-agonist clonidine, or with the alpha 1-antagonist prazosin. The administration of clonidine slightly decreases the antihypertensive action of SKF 72223. The clonidine induced reduction in pulse rate is reversed by SKF 72223. In animals pretreated with prazosin, SKF 72223 elicits an additional decrease in blood pressure. Since SKF 64139 and SKF 72223 interact with alpha 2-adrenoreceptors, it is suggested that blockade of peripheral vascular alpha 2-adrenoreceptors might be in part responsible for their antihypertensive action. However, the antihypertensive action of these two drugs might also be due to some central mechanisms.

Adrenergic alpha-Antagonists↗

PubMed1982

alpha-Adrenergic agents. 3. Behavioral effects of 2-aminotetralins.

Studies with 5-substituted-8-methoxy-2-amino-tetralin compounds suggest that some are alpha 1-adrenoceptor agonists, which readily penetrate the blood-brain barrier. They potentiate the locomotor activity that is induced by apomorphine (AP) in reserpinized mice, an effect that has been suggested to result from activation of central alpha-receptors. This effect is selectively blocked by the preferential alpha 1-antagonist phenoxybenzamine, but not by drugs that block other types of receptors. The effect is also produced by the centrally administered alpha 1-agonists phenylephrine and methoxamine, but not by various types of standard CNS stimulants. When administered in high doses, some of the aminotetralin compounds induce locomotor activity in reserpinized mice without AP, an effect also found with high doses of centrally administered phenylephrine and methoxamine. This effect is blocked by a series of drugs at doses that correspond to their alpha 1-antagonist potencies.

Adrenergic alpha-Antagonists↗

PubMed1982

Studies on the long term effects of SK&F 29661 upon adrenal catecholamines.

SK&F 29661 (1,2,3,4-tetrahydro-7-isoquinoline-sulfonamide) is a potent and selective in vitro and in vivo inhibitor of adrenal phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). Its Ki value for in vitro inhibition of rat adrenal PNMT was 133 nM. In vivo, the adrenal conversion of 3H-norepinephrine to 3H-epinephrine was maximally inhibited by a single oral dose of 100 mg/kg. In long term chronic studies in rats, adrenal epinephrine was reduced by SK&F 29661 in a dose dependent fashion to greater than 90%, without substantial increases in norepinephrine. Urinary excretion of epinephrine was significantly reduced by the drug both basally and following 2-deoxy-D-glucose stimulation. No drug related changes were found in plasma corticosterone values and only small effects were observed on adrenal tyrosine hydroxylase and PNMT enzyme levels. The cardiac norepinephrine pool and its turnover time were both significantly reduced; its turnover rate, however, was only slightly increased. Our studies indicate that SK&F 29661 is a highly effective, non-toxic and novel pharmacological tool which is useful in depleting adrenal epinephrine stores via inhibition of its biosynthesis.

Adrenal Glands↗

PubMed1982

Comparison of central and peripheral alpha 1-adrenoceptors.

A series of alpha-adrenergic agonists and antagonists having diverse chemical structure was examined for both central and peripheral alpha 1-adrenoceptor activity. The agonists tested included several novel aminotetralin derivatives which were potent and selective alpha 1-agonists. Peripheral alpha 1-activity was determined in the isolated rabbit ear artery; central alpha 1-receptor affinity was measured as the ability to inhibit 3H-WB 4101 binding to rat brain homogenates. In the agonist series, an excellent correlation between peripheral alpha 1-activity and central alpha 1-affinity was obtained, providing that partial agonists were excluded. Likewise, the receptor dissociation constant for blockade of the peripheral alpha 1-adrenoceptor correlated well with affinity for the central receptor for all of the alpha-antagonists. These data support the conclusion that central and peripheral alpha 1-adrenoceptors are similar or identical.

Adrenergic alpha-Agonists↗

PubMed1982

alpha-Adrenergic agents. 2. Synthesis and alpha 1-agonist activity of 2-aminotetralins.

Substituted 2-aminotetralins are potent, selective, direct-acting agonists at postjunctional alpha 1 receptors. Within this series, substituent alterations on the ring, as well as on the nitrogen, change the potency of compounds by over three orders of magnitude (EC50 = 12 to greater than 10 000 nM). It has been demonstrated experimentally that substitution at both the 5 and 8 positions of the aromatic ring produces optimum agonist potency. Removal of either substituent results in a loss of potency and efficacy relative to norepinephrine. Substitution at positions 6 and/or 7 is generally detrimental to activity. Methyl, ethyl, or dimethyl substitution on nitrogen is compatible with high agonist potency, while substitution with larger groups is not. The most potent agonist in this series is 5-(thiomethyl)-8-methoxy-2-aminotetralin, which has an EC50 of 12 nM.

Adrenergic alpha-Agonists↗

PubMed1981

Mechanism for gastric antisecretory effects of desmethylimipramine in rats.

The mechanism for the gastric antisecretory action of desmethylimipramine (DMI) was studied using the pylorus-ligated rat preparation. DMI was approximately 40 times more potent in decreasing gastric acid secretion when given into the lateral ventricles of the brain than when administered intravenously. The antisecretory effects of DMI could be blocked by the alpha 2-adrenoceptor antagonists yohimbine and SK&F 72223 and mimicked by central administration of an alpha 2-agonist. It could not be blocked by the alpha 1-antagonist prazosin or mimicked by alpha 1-adrenoceptor agonists. SK&F 72223 and yohimbine themselves produced small increases in gastric acid, but the increase output by SK&F 72223 failed to reduce the antisecretory response to atropine. Since DMI is not an alpha 2-adrenoceptor agonist, but is a potent inhibitor of norepinephrine uptake, these data suggest that the effects of DMI on gastric acid secretion are mediated indirectly via inhibition of catecholamine uptake at central synapses containing alpha 2-adrenoceptors.

Animals↗

PubMed1981

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 3. Bis[tetrahydroisoquinoline]s.

7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (SK&F 64139) is a potent inhibitor of phenylethanolamine N-methyltransferase (IC50 = 10 muM) that may have therapeutic utility in man. A series of related compounds in which two 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline molecules have been bridged from nitrogen to nitrogen by an unbranched alkyl chain have been prepared and have demonstrated potent inhibitory properties (0.08 to 2 muM). In contrast simple substitution on the nitrogen of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline with a variety of substituents gives compounds with greatly diminished inhibitory potencies (IC50 = 2 to greater than 100 muM) relative to SK&F 64139. Kinetic studies with a C6 analogue have shown that it is competitive with respect to phenylethanolamine and uncompetitive with respect to S-adenosylmethionine. The increased potency of some of the bis analogues relative to that seen with the tetrahydroisoquinolines having larger alkyl groups on nitrogen suggests that several of the bis compounds show supplemented or cooperative binding to the enzyme, presumably as a result of the second tetrahydroisoquinoline moiety.

Animals↗

PubMed1981

Alpha-adrenergic agents. 1. Direct-acting alpha 1 agonists related to methoxamine.

A series of phenylethylamines related to methoxamine has been prepared and evaluated for direct alpha 1-receptor agonist activity. It has been observed that for open-chain compounds such as methoxamine, in which the amine-containing portion is free to adopt numerous conformations, an hydroxyl group is necessary for direct alpha 1-adrenergic activity. When the hydroxyl is removed, however, the direct component of activity is greatly reduced unless the amine is incorporated into a more sterically defined structure. From our studies we have concluded that in order for a phenylethylamine to be active as a direct alpha 1-receptor agonist it should have a beta nitrogen in a fully extended conformation relative to a substituted phenyl ring. For optimum potency, the nitrogen should be exocyclic to a saturated six-membered ring. It may be further incorporated exocyclic or endocyclic into an additional ring as long as the amine occupies a well-defined region of space relative to the aromatic portion of a molecule. The ED50 values of some of the more potent compounds as alpha 1-receptor agonists are on the order of 1 X 10(-7) M.

Adrenergic alpha-Agonists↗

PubMed1981

Studies on the adrenergic receptor specificity of inhibitors of phenylethanolamine N-methyltransferase.

We have examined a series of potent PNMT inhibitors for their selectivity on this enzyme vis'-a-vis other adrenergic receptors for which norepinephrine is also an agonist or substrate. The parent compound, SK&F 64139, inhibits PNMT in the nanomolar range and also has moderate affinity as an alpha 2-adrenoceptor antagonist. Moreover, it possesses very weak activity as an MAO inhibitor and alpha 1-adrenoceptor antagonist. With other compounds in the series, it was possible to retain marked PNMT inhibitory activity while substantially decreasing alpha 2-blocking affinity. These drugs, however, have greater central nervous system (CNS) toxicity than SK&F 64139. It was also possible to substantially enhance the PNMT inhibitory activity of a highly polar compound (SK&UF 29661) without decreasing its receptor specificity, although the resulting analogue contains an additional lipophilic chloro substituent and does, unlike SK&F 29661, penetrate into the CNS.

Adrenergic alpha-Antagonists↗