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Biomedical subjects

R G Pendleton

Publications and source records attributed to R G Pendleton.

At least 55 records · Page 3Linked to original sources
PubMed1981

Studies on the mechanisms involved in the cardiovascular response of the rat to hemorrhage.

Acute reductions in blood volume and in arterial pressure produced by hemorrhage in the rat resulted in significant changes in heart rate. In general, when bleeding lowered mean arterial blood pressure to 90 mmHg or less, heart rate fell in proportion to the depth of hypotension, but when arterial pressure remained above 100 mmHg, regardless of the volume of shed blood, heart rate increased. The bradycardia observed when the animals were bled to low pressures (40 mmHg) could be prevented by vagotomy or with a combination of atropine and propranolol. This suggests the effect is reflex action centrally mediated. Propranolol alone had only small effects on the heart rate response, indicating that the reflex is predominantly under vagal influence. Phenoxybenzamine or adrenal demedullation had no effect on heart rate or blood pressure changes during or after hemorrhage. Pargyline, at a dose which significantly inhibited MAO and increased brain stem norepinephrine and dopamine levels, reduced the magnitude of the shock bradycardia. These results are discussed in relation to our earlier report (Pendleton et al., 1980a) which indicates that the potent inhibitor of epinephrine synthesis, SK & F 64139, will prolong the bradycardia and hypotension associated with hemorrhage in this model.

Adrenal Medulla↗
PubMed1980

Comparison of the effects of SK & F 29661 and 64139 upon adrenal and cardiac catecholamines.

After 7 day dosing with SK & F 64139, an inhibitor of adrenal and CNS PNMT, a stoichiometric relationship is observed between epinephrine decrease and norepinephrine increase in adrenal tissue. However, this relationship is not found with the adrenal PNMT inhibitor, SK & F 29661. SK & F 64139 was found to possess significant adrenal MAO inhibitory activity, but SK & F 29661 does not. Three factors are presented which argue against MAO inhibition as the cause of the catecholamine profile difference. We then performed various studies with SK & F 29661 and 64139 to examine whether enzymes in the norepinephrine biosynthetic pathway are differentially affected by these drugs and found that they were not. However. when rats were dosed with either SK & F 29661 or 64139 over 24 h and the adrenal catecholamine stores were then radioactively labeled with a tracer dose of 3H-norepinephrine, the rate of 3H-norepinephrine disappearance was reduced in the SK & F 64139-treated animals as compared with those given SK & F 29661. A similar result was observed in the heart. These results suggest that SK & F 64139 may reduce norepinephrine turnover in the adrenal gland and heart via an effect not related to peripheral PNMT inhibition. These findings also demonstrate quite clearly that in intact animals all PNMT inhibitors do not produce identical endogenous catecholamine profiles.

Adrenal Glands↗
PubMed1980

The blockade of alpha 2-adrenoceptors by the PNMT inhibitaor SK&F 64139.

Three tetrahydroisoquinolines were tested for activity on central alpha 2-adrenoceptors by determining their ability to inhibit [3H]clonidine binding to rat cerebral cortical membrane homogenates. The compounds included the PNMT inhibitors SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) and SK&F 29661 (1,2,3,4-tetrahydroisoquinoline 7-sulfonamide) as well as SK&F 72223 (5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline) a structural analogue inactive as a PNMT inhibitor. SK&F 64139 and SK&F 72223 but not SK&F 29661 inhibited [3H]clonidine binding. Studies in the isolated guinea pig atrium confirmed that SK&F 64139 and SK&F 72223 are alpha 2-adrenoceptor antagonists.

Adrenergic alpha-Antagonists↗
PubMed1980

The effects of PNMT inhibitors upon cardiovascular changes induced by hemorrhage in the rat.

Rapid bleeding in normotensive Sprague-Dawley rats produces a marked fall in arterial blood pressure and a profound decrease in heart rate. The bradycardia, which is abolished by vagotomy and partially antagonized by atropine, was significantly prolonged by pretreatment with SK&F 64139, a potent in vivo inhibitor of peripheral and central (CNS) phenylethanolamine N-methyltransferase (PNMT). This effect of the drug was accompanied by a prolonged hypotensive period and was not seen with SK&F 29661, a selective inhibitor of peripheral (adrenal) PNMT or with SK&F 72223, a structural analog of SK&F 64139 which has no effect on PNMT. These data suggest that the effects of SK&F 64139 are a result of inhibition of central PNMT and that epinephrine may function as a central neurotransmitter mediating cardiovascular responses to hemorrhage, at least under the conditions of these studies.

Adrenal Medulla↗
PubMed1980

Studies on lung N-methyltransferases, a pharmacological approach.

Phenylethanolamine N-methyltransferase (PNMT) was identified as the primary, high affinity N-methylating enzyme for phenylethanolamine (PEA) in rat, dog and Rhesus monkey lung. Human and rabbit lung, however, do not contain this enzyme but possess a more non-specific or general N-methyltransferase with a relatively low affinity for PEA and for which beta-phenethylamine (beta-PE) is also a substrate. The former but not the latter enzyme is markedly inhibited by micromolar concentrations of the PNMT antagonist, SK & F 64139. This evidence indicates that certain species differences exist for the enzyme system(s) available for the N-methylation of phenethylamine-type compounds in pulmonary tissue.

Animals↗
PubMed1980

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.

In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.

Adrenal Glands↗
PubMed1980

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 2. 1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides.

1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides (1-14) related to 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (21,SK&F 29661) were prepared and studied for their ability to inhibit phenylethanolamine N-methyltransferase (PNMT) in vitro. The choice of substituents on the 7-phenyl group of the sulfonanilides was based on the Topliss approach to structure-activity relationship studies. Information about the importance of an acidic hydrogen atom on the sulfonamide nitrogen atom was obtained from the preparation and testing of a tertiary N-methylsulfonanilide (15). Other THIQ's (1,2,3,4-tetrahydroisoquinolines) containing sulfur substituents in the 7 position were prepared and tested and consisted of 7-N-benzyl and 7-N-phenethyl derivatives of SK&F 29661 (16-18) and 7-(phenacylthio)-and 7-(phenacylsulfonyl)-THIQ (19 and 20). The two most potent inhibitors were the 7-p-bromo- and -chlorosulfonanilides, 2 and 6. However, neither was an effective inhibitor of norepinephrine to epinephrine conversion when tested in an in vivo mouse assay at unit doses of 25 or 100 mg/kg.

Adrenal Glands↗
PubMed1980

Studies on the putative anticholinergic effects of desmethylimipramine.

Desmethylimipramine (DMI) and atropine were compared in a variety of organ system tests in rats and mice involving muscarinic receptor function in order to assess the anticholinergic-like activity of this tricyclic antidepressant drug. DMI was similar to atropine in maximally inhibiting basal gastric acid secretion and markedly protecting against restraint-induced stomach ulceration. It did not, however, substantially increase pupil size, reduce fecal pellet output, inhibit cholinergically induced salivation or specifically antagonize the CNS effects of carbachol and oxotremorine as did atropine. From these data and previous work indicating that DMI acts at a site in the central nervous system to inhibit gastric acid secretion, it is concluded that the biological effects of this drug are not mediated through an atropine-like mechanism.

Animals↗
PubMed1979

Studies with a PNMT inhibitor.

DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N-methyltransferase (PNMT). In animal studies, a plasma level of 0.35 microgram/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single-dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 microgram/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.

Adrenal Glands↗
PubMed1979

Effects of ring substitution on the pre- and postjunctional alpha-adrenergic activity of aryliminoimidazolidines.

The pre- and postjunctional alpha-adrenergic agonist potency of a series of aryliminoimidazolidines was determined in the isolated rabbit ear artery. This series included clonidine, an antihypertensive agent thought to act by stimulating brainstem alpha-receptors and known to be a preferentially prejunctional alpha-adrenergic agonist. Although all of the compounds acted preferentially on the prejunctional alpha-adrenoceptor, ring substitution had a dramatic effect on both potency and the degree of selectivity. 2-(3,4-Dihydroxyphenylimino) imidazolidine was both the most potent and most selective prejunctional alpha-agonist in this series.

Adrenergic alpha-Agonists↗
PubMed1979

Studies on SK&F 29661, an organ-specific inhibitor of phenylethanolamine N-methyltransferase.

SK&F 29661 is an effective, reversible inhibitor of both central nervous system and adrenal phenylethanolamine N-methyl-transferase in vitro; its Ki values in our standard assay systems were 6 X 10(-7) M (central nervous system) and 3 X 10(-7) M (adrenal), respectively. In vivo, the drug inhibited the conversion of [3H]norepinephrine to [3H]epinephrine in the rat adrenal gland and upon chronic administration decreased the endogenous adrenal epinephrine/norepinephrine ratio in both the rat and squirrel monkey. SK&F 29661 did not, however, reduce rat brain stem PNMT activity after systemic administration; subsequent radioautographic studies indicated that the compound did not enter the central nervous system, presumably because of its high polarity. This drug may be useful in defining the physiological importance of peripheral phenylethanolamine N-methyltransferase inhibition.

Adrenal Glands↗
PubMed1978

Studies on renal dopamine receptors with a new agonist.

SK & F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) is a new dopamine receptor agonist which selectively increased renal blood flow when administered i.v. to dogs at cumulative doses of 3.3-1333 microgram/kg. Consistent changes in arterial blood pressure heart rate and cardiac output were not observed. The renal response, which was mediated locally in the kidney, was not antagonized by adequate blocking doses of atropine, propranolol, metiamide and/or mepyramine nor by reserpinization or treatment with indomethacin. It was inhibited, however, by the selective peripheral dopamine receptor antagonist, bulbocapnine. Perhaps as a result of its action on renal blood flow, SK & F 38393 produced a diuresis in normally hydrated rats which was characterized by an increased excretion of sodium, potassium and chloride and a increased urinary pH. Compounds of this type may be useful in better defining dopaminergic receptors and in the treatment of disease states where renal ischemia is present.

Animals↗
PubMed1978

Studies on the distribution of phenylethanolamine N-methyltransferase and epinephrine in the rat.

Using two independent criteria, we have found the enzyme phenylethanolamine N-methyltransferase (PNMT) to be present in the adrenals, lungs, brain stem, spleen, heart and skeletal muscle of the rat. The lungs contained more activity than the brain stem or any other extra-adrenal organ. PNMT was not detectable, however, in the kidneys, stomach, liver and plasma. Trace amounts of epinephrine were found in brain stem, lung and heart; norepinephrine, however, was the predominant catecholamine in these tissues. Substantial quantities of epinephrine were found in the adrenal and plasma of decapitated animals, but the latter were essentially eliminated by adrenal demedullation. Our data indicate that although the adrenal is the principal tissue source of epinephrine and PNMT in the rat, small amounts of both substances are present in several body organs.

Adrenal Medulla↗
PubMed1977

Studies on the characterization and inhibition of rat brain phenylethanolamine N-methyltransferase.

The existence of phenylethanolamine N-methyltransferase (PNMT) activity in the rat brain and spinal cord was confirmed using both substrate specificity and selective inhibitors of the adrenal enzyme as biochemical tools. The enzyme was not generally localized throughout the central nervous system but was found primarily in the brain stem and spinal cord with lesser amounts occurring in the midbrain. No significant PNMT activity was found in markedly inhibited both in vitro and in vivo by low concentrations (doses) of SK&F 64139, a potent inhibitor of the adrenal enzyme.

Adrenal Glands↗
PubMed1977

The effects of an inhibitor of phenylethanolamine N-methyltransferase upon stimulated adrenal catecholamine release and excretion in the rat.

SK&F 64139, an inhibitor of adrenal phenylethanolamine N-methyltransferase (PNMT), was found to significantly decrease 2-deoxy-D-glucose (2-DG) induced epinephrine excretion in the conscious rat under conditions where the former agent was administered chromically at 50 and 200 mg/kg/day over a 12-day period and 2-DG was administered after 3, 7 and 11 days of treatment. The reduced epinephrine output caused by SK&F 64139 in response to 2-DG was accompanied by an increased norepinephrine excretion pattern at 200 mg/kg/day of the compound. The reductions in epinephrine excretion were also associated with significant decreases in adrenal epinephrine and increases in the norepinephrine content.

Adrenal Glands↗
PubMed1977

The effect of phenylethanolamine n-methyltransferase concentration and species difference on the inhibitory potency of SK&F 64139.

We have found that the potency of SK&F 64139 in inhibiting rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) is a function of protein concentration when high concentrations of the latter are employed. At lower enzyme levels, however, the degree of inhibition produced by the drug becomes independent of PNMT, allowing for the proper calculation of an inhibition constant. The Ki for the compound under these circumstances was 3 nM. Inhibitor dissociation constants within the same order of magnitude were subsequently obtained using the adrenal enzyme obtained from the rat, cow, dog, human and squirrel monkey. These data provide evidence that the PNMT receptor sites for SK&F 64139 do not differ substantially from species to species and suggest the general utility of this drug as an inhibitor of adrenal epinephrine biosynthesis.

Adrenal Glands↗
PubMed1977

Epinephrine and recovery from punishment.

Motor activity of adrenal demedullated and sham-operated rats was suppressed by punishing footshocks. In subsequent no-punishment sessions, the demedullates more rapidly recovered normal spontaneous activity levels. Only the rate of recovery differentiated demedullates from shams: they were equally suppressed on the day of punishment and at the beginning of the first no-punishment session. Further, spontaneous activity levels were the same in demedullates and shams which were not punished. Administration of epinephrine to the punished demedullates prevented the more rapid recovery. In intact rats, dl-propranolol and SK&F 64139 (7,8-dichloro-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride), an inhibitor of adrenal phenylethanolamine N-methyltransferase, affects recovery in the same way as demedullation. Neither phenoxybenzamine nor d-propranolol had this effect. These results suggest that epinephrine is important in modulating behavioral adaptation to aversive experiences.

Adrenal Glands↗