Robert G. Pendleton

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.

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

SummaryThe pre- and postjunctional α-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 α-receptors and known to be a preferentially prejunctional α-adrenergic agonist. Although all of the compounds acted preferentially on the prejunctional α-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 α-agonist in this series.

Effect of metoclopramide, bethanechol and the cholecystokinin receptor antagonist, L-364,718, on gastric emptying in the rat

The prokinetic effects of metoclopramide, bethanechol and L-364,718 on a semisolid meal and solid pellet gastric emptying were evaluated and compared. Each compound increased the rate of meal emptying as measured 90 min post-dose. L-364,718, a non-peptide CCK antagonist, was the most potent of these three agents with statistically significant activity observed at 0.03, 0.1 and 0.3 mg/kg p.o. Only metoclopramide significantly enhanced pellet emptying in a dose-dependent manner (3-30 mg/kg p.o.). The effects of each test agent and the potential physiologic role of cholecystokinin in regulating gastric emptying are discussed.Abstract The prokinetic effects of metociopramide, beihanechol and L-364,718 on a semisolid meal and solid pellet gastric emptying were evaluated and compared. Each compound increased the rate of meal emptying as measured 90 min post-dose, L-364,718, a non-peptide CCK antagonist, was the most potent of these three agents with statistically significant activity observed at 0.03, 0.1 and 0.3 mg/kg p.o. Only metoclopramide significantly enhanced emptying in a dose-dependent manner (3–30 mg/kg p.o.). The effects of each test agent and the potential physiologic role of cholecystokinin in regulating gastric emptying are discussed.

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

SummaryThe 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 the cerebellum or forebrain. The central enzyme was markedly inhibited both in vitro and in vivo by low concentrations (doses) of SK&F 64139, a potent inhibitor of the adrenal enzyme.

Comparison of central and peripheral alpha1-adrenoceptors

SummaryA series of alpha-adrenergic agonists and antagonists having diverse chemical structure was examined for both central and peripheral alpha1-adrenoceptor activity. The agonists tested included several novel aminotetralin derivatives which were potent and selective alpha1-agonists. Peripheral alpha1-activity was determined in the isolated rabbit ear artery; central alpha1-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 alpha1-activity and central alpha1-affinity was obtained, providing that partial agonists were excluded. Likewise, the receptor dissociation constant for blockade of the peripheral alpha1-adrenoceptor correlated well with affinity for the central receptor for all of the alphaantagonists. These data support the conclusion that central and peripheral alpha1-adrenoceptors are similar or identical.

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.

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.

Effect of bulbocapnine as a peripheral dopamine receptor antagonists in the anesthetized cat.

SummaryWe have found bulbocapnine to be an effective, apparently competitive inhibitor of dopamine depressor responses in the anesthetized, phenoxybenzamine-treated cat. The duration of action of the compound as a dopaminergic antagonist exceeded 3 hrs after an intravenous dose of 8 mg/kg. In the same preparation, however, bulbocapnine did not at all inhibit the depressor responses to acetylcholine, histamine and isoproterenol, indicating a selectivity of action. Although administration of a high dose of propranolol (2 mg/kg, i.v.) did not alter the response of the alpha-receptor blocked cat to dopamine, the subsequent infusion of bulbocapnine remained effective. These results suggest that dopamine is acting as a blood pressure depressor agent via a unique receptor mechanism.

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.

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

SummarySK&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 chronically 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.