Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1323099 (sympathomimetic)
 2,957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have found that (R,S)-1-(phenylthio)-aminopropane (4a), a synthetic alternate substrate for the terminal enzyme of norepinephrine biosynthesis, dopamine beta-monooxygenase (DBM), is both an indirect sympathomimetic and a potent antihypertensive agent in spontaneously hypertensive rats. We demonstrate herein that there is a distinct enantiospecific difference in the activities of (R)-1-(phenylthio)-2-aminopropane (4b) and (S)-1-(phenylthio)-2-aminopropane (4c). We find that 4c, the more potent DBM substrate analogue, exhibits both the indirect sympathomimetic activity and the antihypertensive activity previously observed for the racemate and inhibits the active transport of catecholamines at the nerve terminal. In contrast, 4b, which is less potent as a DBM substrate or as an inhibitor of catecholamine uptake, does not exhibit an indirect sympathomimetic effect and is not an effective antihypertensive agent. These results suggest that the greater selectivity of the S enantiomer for both the catecholamine reuptake transporter and the target enzyme DBM accounts for its greater potency as an indirect-acting sympathomimetic agent as well as its activity as an antihypertensive agent. These results are also consistent with the hypothesized mechanism of action of this class of sulfur-containing DBM substrate analogues.
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PMID:The enantiomeric specificity of the antihypertensive activity of 1-(phenylthio)-2-aminopropane, a synthetic substrate analogue for dopamine beta-monooxygenase. 200 50

In previous work we established that phenyl-2-aminoethyl sulfide (PAES) and derivatives of this basic structure are novel substrate analogs for the adrenergic synthetic enzyme, dopamine beta-monooxygenase (DBM). We examined the in vivo effects of infusions of PAES and ring-hydroxylated (HOPAES) and/or alpha-methylated derivatives (MePAES, HOMePAES) and observed antihypertensive activity in SHR with HOPAES and HOMePAES using an indirect blood pressure measuring protocol. We now wish to report that by employing a direct blood pressure measuring technique we have been able to demonstrate a potent antihypertensive activity of all these derivatives in conscious, unrestrained spontaneously hypertensive rats (SHR) that persisted beyond a 6-h testing period. We found that MePAES, which displayed only a minor antihypertensive activity in the indirect measurements, was the most potent antihypertensive in the direct measuring protocol. In addition, in this report we demonstrate a potent chronic antihypertensive effect for MePAES over a 2-week period in SHR using continuous infusion with implanted osmotic pumps. From a comparison of the effects of the hydroxylated and alpha-methylated derivatives, we conclude that: (a) the locus of the antihypertensive activity is primarily in peripheral adrenergic sites; (b) alpha-methylation of the basic structure imparts an increased affinity for peripheral adrenergic uptake sites that may be responsible for its increased antihypertensive potency; and (c) monoamine oxidase (MAO) catabolism plays a relatively unimportant role in the termination of the activity of these compounds. These results also demonstrate the importance of direct blood pressure measurements in assaying antihypertensive activity of test compounds that possess indirect sympathomimetic activity. The implications of these findings in terms of the mechanism by which these compounds exert their anti-hypertensive activity is discussed.
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PMID:Demonstration of the potent antihypertensive activity of phenyl-2-aminoethyl sulfides. 245 35

In earlier work we have demonstrated that a novel series of phenylethylamine analogs (phenyl-2-aminoethyl sulfides) cause a potent antihypertensive effect in spontaneously hypertensive rats. In addition, we have shown in vitro that these compounds are facile substrates for dopamine beta-hydroxylase, the terminal enzyme of norepinephrine synthesis. While the mechanism of action of these derivatives is as yet hypothetical, we have proposed that, if they are capable of gaining entrance into adrenergic nerve endings and neurotransmitter storage vesicles, these compounds may reduce norepinephrine synthesis by competing with dopamine for oxygenation. In this report, we present results of preliminary studies designed to examine this hypothetical mechanism of action. We find that all derivatives of this series are classical indirect-acting sympathomimetics whose initial cardiovascular activity is blocked by cocaine. These results suggest that compounds of this type gain entrance to adrenergic neurons via the normal norepinephrine uptake mechanism on adrenergic nerve endings. We also present data which demonstrate that the methylated derivative was not only the most potent indirect-acting sympathomimetic, but also the only derivative capable of producing a marked tachyphylaxis. In addition, we find these compounds affect a specific pool of intraneuronal norepinephrine, distinct from that affected by tyramine, a well-known indirect-acting sympathomimetic agent.
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PMID:An investigation of the adrenergic uptake specificity of phenyl-2-aminoethyl sulfides. 324 25

Many of the physiologic consequences of weightlessness and the cardiovascular abnormalities on return from space could be due, at least in part, to alterations in the regulation of the autonomic nervous system. In this article, the authors review the rationale and evidence for an autonomic mediation of diverse changes that occur with spaceflight, including the anemia and hypovolemia of weightlessness and the tachycardia and orthostatic intolerance on return from space. This hypothesis is supported by studies of two groups of persons known to have low catecholamine levels: persons subjected to prolonged bedrest and persons with syndromes characterized by low circulating catecholamines (Bradbury-Eggleston syndrome and dopamine beta-hydroxylase deficiency). Both groups exhibit the symptoms mentioned. The increasing evidence that autonomic mechanisms underlie many of the physiologic consequences of weightlessness suggests that new pharmacologic approaches (such as administration of beta-blockers and/or sympathomimetic amines) based on these findings may attenuate these unwanted effects.
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PMID:The sympathetic nervous system and the physiologic consequences of spaceflight: a hypothesis. 804 55

Enteric neurotransmitters can modulate the biodefensive functions of the intestinal mucosa, but their role in mucosal interactions with enteropathogens is not well defined. Here we tested the hypothesis that norepinephrine (NE) modulates interactions between enterohemorrhagic Escherichia coli O157:H7 (EHEC) and the colonic epithelium. Mucosal sheets from porcine distal colon were mounted in Ussing chambers. Drugs and an inoculum of either Shiga toxin-negative or -positive EHEC were added to the contraluminal and luminal bathing medium, respectively. After 90 min, adherent bacteria were quantified by an adherence assay and by immunohistochemical methods; short-circuit current (I(sc)) was measured continuously to assess changes in active ion transport. NE-treated tissues exhibited concentration-dependent increases in I(sc) and EHEC adherence. NE did not alter adherence of a rodent-adapted, noninfectious E. coli strain or two porcine-adapted non-O157 E. coli strains. The actions of NE on EHEC adherence but not I(sc) were prevented by the alpha-adrenergic antagonist yohimbine and the PKA activator Sp-8-bromoadenosine-3',5'-cyclic monophosphorothioate. Like NE, the PKA inhibitor Rp-8-bromoadenosine-3',5'-cyclic monophosphorothioate or indirectly acting sympathomimetic agents increased EHEC adherence. Nerve fibers immunoreactive for the NE-synthesizing enzymes tyrosine hydroxylase and dopamine beta-hydroxylase appeared to innervate the colonic epithelium. EHEC-like immunoreactivity on the colonic surface had the appearance of bacterial microcolonies and increased after NE treatment by a phentolamine-sensitive mechanism. Through interactions with alpha(2)-adrenergic receptors, NE appears to increase EHEC adherence to the colonic mucosa. Changes in sympathetic neural outflow may alter intestinal susceptibility to infection.
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PMID:Adrenergic modulation of Escherichia coli O157:H7 adherence to the colonic mucosa. 1553 74