Effects ofdl-norephedrine and its enantiomers on norepinephrine uptake and release in isolated rat caudal artery

Hricik, Joseph G.; Johnson, David A.

doi:10.1016/s0165-1838(96)00084-7

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…PPA is not known to release NE from nerve terminals, but PPA contractions are enhanced by ascorbate. PPA does decrease reuptake of NE at nerve terminals (10), suggesting that decreased NE uptake may be the mechanism for ascorbate enhancement of PPA contractions. This is unlikely, because no exogenous NE is present during the PPA experiments.…”

Section: Discussionmentioning

confidence: 94%

Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth muscle

Dillon

Root‐Bernstein

Lieder

2004

American Journal of Physiology-Heart and Circulatory Physiology

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Ascorbate reduces the oxidation rate of catecholamines and, by an independent mechanism, enhances rabbit aortic ring contractions initiated by catecholamines. The largest significantly different fractional increases in force produced by ascorbate enhancement of norepinephrine (NE), epinephrine, phenylpropanolamine (PPA), and ephedrine (Eph) are 5.5, 1.8, 1.6, and 1.3 times, respectively. In physiological salt solutions bubbled with 95% O(2) at 37 degrees C, NE, PPA, and Eph have oxidation rate constants of 1.24, 247, and 643 h, respectively. Ascorbate significantly enhances 100 nM NE contractions by at least twofold at all ascorbate concentrations >15 microM, including the entire physiological range of 40-100 microM. Ascorbate preloading and washout followed by NE exposure produces significantly greater contractions than NE without ascorbate preloading but significantly lower than NE simultaneously with ascorbate. Ascorbate does not enhance K(+)- or angiotensin II-induced contractions. Ascorbate enhancement of catecholamine contractions occurs in addition to the reduction in oxidation rate, because the increases in force occur faster than oxidation can occur, the increases occur with compounds that have negligible oxidation rates, and the increases occur when ascorbate and NE are not physically present together. These results are consistent with ascorbate acting on the adrenergic receptor. Ascorbate may play a role in shock and asthma treatments and potentiate the cardiovascular health consequences of PPA and Eph (Ephedra).

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Section: Discussionmentioning

confidence: 94%

Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth muscle

Dillon

Root‐Bernstein

Lieder

2004

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Introductionmentioning

confidence: 99%

“…However, subsequent studies demonstrated that the cardiovascular effects of phenylpropanolamine result from direct activation of adrenoceptors (e.g., Moya-Huff and Maher, 1987;Hricik and Johnson, 1996). Phenylpropanolamine can inhibit the neuronal uptake of norepinephrine, although this property plays only a minor role in its cardiovascular effects (Hricik and Johnson, 1996). Phenylpropanolamine binds to all three subtypes of ␣ 1 -adrenoceptors (␣ 1A , ␣ 1B , and ␣ 1D ) with relatively low affinity (Buckner et al, 2002) and functions as a low-efficacy agonist at these receptors (Minneman et al, 1983;Minneman and Johnson, 1984;Fox et al, 1985;Alberts et al, 1999;Nishimatsu et al, 1999;Buckner et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Phenylpropanolamine Constricts Mouse and Human Blood Vessels by Preferentially Activating α2-Adrenoceptors

Flavahan¹

2004

J Pharmacol Exp Ther

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Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act on the sympathetic nervous system. Because of concerns regarding incidents of stroke, its use as a nasal decongestant was discontinued. Although considered an ␣ 1 -adrenergic agonist, the vascular adrenergic pharmacology of phenylpropanolamine was not fully characterized. Unlike most other circulations, the vasculature of the nasal mucosa is highly enriched with constrictor ␣ 2 -adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular ␣ 2 -adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective ␣ 1 -adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective ␣ 2 -adrenergic agonist UK14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] caused constriction in tail arteries and in human veins, but not mesenteric arteries. The lack of constriction to UK14,304 was also observed in endothelium-denuded mesenteric arteries. Phenylpropanolamine constricted both types of artery but was 62-fold more potent in tail arteries. In mesenteric arteries, constriction to phenylpropanolamine was not affected by the selective ␣ 2 -adrenergic antagonist, rauwolscine (10 Ϫ7 M) but was abolished by the selective ␣ 1 -adrenergic antagonist, prazosin (3 ϫ 10 Ϫ7 M). In contrast, constriction to phenylpropanolamine in tail arteries and in human veins was inhibited by rauwolscine but not prazosin. Therefore, phenylpropanolamine is a preferential ␣ 2 -adrenergic agonist. At low concentrations, it constricts blood vessels that express functional ␣ 2 -adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular ␣ 1 -adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act by modulating the sympathetic nervous system. First synthesized in 1912, phenylpropanolamine was introduced as a nasal decongestant in the 1930s (Lasanga, 1988). Its therapeutic use, therefore, predated major discoveries in sympathetic neurophysiology, including the identification of the neurotransmitter norepinephrine (von Euler, 1946, cited in Lasanga, 1988, and the concept of adrenoceptors (Ahlquist, 1948, cited in Lasanga, 1988. Because of concerns regarding episodes of stroke in individuals ingesting phenylpropanolamine, it was withdrawn as a therapeutic agent in 2000 (Kernan et al., 2000).An early report suggested that phenylpropanolamine may possess a cardiac-specific, indirect activity to release norepinephrine from sympathetic nerves (Trendelenburg et al., 1962). However, subsequent studies demonstrated that the cardiovascular effects of phenylpropanolamine result from direct activation of adrenoceptors (e.g., Moya-Huff and Maher, 1987...

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“…Pseudoephedrine (PSE) and phenylpropanolamine (PPA) are mixed-acting sympathomimetic amines that have been used commonly as decongestants in the treatment of coughs and colds. [10][11][12][13][14] The effectiveness of PSE and PPA as decongestants is specifically related to the activation of α-adrenergic receptors in the nasal mucosa, resulting in vasoconstriction, reduced blood flow, decreased mucosal edema, and, ultimately, improved nasal patency. 15,16 At mucosal sympathetic nerve endings, these agents directly stimulate adrenergic receptors (direct action) and displace norepinephrine from neuronal storage sites (indirect action).…”

mentioning

confidence: 99%

Evaluation of the Potential for Pharmacodynamic and Pharmacokinetic Drug Interactions Between Selegiline Transdermal System and Two Sympathomimetic Agents (Pseudoephedrine and Phenylpropanolamine) in Healthy Volunteers

Azzaro

VanDenBerg

Ziemniak

et al. 2007

The Journal of Clinical Pharma

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Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.

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Effects ofdl-norephedrine and its enantiomers on norepinephrine uptake and release in isolated rat caudal artery

Cited by 5 publications

References 12 publications

Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth muscle

Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth muscle

Phenylpropanolamine Constricts Mouse and Human Blood Vessels by Preferentially Activating α2-Adrenoceptors

Evaluation of the Potential for Pharmacodynamic and Pharmacokinetic Drug Interactions Between Selegiline Transdermal System and Two Sympathomimetic Agents (Pseudoephedrine and Phenylpropanolamine) in Healthy Volunteers

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