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Elucidation of the profound antagonism of contractile action of phenylephrine in rat aorta effected by an atypical sympathomimetic decongestant

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2017
2991.pdf (1.189Mb)
Authors
Rizvić, Eldina
Janković, Goran
Savić, Miroslav
Article (Published version)
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Abstract
Vasoconstrictive properties of sympathomimetic drugs are the basis of their widespread use as decongestants and possible source of adverse responses. Insufficiently substantiated practice of combining decongestants in some marketed preparations, such are those containing phenylephrine and lerimazoline, may affect the overall contractile activity, and thus their therapeutic utility. This study aimed to examine the interaction between lerimazoline and phenylephrine in isolated rat aortic rings, and also to assess the substrate of the obtained lerimazoline-induced attenuation of phenylephrine contraction. Namely, while lower concentrations of lerimazoline (10(-6) M and especially 10(-7) M) expectedly tended to potentiate the phenylephrine-induced contractions, lerimazoline in higher concentrations (10(-4) M and above) unexpectedly and profoundly depleted the phenylephrine concentration-response curve. Suppression of NO with NO synthase (NOS) inhibitor N-W-nitro-L-arginine methyl ester (L-...NAME; 10(-4)M) or NO scavanger OHB12 (10(-3)M), as well as non-specific inhibition of K+-channels with tetraethylammonium (TEA; 10(-3) M), have reversed lerimazoline-induced relaxation of phenylephrine contractions, while cyclooxygenase inhibitor indomethacin (10(-5) M) did not affect the interaction between two vasoconstrictors. At the receptor level, non-selective 5-HT receptor antagonist methiothepin reversed the attenuating effect of lerimazoline on phenylephrine contraction when applied at 3x10(-7) and 10(-6) M, but not at the highest concentration (10(-4) M). Neither the 5-HT1D-receptor selective antagonist BRL 15572 (10(-6) M) nor 5-HT7 receptor selective antagonist SB 269970 (10(-6) M) affected the lerimazoline-induced attenuation of phenylephrine activity. The mechanism of lerimazoline-induced suppression of phenylephrine contractions may involve potentiation of activity of NO and K+-channels and activation of some methiothepin-sensitive receptors, possibly of the 5-HT2B subtype.

Keywords:
Aorta / Decongestant / Lerimazoline / Phenylephrine / Potentiation
Source:
Korean Journal of Physiology & Pharmacology, 2017, 21, 4, 385-395
Publisher:
  • Korean Journal Of Physiology & Pharmacology, Seoul
Funding / projects:
  • Behavioral ?ffects following repeated administration of newly synthesized ligands selective for distinct subtypes of GABAA receptor benzodiazepine binding site: comparison with standard psychopharmacologic drugs (RS-175076)

DOI: 10.4196/kjpp.2017.21.4.385

ISSN: 1226-4512

PubMed: 28706452

WoS: 000404694000004

Scopus: 2-s2.0-85023779050
[ Google Scholar ]
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2
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/2993
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Rizvić, Eldina
AU  - Janković, Goran
AU  - Savić, Miroslav
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2993
AB  - Vasoconstrictive properties of sympathomimetic drugs are the basis of their widespread use as decongestants and possible source of adverse responses. Insufficiently substantiated practice of combining decongestants in some marketed preparations, such are those containing phenylephrine and lerimazoline, may affect the overall contractile activity, and thus their therapeutic utility. This study aimed to examine the interaction between lerimazoline and phenylephrine in isolated rat aortic rings, and also to assess the substrate of the obtained lerimazoline-induced attenuation of phenylephrine contraction. Namely, while lower concentrations of lerimazoline (10(-6) M and especially 10(-7) M) expectedly tended to potentiate the phenylephrine-induced contractions, lerimazoline in higher concentrations (10(-4) M and above) unexpectedly and profoundly depleted the phenylephrine concentration-response curve. Suppression of NO with NO synthase (NOS) inhibitor N-W-nitro-L-arginine methyl ester (L-NAME; 10(-4)M) or NO scavanger OHB12 (10(-3)M), as well as non-specific inhibition of K+-channels with tetraethylammonium (TEA; 10(-3) M), have reversed lerimazoline-induced relaxation of phenylephrine contractions, while cyclooxygenase inhibitor indomethacin (10(-5) M) did not affect the interaction between two vasoconstrictors. At the receptor level, non-selective 5-HT receptor antagonist methiothepin reversed the attenuating effect of lerimazoline on phenylephrine contraction when applied at 3x10(-7) and 10(-6) M, but not at the highest concentration (10(-4) M). Neither the 5-HT1D-receptor selective antagonist BRL 15572 (10(-6) M) nor 5-HT7 receptor selective antagonist SB 269970 (10(-6) M) affected the lerimazoline-induced attenuation of phenylephrine activity. The mechanism of lerimazoline-induced suppression of phenylephrine contractions may involve potentiation of activity of NO and K+-channels and activation of some methiothepin-sensitive receptors, possibly of the 5-HT2B subtype.
PB  - Korean Journal Of Physiology & Pharmacology, Seoul
T2  - Korean Journal of Physiology & Pharmacology
T1  - Elucidation of the profound antagonism of contractile action of phenylephrine in rat aorta effected by an atypical sympathomimetic decongestant
VL  - 21
IS  - 4
SP  - 385
EP  - 395
DO  - 10.4196/kjpp.2017.21.4.385
ER  - 
@article{
author = "Rizvić, Eldina and Janković, Goran and Savić, Miroslav",
year = "2017",
abstract = "Vasoconstrictive properties of sympathomimetic drugs are the basis of their widespread use as decongestants and possible source of adverse responses. Insufficiently substantiated practice of combining decongestants in some marketed preparations, such are those containing phenylephrine and lerimazoline, may affect the overall contractile activity, and thus their therapeutic utility. This study aimed to examine the interaction between lerimazoline and phenylephrine in isolated rat aortic rings, and also to assess the substrate of the obtained lerimazoline-induced attenuation of phenylephrine contraction. Namely, while lower concentrations of lerimazoline (10(-6) M and especially 10(-7) M) expectedly tended to potentiate the phenylephrine-induced contractions, lerimazoline in higher concentrations (10(-4) M and above) unexpectedly and profoundly depleted the phenylephrine concentration-response curve. Suppression of NO with NO synthase (NOS) inhibitor N-W-nitro-L-arginine methyl ester (L-NAME; 10(-4)M) or NO scavanger OHB12 (10(-3)M), as well as non-specific inhibition of K+-channels with tetraethylammonium (TEA; 10(-3) M), have reversed lerimazoline-induced relaxation of phenylephrine contractions, while cyclooxygenase inhibitor indomethacin (10(-5) M) did not affect the interaction between two vasoconstrictors. At the receptor level, non-selective 5-HT receptor antagonist methiothepin reversed the attenuating effect of lerimazoline on phenylephrine contraction when applied at 3x10(-7) and 10(-6) M, but not at the highest concentration (10(-4) M). Neither the 5-HT1D-receptor selective antagonist BRL 15572 (10(-6) M) nor 5-HT7 receptor selective antagonist SB 269970 (10(-6) M) affected the lerimazoline-induced attenuation of phenylephrine activity. The mechanism of lerimazoline-induced suppression of phenylephrine contractions may involve potentiation of activity of NO and K+-channels and activation of some methiothepin-sensitive receptors, possibly of the 5-HT2B subtype.",
publisher = "Korean Journal Of Physiology & Pharmacology, Seoul",
journal = "Korean Journal of Physiology & Pharmacology",
title = "Elucidation of the profound antagonism of contractile action of phenylephrine in rat aorta effected by an atypical sympathomimetic decongestant",
volume = "21",
number = "4",
pages = "385-395",
doi = "10.4196/kjpp.2017.21.4.385"
}
Rizvić, E., Janković, G.,& Savić, M.. (2017). Elucidation of the profound antagonism of contractile action of phenylephrine in rat aorta effected by an atypical sympathomimetic decongestant. in Korean Journal of Physiology & Pharmacology
Korean Journal Of Physiology & Pharmacology, Seoul., 21(4), 385-395.
https://doi.org/10.4196/kjpp.2017.21.4.385
Rizvić E, Janković G, Savić M. Elucidation of the profound antagonism of contractile action of phenylephrine in rat aorta effected by an atypical sympathomimetic decongestant. in Korean Journal of Physiology & Pharmacology. 2017;21(4):385-395.
doi:10.4196/kjpp.2017.21.4.385 .
Rizvić, Eldina, Janković, Goran, Savić, Miroslav, "Elucidation of the profound antagonism of contractile action of phenylephrine in rat aorta effected by an atypical sympathomimetic decongestant" in Korean Journal of Physiology & Pharmacology, 21, no. 4 (2017):385-395,
https://doi.org/10.4196/kjpp.2017.21.4.385 . .

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