Korean J Physiol Pharmacol.  2017 Jul;21(4):385-395. 10.4196/kjpp.2017.21.4.385.

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

• Rizvić E
• Janković
• Savić MM

• KMID: 2384452
• DOI: http://doi.org/10.4196/kjpp.2017.21.4.385

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 3×10⁻⁷ 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-HT(2B) subtype.

Keyword

Aorta; Decongestant; Lerimazoline; Phenylephrine; Potentiation

MeSH Terms

Animals
Aorta*
Indomethacin
Methiothepin
Nasal Decongestants
Nitric Oxide Synthase
Phenylephrine*
Prostaglandin-Endoperoxide Synthases
Rats*
Relaxation
Serotonin
Sympathomimetics
Tetraethylammonium
Vasoconstrictor Agents
Indomethacin
Methiothepin
Nasal Decongestants
Nitric Oxide Synthase
Phenylephrine
Prostaglandin-Endoperoxide Synthases
Serotonin
Sympathomimetics
Tetraethylammonium
Vasoconstrictor Agents

Figure

• 

  Fig. 1 Comparison of the contractile effect of phenylephrine (n=12) and lerimazoline (n=12) on rat thoracic aorta. Data are shown as mean±S.E.M, expressed for phenylephrine as the percentage of maximum contraction induced by maximum dose of phenylephrine, and for lerimazoline as the percentage of maximum contraction induced by 10−4 M phenylephrine.

• 

  Fig. 2 Vascular responses to phenylephrine in blood vessels exposed to different concentrations of lerimazoline. (A) Concentration-response curves for phenylephrine in the absence (•, n=7) and in the presence of lerimazoline 2.1×10−3 M (∘, n=7). (B) Concentration–response curves for phenylephrine in the absence (•, n=10) and in the presence of lerimazoline 10−4 M (∘, n=10). (C) Concentration–response curves for phenylephrine in the absence (•, n=10) and in the presence of lerimazoline 10−6 M (∘, n=10). (D) Concentration–response curves for phenylephrine in the absence (•, n=9) and in the presence of lerimazoline 10−7 M (∘, n=9). Results (means±S.E.M) were expressed as percentages of the response to the 10−4 M phenylephrine. *p<0.05, **p<0.01 vs. the effect of the respective concentration of phenylephrine.

• 

  Fig. 3 Effects of L-NAME and OHB12 on the vasoconstrictor responses induced by phenylephrine and lerimazoline. (A) Effect of 10−4 M L-NAME on the phenylephrine concentration response curve in rings without 10−4 M lerimazoline. (B) Effect of 10−4 M L-NAME on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. (C) Effect of 10−3 M OHB12 on the phenylephrine concentration response curve in rings without 10−4 M lerimazoline. (D) Effect of 10−3 M OHB12 on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline.Results (means±S.E.M) were expressed as percentages of the response to the 10−4 M phenylephrine. *p<0.05, **p<0.01, ***p<0.001 vs. phenylephrine; #p<0.05, ##p<0.01, ###p<0.001 vs. phenylephrine plus lerimazoline.

• 

  Fig. 4 Effects of indomethacin and TEA on the vasoconstrictor responses induced by phenylephrine and lerimazoline. (A) Effect of 10−5 M indomethacin on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. (B) Effect of 10−3 M TEA on the phenylephrine concentration response curve in rings without 10−4 M lerimazoline. (C) Effect of 10−3 M TEA on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. Results (means±S.E.M) were expressed as percentages of the response to the 10−5 M phenylephrine. *p<0.05, **p<0.01, ***p<0.001 vs. phenylephrine; #p<0.05, ##p<0.01 vs. phenylephrine plus lerimazoline.

• 

  Fig. 5 Effects of methiothepin on the vasoconstrictor responses induced by phenylephrine and lerimazoline. (A) Effect of 10−4 M methiothepin on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. (B) Effect of 10−6 M methiothepin on the phenylephrine concentration response curve in rings without 10−4 M lerimazoline. (C) Effect of 10−6 M methiothepin on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. (D) Effect of 3×10−7 M methiothepin on the phenylephrine concentration response curve in rings without 10−4 M lerimazoline. (E) Effect of 3×10−7 M methiothepin on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. Results (means±S.E.M.) were expressed as percentages of the response to 10−4 M phenylephrine. *p<0.05, **p<0.01, ***p<0.001 vs. phenylephrine; #p<0.05, ##p<0.01 vs. phenylephrine plus lerimazoline.

• 

  Fig. 6 Effects of SB 269970 and BRL 15572 on the vasoconstrictor responses induced by phenyephrine and lerimazoline. (A) Effect of 10−6 M SB 269970 on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. (B) Effect of 10−6 M BRL 15572 on the phenylephrine concentration response curve in rings pretreated with 10−4 M lerimazoline. Results (means±S.E.M) were expressed as percentages of the response to 10−4 M phenylephrine. *p<0.05, **p<0.01, ***p<0.001 vs. phenylephrine; #p<0.05, ##p<0.01 vs. phenylephrine plus lerimazoline.

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