Effect of aromatic fluorine substitution on the alpha and beta adrenoceptor-mediated effects of 3,4-dihydroxytolazoline in the pithed rat

A. J. Nichols, A. Hamada, A. Adejare, Duane Miller, P. N. Patil, R. R. Ruffolo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The alpha and beta adrenoceptor-mediated effects of the catecholimidazoline, 3,4-dihydroxytolazoline, and its 2-, 5- and 6-aromatic fluorine-substituted derivatives have been studied in the cardiovascular system of the pithed rat. All four compounds produced vasopressor responses in beta adrenoceptor blocked (propranolol, 3 mg/kg i.v.) animals. The pressor responses produced by all four compounds were antagonized by the selective alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and were relatively unaffected by the selective alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.), indicating that vasoconstriction produced by the fluorinated imidazolines was mediated exclusively by postjunctional vascular alpha-1 adrenoceptors. The rank order of potency at the alpha-1 adrenoceptor was: 5-fluoro > 2-fluoro > desfluoro > 6-fluoro. At higher doses, 3,4-dihydroxytolazoline and its fluorinated derivatives produced an alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in animals pretreated with prazosin, with all four compounds being equipotent. In rats with complete alpha adrenoceptor blockade [phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.)] whose blood pressure was elevated by constant infusion of angiotensin II (150 ng/kg/min i.v.), high doses of the 2-fluoro, but not the 5-, 6- or desfluoro catecholimidazoline derivatives, produced a beta-2 adrenoceptor-mediated vasodepressor response. All four compounds produced a beta-1 adrenoceptor-mediated positive chronotropic response in pithed rats with the rank order of potency being: 2-fluoro = 5-fluoro > desfluoro > 6-fluoro. With regard to activity at beta adrenoceptors, the 2-fluoro derivative was more potent at beta-2 than at beta-1 adrenoceptors. We conclude that aromatic fluorination of imidazolines has differential effects on agonist activity at alpha-1, alpha-2, beta-1 and beta-2 adrenoceptors. These effects are qualitatively and quantitively different from those produced by aromatic fluorine substitution of phenethylamines, and thus support our previous hypothesis which suggests that imidazolines interact with alpha adrenoceptors in a manner that is different from that of the phenethylamines. Furthermore, these data suggest that imidazolines and phenethylamines may also interact differently with beta adrenoceptors.

Original languageEnglish (US)
Pages (from-to)671-676
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume248
Issue number2
StatePublished - Jan 1 1989

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Fluorine
Adrenergic Receptors
Imidazolines
Phenethylamines
Prazosin
Yohimbine
Phenoxybenzamine
Halogenation
Cardiovascular System
Vasoconstriction
Tachycardia
Propranolol
Angiotensin II
Blood Vessels

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Effect of aromatic fluorine substitution on the alpha and beta adrenoceptor-mediated effects of 3,4-dihydroxytolazoline in the pithed rat. / Nichols, A. J.; Hamada, A.; Adejare, A.; Miller, Duane; Patil, P. N.; Ruffolo, R. R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 248, No. 2, 01.01.1989, p. 671-676.

Research output: Contribution to journalArticle

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