Skip to main content
SpringerLink
Log in

Pharmacological characterization of the imidazoline receptor which mediates inhibition of noradrenaline release in the rabbit pulmonary artery

  • Original articles
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

Imidazoline receptors involved in modulation of noradrenaline release were characterized in the rabbit pulmonary artery preincubated with [3H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Tritium overflow was evoked by transmural electrical stimulation.

The α2-adrenoceptor blocking imidazolines tolazoline, BDF 6100 [2-(2-imidazoline-2-ylamino)-isoindoline] and BDF 7572 (4,7-dichloro-derivative of BDF 6100) increased the electrically evoked 3H overflow; the concentration-response curves were bell-shaped. In contrast, two other imidazolines, i. e. moxonidine and clonidine, two guanidine derivatives structurally related to BDF 6100, i. e. aganodine and BDF 7579 [4-chloro(2-isoindolinel)-guanidine], as well as the catecholamine noradrenaline concentration-dependently inhibited the evoked 3H overflow. The concentration-response curves for moxonidine, clonidine, aganodine, BDF 7579 and noradrenaline were shifted to the right by rauwolscine. The apparent pA2 value of rauwolscine against moxonidine was 8.22, whereas those against clonidine, aganodine, BDF 7579 and noradrenaline were in the range of 6.37–6.77 and, hence, considerably lower than reported for α2-adrenoceptors. In the presence of rauwolscine an inhibitory effect was also observed with the α2-adrenoceptor blocking imidazolines tolazoline, BDF 6100, BDF 7572, and the imidazolineST 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazoline]; the rank order of potency of all guanidines and imidazolines investigated was: aganodine > BDF 7579 > BDF 7572 > BDF 6100 > clonidine > ST 587 > moxonidine > tolazoline. Amiloride, 1-benzylimidazole and histamine were ineffective. After irreversible blockade of α-adrenoceptors by preexposure to phenoxybenzamine, evoked 3H overflow was still inhibited by aganodine, BDF 7579 and noradrenaline. Under this condition the maximal effects obtainable with the guanidines and in particular with noradrenaline were lower than in the presence of rauwolscine.

These findings are compatible with our previous suggestion that imidazoline receptors mediating inhibition of noradrenaline release exist on the sympathetic nerve terminals of the rabbit pulmonary artery. Comparison of the present data with those obtained in other preparations containing imidazoline recognition sites revealed that those sites are different from the present ones. It is conceivable that the receptor characterized here represents an allosteric site of the α2-adrenoceptor or a so far undescribed α-adrenoceptor subtype since it can be activated not only by imidazolines and guanidines but also by noradrenaline and can be blocked by rauwolscine. Comparison of the properties of isoindolines substituted with either aminoimidazoline or guanidine reveals that the imidazolines (e.g. BDF 7572) possess both α2-adrenoceptor antagonistic and imidazoline receptor agonistic properties, whereas the analogous guanidines (e. g. aganodine) are imidazoline receptor agonists as well as α2-adrenoceptor agonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Armah IB (1985) Aganodine (BDF 7570) a novel peripherally active alpha-2-agonist with a preferential venous site of action. Naunyn-Schmiedeberg's Arch Pharmacol 329 [Suppl]:R80

    Google Scholar 

  • Armah IB (1988) Unique presynaptic α2-receptor selectivity and specifity of the antihypertensive agent moxonidine. Drug Res 10:1435–1442

    Google Scholar 

  • Armah IB, Molderings GJ, Göthert M (1990) Effect of temperature on α2- and α1-adrenoceptor-mediated responses in the pithed rat and in the rat vena cava. J Autonom Pharmac 10:249–260

    Google Scholar 

  • Borowski E, Starke K, Ehrl H, Endo T (1977) A comparison of pre- and postsynaptic effects of α-adrenolytic drugs in the pulmonary artery of the rabbit. Neuroscience 2:285–296

    Google Scholar 

  • Bousquet P, Feldman J, Schwartz J (1984) Central cardiovascular effects of alpha adrenergic drugs: differences between catecholamines and imidazolines. J Pharmacol Exp Ther 230:232–236

    Google Scholar 

  • Coupry I, Atlas D, Podevin RA, Uzielli I, Parini A (1990) Imidazolineguanidinium receptive site in renal proximal tubule: asymetric distribution, regulation by cations and interaction with endogenous clonidine displacing substance. J Pharmacol Exp Ther 252:293–299

    Google Scholar 

  • Daly CJ, McGrath JC, Wilson VG (1988) Pharmacological analysis of postjunctional α-adrenoceptors mediating contractions to (−)-noradrenaline in the rabbit isolated lateral saphenous vein can be explained by interacting responses to simultaneous activation of α-1 and α2-adrenoceptors. Br J Pharmacol 95:485–500

    Google Scholar 

  • Docherty JR, Göthert M, Dieckhöfer C, Starke K (1982) Effects of 4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline hydrochloride (BE 6143) at pre- and postsynaptic a-adrenoceptors in rabbit aorta and pulmonary artery. Arzneimittelforschung 32:1534–1540

    Google Scholar 

  • Ernsberger P (1990) Moxonidine, a second-generation centrally-acting antihypertensive, binds selectively to imidazole sites in the ventrolateral medulla (VLM) and kidney. The Pharmacologist 32:191 (abstr)

    Google Scholar 

  • Ernsberger P, Meeley MP, Mann JJ, Reis DJ (1987) Clonidine binds to imidazole binding sites as well as α2-adrenoceptors in the ventrolateral medulla. Eur J Pharmacol 134:1–13

    Google Scholar 

  • Ernsberger P, Giuliano R, Willette RN, Reis DJ (1980) Role of imidazole receptors in the vasodepressor response to clonidine analogs in the rostral ventrolateral medulla. J Pharmacol Exp Ther 253: 408–418

    Google Scholar 

  • Feldman J, Tibrica E, Bricca G, Dontenwill M, Belcourt A, Bousquet P (1990) Evidence for the involvement of imidazoline receptors in the central hypotensive effect of rilmenidine in the rabbit. Br J Pharmacol 100:600–604

    Google Scholar 

  • Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muscholl E (eds) Handbook of experimental pharmacology. Catecholamines, vol XXXIII. Springer, Berlin Heidelberg New York, pp 283–335

    Google Scholar 

  • Gomez R, Ernsberger P, Feinland G, Reis DJ (1990) Rilmenidine acts upon imidazole receptors in the rostral ventrolateral medulla to elicit hypotension and bradycardia. Eur J Pharmacol 183:168–169

    Google Scholar 

  • Göthert M, Hentrich F (1984) Inhibition of α-adrenoceptor-blocking imidazoline derivatives of noradrenaline release in rabbit pulmonary artery. In: Abstract Book of the 9th International Congress of Pharmacology. MacMillan, London (abstr no 370P)

    Google Scholar 

  • Göthert M, Schlicker E, Hentrich F, Zerkowski HR (1984) Modulation of noradrenaline release in human saphenous vein via presynaptic α2-adrenoceptors. Eur J Pharmacol 102:261–267

    Google Scholar 

  • Göthert M, Kollecker P (1986) Subendothelial β2-adrenoceptors in the rat vena cava. Facilitation of noradrenaline release via local stimulation of angiotensin II synthesis. Naunyn-Schmiedeberg's Arch Pharmacol 334:156–165

    Google Scholar 

  • Göthert M, Molderings GJ (1991) Involvement of presynaptic imidazoline receptors in the α2-adrenoceptor-independent inhibition of noradrenaline release by imidazoline derivatives. Naunyn-Schmiedeberg's Arch Pharmacol 343:271–282

    Google Scholar 

  • Hamilton CA, Reid JL, Yakubu MA (1988) [3H]Yohimbine and [3H]idazoxan bind to different sites on rabbit forebrain and kidney membranes. Eur J Pharmacol 146:345–348

    Google Scholar 

  • Hentrich F, Göthert M, Greschuchna D (1986) Noradrenaline release in the human pulmonary artery is modulated by presynaptic α2-adrenoceptors. J Cardiovasc Pharmacol 8:539–544

    Google Scholar 

  • Lachaud-Pettiti V, Podevin RA, Chretien Y, Parini A (1991) Imidazoline-guanidinium and α2-adrenergic binding sites in basolateral membranes from human kidney. Eur J Pharmacol — Mol Pharmacol Sect 206:23–31

    Google Scholar 

  • Langer SZ (1977) Presynaptic receptors and their role in the regulation of transmitter release. Br J Pharmacol 60:481–497

    Google Scholar 

  • Langer SZ (1981) Presynaptic regulation of the release of catecholamines. Pharmacol Rev 32:337–362

    Google Scholar 

  • Langin D, Lafontan M (1989) [3H]idazoxan binding at non-α2-adrenoceptors in rabbit adipocyte membranes. Eur J Pharmacol 159:199–203

    Google Scholar 

  • Langin D, Paris H, Lafontan M (1990a) Binding of [3H]idazoxan and of its methoxy derivative [3H]RX821002 in human fat cells: [3H]idazoxan but not [3H]RX821002 labels additional non-α2-adrenergic binding sites. Mol Pharmacol 37:876–885

    Google Scholar 

  • Langin D, Paris H, Dauzats M, Lafontan M (1990b) Discrimination between α2-adrenoceptors and [3H]idazoxan-labelled non-adrenergic sites in rabbit white fat cells. Eur J Pharmacol — Mol Sect 188:261–272

    Google Scholar 

  • Lattimer N, Rhodes KF (1985) A difference in the affinity of some selective α2-adrenoceptor antagonists when compared on isolated vasa deferentia of rat and rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 329:278–281

    Google Scholar 

  • Limberger N, Hölting T, Starke K (1987) Protection of presynaptic α-adrenoceptors against irreversible blockade by phenoxybenzamine: preservation of the modulatory effects of exogenous noradrenaline and yohimbine. Naunyn-Schmiedeberg's Arch Pharmacol 336: 155–160

    Google Scholar 

  • Limberger N, Mayer A, Zier G, Valenta B, Starke K, Singer EA (1989) Estimation of pA2 values at presynaptic α2-autoreceptors in rabbit and rat brain cortex in the absence of autoinhibition. Naunyn-Schmiedeberg's Arch Pharmacol 340:639–647

    Google Scholar 

  • McGrath JC (1984) α-Adrenoceptor antagonism by apo-yohimbine and some observations on the pharmacology of α-adrenoceptors in the rat anaococcygeus and vas deferens. Br J Pharmacol 82:769–781

    Google Scholar 

  • Michel MC, Insel PA (1989) Are there multiple imidazoline binding sites? Trends Pharmacol Sci 10:342–344

    Google Scholar 

  • Michel MC, Brodde OE, Schnepel B, Behrendt J, Tschada R, Motulsky HJ, Insel PA (1989) [3H]Idazoxan and some other α2-adrenergic drugs also bind with high affinity to a nonadrenergic site. Mol Pharmacol 35:324–330

    Google Scholar 

  • Molderings GJ (1991) Inhibitory presynaptic imidazoline receptors on the sympathetic nerves of rabbit and rat blood vessels. Naunyn-Schmiedeberg's Arch Pharmacol 343 [Suppl]:R93

    Google Scholar 

  • Parini A, Coupry I, Graham RM, Uzielli I, Atlas D, Lanier SM (1989) Characterization of an imidazoline/guanidinium receptive site distinct from the α2-adrenergic receptor. J Biol Chem 264: 11874–11878

    Google Scholar 

  • Ruffolo RR, Sulpizio AC, Nichols AJ, DeMarinis RM, Hieble JP (1987) Pharmacologic differentiation between pre- and postjunctional α2-adrenoceptors by SK&F 104078. Naunyn-Schmiedeberg's Arch Pharmacol 336:415–418

    Google Scholar 

  • Schlicker E, Armah BI, Göthert M (1990) Central presynaptic α2-autoreceptors are involved in the blood pressure-lowering effect of moxonidine. J Cardiovasc Pharmacol 16:15–22

    Google Scholar 

  • Schümann HJ, Lues I (1983) Postjunctional α-adrenoceptors in the isolated saphenous vein of the rabbit. Characterization and influence of angiotensin. Naunyn-Schmiedeberg's Arch Pharmacol 323: 328–334

    Google Scholar 

  • Schulz A, Hasselblatt A (1989a) An insulin-releasing property of imidazoline derivatives is not limited to compounds that block α-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 340:321–327

    Google Scholar 

  • Schulz A, Hasselblatt A (1989b) Dual action of clonidine on insulin release: suppression, but stimulation when α2-adrenoceptors are blocked. Naunyn-Schmiedeberg's Arch Pharmacol 340:712–714

    Google Scholar 

  • Starke K (1977) Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 77:1–124

    Google Scholar 

  • Starke K (1981a) Presynaptic receptors. Ann Rev Pharmacol Toxicol 21:7–30

    Google Scholar 

  • Starke K (1981b) α-Adrenoceptor subclassification. Rev Physiol Biochem Pharmacol 88:199–236

    Google Scholar 

  • Starke K, Göthert M, Kilbinger H (1989) Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 69:864–989

    Google Scholar 

  • Vigne P, Lazdunski M, Frelin C (1989) Guanabenz, guanochlor, guanoxan and idazoxan bind with high affinity to non-adrenergic sites in pig kidney membranes. Eur J Pharmacol 160:295–298

    Google Scholar 

  • Weitzell R, Tanaka T, Starke K (1979) Pre- and postsynaptic effects of yohimbine stereoisomers on noradrenergic transmission in the pulmonary artery of the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 308:127–136

    Google Scholar 

  • Westfall TC (1977) Local regulation of adrenergic neurotransmission. Physiol Rev 57:659–728

    Google Scholar 

  • Yablonsky F, Dausse JP (1991) Non-adrenergic binding sites for the “α2-antagonist” [3H]idazoxan in the rabbit urethral smooth muscle. Biochem Pharmacol 41:701–707

    Google Scholar 

  • Yablonsky F, Riffaud JP, Lacolle JY, Dausse JP (1988) Evidence for non-adrenergic binding sites for [3H]idazoxan in the smooth muscle of rabbit urethra. Eur J Pharmacol 154:209–212

    Google Scholar 

Download references

Author information

Author notes

  1. F. Hentrich

    Present address: Kinderkardiologische Abteilung, Kinderklinik der Universität Essen, Hufelandstrasse 55, W4300, Essen 1, Federal Republic of Germany

Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie der Rheinischen Friedrich-Wilhelms-Universität Bonn, Reuterstrasse 2b, W-5300, Bonn 1, Federal Republic of Germany

    G. J. Molderings & M. Göthert

  2. Pharmakologisches Institut der Universität Essen, Hufelandstrasse 55, W4300, Essen 1, Federal Republic of Germany

    F. Hentrich

Authors
  1. G. J. Molderings
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Hentrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Göthert
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Send offprint requests to M. Göthert at the above address

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molderings, G.J., Hentrich, F. & Göthert, M. Pharmacological characterization of the imidazoline receptor which mediates inhibition of noradrenaline release in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch Pharmacol 344, 630–638 (1991). https://doi.org/10.1007/BF00174746

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00174746

Key words

Search

Navigation