Skip to main content
SpringerLink
Log in

Effects of imidazolines on noradrenaline release in rat isolated kidney

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

Abstract

The aim of the present study was to investigate whether or not activation of imidazoline receptors modulates noradrenaline release in the rat isolated kidney. Kidneys were pre-exposed to 3H-noradrenaline and the renal nerves were stimulated with 6 pulses at 100 Hz. The stimulation induced (S-I) outflow of radioactivity was taken as an index of endogenous noradrenaline release. The imidazoline derivatives clonidine (1–1000 nmol/l) and moxonidine (10–1000 nmol/l) inhibited S-I outflow of radioactivity with an EC50 of 6.8 nmol/l and 62.5 nmol/l and a maximum of 88% and 97%, respectively. The concentration response curves for clonidine and moxonidine were shifted to the right by the selective α2-adrenoceptor antagonist rauwolscine (0.1 μmol/l) in a parallel manner with identical pKB's of 8.52 and 8.46, respectively. Furthermore, the α-adrenoceptor agonist (−)-α-methylnoradrenaline (0.1–30nmol/l), which has no affinity for imidazoline binding sites, inhibited S-I outflow of radioactivity with an EC50 of 2.4 nmol/l and a maximum of 94%. Rauwolscine (0.1 μmol/l) again shifted the concentration response curve for this α-adrenoceptor agonist to the right with a pKB of 8.40. Moreover, the selective α2-adrenoceptor antagonist 2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline HCl(RX 821002,0.01 μmol/l) shifted the concentration response curves for clonidine and moxonidine to the right with pKB's of 9.46 and 9.18, respectively. The α2-adrenoceptor antagonist 4-chloro-2-(2-imidazoline-2-ylamino)-isoindoline HCl (BDF 6143, 1–1000 nmol/l), which, in the presence of α2-adrenoceptor blockade, has been shown to inhibit noradrenaline release through activation of imidazoline receptors, inhibited S-I outflow of radioactivity with an EC50 of about 20.5 nmol/l (with 1000 nmol/l producing 60% inhibition). The inhibitory effects of BDF 6143 and clonidine were abolished after pretreatment of the kidneys with the irreversible α2-adrenoceptor antagonist phenoxybenzamine (1 μmol/l). However, RX 821002 did not alter and rauwolscine slightly antagonized the inhibitory effect of BDF 6143. It is concluded that the imidazoline derivatives clonidine and moxonidine as well as the phenylethylamine (−)-α-methylnoradrenaline inhibit noradrenaline release in rat isolated kidney exclusively through activation of prejunctional α2-adrenoceptors. BDF 6143 inhibits noradrenaline release in rat isolated kidney through an α2-adrenoceptor-independent, possibly an imidazoline receptor mechanism.

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

  • Bidet M, Poujeol P, Parini A (1991) The imidazoline-guanidinium receptive site, a target for some alpha-2 adrenergic agonists, is involved in inhibition of Na+/H+ exchange in renal proximal tubule cells. J Hypertens 9 [Suppl 6]:216–217

    Google Scholar 

  • Bohmann C, Schollmeyer P, Rump LC (1993a) α2-Autoreceptor subclassification in rat isolated kidney by use of short trains of electrical stimulation. Br J Pharmacol 108:262–268

    Google Scholar 

  • Bohmann C, Schollmeyer P, Rump LC (1993b) Methoxamine inhibits noradrenaline release through activation of α1- and α2-adrenoceptors in rat isolated kidney: involvement of purines and prostaglandins. Naunyn-Schmiedebergs Arch Pharmacol 347:273–279

    Google Scholar 

  • Bricca G, Dontenwill M, Molines A, Feldman J, Belcourt A, Bousquet P (1989) The imidazoline preferring receptor: binding studies in bovine, rat and human brainstem. Eur J Pharmacol 162:1–9

    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 an endogenous clonidine displacing substance. J Pharmacol Exp Ther 252:293–299

    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 α-adrenoceptors in rabbit aorta and pulmonary artery. Arzneimittelforschung 32:1534–1540

    Google Scholar 

  • Ernsberger P, Giuliano R, Willette RN, Reis DJ (1990a) Role of imidazoline receptors in the vasodepressor response to clonidine analogs in the rostral ventrolateral medulla. J Pharmacol Exp Ther 253:408–418

    Google Scholar 

  • Ernsberger P, Feinland G, Meely MP, Reis DJ (1990b) Characterization and visualization of clonidine-sensitive imidazole sites in rat kidney which recognize clonidine-displacing substance. Am J Hypertens 3:90–97

    Google Scholar 

  • Ernsberger PR, Westbrooks KL, Christen MO, Schiffer SG (1992) A second generation of centrally acting antihypertensive agents act on putative I1-imidazoline receptors. J Cardiovasc Pharmacol 20 [Suppl 4]:1–10

    Google Scholar 

  • Fuder H, Schwarz P (1993) Desensitization of inhibitory prejunctional α2-adrenoceptors and putative imidazoline receptors on rabbit heart sympathetic nerves. Naunyn-Schmiedebergs Arch Pharmacol 348:127–133

    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) Catecholamines: Handbook of experimental pharmacology, vol 33. Springer, Berlin Heidelberg New York, pp 283–335

    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-Schmiedebergs 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 

  • 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 

  • Langin D, Paris H, Lafontan M (1990) 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 

  • 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-Schmiedebergs Arch Pharmacol 340:639–647

    Google Scholar 

  • Limon I, Coupry I, Tesson F, Lachaud- Pettiti V, Parini A (1992) Renal imidazoline-guanidinium receptive site: a potential target for antihypertensive drugs. J Cardiovasc Pharmacol 20[Supp] 4]:21–23

    Google Scholar 

  • MacKinnon AC, Stewart M, Olverman HJ, Spedding M, Brown CM (1993) [3H]p-aminoclonidine and [3H]idazoxan label different populations of imidazoline sites on rat kidney. Eur J Pharmacol 232:79–87

    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 (1988) [3H]Idazoxan and some other α2-adrenergic drugs also bind with high affinity to a nonadrenergic site. Mol Pharmacol 35:324–330

    Google Scholar 

  • Miralles A, Olmos G, Sastre M, Barturen F, Martin I, Garcia-Sevilla JA (1993) Discrimination and pharmacological characterization of I2-imidazoline sites with [3H]idazoxan and alpha-2 adrenoceptors with [3H]RX 821002 (2-methoxy idazoxan) in the human and rat brains. J Pharmacol Exp Ther 264:1187–1197

    Google Scholar 

  • Molderings GJ, Hentrich F, Göthert M (1991) Pharmacological characterization of the imidazoline receptor which mediates inhibition of noradrenaline release in the rabbit pulmonary artery. Naunyn-Schmiedebergs Arch Pharmacol 344:630–638

    Google Scholar 

  • Molderings GJ, Michel MC, Göthert M, Schäfer SG (1992) Imidazolrezeptoren: Angriffsort einer neuen Generation von antihypertensiven Arzneimitteln. Aktueller Stand und Zukunftsperspektiven. Dtsch Med Wochenschr 117(2):67–71

    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-Schmiedebergs Arch Pharmacol 336:415–418

    Google Scholar 

  • Rump LC (1987) Modulation of renal noradrenaline release by prejunctional receptor systems in vitro. Clin Exp Pharmacol Physiol 14:423–428

    Google Scholar 

  • Rump LC, Majewski H (1987) Modulation of norepinephrine release through α1- and α2-adrenoceptors in rat isolated kidney. J Cardiovasc Pharmacol 9:500–507

    Google Scholar 

  • Rump LC, Schollmeyer P (1989) Modulation der renalen Transmitter-Freisetzung durch präsynaptische Rezeptoren. Klin Wochenschr 67:865–869

    Google Scholar 

  • Rump LC, Wilde K, Bohmann C, Schollmeyer P (1992) Effects of the novel dopamine DA2-receptor agonist carmoxirole (EMD 45609) on noradrenergic and purinergic neurotransmission in rat isolated kidney. Naunyn-Schmiedebergs Arch Pharmacol 345:300–308

    Google Scholar 

  • Rump LC, Schwertfeger E, Schuster MJ, Schaible U, Frankenschmidt A, Schollmeyer PJ (1993) Dopamine DA2-receptor activation inhibits noradrenaline release in human kidney slices. Kid Int 43:197–204

    Google Scholar 

  • Smyth DD, Li P (1991) Differential renal effects following stimulation of imidazoline receptors and α2-adrenoceptors in the anesthetized rat. FASEB J 5:A502

    Google Scholar 

  • Smyth DD, Li P, Blandford DE, Penner SB (1992a) Opposite rank order of potency for alpha-2 adrenoceptor agonists on water and solute excretion in the rat: two sites and/or receptors? J Pharmacol Exp Ther 261:1080–1086

    Google Scholar 

  • Smyth DD, Allan DR, Li P, Penner SB (1992b) Direct renal actions of moxonidine are distinct from renal alpha-2 adrenoceptors. Fund Clin Pharmacol 6[Suppl]:50s

  • Starke K (1987) Presynaptic α-autoreceptors. Rev Physiol Biochem Pharmacol 107:73–146

    Google Scholar 

  • Valenta B, Drobny H, Singer ES (1988) Presynaptic autoinhibition of central noradrenaline release in vitro: opertional characteristics and effects at alpha-2 adrenoceptors in the presence of uptake inhibition. J Pharmacol Exp Ther 245:944–949

    Google Scholar 

  • Wand DR (1975) Analysis of dose-response curves. In: Daniel EE, Paton DM (eds) Methods in pharmacology, vol 3. Plenum Press, New York London, pp 471–506

    Google Scholar 

  • Wikberg JES, Uhlen S, Chhajlani V (1991) Medetomidine stereoisomers delineate two closely related subtypes of idazoxan (imidazoline) I-receptors in the guinea pig. Eur J Pharmacol 193:335–340

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Universitätsklinik Freiburg, Innere Medizin IV, Hugstetter Strasse 55, D-79106, Freiburg, Germany

    C. Bohmann, P. Schollmeyer & L. C. Rump

Authors
  1. C. Bohmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Schollmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. C. Rump
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Correspondence to: L. C. Rump at the above address

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bohmann, C., Schollmeyer, P. & Rump, L.C. Effects of imidazolines on noradrenaline release in rat isolated kidney. Naunyn-Schmiedeberg's Arch Pharmacol 349, 118–124 (1994). https://doi.org/10.1007/BF00169827

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00169827

Key words

Search

Navigation