Mechanisms of beta-adrenergic receptor-mediated venodilation in humans.
OBJECTIVE
Recent studies suggest that stimulation of beta-adrenergic receptors results in both endothelium-dependent and endothelium-independent venodilation, but results of former studies are inconsistent. This study was designed to elucidate the underlying mechanisms of isoproterenol (INN, isoprenaline)-induced venodilation by investigation of dorsal hand vein responses.


METHODS
In phenylephrine-constricted veins, isoproterenol (2-514 ng/min) was infused with and without oral pretreatment with 1 g acetylsalicylic acid (n = 7) or 5 mg of the selective beta(1)-adrenergic receptor antagonist bisoprolol (n = 7). In addition, isoproterenol was coinfused with the nitric oxide inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (6.3 micromol/min [n = 6]), with selective blockers of calcium (Ca(++))-dependent potassium (K(+)) channels (tetraethylammonium, 300 microg/min [n = 6]) and adenosine triphosphate (ATP)-sensitive K(+) channels (glyburide [INN, glibenclamide], 20 microg/min [n = 6]) or with the cyclic guanosine monophosphate inhibitor methylene blue (13 microg/min [n = 6]). Finally, L-NMMA was coinfused with potassium chloride (20 mmol/L) to inhibit hyperpolarization (n = 6).


RESULTS
Isoproterenol induced dose-dependent venodilation to 67.4% +/- 6.8%. Oral pretreatment with bisoprolol (P =.340) or acetylsalicylic acid (P =.760) did not affect isoproterenol-induced venodilation. Coinfusion of isoproterenol and L-NMMA relaxed the veins to the same extent as in the presence of isoproterenol alone. Neither inhibition of ATP-sensitive K(+) channels (P =.196) nor blockade of Ca(++)-dependent K(+) channels (P =.640) modulated isoproterenol-induced venodilation. In contrast, methylene blue reduced the maximum response to isoproterenol by about one third (68.5% +/- 4.3% versus 41.7% +/- 5.5%, P =.001). Infusion of L-NMMA alone raised vein size to 38.8% +/- 6.5%, yielding an L-NMMA-sensitive increase of 20% (P =.001), which was antagonized by coinfusion of potassium chloride to 17.1% +/- 6.7% (P =.02).


CONCLUSIONS
Isoproterenol dilates human hand veins exclusively via beta(2)-adrenergic receptors without involvement of endothelium-derived epoprostenol. Although a contribution of endothelium-derived nitric oxide appears unlikely, the venodilating effect of L-NMMA could have obscured the nitric oxide component of isoproterenol. beta(2)-Adrenergic receptor-mediated dilation is mediated in part by cyclic guanosine monophosphate-dependent mechanisms, whereas ATP- and Ca(++)-dependent K(+) channels are not involved, excluding a significant contribution of smooth muscle cell hyperpolarization. In addition, high concentrations of the nitric oxide synthase blocker L-NMMA dilate human hand veins via activation of endothelium-derived hyperpolarizing factors.
Schindler
Christoph
C
Institute of Clinical Pharmacology, Medical Faculty, Dresden University of Technology, Germany. christoph.schindler@maiilbox.tu-dresden.de
Dobrev
Dobromir
D
Grossmann
Matthias
M
Francke
Klaus
K
Pittrow
David
D
Kirch
Wilhelm
W
D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D001241:Aspirin; D017298:Bisoprolol; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D005905:Glyburide; D006225:Hand / Q000098:blood supply; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008751:Methylene Blue; D011189:Potassium Chloride; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D019789:Tetraethylammonium; D014664:Vasodilation / Q000187:drug effects*; D014680:Veins / Q000187:drug effects; D019323:omega-N-Methylarginine
D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D019323:omega-N-Methylarginine; D019789:Tetraethylammonium; D011189:Potassium Chloride; D007545:Isoproterenol; D001241:Aspirin; D005905:Glyburide; D008751:Methylene Blue; D017298:Bisoprolol