Alpha2C-adrenoceptors play a prominent role in sympathetic constriction of porcine pulmonary arteries

Abstract

Enhanced pulmonary vasoconstriction in response to injuries of the central nervous system and hypoxia result in pulmonary edema due to increased sympathetic activation. This study aimed to characterize α(2)-adrenoceptor (AR)-mediated responses in porcine pulmonary arteries. α(2)-AR-mediated vasoconstriction was studied using a tissue bath protocol. α(2)-AR protein was determined by Western blotting. UK14304 (α(2)-AR agonist) elicited only a slight contraction in pulmonary arteries compared to veins. Verapamil (voltage-operated Ca(2+) channel blocker), 2-APB (store-operated Ca(2+) channel inhibitor), and P1075 (K(ATP) channel opener) induced a marked decrease of the basal tone in veins, but not in arteries. The UK14304-induced contraction in arteries was enhanced by (S)-(-)-Bay K 8644 (L-type Ca(2+) channel activator), N (ω)-nitro-L: -arginine methyl ester hydrochloride (L-NAME, eNOS inhibitor), and (S)-(-)-Bay K 8644 plus L-NAME to the same extent. Endothelium denudation failed to affect the UK14304 response. (S)-(-)-Bay K 8644 did not increase the maximal noradrenaline (non-selective α-AR agonist) or phenylephrine (α(1)-AR agonist) response. The rightward shift of the concentration-response curve to noradrenaline by prazosin (α(1)-AR antagonist) plus (S)-(-)-Bay K 8644 was smaller and non-parallel compared to that in the presence of prazosin alone. UK14304 responses were inhibited by MK912 (α(2C)-AR antagonist). Affinity of MK912 (pA(2) 9.76) and Western blotting analysis argue for an involvement of α(2C)-ARs in noradrenaline-induced contraction of pulmonary arteries. It is concluded that postjunctional α(2C)-ARs predominantly mediate contraction in porcine pulmonary arteries when the cytosolic Ca(2+) concentration is elevated. α(2C)-AR antagonists may be beneficial in the treatment of pulmonary edema.

Long-Term High-Altitude Hypoxia and Alpha Adrenoceptor-Dependent Pulmonary Arterial Contractions in Fetal and Adult Sheep

“…Because yohimbine blocked PE-mediated contractions only in arteries from the normoxic fetal group, studies were performed to further delineate the potential influence of α 2 -AR activation on arterial contraction (Shebuski et al, 1987; Jantschak and Pertz, 2012) as well as relaxation (Magnenant et al, 2003) in the fetal normoxic group. Evaluation of vessel reactivity was achieved by stimulating normoxic fetal arteries with the selective α 2 -AR agonist, dexmedetomidine (Toyama et al, 2009).…”

“…The role for α 2 -adrenoreceptors in the fetus was unanticipated as PE is fairly selective for the α 1 -AR; however, α 2 -ARs appear to be important for sympathetic pulmonary arterial contraction before birth and antenatal LTH attenuates their role in fetal vessels. Prior studies indicated that α 2 -ARs were expressed in the pulmonary vasculature and involved in arterial contractions, even before birth (Magnenant et al, 2003; Jantschak and Pertz, 2012). Much like our studies, postnatal maturation seems to contribute to downregulation of α 2 -AR-mediated responses (Starke, 2001).…”

“…Indeed, there is precedent for direct α 2 -AR-dependent contraction in porcine pulmonary arteries where α 2 c-ARs mediate myocyte contraction when the cytosolic Ca 2+ concentration is elevated. In these arteries, norepinephrine activates α 2 c-AR following α 1 -AR-stimulation and concomitant myocyte Ca 2+ increases (Jantschak and Pertz, 2012). Such findings are not restricted to the pulmonary vasculature.…”

Quantitative determination of α2B-adrenoceptor-evoked myosin light chain phosphorylation in vascular smooth muscle cells

“…As increased intracellular calcium is needed for smooth muscle contraction evoked by α 2 -adrenoceptors, the interplay between postjunctional α 1 -and α 2 -adrenoceptors may be important on the physiological level. Noradrenaline and adrenaline activate both α 1 -and α 2 -adrenoceptors, and due to the α 1 -adrenoceptor-mediated increase in intracellular calcium, concurrent α 2 -adrenoceptor-mediated constriction is potentiated (Jantschak & Pertz, 2012).…”

Dexmedetomidine inhibits vasoconstriction via activation of endothelial nitric oxide synthase

“…Jantschak [29] reported that contractile α 2 -adrenoceptors play a minor role in porcine pulmonary arteries compared to veins under normal in vitro experimental conditions. Therefore, we suggest that it is premature to conclude that DEX does not affect pulmonary vascular resistance in healthy subjects.…”