Biomedical subjects

F Goirand

Publications and source records attributed to F Goirand.

5 recordsLinked to original sources

PubMed2005

Stimulation of the ADRB3 adrenergic receptor induces relaxation of human placental arteries: influence of preeclampsia.

Preeclampsia, which complicates 3-8% of pregnancies, is one of the leading causes of neonatal morbidity and mortality. Its pathophysiology remains unclear. The aim of the present study was to investigate the presence and the role of beta2- and beta2-adrenergic receptors (ADRB2 and ADRB3, respectively) in human placental arteries and to assess the influence of preeclampsia on ADRB responsiveness. SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respectively) induced a concentration-dependent relaxation of placental artery rings obtained from women with uncomplicated or preeclamptic pregnancies. SR 59119A-induced relaxation was unaffected by the blockade of ADRB1 and ADRB2 by 0.1 microM propranolol but was significantly decreased by the blockade of ADRB1, ADRB2, and ADRB3 by 10 microM propranolol. Both SR 59119A and salbutamol were associated with a significant increase in cAMP production that was significantly inhibited by pretreatment with 0.1 microM propranolol only for salbutamol. SR 59119A-induced relaxation (E(max) = 28% +/- 5% vs. 45% +/- 4%, respectively) and cAMP production (2.7 +/- 0.5 vs. 4.9 +/- 0.4 pmol/mg of protein, respectively; P < 0.01) were decreased in arteries obtained from preeclamptic compared to normotensive women. Both ADRB2 and ADRB3 transcripts were expressed at the same level between arteries from normotensive and preeclamptic women. Western blot analysis, however, revealed a decreased expression of the ADRB3 immunoreactive protein in arteries from preeclamptic compared to normotensive women. We suggest the presence of functional ADRB2 and ADRB3 in human placental arteries. Even if preeclampsia is associated with an impairment of the ADRB3 responsiveness, ADRB3 agonists may have future pharmaceutical implications in the management of pregnancy-related disorders.

Adrenergic beta-2 Receptor Agonists↗

PubMed2001

Effects of phosphodiesterase inhibitors on hypoxic pulmonary vasoconstriction. Influence of K(+) channels and nitric oxide.

We studied the relaxant effects of the cyclic nucleotide phosphodiesterase inhibitors theophylline (non-selective), rolipram (type IV, 3',5'-cyclic monophosphate (cAMP)-specific) and zaprinast (type V, 3',5'-cyclic monophosphate (cGMP)-specific) on the hypoxic vasoconstriction in the isolated perfused rat lung and the involvement of K(+) channels and nitric oxide (NO) in these effects. K(+) channels were inhibited by glibenclamide, charybdotoxin, apamin and 4-aminopyridine and nitric oxide synthase by L-N(G)-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response. L-NAME and 4-aminopyridine increased this response. Rolipram, zaprinast and theophylline shared the ability to oppose the hypoxic pulmonary vasoconstriction. The order of potency was zaprinast>rolipram>theophylline. Glibenclamide partially inhibited the relaxant effects of rolipram and theophylline. Charybdotoxin inhibited the dilator response to rolipram. Apamin inhibited partially the vasodilation induced by rolipram and zaprinast. 4-Aminopyridine inhibited partially the relaxant effects of theophylline. L-NAME failed to block the effects of the three compounds. These data illustrate different pharmacological profiles according to the phosphodiesterase inhibitors and support the potential interest of selective inhibitors as relaxant agents in pulmonary vessels.

4-Aminopyridine↗

PubMed2001

Hypoxic vasoconstriction of rat main pulmonary artery: role of endogenous nitric oxide, potassium channels, and phosphodiesterase inhibition.

This study investigated the influence of NO, potassium (K+) channel blockade, and the phosphodiesterase inhibitors (PDEIs) theophylline (non-selective PDEI), siguazodan (PDE3I), rolipram (PDE4I), and zaprinast (PDE5I) on rat isolated main pulmonary artery hypoxic (95% N2 and 5% CO2) vasoconstriction. Hypoxic vasoconstriction increased by 27% (p < 0.01) in the presence of the NO synthase inhibitor L-NAME (10(-4) M), and by 15% (p < 0.05) in the presence of the K(ATP) channel blocker glibenclamide (10(-6) M), without potentiation by the combination of these two drugs. Hypoxic vasoconstriction decreased by 28% (p < 0.01) in presence of the Kv,-voltage-dependent channel blocker 4-aminopyridine (10(-3) M), whereas the other K+ channel blockers, charybdotoxin (BKCa, large-conductance Ca2+-sensitive K+ channels) and apamin (SKCa, small-conductance Ca2+-sensitive K+ channels) had no effect. The nonselective PDEI theophylline induced a concentration-dependent relaxation (pD2 = 4.05, Emax = 90% [expressed as a percentage of maximal relaxation induced by papaverine 10(-4) M]). Among the selective PDEIs, siguazodan was significantly (p < 0.01) more efficient than rolipram and zaprinast (Emax values were 84%, 67%, and 58%, respectively) and significantly (p < 0.05) more potent than zaprinast (pD2 values were 6.48, 6.34, and 6.16 for siguazodan, rolipram, and zaprinast). Glibenclamide and L-NAME significantly (p < 0.05) shifted the concentration-response curve (CRC) for zaprinast to the right, and L-NAME shifted the CRC significantly to the right for siguazodan. In the presence of L-NAME, glibenclamide had no effect on the CRC of zaprinast. We conclude that (a) NO exerts a permanent inhibitory effect against hypoxic vasoconstriction that might be mediated in part by an activation of K(ATP) channels; (b) a 4-aminopyridine-sensitive K+ channel is involved in vasoconstriction under hypoxic conditions; (c) PDEs 3 and 5 are the predominant PDE isoforms in rat pulmonary artery relaxation; and (d) NO and K(ATP), but neither BK(Ca), SK(Ca), nor Kv channels, are involved in the relaxant effect of PDEIs.

Animals↗

PubMed1999

Hypoxic pulmonary vasoconstriction.

Hypoxic vasoconstriction is unique to pulmonary circulation. The pulmonary response is part of a self-regulatory mechanism by which pulmonary capillary blood flow is automatically adjusted to alveolar ventilation for maintaining the optimal balance of ventilation and perfusion. In pathological conditions, hypoxic pulmonary vasoconstriction may occur as an acute episode or as a sustained response with pulmonary hypertension and vascular remodeling. Vasoactive substances produced from the endothelial cells (prostanoids, nitric oxide, or endothelin) or other mediators such as 5 hydroxytryptamine have been examined as possible mediators of hypoxic vasoconstriction. These appear more likely to be modulators than mediators of the vasoconstrictor response to hypoxia. Recent hypotheses have emerged indicating that O2 levels per se can regulate ion channel activity. The modulation of both K+ and Ca2+ channels differs according to the conduit or resistance pulmonary vessel type, tending to extend the former and contract the latter, thereby opposing the ventilation to perfusion mismatching. In the absence of drugs that act selectively on pulmonary circulation, inhaled therapy is an alternative in the treatment of pulmonary hypertension. According to its short half-life and to its potential cytotoxicity, nitric oxide is only of value in the management of patients with acute respiratory disease. Aerosolized prostacyclin and iloprost result in a sustained efficacy of the inhaled vasodilator regimen in patients with severe pulmonary hypertension and offer a new strategy for treatment of this disease. At the moment, therapy aimed at reversing the structural remodeling and matrix deposition in pulmonary arteries remains experimental. New drugs such as potassium channel openers or endothelin receptor antagonists warrant further investigations as possible therapeutic candidates in the treatment of pulmonary hypertension.

Animals↗

PubMed1999

Role of potassium channels and nitric oxide in the relaxant effects elicited by beta-adrenoceptor agonists on hypoxic vasoconstriction in the isolated perfused lung of the rat.

1. The aims of this study were to compare, in the rat isolated perfused lung preparation, the antagonist effects of a nonselective beta-adrenoceptor agonist (isoprenaline), a selective beta2-adrenoceptor agonist (salbutamol) and a selective beta3-adrenoceptor agonist (SR 59104A) on the hypoxic pulmonary pressure response, and to investigate the role of K+ channels, endothelium derived relaxing factor and prostaglandins in these effects. K+ channels were inhibited by glibenclamide, charybdotoxin or apamin, NO synthase and cyclo-oxygenase were inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME) and indomethacin, respectively. 2. Hypoxic ventilation produced a significant increase in perfusion pressure (+65%, P<0.001) and L-NAME significantly increased this response further (+123%, P<0.01). After apamin, L-NAME, indomethacin, post-hypoxic basal pressure did not return to baseline values (P<0.001). 3. Glibenclamide partially inhibited the relaxant effects of isoprenaline (P<0.05) and salbutamol (P<0.001) but not that of SR 59104A. In contrast, charybdotoxin and apamin partially inhibited the relaxant effects of SR 59104A (P=0.053 and <0.01, respectively) but did not modify the effects of isoprenaline and salbutamol. L-NAME partially inhibited the dilator response of salbutamol (P<0.01) and SR 59104A (P<0.05) but not that of isoprenaline. 4. We conclude that (a) EDRF exerts a significant inhibition of the hypoxic pulmonary response, (b) SK(Ca) channel activation, EDRF and prostaglandins contribute to the reversal of the hypoxic pressure response, (c) the vasodilation induced by isoprenaline is mediated in part by activation of K(ATP) channels, that of salbutamol by activation of K(ATP) channels and EDRF. In contrast, SR 59104A partly operates through BK(Ca), SK(Ca), channels and EDRF activation, differing in this from the beta1 and beta2-adrenoceptor agonists.

Adrenergic beta-Agonists↗