Effects of hydralazine on contractile responses to α1 and α2-adrenoceptor agonists in isolated rubbed rat aorta

Moina, M.J.; Bardan, B.; Campos‐Toimil, Manuel; Alzueta, Alejandro Fdez; Gil‐Longo, José; Orallo, Francisco

doi:10.1016/0306-3623(94)90028-0

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…Our results show that the α # -adrenoceptor agonist clonidine induced contractions in intact aortic segments from the four groups of rats used, and these contractions were increased by removal of the endothelium, indicating that α # -adrenoceptors are present in both endothelial and smooth muscle cells, in agreement with other reports [11,33]. The absence of endothelium increased not only the contractions caused by clonidine but also the sensitivity (EC &!…”

Section: Discussionsupporting

confidence: 93%

Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta

et al. 1999

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The aim of this study was to determine the possible influence of sex hormones on the contractile responses induced by clonidine, an agonist of alpha2-adrenoceptors, as well as the endothelial modulation of these responses. For this purpose, thoracic aorta segments from male (control and castrated) and female (in oestrous phase and ovariectomized) rats were used. In intact segments from the four groups of rats, clonidine (0.01-10 micromol/l) induced concentration-dependent contractions, which were increased by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (0.1 mmol/l) or by endothelium removal, but were reduced by 1 micromol/l yohimbine (an alpha2-adrenoceptor antagonist) in all animals and by 1 micromol/l indomethacin (a cyclo-oxygenase inhibitor) in control males only. The rank order of the magnitude of the maximal response was: oestrous females>ovariectomized females>control males>castrated males, whereas the sensitivity to clonidine (EC50 value) was similar in all animals. In endothelium-denuded segments, the rank order was: oestrous females=control males>ovariectomized females=castrated males. These results suggest that: (1) the presence of oestrogen or androgen increases the contraction caused by alpha2-adrenoceptor activation with clonidine; (2) endothelium negatively modulates the response to this agonist in the four groups of rats, due to endothelial NO release (entirely in females and in part in males); (3) androgen also seems to modulate the response by stimulating the release of an endothelial contracting factor, probably a prostanoid; and (4) the endothelium of males has a greater capacity than that of comparable females for negative regulation of the tension generated by the underlying vascular smooth muscle.

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Section: Discussionsupporting

confidence: 93%

Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta

et al. 1999

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“…However, this vasorelaxant activity of HPS‐10 in rat endothelium‐denuded rat aorta rings was more potent than the vasodilator action previously described for hydralazine in rat isolated rubbed aorta (Orallo, 1984; Moína et al , 1994). Furthermore, there is a good correlation between the non‐selective effect of HPS‐10 on the vasoconstrictor responses induced by NA and AII in vivo (anaesthetized normotensive rat) and in vitro (rat isolated aorta), which suggests that the direct vasodilator action of HPS‐10 observed in vitro at high concentrations may be responsible for its hypotensive activity noted in vivo , as previously shown for hydralazine (see Introduction).…”

Section: Discussionmentioning

confidence: 61%

“…Hydralazine is a peripheral vasodilator, which has been used for many years in the treatment of essential hypertension (Campos‐Toimil & Orallo, 1996a). There is general agreement that the fall in blood pressure produced by hydralazine results from a direct action of the drug on vascular smooth muscle (Khayyal et al , 1981; Orallo et al , 1991; Moína et al , 1994). Although the basis for its direct vasodilator effects has been studied extensively, the mechanism has not been clearly established.…”

Section: Introductionmentioning

confidence: 99%

Study of the in vivo and in vitro cardiovascular effects of a hydralazine‐like vasodilator agent (HPS‐10) in normotensive rats

Orallo

1997

British J Pharmacology

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1 In this work, the cardiovascular e ects of HPS-10, a new vasodilator agent, were studied in rats. 2 In conscious normotensive rats, oral administration of HPS-10 (4 ± 9 mg kg 71 ) produced a doserelated and long-lasting fall in systolic arterial blood pressure (ED 30 of 5.32 mg kg 71 ), accompanied by an increase in heart rate (ED 30 of 8.43 mg kg 71 ). This tachycardia was totally inhibited by pretreatment with (+)-propranolol (10 mg kg 71 , p.o.). In rat isolated rubbed aorta, HPS-10 (0.1 ± 1 mM) non-competitively and with almost equal e ectiveness antagonized the contractions induced by NA, AII (in normal Krebs solution) and Ca 2+ (in depolarizing Ca 2+ -free high-K + 50 mM solution). In the experiments in Ca 2+ -free medium, HPS-10 (1 mM) considerably inhibited the contractions induced by NA, AII and ca eine in rat aorta. 5 Furthermore, in the studies with radioactive Ca 2+ , HPS-10 (1 mM) did not modify the basal uptake of 45 Ca 2+ but strongly decreased the in¯ux of 45 Ca 2+ induced by NA, AII and K + in rat aortic rings. 6 In rat isolated atria, HPS-10 (1 mM) produced a positive inotropic/negative chronotropic e ect. 7 HPS-10 (0.3 mM) signi®cantly inhibited the sustained and transient Ba 2+ inward current (I Ba ) recorded in whole-cell clamped rat aortic myocytes. 8 These results indicate that the non-selective vasorelaxant e ects of HPS-10 in rat aortic rings can be attributed to transmembrane Ca 2+ -antagonist activity and an intracellular action on smooth muscle cells. The direct vasodilator action of HPS-10 observed in rat isolated aorta may be responsible for the HPS-10 hypotensive activity in anaesthetized normotensive rats.

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“…Hydralazine also displayed the same slow onset of action and recovery in pulmonary artery as previously reported in aorta (Gurney & Allam, 1995) and in agreement with earlier studies (e.g. Moína et al ., 1994; Gurney & Allam, 1995), its relaxant effect did not require the presence of endothelium. The results further show that the relaxant effect of hydralazine did not require an intact cell membrane, but was mediated by an action on the SR of vascular smooth muscle, to inhibit Ca 2+ release.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery

Ellershaw

Gurney

2001

British J Pharmacology

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1 The directly acting vasodilator hydralazine has been proposed to act at an intracellular site in vascular smooth muscle to inhibit Ca 2+ release. 2 This study investigated the mechanism of action of hydralazine on rabbit aorta and pulmonary artery by comparing its e ects on the tension generated by intact and b-escin permeabilized vessels and on the cytoplasmic Ca 2+ concentration, membrane potential and K + currents of isolated vascular smooth muscle cells. 3 Hydralazine relaxed pulmonary artery and aorta with similar potency. It was equally e ective at inhibiting phasic and tonic contractions evoked by phenylephrine in intact vessels and contractions evoked by inositol 1,4,5 trisphosphate (IP 3 ) in permeabilized vessels. 4 Hydralazine inhibited the contraction of permeabilized vessels and the increase in smooth muscle cell Ca 2+ concentration evoked by ca eine with similar concentration dependence, but with lower potency than its e ect on IP 3 contractions. 5 Hydralazine had no e ect on the relationship between Ca 2+ concentration and force generation in permeabilized vessels, but it slowed the rate at which maximal force was developed before, but not after, destroying sarcoplasmic reticulum function with the calcium ionophore, ionomycin. 6 Hydralazine had no e ect on membrane potential or the amplitudes of K + currents recorded from isolated smooth muscle cells over the concentration range causing relaxation of intact vessels. 7 The results suggest that the main action of hydralazine is to inhibit the IP 3 -induced release of Ca 2+ from the sarcoplasmic reticulum in vascular smooth muscle cells.

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Effects of hydralazine on contractile responses to α1 and α2-adrenoceptor agonists in isolated rubbed rat aorta

Cited by 12 publications

References 26 publications

Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta

Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta

Study of the in vivo and in vitro cardiovascular effects of a hydralazine‐like vasodilator agent (HPS‐10) in normotensive rats

Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery

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