The Experts below are selected from a list of 6 Experts worldwide ranked by ideXlab platform
S G Haworth - One of the best experts on this subject based on the ideXlab platform.
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Vasoconstriction of intrapulmonary arteries to P2-receptor nucleotides in normal and pulmonary hypertensive newborn piglets
British Journal of Pharmacology, 1999Co-Authors: M R Mcmillan, Geoffrey Burnstock, S G HaworthAbstract:The vasoconstrictor responses of isolated intrapulmonary arteries (IPA) to P2-receptor agonists was investigated during adaptation to extrauterine life in the normal piglet and the effect of pulmonary hypertension was studied following exposure of newborn animals to chronic hypobaric hypoxia (51 kPa) for 3 days. At resting tone, α,β-methyleneATP (α,β-meATP) (P2X-receptor agonist) contracted intrapulmonary arteries from adult, but not immature pigs, and repeated application desensitized the response. Adenosine 5′-triphosphate (ATP) induced endothelium-independent relaxation at low concentrations at all ages, a variable contractile response to high concentrations developed by 3 days, becoming larger and consistent by 14 days of age. Uridine 5′-triphosphate (UTP) evoked a contractile response in normal intrapulmonary arteries from foetal to adult life, the magnitude of the response increasing with age. Endothelial removal and pre-incubation with Nω-nitro-L-arginine methyl ester (L-NAME) (100 μM) increased the contractile response of adult vessels. Pre-incubation with α,β-meATP (100 μM), increased the contractile response to UTP in both newborn and adult vessels. ATP-induced relaxations were reduced in newborn vessels but there was no effect on the responses of adult vessels. Responses to UTP, ATP and α,β-meATP of intrapulmonary arteries from newborn piglets exposed to chronic hypobaric hypoxia for 3 days were normal. In summary, UTP elicited marked Vasoconstriction of porcine IPA at all ages. UTP and ATP responses were consistent with activation of the P2Y4-receptor recently identified in vascular smooth muscle by others. α,β-meATP induced a small Vasoconstriction in the adult probably via the P2X1-receptor. Responses remained normal in neonatal pulmonary hypertension. Keywords: Pyrimidine, purine, pulmonary artery, neonatal hypertension, Vasoconstriction Introduction The pulmonary vascular resistance is high in utero and remains elevated in persistent pulmonary hypertension of the newborn (PPHN), a clinical syndrome most commonly associated with hypoxic Lung disease (Haworth, 1979; 1993). Whether or not nucleotides play a role in maintaining a high resistance in either of these circumstances is not known. ATP can produce either relaxation or contraction depending upon the P2-receptor subtype(s) present in the tissue and the tone of the vessel investigated (Burnstock, 1997), suggesting that the pulmonary arterial response to ATP might change with age in normal pulmonary arteries as the vascular resistance falls after birth due to maturation of vascular reactivity and structure (Allen & Haworth, 1998; Hall & Haworth, 1987; Haworth et al., 1987; Levy et al., 1995; Liu et al., 1992). At low vascular tone, Vasoconstriction to ATP is the dominant response, mediated by P2X-receptor(s), partly via the P2X1 subtype on smooth muscle and partly by P2X subtypes which have not yet been clearly identified (Benham & Tsien, 1987; Neely et al., 1991; 1996). Currently there are seven recognized P2X-receptors, including the non-selective ion pore P2X7 (formerly P2Z) (Burnstock, 1997). Transcripts of receptor mRNA for the P2X1,2 and 4-receptor sub-units have been co-localized by in situ hybridization in adult rat aortic and pulmonary arterial smooth muscle (Nori et al., 1998). The metabolically stable ATP analogue α,β-meATP evoked a contractile response in the isolated guinea-pig taenia coli and then desensitized P2X-receptors, without significant vasodilator activity (Kasakov & Burnstock, 1983; Kennedy & Leff, 1995). ATP induces a contraction in isolated adult human and rat pulmonary artery and α,β-meATP can block the response suggesting that these agonists act via a common receptor (Liu et al., 1989a,1989b). However, in the isolated perfused adult rat Lung, Vasoconstriction to ATP was only partially inhibited by α,β-meATP (Rubino & Burnstock, 1996). Pyrimidines (uridine nucleotides) are also known to evoke α,β-meATP-insensitive Vasoconstriction of some systemic and pulmonary vessels (Juul et al., 1993; Matsumoto et al., 1997; Ralevic & Burnstock, 1991; 1998; Saiag et al., 1987; 1990); von Kugelgen & Starke, 1990). They can be released from the vascular endothelium of rabbit thoracic aorta, and from platelets, suggesting physiological sources (Goetz et al., 1971; Saiag et al., 1995). Pyrimidine-induced Vasoconstrictions reported for the adult rat small pulmonary artery and adult rabbit coronary artery were thought to be mediated by members of the G-protein coupled, P2Y-receptor family, which can activate phospholipase C through Gq11 and subsequently stimulate a rise of intracellular calcium (Burnstock 1997; Nicholas et al., 1996; Hartley et al., 1998; Matsumoto et al., 1997). Recently, adult rat aorta smooth muscle has been shown to express P2Y2,4, and 6, subtypes, which are known to be activated by pyrimidines (Harper et al., 1998). Persistent pulmonary hypertension of the newborn is a potentially fatal condition, which results in abnormal remodelling of the intrapulmonary arteries during the first few days of life (Allen & Haworth, 1986; Haworth, 1979; 1993). The marked hypertrophy of the IPA smooth muscle cells has been taken to indicate an increase in contractile response to different stimuli, including hypoxia. The role of purines and pyrimidines in this condition is unknown. In an experimental study using the perfused adult rat Lung, the vasoconstrictor response to acute alveolar hypoxia could not be attributed to up-regulation of α,β-methylene-sensitive P2X-receptors (McCormack et al., 1989). In the present study, the response of normal, isolated porcine IPA to cumulative doses of ATP, α,β-meATP and UTP was investigated from foetal to adult life. We also studied P2X-receptor desensitization by α,β-meATP on the response to ATP and UTP. The effect of neonatal pulmonary hypertension was determined in the IPA of newborn piglets which had been exposed to chronic hypobaric hypoxia for 3 days (Tulloh et al., 1997).
M R Mcmillan - One of the best experts on this subject based on the ideXlab platform.
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Vasoconstriction of intrapulmonary arteries to P2-receptor nucleotides in normal and pulmonary hypertensive newborn piglets
British Journal of Pharmacology, 1999Co-Authors: M R Mcmillan, Geoffrey Burnstock, S G HaworthAbstract:The vasoconstrictor responses of isolated intrapulmonary arteries (IPA) to P2-receptor agonists was investigated during adaptation to extrauterine life in the normal piglet and the effect of pulmonary hypertension was studied following exposure of newborn animals to chronic hypobaric hypoxia (51 kPa) for 3 days. At resting tone, α,β-methyleneATP (α,β-meATP) (P2X-receptor agonist) contracted intrapulmonary arteries from adult, but not immature pigs, and repeated application desensitized the response. Adenosine 5′-triphosphate (ATP) induced endothelium-independent relaxation at low concentrations at all ages, a variable contractile response to high concentrations developed by 3 days, becoming larger and consistent by 14 days of age. Uridine 5′-triphosphate (UTP) evoked a contractile response in normal intrapulmonary arteries from foetal to adult life, the magnitude of the response increasing with age. Endothelial removal and pre-incubation with Nω-nitro-L-arginine methyl ester (L-NAME) (100 μM) increased the contractile response of adult vessels. Pre-incubation with α,β-meATP (100 μM), increased the contractile response to UTP in both newborn and adult vessels. ATP-induced relaxations were reduced in newborn vessels but there was no effect on the responses of adult vessels. Responses to UTP, ATP and α,β-meATP of intrapulmonary arteries from newborn piglets exposed to chronic hypobaric hypoxia for 3 days were normal. In summary, UTP elicited marked Vasoconstriction of porcine IPA at all ages. UTP and ATP responses were consistent with activation of the P2Y4-receptor recently identified in vascular smooth muscle by others. α,β-meATP induced a small Vasoconstriction in the adult probably via the P2X1-receptor. Responses remained normal in neonatal pulmonary hypertension. Keywords: Pyrimidine, purine, pulmonary artery, neonatal hypertension, Vasoconstriction Introduction The pulmonary vascular resistance is high in utero and remains elevated in persistent pulmonary hypertension of the newborn (PPHN), a clinical syndrome most commonly associated with hypoxic Lung disease (Haworth, 1979; 1993). Whether or not nucleotides play a role in maintaining a high resistance in either of these circumstances is not known. ATP can produce either relaxation or contraction depending upon the P2-receptor subtype(s) present in the tissue and the tone of the vessel investigated (Burnstock, 1997), suggesting that the pulmonary arterial response to ATP might change with age in normal pulmonary arteries as the vascular resistance falls after birth due to maturation of vascular reactivity and structure (Allen & Haworth, 1998; Hall & Haworth, 1987; Haworth et al., 1987; Levy et al., 1995; Liu et al., 1992). At low vascular tone, Vasoconstriction to ATP is the dominant response, mediated by P2X-receptor(s), partly via the P2X1 subtype on smooth muscle and partly by P2X subtypes which have not yet been clearly identified (Benham & Tsien, 1987; Neely et al., 1991; 1996). Currently there are seven recognized P2X-receptors, including the non-selective ion pore P2X7 (formerly P2Z) (Burnstock, 1997). Transcripts of receptor mRNA for the P2X1,2 and 4-receptor sub-units have been co-localized by in situ hybridization in adult rat aortic and pulmonary arterial smooth muscle (Nori et al., 1998). The metabolically stable ATP analogue α,β-meATP evoked a contractile response in the isolated guinea-pig taenia coli and then desensitized P2X-receptors, without significant vasodilator activity (Kasakov & Burnstock, 1983; Kennedy & Leff, 1995). ATP induces a contraction in isolated adult human and rat pulmonary artery and α,β-meATP can block the response suggesting that these agonists act via a common receptor (Liu et al., 1989a,1989b). However, in the isolated perfused adult rat Lung, Vasoconstriction to ATP was only partially inhibited by α,β-meATP (Rubino & Burnstock, 1996). Pyrimidines (uridine nucleotides) are also known to evoke α,β-meATP-insensitive Vasoconstriction of some systemic and pulmonary vessels (Juul et al., 1993; Matsumoto et al., 1997; Ralevic & Burnstock, 1991; 1998; Saiag et al., 1987; 1990); von Kugelgen & Starke, 1990). They can be released from the vascular endothelium of rabbit thoracic aorta, and from platelets, suggesting physiological sources (Goetz et al., 1971; Saiag et al., 1995). Pyrimidine-induced Vasoconstrictions reported for the adult rat small pulmonary artery and adult rabbit coronary artery were thought to be mediated by members of the G-protein coupled, P2Y-receptor family, which can activate phospholipase C through Gq11 and subsequently stimulate a rise of intracellular calcium (Burnstock 1997; Nicholas et al., 1996; Hartley et al., 1998; Matsumoto et al., 1997). Recently, adult rat aorta smooth muscle has been shown to express P2Y2,4, and 6, subtypes, which are known to be activated by pyrimidines (Harper et al., 1998). Persistent pulmonary hypertension of the newborn is a potentially fatal condition, which results in abnormal remodelling of the intrapulmonary arteries during the first few days of life (Allen & Haworth, 1986; Haworth, 1979; 1993). The marked hypertrophy of the IPA smooth muscle cells has been taken to indicate an increase in contractile response to different stimuli, including hypoxia. The role of purines and pyrimidines in this condition is unknown. In an experimental study using the perfused adult rat Lung, the vasoconstrictor response to acute alveolar hypoxia could not be attributed to up-regulation of α,β-methylene-sensitive P2X-receptors (McCormack et al., 1989). In the present study, the response of normal, isolated porcine IPA to cumulative doses of ATP, α,β-meATP and UTP was investigated from foetal to adult life. We also studied P2X-receptor desensitization by α,β-meATP on the response to ATP and UTP. The effect of neonatal pulmonary hypertension was determined in the IPA of newborn piglets which had been exposed to chronic hypobaric hypoxia for 3 days (Tulloh et al., 1997).
B.b. Vargaftig - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological differentiation by pertussis toxin of the in vivo acute responses to fMLP and PAF in guinea-pig Lungs.
British Journal of Pharmacology, 1993Co-Authors: C. D. Arreto, M.f. Bureau, Atsushi Imaizumi, B.b. VargaftigAbstract:Abstract 1. The effects of pertussis toxin on the N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and platelet-activating factor (PAF)-induced variations in pulmonary capillary albumin exchanges, blood volume, leucocyte or platelet sequestration were studied in the guinea-pig, by use of radioactive tracers. The effects of pertussis toxin on pulmonary insufflation pressure were studied in parallel. 2. The i.v. administration of fMLP and PAF to the guinea-pig was followed by bronchoconstriction, increased Lung capillary albumin exchanges (vasopermeability) sequestration of leucocytes, leucopenia and reduction of blood volume (Vasoconstriction). PAF also induced platelet sequestration in Lungs and thrombocytopenia. 3. Pertussis toxin (10 micrograms kg-1, i.v., 72 h before the experiment) prevented all the studied fMLP-induced effects, but failed to modify PAF-induced bronchoconstriction, Lung Vasoconstriction, platelet sequestration, thrombocytopenia and the increased capillary vasopermeability. In the same conditions the Lung leucocyte sequestration was not significantly affected when leucopenia was partially reduced. 4. It is suggested that the effects of fMLP, but not those of PAF, involve a Gi-like protein.
Geoffrey Burnstock - One of the best experts on this subject based on the ideXlab platform.
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Vasoconstriction of intrapulmonary arteries to P2-receptor nucleotides in normal and pulmonary hypertensive newborn piglets
British Journal of Pharmacology, 1999Co-Authors: M R Mcmillan, Geoffrey Burnstock, S G HaworthAbstract:The vasoconstrictor responses of isolated intrapulmonary arteries (IPA) to P2-receptor agonists was investigated during adaptation to extrauterine life in the normal piglet and the effect of pulmonary hypertension was studied following exposure of newborn animals to chronic hypobaric hypoxia (51 kPa) for 3 days. At resting tone, α,β-methyleneATP (α,β-meATP) (P2X-receptor agonist) contracted intrapulmonary arteries from adult, but not immature pigs, and repeated application desensitized the response. Adenosine 5′-triphosphate (ATP) induced endothelium-independent relaxation at low concentrations at all ages, a variable contractile response to high concentrations developed by 3 days, becoming larger and consistent by 14 days of age. Uridine 5′-triphosphate (UTP) evoked a contractile response in normal intrapulmonary arteries from foetal to adult life, the magnitude of the response increasing with age. Endothelial removal and pre-incubation with Nω-nitro-L-arginine methyl ester (L-NAME) (100 μM) increased the contractile response of adult vessels. Pre-incubation with α,β-meATP (100 μM), increased the contractile response to UTP in both newborn and adult vessels. ATP-induced relaxations were reduced in newborn vessels but there was no effect on the responses of adult vessels. Responses to UTP, ATP and α,β-meATP of intrapulmonary arteries from newborn piglets exposed to chronic hypobaric hypoxia for 3 days were normal. In summary, UTP elicited marked Vasoconstriction of porcine IPA at all ages. UTP and ATP responses were consistent with activation of the P2Y4-receptor recently identified in vascular smooth muscle by others. α,β-meATP induced a small Vasoconstriction in the adult probably via the P2X1-receptor. Responses remained normal in neonatal pulmonary hypertension. Keywords: Pyrimidine, purine, pulmonary artery, neonatal hypertension, Vasoconstriction Introduction The pulmonary vascular resistance is high in utero and remains elevated in persistent pulmonary hypertension of the newborn (PPHN), a clinical syndrome most commonly associated with hypoxic Lung disease (Haworth, 1979; 1993). Whether or not nucleotides play a role in maintaining a high resistance in either of these circumstances is not known. ATP can produce either relaxation or contraction depending upon the P2-receptor subtype(s) present in the tissue and the tone of the vessel investigated (Burnstock, 1997), suggesting that the pulmonary arterial response to ATP might change with age in normal pulmonary arteries as the vascular resistance falls after birth due to maturation of vascular reactivity and structure (Allen & Haworth, 1998; Hall & Haworth, 1987; Haworth et al., 1987; Levy et al., 1995; Liu et al., 1992). At low vascular tone, Vasoconstriction to ATP is the dominant response, mediated by P2X-receptor(s), partly via the P2X1 subtype on smooth muscle and partly by P2X subtypes which have not yet been clearly identified (Benham & Tsien, 1987; Neely et al., 1991; 1996). Currently there are seven recognized P2X-receptors, including the non-selective ion pore P2X7 (formerly P2Z) (Burnstock, 1997). Transcripts of receptor mRNA for the P2X1,2 and 4-receptor sub-units have been co-localized by in situ hybridization in adult rat aortic and pulmonary arterial smooth muscle (Nori et al., 1998). The metabolically stable ATP analogue α,β-meATP evoked a contractile response in the isolated guinea-pig taenia coli and then desensitized P2X-receptors, without significant vasodilator activity (Kasakov & Burnstock, 1983; Kennedy & Leff, 1995). ATP induces a contraction in isolated adult human and rat pulmonary artery and α,β-meATP can block the response suggesting that these agonists act via a common receptor (Liu et al., 1989a,1989b). However, in the isolated perfused adult rat Lung, Vasoconstriction to ATP was only partially inhibited by α,β-meATP (Rubino & Burnstock, 1996). Pyrimidines (uridine nucleotides) are also known to evoke α,β-meATP-insensitive Vasoconstriction of some systemic and pulmonary vessels (Juul et al., 1993; Matsumoto et al., 1997; Ralevic & Burnstock, 1991; 1998; Saiag et al., 1987; 1990); von Kugelgen & Starke, 1990). They can be released from the vascular endothelium of rabbit thoracic aorta, and from platelets, suggesting physiological sources (Goetz et al., 1971; Saiag et al., 1995). Pyrimidine-induced Vasoconstrictions reported for the adult rat small pulmonary artery and adult rabbit coronary artery were thought to be mediated by members of the G-protein coupled, P2Y-receptor family, which can activate phospholipase C through Gq11 and subsequently stimulate a rise of intracellular calcium (Burnstock 1997; Nicholas et al., 1996; Hartley et al., 1998; Matsumoto et al., 1997). Recently, adult rat aorta smooth muscle has been shown to express P2Y2,4, and 6, subtypes, which are known to be activated by pyrimidines (Harper et al., 1998). Persistent pulmonary hypertension of the newborn is a potentially fatal condition, which results in abnormal remodelling of the intrapulmonary arteries during the first few days of life (Allen & Haworth, 1986; Haworth, 1979; 1993). The marked hypertrophy of the IPA smooth muscle cells has been taken to indicate an increase in contractile response to different stimuli, including hypoxia. The role of purines and pyrimidines in this condition is unknown. In an experimental study using the perfused adult rat Lung, the vasoconstrictor response to acute alveolar hypoxia could not be attributed to up-regulation of α,β-methylene-sensitive P2X-receptors (McCormack et al., 1989). In the present study, the response of normal, isolated porcine IPA to cumulative doses of ATP, α,β-meATP and UTP was investigated from foetal to adult life. We also studied P2X-receptor desensitization by α,β-meATP on the response to ATP and UTP. The effect of neonatal pulmonary hypertension was determined in the IPA of newborn piglets which had been exposed to chronic hypobaric hypoxia for 3 days (Tulloh et al., 1997).
C. D. Arreto - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological differentiation by pertussis toxin of the in vivo acute responses to fMLP and PAF in guinea-pig Lungs.
British Journal of Pharmacology, 1993Co-Authors: C. D. Arreto, M.f. Bureau, Atsushi Imaizumi, B.b. VargaftigAbstract:Abstract 1. The effects of pertussis toxin on the N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and platelet-activating factor (PAF)-induced variations in pulmonary capillary albumin exchanges, blood volume, leucocyte or platelet sequestration were studied in the guinea-pig, by use of radioactive tracers. The effects of pertussis toxin on pulmonary insufflation pressure were studied in parallel. 2. The i.v. administration of fMLP and PAF to the guinea-pig was followed by bronchoconstriction, increased Lung capillary albumin exchanges (vasopermeability) sequestration of leucocytes, leucopenia and reduction of blood volume (Vasoconstriction). PAF also induced platelet sequestration in Lungs and thrombocytopenia. 3. Pertussis toxin (10 micrograms kg-1, i.v., 72 h before the experiment) prevented all the studied fMLP-induced effects, but failed to modify PAF-induced bronchoconstriction, Lung Vasoconstriction, platelet sequestration, thrombocytopenia and the increased capillary vasopermeability. In the same conditions the Lung leucocyte sequestration was not significantly affected when leucopenia was partially reduced. 4. It is suggested that the effects of fMLP, but not those of PAF, involve a Gi-like protein.
