Biomedical subjects

J C McGrath

Publications and source records attributed to J C McGrath.

At least 19 recordsLinked to original sources

PubMed1995

The relationship between the adrenoceptor and nonadrenoceptor-mediated effects of imidazoline- and imidazole-containing compounds.

This article brings together work on imidazoline or imidazole-containing compounds concerned with the pharmacology of alpha-adrenoceptors, principally on smooth muscle, to illustrate how imidazolines have contributed to the subclassification of alpha-adrenoceptors and how, against this background, attempts have been made to use this knowledge to uncover "nonadrenoceptor"-mediated biological effects of previously uncharacterized compounds, notably imidazole-containing dipeptides and "clonidine displacing substance" (CDS). Recent data are included on (1) the pharmacology of UK-14304, (2) nonadrenoceptor actions of phentolamine, (3) the pharmacology of tissue extracts containing imidazole-containing dipeptides and CDS activity, and (4) ligand binding data at I1 and I2 sites.

Animals↗

PubMed1995

Contractile effects of prostanoids on fetal rabbit ductus arteriosus.

We wished to determine whether any evidence indicates that the ductus arteriosus has prostanoid receptors coupled to contractile pathways and whether the sensitivity of the ductus to the dilator effect of prostaglandin E2 (PGE2) was inhibited by other prostanoids. Rings of ductus arteriosus were isolated from fetal New Zealand White rabbits (28 days of gestation) and mounted in vitro. In the presence of 1 microM indomethacin, the vessel was relaxed with either 300 nM forskolin or 10 nM PGE2, and cumulative concentration-contraction response curves to several synthetic prostanoids were obtained with or without a receptor antagonist when available. The vessel was also precontracted with 1 microM indomethacin and 25 mM K+ in 13-14.5 kPa O2, and cumulative concentration-relaxation response curves to PGE2 were obtained with and without addition of prostanoids. In 300 nM forskolin, both U46619 and sulprostone caused concentration-dependent contractions of the ductus in the nanomolar range (EC50 values, i.e., the interpolated molar concentration of the drug causing 50% of its own eventual maximum response of 33 and 42 nM, respectively). Responses to GR63799X and PGF2 alpha were complicated by the fact that these agonists caused relaxation at high concentrations (> or = 30 nM). The response to U46619 was shifted to the right by the thromboxane receptor antagonist EP 092. In 10 nM PGE2, U46619, sulprostone, and GR63799X elicited similar contractile responses, whereas PGF2 alpha had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

The role of alpha 2-adrenoceptors in the vasculature of the rat tail.

1. The effects of alpha 2-adrenoceptor agonists and antagonists on rat tail skin temperature (tts), an indicator of local cutaneous blood flow, were studied in conscious and anaesthetized rats and in the isolated, Krebs perfused, vascular bed of the rat tail. 2. In conscious rats, at an ambient temperature of 18.5-20 degrees C, tts was 21.0 +/- 0.2 degrees C and core (rectal) temperature (tc) was 38.2 +/- 0.04 degrees C (n = 126). The alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197; 1 mg kg-1, s.c., n = 6), produced a rapid elevation in tts to 29.1 +/- 0.7 degrees C (P < 0.001 vs. saline-treated control group), attained 10 min after injection. tc fell slightly, by 1.0 +/- 0.1 degrees C. The tts response was dose-related over the dose-range tested (0.01-1 mg kg-1, s.c.), with an ED50 of 17 micrograms kg-1, s.c. (n = 6 per dose). 3. The maximum increases in tts in response to a dose of 1 mg kg-1, s.c. of alpha 2-adrenoceptor antagonists were as follows (n = 6 per drug): delequamine (+9.6 +/- 0.8 degrees C) > yohimbine (+9.0 +/- 1.0 degrees C) > WY-26703 (+7.9 +/- 1.3 degrees C) > piperoxan (+5.6 +/- 1.7 degrees C) > idazoxan (+4.6 +/- 1.3 degrees C) > imiloxan (+4.1 +/- 1.3 degrees C) > SKF 104078 (+2.0 +/- 1.9 degrees C) > BDF-6143 (+1.3 +/- 0.8 degrees C). 4. Prazosin (0.3 mg kg-1, s.c.), hydralazine (10 mg kg-1, s.c.) and nifedipine (3 mg kg-1, s.c.) did not increase tts, whereas propranolol (10 mg kg-1, s.c.) evoked a small increase in tts (+2.9 +/- 1.0 degrees C). Pentolinium (2-10 mg kg-1, s.c.) elicited a dose-related increase in tts, which was elevated by 4.4 +/- 1.3 degrees C after a dose of 10 mg kg-1; tc was reduced in a dose-related manner. Drug vehicles (1 ml kg-1, s.c.) had no effect on tts or tc. 5. In anaesthetized rats, idazoxan (300 microg, i.v.) produced a rapid increase in tts which was detectable 2 min after beginning the injection, reaching a peak after 7 min. When the same dose was administered i.c.v., tts also rose, but more slowly. The peak response (+ 3.6 +/- 0.70C, n = 5) was significantly smaller than when idazoxan was administered intravenously (+ 6.3 +/- 1.2 C, n = 5), which suggests that the increase in tts following systemic administration of M2-adrenoceptor antagonists is not due to a central effect. The change in tts was not secondary to changes in blood pressure.6. In the isolated, Krebs perfused, tail vascular bed of the rat, at an ambient temperature of 20-21C,under constant flow conditions (3.5-4.0 ml min-1; n = 4), baseline perfusion pressure was 57 +/- 4 mmHg.5-Hydroxytryptamine (5-HT; 70-150 nM) increased perfusion pressure by 56+/- 9 mmHg. The alpha2-adrenoceptor agonist, UK-14,304 (10 nmol), elicited a further increase in perfusion pressure by27.5 +/- 15 mmHg but had no effect in the absence of 5-HT; this response to UK-14,304 was abolished by rauwolscine (1 microM).7. Under constant pressure conditions (-100 mmHg; n = 9), baseline mean perfusion flow was 2.1 +/- 0.2 ml min-1, and mean tail skin temperature was 31.6 +/- 0.6C. 5-HT (119 +/- 28 nM) decreased tts.by 3.3 +/- 2.0 C and reduced flow by 1.2 +/- 0.3 ml min-1. UK-14,304 (10 nmol) further reduced tts by 3.0 +/- 0.3 C without significant effect on flow; this effect was also abolished by 1 microM rauwolscine.8. We conclude that post-junctional M2-adrenoceptors in the vasculature of the rat tail have a major vasoconstrictor role, controlling both the flow and distribution of blood within the tail and thereby thermoregulatory heat loss from its surface.

Adrenergic Antagonists↗

PubMed1994

Mechanical and biochemical responses to endothelin-1 and endothelin-3 in human bronchi.

In human bronchi, contractions to endothelin-1 were unaltered by atropine (10(-5) M), indomethacin (10(-6) M), nifedipine (10(-5) M), or phosphoramidon (3.67 x 10(-5) M). Endothelin-3-evoked contractions were markedly enhanced by phosphoramidon (3.67 x 10(-5) M), unaffected by atropine (10(-5) M), and attenuated by indomethacin (10(-6) M) or nifedipine (10(-5) M). Phorbol 12,13-dibutyrate (PDB, 10(-8) M) enhanced both endothelin-1- and endothelin-3 (plus phosphoramidon)-evoked responses, an effect abolished by Ro 31-8220 (3 x 10(-8) M). Contractions to endothelin-1 or endothelin-3 alone were unaltered by staurosporine 10(-8)-3 x 10(-7) M) or Ro 31-8220 (3 x 10(-9)-3 x 10(-8) M). Endothelin-1 (3 x 10(-7) M), but not endothelin-3 (10(-10)-3 x 10(-7) M), evoked a rise in levels of inositol (1,4,5) trisphosphate (Ins(1,4,5)P3). These results suggest that endothelin-1 does not act via cyclo-oxygenase metabolites nor require Ca2+ influx via dihydropyridine-sensitive channels. It evokes Ins(1,4,5)P3 production, but does not rely upon protein kinase C activation for contraction. Endothelin-3-evoked contractions are partly mediated by cyclo-oxygenase metabolites. Endothelin-3 does not stimulate phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, nor utilise protein kinase C to produce contraction, but its actions may rely upon extracellular Ca2+.

Atropine↗

PubMed1994

Angiotensin II enhances responses to endothelin-1 in bovine bronchial smooth muscle.

Angiotensin II and endothelin-1 are putative mediators in asthma. In this study we have examined the effect of angiotensin II on endothelin-1-induced contractions in bovine bronchi and the receptor types involved in the response to these agonists. Angiotensin II alone is very low in potency, producing only small contractions. In the presence of angiotensin II 10(-7) or 3 x 10(-7) M, contractions evoked by endothelin-1 were markedly enhanced. The AII1-receptor antagonist, losartan, abolished this enhancement suggesting that angiotensin II exerts this effect via an AII1-receptor. The contraction evoked by endothelin-1 is mediated via an EtA-receptor subtype since the EtA-receptor antagonist FR139317 attenuated the response. This is offset by an inhibitory EtB-type receptor, resulting in a larger contraction when these receptors are desensitized. Indeed, the EtB-receptor agonist sarafotoxin S6c reversed methacholine-evoked tone in a concentration-dependent manner. In conclusion, angiotensin II potentiates contractions evoked by endothelin-1 in bovine bronchi. This may be a mechanism by which angiotensin II--which has little activity in bronchi--may evoke substantial changes in airway tone. Angiotensin II evokes this potentiation via AII1-receptors, whilst endothelin-1 evokes contraction via EtA-receptors, an action which is offset by an inhibitory effect of EtB-receptors.

Angiotensin II↗

PubMed1994

Atrial natriuretic peptide counteracts the vasoconstrictor effects of 5-hydroxytryptamine, U46619 and endothelin-1 in the human umbilical artery.

A role for atrial natriuretic peptide (ANP) in maintaining low vascular resistance within the fetoplacental circulation was investigated using isolated strips of human umbilical artery (HUA). Physiological levels of ANP significantly reduced the isometric contractile response of the HUA to U46619 (a stable thromboxane A2 mimetic), to 5-hydroxytryptamine and to endothelin-1, though no effect on agonist sensitivity could be demonstrated. These data suggest that ANP may modify vascular tone in vivo thereby counterbalancing several humoral factors which act to increase vascular resistance within the fetoplacental circulation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1994

Modulation of the effect of atrial natriuretic peptide in human and bovine bronchi by phosphoramidon.

1. We have previously shown that atrial natriuretic peptide causes bronchodilatation and reduces bronchial reactivity when administered intravenously or by inhalation to asthmatic patients. We wished to determine the direct effect of exogenously applied atrial natriuretic peptide on isolated airway and the role of proteases important in atrial natriuretic peptide degradation in other organ systems. 2. The ability of atrial natriuretic peptide (alpha-human atrial natriuretic peptide 28-amino acid) to relax precontracted tissues and to protect against methacholine-induced contraction was studied in human and bovine tissue. The role of neutral endopeptidase-24.11 and other proteases in regulating the effect of atrial natriuretic peptide on bronchial smooth muscle was also examined by studying the influence of phosphoramidon, a protease inhibitor, whose actions include the inhibition of neutral endopeptidase-24.11, and the protease inhibitors leupeptin, aprotinin and soybean trypsin inhibitor on the airway response to atrial natriuretic peptide. 3. In human and bovine tissue atrial natriuretic peptide (10(-6) mol/l) caused a slight relaxation of methacholine-contracted tissue [mean (SEM) percentage inhibition of contraction of 13.2 (3.02)% and 9.41 (2.63)% respectively] and evoked a significant rightward shift of the cumulative concentration-response curve to methacholine [pD2 5.15 (0.23) and 4.85 (0.1) compared with control values of 6.14 (0.1) and 5.85 (0.16), respectively]. 4. Phosphoramidon potentiated atrial natriuretic peptide-induced relaxation of methacholine-induced tone and the ability of atrial natriuretic peptide to protect against methacholine-induced contraction. The combination of leupeptine, aprotinin and soybean trypsin inhibitor did not significantly alter the bronchial response to atrial natriuretic peptide in either human or bovine tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Mechanical and biochemical responses to endothelin-1 and endothelin-3 in bovine bronchial smooth muscle.

1. In this study, mechanical responses to endothelin-1 and endothelin-3 were examined in bovine bronchial smooth muscle. In addition, the involvement of phosphatidylinositol 4,5-bisphosphate hydrolysis (PIP2) in the responses to these peptides was assessed by measurement of inositol (1,4,5) trisphosphate (I(1,4,5)P3) production using a specific mass assay. 2. ET-1 evoked contractions of bovine bronchi which were concentration-dependent and initiated at between 10(-9) M and 10(-8) M. ET-1-evoked responses were unaffected by slight elevation of tone with potassium chloride (3 x 10(-2) M), methacholine (10(-6) M) or U46619 (10(-7) M). 3. Contractions to ET-1 were not altered by pre-incubation with atropine (10(-5) M), indomethacin (10(-5) M), nifedipine (10(-5) M), phosphoramidon (3.67 x 10(-5) M) or by removal of the epithelium. 4. ET-3 evoked small contractions which were not concentration-dependent. In the presence of phosphoramidon (3.67 x 10(-5) M) however, concentration-dependent contractions were obtained to ET-3 which were unaffected by atropine (10(-5) M) or by removal of the epithelium, but were significantly attenuated by indomethacin (10(-5) M). Nifedipine (10(-5) M) virtually abolished this response. 5. Both ET-1 and ET-3 (in the presence of phosphoramidon)-evoked contractions were significantly enhanced by the presence of the phorbol ester phorbol 12,13-dibutyrate (10(-8) M). Neither ET-1-, nor ET-3-mediated responses were antagonized by the protein kinase C (PKC) inhibitor, Ro 31-8220 (3 x 10(-9) - 3 x 10(-8) M). 6. ET-1 (3 x 10(-7) M) evoked a biphasic rise in levels of I(1,4,5)P3 which was unaltered by preincubation with atropine, whilst ET-3 (10(-10) - 3 x 10(-7) M) failed to alter levels of I(1,4,5)P3 at any time point examined, even in the presence of phosphoramidon (3.67 x 10(-5) M). 7. These results suggest that, in bovine bronchial smooth muscle, ET-l does not evoke contraction via cyclo-oxygenase metabolites, does not evoke release of the neurotransmitter substance acetylcholine, or require calcium influx via dihydropyridine-sensitive channels. ET-1 evokes 1(1,4,5)P3 production, but stimulation of protein kinase C may not be critical for the associated contraction. In contrast,ET-3-evoked contractions are partly mediated by cyclo-oxygenase metabolites. ET-3 does not stimulate PIP2 hydrolysis, nor activate PKC, but may, either directly or as a requirement of intermediates released in response to ET-3, rely upon extracellular calcium.

Animals↗

PubMed1994

Interactions between indomethacin, noradrenaline and vasodilators in the fetal rabbit ductus arteriosus.

1. Interactions between indomethacin, noradrenaline and vasodilators were studied in rings of ductus arteriosus isolated from fetal rabbits. The effect of incubation with prostaglandin E2 (PGE2) on the noradrenaline concentration-contraction response curve was studied in the presence and absence of indomethacin. Also, the ductus was pre-contracted with 10 microM noradrenaline and concentration-relaxation response curves (CRRC) to PGE2, cicaprost, cromakalim and forskolin were obtained in the presence and absence of indomethacin. 2. In the absence of indomethacin, PGE2 (from 1 nM to 100 nM) decreased the pEC50 to noradrenaline to a maximum of 0.4 to 0.5 log units (i.e. an approximately three fold increase in EC50 [M]). In the presence of 1 microM indomethacin, PGE2 (0.1 nM to 100 nM) decreased the pEC50 to noradrenaline by 2.39 log units (i.e. a 245 fold increase in EC50). By comparing the control pEC50 to noradrenaline with the relationship between the pEC50 to noradrenaline and [PGE2] in 1 microM indomethacin, the effect of endogenous PGE2 synthesized in the vessel wall was estimated as being equivalent to a bath concentration of approximately 1 nM exogenous PGE2. 3. When the vessel was pre-contracted with 10 microM noradrenaline, indomethacin had no effect on the CRRC to PGE2 but did alter the CRRC to other vasodilators. The sensitivity of the vessel to cicaprost, cromakalim and forskolin was decreased in 1 microM indomethacin compared with control. Forskolin caused complete relaxation in the presence and absence of indomethacin. Indomethacin decreased the maximum response to cromakalim but increased the maximum response to cicaprost. PGE2, 0.3 nm, partially reversed the effect of indomethacin on the sensitivity of the vessel to forskolin.4. We conclude that under varying experimental conditions, indomethacin increased the sensitivity of the ductus to the effects of PGE2 but decreased its sensitivity to other vasodilators. Both effects can be explained by elimination of endogenous PGE2. However, indomethacin increased the maximum response to cicaprost, which cannot be explained by elimination of endogenous PGE2 but may be due to elimination of endogenous prostacyclin.

Animals↗

PubMed1994

The interaction of alpha-human atrial natriuretic peptide (ANP) with salbutamol, sodium nitroprusside and isosorbide dinitrate in human bronchial smooth muscle.

1. Contractions in human bronchial rings evoked by methacholine (10(-6) M) were reversed by single contractions of alpha-human atrial natriuretic peptide (10(-6) M), salbutamol (10(-6) M), sodium nitroprusside (10(-6) M) or isosorbide dinitrate (4.2 x 10(-5) M) and the extent of the relaxations compared. The activity of combinations of ANP with salbutamol, sodium nitroprusside and isosorbide dinitrate were compared with those for each agonist alone. 2. ANP and salbutamol were equipotent in reversing methacholine-evoked contraction and, in combination these agonists evoked an additive response. ANP and sodium nitroprusside also evoked similar degrees of relaxation and were additive, as were ANP and isosorbide dinitrate; however, with isosorbide dinitrate a higher concentration was required to evoke the same degree of relaxation as ANP, sodium nitroprusside or salbutamol. 3. Cumulative concentration-response curves to methacholine (10(-9)-3 x 10(-4) M) were examined in the presence and absence of the above bronchodilator substances, alone and in combination allowing their abilities to protect against contraction to be compared. ANP (10(-6) M) and salbutamol (10(-6) M) each attenuated subsequent contractions evoked by methacholine, an ability not shared with sodium nitroprusside (10(-6) M) or isosorbide dinitrate (4.2 x 10(-5) M). Indeed at lower concentrations of methacholine (< 3 x 10(-7) M), sodium nitroprusside evoked a paradoxical enhancement of methacholine-evoked contractions. 4. In combination, ANP and salbutamol attenuated contractions evoked by methacholine to a significantly greater degree than that seen with either agonist alone, whilst a combination of ANP and sodium nitroprusside evoked no greater effect than that seen with ANP alone. By contrast, isosorbide dinitrate and ANP together evoked a greater inhibition than ANP alone.5 These results suggest that a combination of agents such as ANP and salbutamol evokes a greater effect than either alone, both in reversing and protecting against methacholine-evoked contractions.Such combinations may be of benefit in the treatment of patients, allowing lower doses of drug to be used. Combinations of ANP and isosorbide dinitrate may likewise be of interest; however, the mechanism underlying the enhancement of ANP responses by isosorbide dinitrate requires further study.

Albuterol↗

PubMed1994

Endogenous nitric oxide modulates vasopressor responses, but not depressor responses, to spinal sympathetic nerve stimulation in pithed rats.

The effects of N omega-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide (NO) synthase (1,5, and 10 mg/kg) on vasopressor and depressor responses to segmental sympathetic nerve stimulation were studied in the pithed rat preparation. Vasopressor responses were evoked by stimulation of the spinal sympathetic outflow at T6-T8 (30 V, 0.05 ms at 5 Hz with 10 pulses). This pressor response was biphasic: An initial transient response (to nerve stimulation) was followed by a later prolonged response (to adrenal catecholamine release). L-NAME 1, 5, and 10 mg/kg increased mean arterial blood pressure (MAP); this effect was maximal at 1 mg/kg L-NAME, but had no effect on heart rate (HR). L-NAME 1, 5, and 10 mg/kg potentiated both phases of the pressor response; the effect was maximal at 10 mg/kg. Vasodepressor responses were evoked by stimulation of the spinal sympathetic outflow at S2-L6 (30 V, 0.05 ms at 5 Hz with 10 pulses). L-NAME 1, 5, and 10 mg/kg did not inhibit these depressor responses. We conclude that inhibition of the synthesis of endogenous NO causes a hypertension in pithed rats that is associated with increased vasoconstriction in response to sympathetic nerve stimulation and adrenal catecholamine release. Systemic vascular depressor responses to segmental sympathetic nerve stimulation are not affected, however; therefore, NO cannot be the major mediator of these responses.

Animals↗

PubMed1994

Characterization of dilator prostanoid receptors in the fetal rabbit ductus arteriosus.

The purpose of this study was to determine which receptors mediate the dilator effects of prostaglandins (PGs) on the ductus arteriosus of the fetal rabbit. Isolated rings of the vessel from fetal New Zealand White rabbits were precontracted with indomethacin (1 microM) and potassium (25 mM) in 100 to 110 mmHg oxygen, and the dilator effects of a range of synthetic prostanoids were quantified by cumulative relaxant concentration-effect curves. The potencies of agonists were quantified with reference to PGE2 by the equieffective molar ratio (EMR): EC50 test agonist/EC50 PGE2. The effects on these responses of available antagonists were also studied. None of a range of synthetic prostanoids with selective agonism of EP1, EP2 or EP3 receptors was as potent as PGE2. The rank order of potency was as follows: PGE2 (EC50 = 0.36 nM [95% confidence intervals [CI] = 0.32-0.41, n = 44], EMR = unity) >> misoprostol (EMR 145, 95% CI 73-217) > [1R-[1 alpha (Z),2 beta (R*),3 alpha]]-4-(benzoyl-amino)phenyl 7-[3 hydroxy-2(2-hydroxy-3-phenoxypropoxy)-5- oxocyclopentyl]-4-heptenoate, single enantiomer (GR 63799K) (EMR 685, 95% CI 427-944) >> ((+/-)-trans-2-[4[(1-hydroxphenyl) phenyl]-5-oxocylopentaneheptanoic acid (AH13205) (EMR > 100,000) > or = sulprostone (EMR > 10,000) > or = 0. The EP1 antagonists, 6-isopropoxy-9-oxoxanthine-2-carboxylic acid (AH6809) (10 microM) and 8-clorodi-benz[b,f][1,4]oxazepine-10 (11H)-carboxylic acid, 2-acetylhydrazide (SC19220) (30 microM), had no significant effect on the sensitivity of the ductus to PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Characterisation of the effect of oxygen tension on response of fetal rabbit ductus arteriosus to vasodilators.

OBJECTIVE: The aims of the study were (1) to elucidate the effects of raised oxygen tension on the response of the ductus arteriosus to a range of vasodilators; and (2) to establish the effect, if any, of cyclo-oxygenase inhibition on the interaction between oxygen and prostaglandin (PG)E2. METHODS: Rings of ductus arteriosus were isolated from fetal New Zealand White rabbits at 28 d gestation (term = 31) and precontracted with 10 microM noradrenaline in the presence of the cyclo-oxygenase inhibitor indomethacin (1 microM). Cumulative relaxation response curves were obtained from a range of vasodilators and their pEC50 (-log10 of the interpolated molar concentration causing 50% of the maximum response) and maximum relaxant response (MRR) were determined in 15% oxygen (neonatal oxygen tension, 13-14.3 kPa) and 2% oxygen (fetal oxygen tension, 2.5-3.0 kPa). In addition, the effects of (1) omitting indomethacin and (2) its substitution by 1 microM flubriprofen were studied on the interaction between oxygen and PGE2. RESULTS: In 1 microM indomethacin, nifedipine and atrial natriuretic peptide had no effect on ductal tone in either oxygen tension. In 15% oxygen, the rank order of MRR was forskolin > cicaprost > PGE2 >> cromakalim >> sodium nitroprusside approximately adenosine approximately 0. The MRR of all agonists was increased in 2% oxygen except forskolin which caused complete relaxation in 15% oxygen. In 15% oxygen, the rank order of pEC50 was PGE2 >> cicaprost approximately cromakalim approximately forskolin. PGE2 was 70.8 times more potent than cicaprost. The pEC50 of all four agonists was increased in 2% oxygen. The increase in pEC50 could not be explained by a decreased extent of precontraction. The MRR to PGE2 in 15% oxygen and the magnitude of the increase in pEC50 to PGE2 going from 15% to 2% oxygen were the same in 1 microM flubriprofen, 1 microM indomethacin, or in the absence of these drugs. However, in 2% oxygen, the MRR to PGE2 was increased in 1 microM indomethacin or 1 microM flubriprofen compared with control. CONCLUSIONS: (1) Increasing oxygen tension from fetal to neonatal levels desensitises the ductus arteriosus to a range of vasodilators. (2) There is evidence that prostacyclin has a physiological role in the control of the rabbit ductus arteriosus. (3) The effect of oxygen on the potency of PGE2 is independent of cyclo-oxygenase products, whereas its effect on the efficacy of PGE2 is modulated by an endogenous cyclo-oxygenase product.

Adenosine↗

PubMed1993

Influences of the endothelium and hypoxia on neurogenic transmission in the isolated pulmonary artery of the rabbit.

1. The effects of nitric oxide (10(-6) M), N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M, an inhibitor of nitric oxide synthase), endothelium removal, hypoxia and selective alpha-adrenoceptor antagonists on responses to nerve electrical field-stimulation (EFS) were studied in the rabbit isolated pulmonary artery. 2. EFS induced frequency-dependent contractions which were abolished by prazosin (alpha 1-adrenoceptor antagonist) and unaffected by rauwolscine (alpha 2-adrenoceptor antagonist). EFS-induced responses were potentiated by L-NAME and inhibited by nitric oxide. The effect of L-NAME was reversed by the presence of L-arginine (2 x 10(-4) M), which had no effect on its own. In the presence of L-NAME, the EFS-induced responses were reduced by rauwolscine and the residual responses were abolished by prazosin. 3. Removal of the vascular endothelium increased the maximum contractile response to EFS but did not inhibit the ability of L-NAME to potentiate contractile responses to EFS. 4. Hypoxia inhibited the contractile response to EFS. This effect of hypoxia was also seen in the presence of L-NAME and in endothelium rubbed preparations. 5. In conclusion, the endothelium modulates EFS-induced contractions in the rabbit pulmonary artery. The contraction induced by EFS was inhibited by nitric oxide, but potentiated by the nitric oxide-synthase inhibitor, L-NAME. The effect of L-NAME was not mediated solely through the endothelium and revealed involvement of alpha 2-adrenoceptors in EFS-induced contraction. Hypoxia inhibited neurogenic responses in rabbit isolated pulmonary arteries.

Adrenergic alpha-Antagonists↗

PubMed1993

Influences of the endothelium and hypoxia on alpha 1- and alpha 2-adrenoceptor-mediated responses in the rabbit isolated pulmonary artery.

1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide. Experimental hypoxia had differential effects on all three agonists and did not mimic the effect of nitric oxide synthase inhibition.

Adrenergic alpha-Agonists↗

PubMed1993

Thromboxane A2 analogue, U-46619, potentiates calcium-activated force in human umbilical artery.

It has previously been shown that human umbilical artery (HUA) smooth muscle produces thromboxane A2 in response to increasing oxygen levels and that this thromboxane promotes contraction. To investigate the intracellular action of thromboxane A2, strips of HUA longitudinal smooth muscle were permeabilized using alpha-toxin from the bacterium Staphylococcus aureus. This treatment rendered the surface membrane permeable to low-molecular-weight substances but left functional thromboxane A2 receptors. Tension measurements were used to investigate the effect of the stable thromboxane A2 analogue, U-46619, on the Ca2+ sensitivity of smooth muscle contractile proteins. U-46619 (1 nM to 1 microM) potentiated submaximal Ca(2+)-activated force (generated by [Ca2+], 50 nM to 3 microM) but not maximal Ca(2+)-activated force (generated by [Ca2+], 10-100 microM). The specific thromboxane A2 receptor antagonist, GR-32191B (1 microM), inhibited the action of U-46619 (0.1 microM). The potentiation of submaximal Ca(2+)-activated force produced by the muscle in response to U-46619 (0.1 microM) was antagonized by guanosine 5'-O-(2-thiodiphosphate) (1 mM), the nonhydrolyzable analogue of GDP, and mimicked by guanosine 5'-O-(3-thiotriphosphate) (100 microM), the nonhydrolyzable analogue of GTP. These results suggest that U-46619 acts via the previously identified thromboxane A2 receptor to promote Ca2+ sensitivity of tension production in HUA smooth muscle. Furthermore, this effect appears to be mediated via a G protein.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

The effect of ethanol on responses of the isolated rabbit ileocolic artery.

Antagonist drugs were used to separate the purinergic and adrenergic contributions involved in the sympathetic vasopressor responses produced by electrical field stimulation in the ileocolic artery of the rabbit. Blocking drugs were applied either alone or in various combinations and sequences. The effect of ethanol was studied in conditions of alpha-adrenoceptor blockade, P2x purinoceptor desensitisation, or in the absence of antagonists. From these studies it is concluded that ethanol has a selective potentiating effect on alpha-adrenoceptor-mediated responses.

Adenosine Triphosphate↗

PubMed1992

Endogenous nitric oxide modulates sympathetic neuroeffector transmission in the isolated rabbit lateral saphenous vein.

The rabbit isolated lateral saphenous vein (RLSV) has a heterogeneous population of alpha-adrenoceptors. Responses to electrical field stimulation, in the presence of cocaine, exhibit both alpha 1- and alpha 2-adrenoceptor-mediated components. The present study examined sympathetic neuroeffector transmission and the response to exogenous catecholamines after inhibition of nitric oxide (NO) synthesis with N omega-nitro-L-arginine methyl ester (L-NAME). A comparison of the response in the presence and absence of a functional endothelium was also carried out. L-NAME potentiated the first and second components of the response to nerve stimulation on the order of 300 and 500%, respectively. L-NAME also significantly potentiated responses to norepinephrine (NE), phenylephrine (PE), and UK 14304. Selective antagonism of the first phase was seen with prazosin (alpha 1-antagonist, 0.1 microM) and the second phase with rauwolscine (alpha 2-antagonist, 1 microM). In the presence of L-NAME, the remaining (uninhibited) components were potentiated. Removal of endothelial function induced by gentle rubbing of the intimal surface abolished potentiation to exogenous NE, PE, and UK14304 by L-NAME. However, a significant degree of potentiation of the neurogenic response was observed in the rubbed tissues in response to L-NAME. This suggests that there may be a nonendothelial source of NO that can modulate the neurogenic response to electrical field stimulation.

Adrenergic alpha-Agonists↗