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Biomedical subjects

A H Chester

Publications and source records attributed to A H Chester.

71 records · Page 4Linked to original sources
PubMed1992

Effects of vasoactive neuropeptides on human saphenous vein.

OBJECTIVE: To assess the role of neuropeptides in the control of vascular tone in the human saphenous vein the actions of substance P, vasoactive intestinal peptide, calcitonin gene related peptide, neuropeptide Y, and somatostatin on this blood vessel were examined. METHODS: In vitro organ bath techniques were used with preparations of saphenous veins obtained from 29 patients (aged 41-66) who were undergoing coronary bypass surgery. RESULTS: Substance P, vasoactive intestinal peptide, and calcitonin gene related peptide relaxed pre-constricted vessels in a dose dependent manner with a rapid onset of action, taking one to two minutes to reach a plateau at each dose. Substance P (10(-9) to 10(-6) mol/l) induced relaxation with a maximum response (mean (SEM)) 23.0 (6.6)% of the total relaxation induced by glyceryl trinitrate 1 microgram/ml and a 50% maximal effective concentration of 6.8 x 10(-9) mol/l. Vasoactive intestinal peptide (10(-10) to 10(-7) mol/l) produced a relaxation of 27.0 (5.1)% at 10(-7) mol/l. The maximum responses induced by substance P and vasoactive intestinal peptide were significantly reduced, to 3.7 (2.8)% and 4.7 (2.0)% respectively, after removal of the endothelium. Calcitonin gene related peptide (10(-10) to 10(-7) mol/l) elicited only 14.3 (2.6)% relaxation at 10(-7) mol/l, and this was not affected by removal of the endothelium. By contrast, neuropeptide Y and somatostatin exerted concentration dependent constriction on resting vessels. Neuropeptide Y (10(-10) to 10(-7) mol/l) caused prolonged contraction (roughly 20 minutes to reach a maximum plateau at each dose). At 10(-7) mol/l, the constriction amounted to 28.0 (12.0)% of the response to 90 mM KCl, in ring segments with or without endothelium. Somatostatin (10(-10) to 10(-6) mol/l) quickly caused contraction with a maximum response of 42.7 (15.0)% and a maximum response of 42.7 (15.0)% and a 50% maximal effective concentration of 6.7 x 10(-6) mol/l. The constriction was greatly increased when endothelium was removed, with a maximum response of 78.2 (16.8)% and a 50% maximal effective concentration of 4.3 x 10(-7) mol/l. CONCLUSIONS: Vasoactive peptides have diverse effects on the vascular tone these effects are endothelium dependent. The exact physiological role and implication for performance of bypass grafts require further investigation.

Adult↗
PubMed1992

Effects of leukotrienes C4 and D4 on human isolated saphenous veins.

1. Vascular injury during the intra-operative procedures of bypass surgery may be the initiating event in the gradual deterioration in the patency of the graft. Adhesion of leukocytes to the vascular endothelium frequently accompanies preparation and insertion of the graft. However, little is known about the effects of vasoactive substances released from leukocytes on vein graft performance. 2. To determine whether leukotrienes are capable of affecting the tone of blood vessels used as coronary artery bypass grafts we studied the human saphenous vein as intact rings using an isolated organ bath technique. 3. LTC4 and LTD4 caused weak endothelium-dependent relaxations at lower concentrations (1 pM to 1 nM) and powerful endothelium-independent contractions at higher concentrations (3 nM to 0.1 microM). The maximum responses to LTC4 and LTD4 for relaxations were 21.1 +/- 4.8% and 28.6 +/- 3.4% (% of noradrenaline induced tone) respectively and 64.6 +/- 9.9% and 59.1 +/- 7.9% (% response to KCl) respectively for contractions. 4. The inhibitor of nitric oxide formation, L-NG-monomethyl L-arginine, prevented the relaxations to LTD4, but not LTC4 and unmasked endothelium-dependent contractions to LTD4 (32.9 +/- 11.3%). NG-monomethyl L-arginine had no effect on the contractions produced by LTC4 or LTD4. 5. Indomethacin augmented relaxations and contractions of saphenous vein to LTC4 from 22.5 +/- 5.6 to 40.02 +/- 8.7 (P < 0.05) and 48.8 +/- 5.5% to 74.7 +/- 7.6% (P < 0.01) respectively. LTD4 responses were not affected by indomethacin treatment. 6. In conclusion, leukotrienes mediate biphasic responses in the human saphenous vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗
PubMed1991

Vascular reactivity of human internal mammary and gastroepiploic arteries.

Patency rates of bypass graft conduits are thought to be influenced by the determinants of vascular tone. This study has comparatively examined the response of the human internal mammary and gastroepiploic arteries to potassium, noradrenaline, dopamine, 5-hydroxytryptamine, thromboxane, and histamine. The response to potassium was significantly greater in the gastroepiploic artery (Emax = 79.5 +/- 9.6 mN) than in the internal mammary artery (Emax = 27.0 +/- 6.4 mN). Dose-related constrictions were observed in both vessels to all agonists except histamine, which was ineffective in the gastroepiploic artery. Noradrenaline and dopamine produced comparable dose-related constrictions in each vessel, with similar EC50 and Emax (expressed as a percentage of potassium response) values, but 5-hydroxytryptamine (Emax, gastroepiploic = 10.8% +/- 1.9%; internal mammary = 71.8% +/- 21.2%) and thromboxane (Emax, gastroepiploic = 116.7% +/- 4.0%; internal mammary = 169.6% +/- 19.4%) were more efficacious in their constriction of the mammary artery; the potencies were similar. We conclude that there is a heterogeneity of response to some vasoconstrictors between the human internal mammary and gastroepiploic arteries. The internal mammary artery may be more predisposed to events that initiate vasospastic disorders.

Adolescent↗
PubMed1991

Role of potassium concentration in cardioplegic solutions in mediating endothelial damage.

We studied the effect of potassium concentration in cardioplegic solutions on endothelial function by examining its influence on 5-hydroxytryptamine- (5-HT) and nitroglycerin-induced vasodilation in the isolated rat heart. Forty-eight rat hearts were perfused on a modified Langendorff preparation. After a baseline record of increase in coronary flow induced by 10(-7) M 5-HT and 10 micrograms/mL nitroglycerin, the hearts were perfused for 30 or 60 minutes with either St. Thomas' solution or Bretschneider solution containing 20 mmol/L of potassium or for 30 minutes with either solution containing 30 mmol/L of potassium (n = 8 in each). Initially, 5-HT and nitroglycerin caused a 39.0% +/- 3.3% and 39.7% +/- 2.8% increase in coronary flow, respectively. After 30 or 60 minutes' perfusion with St. Thomas' solution containing 20 mmol/L of potassium, there was little change in the response to 5-HT or nitroglycerin (5-HT, 43.1% +/- 4.1%; nitroglycerin, 38% +/- 3.2%). Similarly, perfusion with Bretschneider solution (20 mmol/L K+) for 30 or 60 minutes did not alter the degree of vasodilation (5-HT, 39.2% +/- 2.9%; nitroglycerin, 38.0% +/- 3.3%). However, perfusion with St. Thomas' solution containing 30 mmol/L of potassium for 30 minutes abolished the endothelial-dependent 5-HT-induced vasodilation (5-HT, -1.6% +/- 1.4%; nitroglycerin, 36.9% +/- 2.2%). Perfusion with Bretschneider solution (30 mmol/L K+) gave similar results (5-HT, -2.1% +/- 1.2%; nitroglycerin, 36.4% +/- 1.7%). We conclude that the concentration of potassium in cardioplegic solutions plays a critical role in causing functional endothelial damage.

Animals↗
PubMed1991

5-Hydroxytryptamine mediates endothelium dependent coronary vasodilatation in the isolated rat heart by the release of nitric oxide.

STUDY OBJECTIVE: The aim was to investigate further the endothelium dependent vasodilator action of 5-hydroxytryptamine (5-HT) on the rat coronary circulation. DESIGN: Using saponin to damage the endothelium and L-NMMA (NG-monomethyl-L-arginine), the selective inhibitor of nitric oxide formation, we examined the role of endothelium and nitric oxide in causing 5-HT induced vasodilatation in the isolated rat heart. EXPERIMENTAL MATERIAL: 56 rat hearts were excised and perfused on a Langendorff preparation. MEASUREMENTS AND MAIN RESULTS: 5-HT at (10(-9) to 10(-5) M) and glyceryl trinitrate at (10(-5) to 10(-3) M) (n = 24) induced a dose dependent increase in coronary flow. Chemical removal of the endothelium by exposure to saponin (30 micrograms.ml-1) (n = 8) abolished the 5-HT induced vasodilatation but had no effect on the response to glyceryl trinitrate. Pretreatment of rats (n = 8) with L-NMMA (100 mg.kg-1) unmasked a strong vasoconstrictor effect of 5-HT but did not affect the glyceryl trinitrate induced vasodilatation. Perfusion of L-NMMA pretreated hearts with L-arginine at 10(-4) M (n = 8) restored the vasodilatation induced by 5-HT but L-arginine perfusion had no effect on the extent of 5-HT or glyceryl trinitrate induced vasodilatation in normal hearts (n = 8). CONCLUSIONS: In the coronary circulation of the isolated rat heart, 5-HT mediates its vasodilator effect via endothelium dependent release of nitric oxide.

Animals↗
PubMed1991

Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries.

OBJECTIVE: It has been hypothesised that compromised endothelial function can contribute to the toxic manifestations associated with cyclosporin therapy. In vitro animal studies have implicated inhibition of release of the endothelium derived relaxing factor, nitric oxide; however, this has not been investigated in human tissue. The present study investigated the effect of cyclosporin A on nitric oxide release in human coronary arteries. DESIGN: Study of in vitro organ bath preparations and in vivo angiographic measurements in the coronary circulation. PATIENTS: For the in vitro experiments coronary arteries were harvested from the excised hearts of 10 patients requiring transplantation for reasons other than ischaemic heart disease. Three of these patients were being re-transplanted for obliterative bronchiolitis and had been receiving cyclosporin for a mean of 22 months. The in vivo study was performed on a group of 12 cardiac transplant recipients who were clinically well 1-5 years postoperatively and were not undergoing allograft rejection at the time of assessment. RESULTS: Isolated vessel segments in vitro relaxed in a dose dependent manner in response to substance P (10(-11)-10(-7) mol/l). The maximum response was 76.6 (7.4)% of the response to 1 microgram/ml glyceryl trinitrate. Incubation with 1000 and 2000 ng/ml cyclosporin reduced the response to 63.0 (11.5)% and 62.2 (11.1)% respectively; this was not statistically significant. In segments taken from the explanted hearts of three patients requiring re-transplantation, the mean maximum response was 78.0 (11.0)% and there was no correlation between maximum response in segments from each patient and the duration of cyclosporin therapy. The effect of intracoronary substance P in 12 cardiac transplant recipients was also examined (mean cyclosporin blood concentration 228.9 (42.8) ng/ml). The mean maximum dilatations measured as the percentage diameter change induced by substance P and isosorbide dinitrate were 22.1 (3.2)% and 26.0 (2.5)% respectively. There was no correlation between the degree of endothelium mediated vasodilatation in response to substance P and cyclosporin concentration. CONCLUSIONS: The nitric oxide response was preserved in the coronary arteries of patients exposed to cyclosporin. The mechanisms that initiate cyclosporin associated toxicity remain to be elucidated.

Coronary Vessels↗
PubMed1991

Endothelial function of human gastroepiploic artery. Implications for its use as a bypass graft.

The human gastroepiploic artery has been used as a coronary artery bypass conduit in a limited number of clinical studies. It has been postulated that the capacity of the endothelium to release vasoactive substances may contribute to differing patency rates observed in established bypass grafts. We have now examined endothelial function in the human gastroepiploic artery. Endothelium-dependent relaxations to substance P were observed. A maximum relaxation of 83.25% +/- 8.2% (mean +/- standard error) was attenuated to 48.5% +/- 16.4% in the presence of L-NG-monomethyl-arginine, a specific inhibitor of endogenous nitric oxide synthesis. Removal of the endothelium abolished the relaxations. With a specific radioimmunoassay, concomitant changes in levels of cyclic guanosine 3',5'-monophosphate, the second messenger that elicits smooth muscle relaxation after release of the endothelium-derived relaxing factor, were measured. It was found that the gastroepiploic artery had significantly higher resting and stimulated levels of cyclic guanosine 3',5'-monophosphate than either the internal mammary artery or the saphenous vein. In the presence of the cyclooxygenase inhibitor indomethacin, and indomethacin plus L-NG-monomethylanginine, the maximum relaxation was decreased to 70% +/- 9.5% and 59% +/- 10.8%, respectively. Our data demonstrate that endothelium-derived relaxing factor and prostacyclin may exhibit synergy in the control of vascular tone in this vessel. It is concluded that the endothelium of the gastroepiploic artery has a strong capacity to secrete vasodilators and inhibitors of platelet activity. This could have important influence on long-term patency.

Arginine↗
PubMed1990

Low basal and stimulated release of nitric oxide in atherosclerotic epicardial coronary arteries.

Endothelium-dependent relaxations in response to substance P and bradykinin were lower in atherosclerotic than in normal human coronary arteries. The relaxation induced by substance P was inhibited by L-NG-monomethylarginine (L-NMMA), which shows that release of nitric oxide is involved in the mediation of endothelium-dependent relaxation in these arteries. L-NMMA also inhibited a basal component of endothelium-dependent relaxation. The basal secretion of nitric oxide was significantly lower in diseased than in normal arteries. These findings suggest that atherosclerotic human coronary arteries lack an important protective mechanism that normally guards against vasospasm and thrombosis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

The role of nitric oxide in mediating endothelium dependent relaxations in the human epicardial coronary artery.

We have examined the ability of the endothelium of human epicardial coronary arteries to secrete vasorelaxant substances in response to pharmacological stimulation and under basal conditions. In addition, we have attempted to characterise the chemical identity and biochemical pathway for the synthesis of endothelial derived relaxing factor. Human epicardial coronary arteries were removed from patients who were undergoing heart transplantation for reasons other than ischaemic heart disease. Arteries were cut into segments and suspended in 5 ml organ baths containing a modified Tyrodes solution at 37 degrees C, and gassed with a mixture of 95% oxygen and 5% carbon dioxide. Substance P (10(-10) - 10(-7) M) elicited a dose-dependent relaxation of the coronary segments but this action of substance P was dependent upon an intact endothelium. The maximum response of substance P was equivalent to 89 +/- 8.5% of the maximum effect induced by 1 microgram/ml glyceryl trinitrate. This vasorelaxant effect of substance P was unaffected by the presence of 10(-6) M indomethacin. L-NG-monomethyl-arginine (10(-4) M), a specific inhibitor of formation of nitric oxide from L-arginine, antagonised the relaxations induced by substance P, decreasing the maximum response of substance P to 34 +/- 10.5% of the response to glyceryl trinitrate. Upon application, L-NG-monomethyl-arginine caused a further 23.1 +/- 3.0 increase in tension on preconstricted vessels. This increase in tension was reversed with the addition of L-arginine, but was unaffected by D-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

5-Hydroxytryptamine receptor profile in healthy and diseased human epicardial coronary arteries.

STUDY OBJECTIVE: The aim of the study was to investigate the receptor events that mediate the vascular effects of 5-hydroxytryptamine (5-HT) on human coronary arteries, since 5-HT has long been thought to play a role in coronary artery vasospasm. DESIGN: Recently available selective receptor agonists and antagonists were used to examine the 5-HT receptor subtypes present in human epicardial coronary arteries using in vitro organ baths. EXPERIMENTAL MATERIAL: 138 segments of coronary arteries were obtained from 21 patients aged 2-66 years undergoing heart transplantation. MEASUREMENTS AND MAIN RESULTS: 5-HT produced only concentration dependent contractions of coronary artery segments. No evidence was obtained for 5-HT receptors mediating either endothelium dependent or endothelium independent vasorelaxation. In tissue from patients without ischaemic heart disease, 5-HT effects were mimicked by (+/-)-alpha-methyl-5-HT (alpha-me-5-HT), a selective agonist at 5-HT2 receptors. In addition, the selective 5-HT1-like receptor agonist GR43175 produced contractions which achieved 30% of the maximum response to 5-HT. Responses to alpha-me-5-HT were surmountably antagonised by the non-selective antagonist methiothepin (0.1 mumol.litre-1) as well as the 5-HT2 receptor antagonist ketanserin (0.1 mumol.litre-1). In contrast GR43175 effects were resistant to blockade by ketanserin, but remained sensitive to methiothepin. Responses to the two agonists were not antagonised by the 5-HT3 receptor antagonist MDL72222 (1.0 mumol.litre-1). Vessel segments from ischaemic heart disease patients also contracted to alpha-me-5-HT and GR43175. Diseased arteries contracted with a decrease in the maximal response induced by both alpha-me-5-HT and by 90 mM K+ depolarisation compared to "normal" vessels, but the effect of GR43175 was preserved in the diseased arteries. Vascular rings adjacent to an atheromatous lesion were more reactive to GR43175 than serial segments taken distal to the lesion. CONCLUSIONS: These results show that both 5-HT1-like and 5-HT2 receptors mediate contraction of human epicardial coronary arteries and indicate that effects mediated by 5-HT1-like receptors but not 5-HT2 receptors are preserved in patients with ischaemic heart disease.

Adolescent↗
PubMed1989

Influence of endothelin on human coronary arteries and localization of its binding sites.

Endothelin, a 21 amino acid peptide synthesized by cultured porcine aortic endothelial cells, has recently been identified and shown to produce a potent and prolonged constriction of mammalian blood vessels in vitro. Using tissue obtained from explanted hearts at the time of cardiac transplantation, the response of isolated human epicardial coronary arteries to endothelin was studied. The presence of endothelin binding sites was demonstrated in these vessels using an autoradiographic technique. Endothelin produced a dose-dependent increase of tension in the isolated coronary vessels with a maximal tension achieved equal to 135% of that induced by 90 mM of potassium. The maximal response was slow to develop and had a prolonged duration of 15 to 20 minutes. Nicardipine (4 microM) failed to affect the contraction induced by low doses of endothelin, but decreased the tension obtained at high doses. However, adenosine, substance P and glyceryl trinitrate were all effective in reversing the contraction induced by endothelin, while indomethacin and acetylcholine were ineffective. These features differ from those of other endogenous constrictor agents and make endothelin a potential candidate for long-term modulation of vascular tone.

Autoradiography↗
PubMedDate not supplied

Biological mechanisms influencing the function of the aortic root.

Optimal function of the aortic root relies upon the ability of its component structures to move in a coordinated fashion. Some of the cells that make up the structures of the aortic root have been shown to contain nerves, receptors, and contractile elements. The ability to contract or relax may contribute to the successful function of the valve by allowing it to move in a coordinated manner in response to biological stimuli. It is known that cusp tissue receives primary, sensory, and autonomic nerves, suggesting a role for neuronal regulation of cusp function. In addition, cusp tissue has been shown to express a wide variety of receptors and to contract to a range of common vasoactive agents. The cells that constitute the valve have also shown secretory and proliferative responses. The biological signals that mediate the cross-talk between the different parts of the root have not been established. This review will examine the mechanisms that have been documented to be present and to assess their potential contribution in affecting aortic valve function.

Aorta, Thoracic↗
PubMedDate not supplied

Reactivity of small intramyocardial arteries from atherosclerotic and non-atherosclerotic human hearts.

Little is known about how the vascular reactivity of the coronary microcirculation is affected by upstream atherosclerotic disease. We have examined, with a wire myograph, the responses of intramyocardial arteries from hearts in which the epicardial vessels were either free of atherosclerotic lesions (non-diseased group) or were affected by atherosclerosis (diseased group). Vasodilator responses of preconstricted vessels to substance P (84.1 +/- 12.6 compared to 42.0 +/- 19.7%) were less in vessels from the diseased group (p < 0.05). In contrast, the relaxation to bradykinin (70.2 +/- 21.2 compared to 100.6 +/- 7.9%) was increased in vessels from the diseased group (p < 0.05). The dilator responses to acetylcholine, adenosine diphosphate, histamine and sodium nitroprusside showed no significant differences between arteries from each group. 5-Hydroxytryptamine was without any significant vasodilator effect in arteries from either group. Assessment of contractile function revealed that the responses to 5-hydroxytryptamine, acetylcholine, U46619, endothelin-1 and L-N(G)-monomethylarginine in each group were not significantly different. Histamine, noradrenaline and dopamine were without any significant contractile response. These results demonstrate that upstream atherosclerosis does not confer any global impairment of endothelium-dependent vasorelaxant responses or smooth muscle hyperreactivity to vasoconstrictors in the arteries that penetrate the myocardium.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMedDate not supplied

Calcitonin gene-related peptide in healthy and atheromatous human epicardial coronary arteries. Function and receptor characterization.

To examine the possible role of calcitonin gene-related peptide (CGRP) in the control of human coronary vascular tone, we have investigated the action of this peptide in healthy and atheromatous human epicardial coronary arteries and localised [125I]CGRP-binding sites in these vessels. Isolated arteries were obtained from 10 cardiomyopathic patients and 6 patients with ischaemic heart disease (IHD), who were undergoing heart transplantation. CGRP elicited concentration-dependent vasodilatation in preconstricted vessels. Both healthy and diseased coronary arteries exhibited similar maximum responses and sensitivity to this peptide. Removal of the endothelium did not diminish the vasodilator action of CGRP in non-atherosclerotic coronary arteries. [125I]CGRP bound to tissue sections in a concentration-dependent manner. Binding was similar in healthy and atheromatous vessels, with a Bmax value of 10.2 +/- 5.6 and 18.9 +/- 3.0 amol/mg protein, and dissociation constant (Kd) of 0.07 +/- 0.1 and 0.18 +/- 0.1 nM, respectively. Dense [125I]CGRP binding was mainly associated with vascular smooth muscle cells of both normal and diseased vessels with some patches of binding to regions of atherosclerotic plaque in vessels from patients with IHD. These data indicate that CGRP is a potent endothelium-independent vasodilator in the human coronary vasculature. The preservation of dilator function and CGRP receptor binding in atherosclerotic coronary arteries suggests that this peptide may play a role in the control or maintenance of vascular tone in certain disease states.

Adult↗
PubMedDate not supplied

Differential effect of hypothermia on the vascular tone and reactivity of the human coronary artery and graft vessels.

Hypothermia may contribute to vascular spasm during bypass surgery. The effect of cooling on the reactivity of the human coronary artery (CA), saphenous vein (SV) and internal mammary artery (IMA) was studied in vitro. In CA and IMA cooling diminished the resting tension and the contraction to potassium, noradrenaline and 5-hydroxytryptamine. In contrast, in SV the contraction to noradrenaline and 5-hydroxytryptamine was augmented by cooling. The effect of cold was reversible. These results demonstrate different effects of hypothermia in CA and the graft vessels. Thus, hypothermia augments the receptor-mediated contraction in SV but depresses it in IMA which thereby resembles CA. The difference is most marked in the contractile response to 5-hydroxytryptamine, which may accumulate during surgery. This may contribute to spasm in the saphenous vein grafts and may be involved in the mechanisms responsible for the inferior patency of SV compared to IMA as a graft vessel.

Adolescent↗