Endothelial function and vasodilator profile of the inferior epigastric artery.

In the inferior epigastric artery, endothelium-dependent relaxations in response to substance P, histamine, and acetylcholine were present. These were greater than reported values in saphenous veins but less than the documented responses in internal mammary and gastroepiploic arteries. Endothelium-independent stimulation with nifedipine, papaverine, sodium nitroprusside, and glyceryl trinitrate induced relaxations that also were reduced compared with established arterial conduits. These findings appear to justify the clinical use of the inferior epigastric artery as a coronary bypass graft with monitoring of its long-term results and possibly perioperative pharmacologic manipulations.

Effect of mode of application of papaverine on the contractile response of the internal mammary artery.

A study was performed to investigate the duration of action of papaverine applied either intraluminally or in a combined intraluminal and extraluminal fashion in vitro, and how the reactivity of the internal mammary artery (IMA) to a range of vasoconstrictors is affected. Segments of IMA exposed to only intraluminal papaverine (10(-4) mol/l) for 15 min recovered their contractile response to 90 mmol/l potassium chloride to pretreatment levels within 2 h. In contrast, combined intraluminal and extraluminal administration of papaverine resulted in a significant depression of the contractile response to 90 mmol/l potassium chloride (P < 0.001), which persisted for at least 5 h. Responses to 5-hydroxytryptamine, noradrenaline, the thromboxane mimetic U46619, histamine and dopamine were not significantly different between control tissues and those that had received intraluminal papaverine. The duration of action of papaverine is affected by its route of delivery and there are no significant short-term effects on the contractile mechanisms in the arterial wall after intraluminal administration.

Effect of surgical preparation and arterialization on vasomotion of human saphenous vein.

To gain an insight into venous physiologic adaptation to arterialization, this study examined the effects of thromboxane, 5-hydroxytryptamine, endothelin, leukotriene C4, and norepinephrine on isolated segments of native and distended human saphenous vein, short-term (up to 1 year) grafts, and long-term (1 to 10 year) grafts. The mean maximum constrictor responses, expressed as percentage of maximum potassium depolarization, were as follows: thromboxane analog U46619: native vein 147.0% +/- 10.5%, distended vein 251.2% +/- 29.1%, short-term graft 174.6% +/- 33.8%, long-term graft 220.9% +/- 21.7%; 5-hydroxytryptamine: native vein 115.6% +/- 6.1%, distended vein 129.9% +/- 13.3%, short-term graft 80.0% +/- 15.0%, long-term graft 95.1% +/- 12.1%; endothelin-1: native vein 126.5% +/- 22.1%, distended vein 138.1% +/- 24.7%, short-term graft 120.7% +/- 43.3%, long-term graft 171.4% +/- 26.0%; leukotriene C4: native vein 49.9% +/- 8.7%, distended vein 78.9% +/- 11.8%, short-term graft 90.8% +/- 39.1%, long-term graft 7.4% +/- 5.0%; and norepinephrine: native vein 127.0% +/- 9.3%, distended vein 155.0% +/- 17.8%, short-term graft 61.6% +/- 11.3%, long-term graft 80.1% +/- 7.7%. The vasoconstriction elicited by each agonist, in absolute terms (in millinewtons), diminished with age of graft. We conclude that surgical treatment of saphenous vein immediately renders it more responsive to U46619, norepinephrine, and leukotriene C4. An agonist-specific profile of response was evident up to 10 years after operation, which may affect myocardial blood supply when luminal bore is diminished by vein graft disease.

Vasoconstrictor profile of the inferior epigastric artery.

The inferior epigastric artery is a putative arterial bypass graft. The receptor mechanisms that control vascular tone are thought to play a role in the performance of bypass conduits. We have compared the vascular reactivity of the inferior epigastric artery with that of the internal mammary artery. Segments from a total of 15 inferior epigastric and 12 internal mammary arteries were examined for their response to increasing concentrations of noradrenaline, 5-hydroxytryptamine, dopamine, histamine, endothelin-1, or the thromboxane analogue U46619. The responsiveness of the smooth muscle was significantly greater in the inferior epigastric artery (p < 0.05) as judged by contractions elicited by 90 mmol/L potassium chloride. However, although the response of the inferior epigastric artery tended to be greater, this significant enhancement of smooth muscle function was not paralleled by the maximal responses of noradrenaline, 5-hydroxytryptamine, dopamine, histamine, or endothelin-1. However, the tension generated in response to U46619 did differ significantly, with maximal responses in the inferior epigastric and internal mammary arteries of 59.2 +/- 8.3 mN and 35.0 +/- 3.6 mN, respectively. When receptor function was compared by expressing the response as a percentage of that of 90 mmol/L potassium chloride, it was revealed that noradrenaline was capable of inducing significantly greater relative contractions in the internal mammary artery (114.8% +/- 20.5%) as compared with the inferior epigastric artery (49.9% +/- 19.1%); the potency of this constrictor was sixfold greater in the internal mammary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Different responses of the human gastroepiploic and internal mammary arteries to vasoactive peptides.

Peptidergic influences have been implicated in the control of tone in human arteries. We have examined the response of human gastroepiploic arteries (GEA) and internal mammary arteries (IMA) to three vasoactive peptides in vitro. Vasoactive intestinal peptide (VIP, 10(-11) to 3 x 10(-7) M) elicited relaxations in the GEA and IMA [maximum generated response (Emax) 74.6 +/- 9.4 and 56.5 +/- 7.7%, respectively] that were significantly reduced after removal of endothelium. NG-monomethyl-L-arginine (L-NMMA) and indomethacin partially inhibited the response of the GEA to VIP (P < 0.05). In the IMA, VIP-induced relaxation was significantly attenuated by L-NMMA but not indomethacin. Bombesin (10(-10) to 3 x 10(-6) M) produced endothelium-dependent relaxation selectively in the GEA, which was only inhibited by indomethacin (Emax reduced from 59.0 +/- 10.0 to 12.8 +/- 4.9%, P < 0.001). Bombesin elicited a weak endothelium-independent constriction in the IMA, giving 12.7 +/- 1.2% of the response to 90 mM KCl. Gastrin (10(-10) to 3 x 10(-7) M) had no effect on IMA segments but induced a relaxation of 40.0 +/- 3.2% in the GEA via a direct action on the smooth muscle. It is concluded that human GEA and IMA exhibit heterogenous responses to VIP, bombesin, and gastrin that may have important physiological and clinical implications.

Effect of peri-operative storage solution on the vascular reactivity of the human saphenous vein.

The performance of the saphenous vein as a bypass conduit in myocardial revascularisation may, in part, be determined by its vascular reactivity. The present study investigates whether the choice of peri-operative storage solution influences the response of this vessel to a range of vasoconstrictors and vasodilators. Saphenous vein ring segments (210) were obtained from 24 patients undergoing coronary artery bypass surgery, and following a 1 h incubation in either (1) heparinised blood, (2) heparinised saline, (3) 199-TC solution, (4) St. Thomas' cardioplegic solution or (5) plasma-lyte solution, rings of vein were set up as organ bath preparations. The relative magnitude of control constrictor response was: noradrenaline = 5-hydroxytryptamine > or = dopamine > histamine > acetylcholine. There was a significantly different (P < 0.05) enhanced response to noradrenaline and 5-hydroxytryptamine in segments stored in heparinised saline compared to 199-TC; similarly, dopamine and noradrenaline responses were significantly potentiated (P < 0.05) following storage in heparinised saline compared to cardioplegia. Storage in plasma-lyte enhanced the response significantly storage in heparinised saline compared to cardioplegia. Storage in plasma-lyte enhanced the response significantly (P < 0.05) to acetylcholine alone. None of the solutions had a significant effect on the potency (EC50) of the constrictors. Relaxations of pre-constricted segments were recorded to acetylcholine and sodium nitroprusside, but there was no difference in efficacy or potency in these responses following storage in the different solutions. This study demonstrates that the choice of peri-operative storage solution may influence the vascular reactivity of the human saphenous vein.

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.

Effect of endothelin on normal and diseased human coronary arteries.

We have examined the action of endothelin on healthy and diseased human epicardial coronary arteries to assess its possible role in coronary vascular disorders such as vasospasm and atherosclerosis. Endothelin (10(-10) mol l-1-10(-7) mol l-1) produced dose-dependent contractions in both normal and diseased vessels. The level of constriction was significantly greatly in healthy vessels at 10(-8) mol l-1 endothelin. A greater response was recorded in smaller, more distal vessel segments, irrespective of the pathology of the tissue. Endothelium denudation of disease-free segments had no significant effect on the response to endothelin. In the presence of a threshold dose of endothelin (10(-9) mol l-1), there was no measurable increase in the tension generated by potassium chloride, the thromboxane-mimetic U46619, noradrenaline and histamine. However, the response to 5-HT showed a large increase in arteries from four patients (440-147%) but slight or no increase in arteries from another three patients. We conclude that the interaction with other vasoconstrictor substances is a possible mechanism whereby endothelin may be involved in coronary artery vasospasm. In addition, endothelin may also be involved in the regulation of vascular tone of the small vessels of the heart.

Comparison of cyclic GMP in human internal mammary artery and saphenous vein: implications for coronary artery bypass graft patency.

OBJECTIVE: The aim was to examine the capacity of the human saphenous vein (native and surgically prepared) and the internal mammary artery to generate cyclic GMP, the second messenger that mediates smooth muscle relaxation following production of nitric oxide. METHODS: 209 vessel segments were used from 22 patients undergoing coronary revascularisation. Isolated vessel segments were stimulated with a range of endothelium dependent and endothelium independent agonists and flash frozen for radioimmunoassay for cyclic GMP. RESULTS: Control/basal levels of cyclic GMP were significantly higher in the internal mammary artery than either native or distended saphenous vein. Endothelium dependent agonist stimulation with acetylcholine, bradykinin, or substance P induced significant increases in cyclic GMP in internal mammary artery and native saphenous vein, whereas distended veins showed non-significant changes in response to agonist stimulation. Endothelium removal abolished agonist stimulated increases in cyclic GMP. Glyceryl trinitrate and sodium nitroprusside elicited significant further increases in cyclic GMP in native vein and internal mammary artery. All values obtained were significantly greater in arterial than in venous tissue. CONCLUSION: Differences in basal and stimulated cyclic GMP activity in arteries and veins have been shown. This could represent an additional protective mechanism against constrictor influences in arterial bypass grafts, which may explain their documented better long term performance.

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.

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.

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.

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)

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.

Tachykinins in the central and peripheral nervous system of the ascidian Ciona intestinalis.

Immunochemical studies were carried out on the ascidian Ciona intestinalis to determine the character and distribution of the tachykinins neurokinin A (NKA) and substance P (SP). Antisera specific for the C-terminus of mammalian SP, and for the N-terminus of mammalian SP and NKA, were used to monitor tissue extracts from Ciona. Parallel immunocytochemical studies assessed the distribution of these tachykinins in the central and peripheral nervous systems as well as their occurrence in endocrine cells. HPLC and radioimmunoassay established the presence of both C-terminal SP and NKA-like material in extracts from neural ganglion and body wall/pharynx. Immunocytochemistry revealed the C-SP material to be present in a population of small neuronal cell bodies and fibers in the ganglion as well as in cell bodies and fibers in the periphery. The NKA-like material was restricted to separate and larger neuronal perikarya in the ganglion while in the periphery its distribution reflected that of the C-SP-like material. Endocrine cells in the pharyngeal epithelium were reactive only with the C-terminal SP antiserum. N-terminal SP antisera were unreactive both in radioimmunoassay and immunocytochemistry. These findings are in accord with the idea that the tachykinin family is represented by at least two of its members at the prevertebrate stage of evolution. Interestingly, the SP-like material shows strong C-terminal homology with the mammalian peptide but little N-terminal similarity. Furthermore, the NKA-like peptide is restricted to the nervous system while SP-like molecules may be found in both central and peripheral neurons as well as endocrine cells in the pharynx.