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Receptor Activation in Human Arteries and Veins

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Receptor Activation in Human Arteries and Veins TISSUE CONCENTRATIONS OF ENDOTHELINS AND FUNCTIONAL EFFECTS OF ENDOTHELIN- RECEPTOR ACTIVATION IN HUMAN ARTERIES AND VEINS Peter Holm, MD In the present study, the tissue content and functional effects of endothelin-1 Anders Franco-Cereceda, MD, PhD and endothelin-3 were examined in human vessels of importance in coronary bypass operations. Human coronary arteries (i.e., the left anterior descending coronary artery) were obtained from eight cardiac valve donors within 6 hours after death, pulmonary arteries were perioperatively obtained from 15 patients operated on because of lung tumors, and internal thoracic arteries and great saphenous and cephalic veins were obtained at coronary bypass operations from a total of 28 patients. Endothelin-1 and endothelin.3 content was quantified by radioimmunoassay. For functional experiments, the vessels were mounted in organ baths for recordings of isometric contractions in response to endothelin-1, endothelin-3, and the endothelin A- receptor agonist sarafotoxin 6c. In all vessels investigated, the endothelin-1 content was higher than that of endothelin-3. The highest levels were found in the left anterior descending coronary artery, followed in declining order by the internal thoracic artery, pulmonary artery, saphenous vein, and cephalic vein. Endothelin-1 contracted all vessels in a concentration-dependent fashion. This effect was enhanced in the left anterior descending and internal thoracic arteries by inhibition of nitric oxide and prostaglandin formation. The contractile effect was attenuated in a concentration-dependent fashion in all vessels by incubation with the endothelinA-receptor blocker BQ-123. Furthermore, contractions evoked by endothelin-1 in the left anterior descending coronary and pulmonary arteries were antagonized by the combined endothelinA- and endothelinB-receptor blocker bosentan. Endothelin-3 contracted the left anterior descending coro- nary and pulmonary arteries and the saphenous vein, but not the internal thoracic artery, in a BQ-123-sensitive fashion. However, after inhibition with nitric oxide or prostaglandin, endothelin-3 also contracted the internal tho- racic artery, and the response in the left anterior descending coronary artery was enhanced. Sarafotoxin 6c evoked a BQ-123-sensitive contraction of the left anterior descending coronary artery. It is concluded that endothelin A receptors mediate the major portion of the vasoconstriction observed on exposure to endothelin-1, endothelin-3, and sarafotoxin 6c in the left anterior descending coronary, pulmonary, and internal thoracic arteries and the saphenous vein. Furthermore, endothelinB-receptor activation, with subsequent formation of nitric oxide or prostaglandin (or both), counteracts the vasoconstrictor re- sponse to endothelin in the left anterior descending coronary and internal thoracic arteries, but not in the pulmonary artery or saphenous vein. The present findings therefore suggest that endothelinA-receptor antagonism might prove beneficial in preventing possible endothelin-induced coronary graft spasm. (J Thorac Cardiovasc Surg 1996;112:264-72) From the Department of Thoracic Surgery, Karolinska Hospital, Received for publication July 20, 1995; revisions requested Oct. 9, Stockholm, Sweden. 1995; revisions received Nov. 17, 1995; accepted for publica- Supported by grants from the Swedish Medical Research tion Jan. 3, 1996. Council, the Heart and Lung Foundation, the Address for reprints: Anders Franco-Cereceda, MD, PhD, De- Wiberg Foundation, the Wallenberg Foundation, the partment of Thoracic Surgery, Karolinska Hospital, 171 76 Thuring Foundation, the Swedish Society for Medicine, Stockholm, Sweden. the Salus Foundation, and funds from the Karolinska Copyright © 1996 by Mosby-Year Book, Inc. Institute. 0022-5223/96 $5.00 + 0 12/1/71601 264 The Journal of Thoracic and Cardiovascular Surgery Holm and Franco-Cemceda 2 6 5 Volume 112, Number 2 he endothelium is involved in the regulation of these vessels and in the cephalic vein (CV) has been T local vascular tone through release of both vaso- determined. dilator and vasoconstrictor substances. 1 Experi- ments showing potent vasoconstrictor effects of me- Methods dia obtained from cultured aortic endothelial cells This study was approved by the Ethics Committee of suggested the existence of an endothelium-derived the Karolinska Hospital. vasoconstrictor substance) The endothelium was Functional experiments. Coronary arteries with an in- later shown to synthesize the vasoactive peptide ner diameter of 0.8 to 1.2 mm (segments 7 and 8 of the LAD according to the American Heart Association Com- endothelin (ET) through enzymatic cleavage of the mittee Report, 1975) were obtained within 6 hours after propeptide big ET. 3 Studies have revealed a group death from eight cardiac valve donors (five men and three of ET isopeptides named ET-1, ET-2, and ET-3. 4 women, 33 + 7 years of age) with total cerebral infarction ET has been shown to evoke a variety of effects in resulting from intracranial bleeding or trauma (or both). the cardiovascular system, including vasoconstric- PAs of a similar size were obtained from 15 patients undergoing operations for lung tumors (10 men and five tion,3 vasodilatation,5, 6 and positive inotropic and women, 67 -+ 3 years of age). Distal ITAs and SVs were chronotropic actions, 7' 8 as well as negative inotropic obtained from 25 patients undergoing coronary artery effects. 9 The variability of the effects of the three bypass operations (16 men and nine women, 66 + 2 years isopeptides in different vascular beds indicates the of age). All vessels (1 to 2 mm in length) were dissected existence of multiple ET receptor subtypes. Thus out under a microscope and mounted in 2 ml organ baths on two L-shaped holders (diameter 0.3 mm). A resting the vascular effects of ET are mediated through tension of 10 mN was then applied by adjusting one of the interaction with putative ET A and ET B receptors. metal holders. The other holder was connected to a Grass The ET A receptor is selective for ET-1 and causes polygraph model 7B (Grass Instrument Co., West War- vasoconstriction, whereas the ET B receptor is non- wick, R.I.) for recordings of isometric tension. The resting selective for the ET isopeptides and mediates vaso- tension was chosen on the basis of preliminary experi- ments in which reproducible contractions were obtained dilatation] ° Recent reports in addition suggest the at this resting tension. 16 The vessels were kept in Tyrode's existence of ET B receptor subtypes: the ET m recep- solution (pH 7.4) of the following composition (in milli- tor on the endothelium mediates endothelium- moles per liter): NaC1 137, KC1 2.7, CaC1e 1.8, MgC12 1.05, dependent vasodilatation; the ETB2 receptor on NaHCO 3 11.9, NaH2PO 4 0.42, and glucose 5.6. The smooth muscle cells causes vasoconstriction. 11' 12 A Tyrode's solution was aerated with 95% oxygen and 5% carbon dioxide at 37 ° C. After 60 minutes of equilibration family of snake venom peptides, the sarafotoxins, during which the resting tension was adjusted to compen- show a remarkable structural resemblance to ET sate for the spontaneous decline in arterial tension, circu- and act on the same receptor as ET. 13 Among these lar contractions were induced by Tyrode's solution in peptides, sarafotoxin 6c is considered to activate which the NaC1 had been replaced with equimolar ETB receptors. I1' 13 amounts of KC1 to give a final K + concentration of 127 mmol/L. Only vessels responding with two reproducible A variety of pathophysiologic disorders are asso- contractions to K + exposure were used, giving a total of 31 ciated with increased circulating plasma levels of LADs, 47 PAs, 29 ITAs, and 30 SVs. Each experimental ET. It was recently demonstrated that the concen- procedure was performed in vessels from at least five tration of ET in the coronary sinus is increased patients. ET-1, ET-3, sarafotoxin 6c, or the ETB-receptor during coronary bypass operations, 1< is although agonist Alai'3'11'~SET-1m was added to the organ baths either at single concentrations or in a cumulative fashion. the mechanism of this release remains unclear, is The functional effects of these agents were studied under Furthermore, ET is a potent constrictor of human control conditions and after ETa-receptor blockade using coronary arteries 16 and of vessels used in coronary BQ-12319 or combined ET A and ET B blockade using revascularization, 17 whereas ET causes a tone-de- bosentan. 12 In addition, the effects of inhibition of pros- pendent vasoconstriction or vasodilatation of pul- taglandin and nitric oxide formation were evaluated by monary arteries. ~s In the present study, therefore, a incubating the vessels for 1 hour with the cyclooxygenase inhibitor indomethacin (10 5 mol/L) and the nitric oxide- comparison of the functional effects of ET-1 and synthase inhibitor Ng-monomethyl-L-arginine (L-NMMA; ET-3 on human coronary (i.e., left anterior descend- 10 -4 tool/L), which were thereafter present throughout ing [LAD]), pulmonary (PA), and internal thoracic the experiments. 18 Whereas BQ-123 and bosentan did not (ITA) arteries and great saphenous vein (SV) in influence basal contractile tone per se, pretreatment with vitro has been made. To further evaluate the influ- indomethacin and L-NMMA evoked a minor, but incon- sistent, increase in resting tension. ence of ETB-receptor activation, we studied the Tissue determination of ET-1 and ET-3. Vessels were effects of sarafotoxin 6c on the LAD and PA. In obtained from the above-mentioned patients and, in ad- addition, the tissue content of ET-1 and ET-3 in dition, CV specimens were obtained from another two The Journal of Thoracic and 2 6 6 Holm and Franco-Cereceda Cardiovascular Surgery August 1996 Table I. Tissue content of ET-1 and ET-3 in some human vessels ET-1 ET-3 NPY CGRP LAD 1.14 -+ 0.13 0.27 _+ 0.05 9.7 + 1.33 2.48 -+ 0.17 IMA 1.07 -+ 0.18 0.18 + 0.02 2.67 -+ 0.5 1.02 -+ 0.16 PA 0.22 _+ 0.06 0.17 -+ 0.03 0.44 -+ 0.07 ND SV 0.21 -+ 0.02 0.05 -+ 0.01 4.62 -+ 1.14 0.22 -+ 0.03 CV 0.17 -+ 0.03 0.07 -+ 0.03 ND 0.17 -+ 0.02 For comparison the concentrations of neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) have been determined.
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