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Ann Thorac Surg 1996;62:1392-1395
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Hypertension Increases the Contractions to Sumatriptan in the Human Internal Mammary Artery

Ouzhan Yildiz, MD, PhD, Sertaç Çiçek, MD, lknur Ay, MD, Ufuk Demirkiliç, MD, Meral Tuncer, MD, PhD

Department of Pharmacology, Faculty of Medicine, Hacettepe University, and Departments of Pharmacology and Cardiovascular Surgery, GATA Gülhane Faculty of Medicine, Ankara, Turkey.

Accepted for publication June 13, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. The internal mammary artery is the graft of choice for myocardial revascularization. The tendency to spasm increases toward the distal end of the internal mammary artery, which is the portion generally used for anastomosis. The distal internal mammary artery is more pharmacologically responsive to 5-hydroxytryptamine and several other vasoconstrictor agents than its midsection.

Methods. We examined the effects of 5-hydroxytryptamine and a 5-hydroxytryptamine₁–like receptor agonist sumatriptan on internal mammary artery segments (length, 3–4 mm) obtained from patients undergoing coronary artery bypass grafting. To unmask a 5-hydroxytryptamine₁–like receptor–mediated contractile response, threshold concentrations of potassium chloride were used.

Results. 5-Hydroxytryptamine induced concentration-dependent contractions in all, quiescent and potassium chloride precontracted, preparations. Sumatriptan induced marked contraction in some of the quiescent internal mammary artery rings, whereas it elicited marked and concentration-dependent contractions in all of the preparations given a moderate tone by a threshold concentration of potassium chloride. The sensitivity to sumatriptan was higher in potassium chloride–precontracted distal arteries than it was for the quiescent distal segments. Additionally, the sensitivity to and the efficacy of sumatriptan were much more markedly potentiated by precontraction in the preparations taken from hypertensive patients.

Conclusions. The more marked potentiation of the responses in arteries from hypertensive patients may be one of the factors influencing the patency rates.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1396.

The internal mammary artery (IMA) has become the graft of choice for myocardial revascularization because of its superior patency rates and because the clinical results associated with its use are better than those associated with the use of saphenous vein grafts [1]. Because of its excellent patency rate and associated flow dynamics, the IMA is frequently grafted to the diseased coronary vessel, usually the left anterior descending artery. As with any other small vessel, it has a tendency to spasm during operation or in the early postoperative period. Perioperative spasm of the IMA is a serious condition that can result in significant morbidity and mortality [2]. Additionally, a recent report has revealed that the patency rate for the distal bifurcation is poor [3]. Anatomicopathologic studies have shown that the IMA is elastic along its length, except at the distal end, beginning from 3 to 4 cm proximal to the bifurcation, where it has the characteristics of an elastomuscular artery [4]. Numerous pharmacologic studies on the IMA have shown that it is very active and that pharmacologic reactivity increases toward the distal end [5, 6]. The artery contracts strongly in response to several vasoconstrictor agents such as thromboxane A₂, alpha-adrenoreceptor agonists, and serotonin (5-hydroxytryptamine [5-HT]) [7].

Cardiopulmonary bypass affects all organ systems at macro and micro levels. The post–cardiopulmonary bypass period may be regarded as a state of deranged homeostasis. Various mediators such as catecholamines and thromboxane A₂ released into the circulation during this period may predispose the IMA to spasm. The distal section of the IMA, which has been shown to be pharmacologically more responsive, is often anastomosed to the coronary artery. The greater tendency of the distal end of the IMA to spasm is clinically a critical issue for surgeons: To use or not to use the distal part for anastomosis?

It has been reported that a 5-HT₂–type receptor mediates the response to 5-HT in the IMA [8]. In this study we tested the effect of the 5-HT₁–like receptor agonist sumatriptan on IMA segments and attempted to show a 5-HT₁–like receptor–mediated component of the response to 5-HT. This component requires precontraction to be unmasked [9–14]. In our recent study [15], in which we used potassium chloride and angiotensin II as precontracting agents, we showed a "masked" 5-HT₁–like receptor–mediated contractile response in the IMA. The present study also examined the influence of hypertension on vasospasm of the IMA and the variability of the contractile responses of the IMA to 5-HT receptor agonists as a function of certain diseases. This involved studying the effects of 5-HT and sumatriptan on IMAs obtained from normotensive and hypertensive patients.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Internal mammary arteries were harvested intraoperatively from patients undergoing coronary artery bypass operations. The ages of the patients within the groups were comparable and ranged between 46 and 65 years. The patients with systolic and diastolic blood pressures above 95 mm Hg and 160 mm Hg, respectively, were regarded as hypertensive. Approval to use discarded IMA tissue was granted by the ethics committee of GATA Gülhane Faculty of Medicine (January 1994). After median sternotomy, the left IMA was carefully dissected with a wide pedicle, including pleura, extrapleural fat, and surrounding veins. Heparin was administered, the artery was cut distally, and papaverine was sprayed on the pedicle. After the institution of cardiopulmonary bypass, the length of the graft needed for grafting to the coronary artery was measured. The discarded distal (2 to 3 cm proximal to the bifurcation) and proximal (the remaining proximal part of the IMA) sections were carefully removed and put into ice-cold physiologic salt solution (Krebs-Henseleit), cleaned and freed of surrounding connective tissue, than transferred to the laboratory, where the endothelium was removed. The arteries (11 distal and four proximal sections) were cut into rings (each, 3–4 mm long) and opened by a transverse cut to form rectangular strips. The delay from the operating room to the laboratory was 1 to 3 hours. The strips were mounted in an organ bath containing 20 mL of Krebs-Henseleit solution (NaCl, 118 mmol/L; KCl, 4.7 mmol/L; CaCl₂, 2.5 mmol/L; KH₂PO₄, 1.2 mmol/L; MgSO₄, 1.2 mmol/L; glucose, 10 mmol/L; and NaHCO₃, 25 mmol/L) maintained at 37°C and bubbled with a gas mixture of 95% oxygen and 5% carbon dioxide. They were allowed to equilibrate for 2 hours under a resting tension of 1 g, with repeated washing every 15 minutes. The responses were recorded isometrically by a force-displacement transducer (Grass FT 03C; Grass Instruments, Quincy, MA) on a polygraph (Grass model 7B).

Experimental Protocol
After the equilibration period, the rings were first contracted by a maximally effective concentration (EC) of phenylephrine (PE) (30 µmol/L). After a further 30-minute period of resting, with repeated washing every 15 minutes, tissues were challenged with 5-HT or sumatriptan, either at rest or after the tone had been moderately increased by a threshold concentration of KCl (from EC₁₀ to EC₂₀, ie, 5 to 10 mmol/L). The 5-HT and sumatriptan were added cumulatively. Only one agonist was tested in each preparation. Two successive concentration-response curves for each agonist were constructed to determine whether the responses were reproducible. In all experiments, n represents the number of patients from whom the arteries were obtained.

Data Analysis
Contractions induced by 5-HT and sumatriptan were expressed as the percentage of the maximum PE contraction. The values for the maximum contractile response (E_max), the concentration of drug at which 50% of maximum response was obtained (EC₅₀), and the -log EC₅₀ (pD₂) were given as means ± the standard error of the mean. Data for the preparations taken from hypertensive and normotensive patients were also evaluated separately. Statistical comparisons were done using the paired or unpaired Student's t test. A p level of less than 0.05 was considered significant.

Drugs
The 5-HT creatinine sulfate came from Sandoz (Basel, Switzerland), the phenylephrine hydrochloride from Sigma Chemical Co. (St. Louis, MO), and the potassium chloride from Merck (Darmstadt, Germany). The sumatriptan was provided free by Glaxo (Greenford, UK). Stock solutions and subsequent dilutions of all drugs were freshly prepared in distilled water.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Effects of 5-HT and Sumatriptan in IMA Segments
The 5-HT elicited concentration-dependent contractions when added to the resting and KCl-precontracted distal IMA rings (E_max = 93.14% ± 12.28% and 110.50% ± 17.59% of PE maximum contraction, respectively; p > 0.05; n = 11). In KCl-precontracted preparations, the sensitivity to 5-HT (pD₂ = 7.89 ± 0.13) was significantly greater (p < 0.05) than that in the quiescent rings (pD₂ = 7.23 ± 0.22).

Sumatriptan induced a concentration-dependent contraction of quiescent distal segments (E_max = 67.63% ± 15.62% of PE maximum contraction; pD₂ = 6.67 ± 0.12; n = 11). In four of the 11 quiescent preparations, sumatriptan induced small contractions (less than 30% of PE maximum) or no response. However, when the tissues were precontracted by a threshold concentration of KCl, sumatriptan was found to elicite concentration-dependent contractions in all of the distal segments (E_max = 81.09% ± 16.79% of PE maximum contraction and about 80% of 5-HT contraction; pD₂ = 7.11 ± 0.16). The pD₂ for KCl-precontracted segments was significantly greater (p < 0.05) than that for quiescent preparations.

5-Hydroxytryptamine and sumatriptan elicited concentration-dependent contractions when added to the resting proximal IMA rings (E_max = 67.04% ± 12.89% and 49.00% ± 21.47% of PE maximum contraction; pD₂ = 7.22 ± 0.20 and 6.86 ± 0.52, respectively) and KCl-precontracted proximal IMA rings (E_max = 97.25% ± 19.57% and 64.00% ± 7.30% of PE maximum contraction; pD₂ = 7.55 ± 0.13 and 6.93 ± 0.26, respectively) (n = 4 for each agonist). The responses to both agonists in the KCl-precontracted proximal preparations were not significantly greater than those in the quiescent proximal segments.

The responses to 5-HT in quiescent proximal and distal segments were compared, as were the responses in precontracted proximal and distal segments. The same was done for sumatriptan. The responses to both agonists were slightly but not significantly greater in the distal segments than they were in the proximal ones, except that the efficacy of sumatriptan was greater (p < 0.05) in the precontracted distal end than it was in the precontracted proximal segments.

The Influence of Hypertension on 5-HT and Sumatriptan Responses in the Distal IMA
Precontraction by KCl influenced the responses to 5-HT slightly but not significantly in the segments obtained from hypertensive patients (Fig 1), but the responses to sumatriptan were markedly potentiated (p < 0.05) in the KCl-precontracted preparations taken from hypertensives (Fig 2).

View larger version (34K): [in this window] [in a new window]   Fig 1. . Concentration-response curves for the contractile effect of 5-hydroxytryptamine in the quiescent (A) and in the potassium chloride (from EC10 to EC20)–precontracted (B) distal internal mammary arterial segments taken from normotensive (circles; n = 6) and hypertensive (squares; n = 5) patients. Vertical bars represent standard error of the mean. (PE = phenylephrine.)

View larger version (39K): [in this window] [in a new window]   Fig 2. . Concentration-response curves for the contractile effect of sumatriptan in the quiescent (A) and in the potassium chloride (from EC10 to EC20)–precontracted (B) distal internal mammary arterial segments taken from normotensive (circles; n = 6) and hypertensive (squares; n = 5) patients. Vertical bars represent standard error of the mean. (PE = phenylephrine; *p < 0.05 versus normotensives.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In this study, 5-HT was found to be a potent agonist causing the contraction of the IMA. No priming was required to potentiate the actions of 5-HT, whereas precontraction with KCl unmasks a prominent constrictor effect of the specific 5-HT₁–like receptor agonist sumatriptan in tissues that were virtually unresponsive to this agent under our control conditions. A wide variety of precontracting substances such as prostaglandin F₂, histamine, norepinephrine, PE, angiotensin II, and the depolarizing agent KCl can unmask 5-HT₁–like receptors [13]. The final step in the mechanism of this unmasking effect seems to be an increase in intracellular calcium levels, eventually bringing the calcium level closer to the threshold level needed for contraction [13].

The results of our recent study [15] indicate that sumatriptan evokes contraction of the IMA through stimulation of a 5-HT₁–like receptor, but 5-HT induces contraction through stimulation of both 5-HT₁–like and 5-HT_2A receptors. These two types of receptors have also been observed in human mesenteric and coronary arteries [16, 17]. Sumatriptan may constrict human coronary arteries and can cause cardiac ischemia and even myocardial infarction [18, 19]. Sumatriptan may cause constriction of IMA grafts, as well.

The efficacy of sumatriptan was higher in the distal end than in the proximal segments. This finding is consistent with that for other studies [5–7] in which the artery was noted to contract strongly in response to several vasoconstrictor agents such as thromboxane A₂, alpha-adrenoreceptor agonists, and 5-HT; and the contractility increases toward the distal end of the artery.

Our results also show that the reported increase in contractility of the IMA in response to 5-HT toward the distal end of the artery may in part result from the difference in amplification of the 5-HT₁–like receptor–mediated contractions. Considering the greater contractile response of the distal IMA to 5-HT and sumatriptan as well as to other various agonists, it is best to avoid using the distal part, and mainly the bifurcation, for coronary artery bypass grafting. Age and other risk factors such as hypertension, diabetes, hyperlipidemia, and obesity may influence the long-term survival rates in patients undergoing coronary artery bypass grafting [20, 21]. Many factors such as the reactivity and size of the IMA grafts, flow status, the quality of the vessel, and the operative technique used may influence the outcome from the coronary revascularization operations. These factors become particularly important when inotropic agents that possess alpha-adrenergic properties are required to treat hypotension and when neurogenic catecholamine release may occur [7, 20]. These results indicate that care should be taken in prescribing sumatriptan for the treatment of migraine in patients with IMA grafts. The more marked potentiation of the responses in arteries from hypertensive patients may be one of the factors influencing the patency rates in these patients and requires further study.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Prof S. Ouz Kayaalp, Prof M. Ali Gündoan, and Dr Ferah Yildiz for their nice remarks and Glaxo for providing the sumatriptan. We also appreciate the great help and support of surgeons, residents, nurses, and technicians at the GATA Department of Cardiovascular Surgery.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Tuncer, Department of Pharmacology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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