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Am J Physiol Heart Circ Physiol 284: H1080-H1086, 2003. First published December 19, 2002; doi:10.1152/ajpheart.00465.2002
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Vol. 284, Issue 4, H1080-H1086, April 2003

Mechanism of thrombin-induced vasodilation in human coronary arterioles

John J. Bosnjak1, Ken Terata1, Hiroto Miura1, Atsushi Sato1, Alfred C. Nicolosi2, Monica McDonald3, Sara A. Manthei1, Takashi Saito4, Ossama A. Hatoum1, and David D. Gutterman1

1 Medical College of Wisconsin, Cardiovascular Center, 2 Veterans Affairs Medical Center, and 3 Midwest Heart Surgery Institute, Milwaukee, Wisconsin 53226; and 4 Second Department of Internal Medicine, Akita University, Akita City 0108543, Japan


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Thrombin (Thromb), activated as part of the clotting cascade, dilates conduit arteries through an endothelial pertussis toxin (PTX)-sensitive G-protein receptor and releases nitric oxide (NO). Thromb also acts on downstream microvessels. Therefore, we examined whether Thromb dilates human coronary arterioles (HCA). HCA from right atrial appendages were constricted by 30-50% with endothelin-1. Dilation to Thromb (10-4-1 U/ml) was assessed before and after inhibitors with videomicroscopy. There was no tachyphylaxis to Thromb dilation (maximum dilation = 87.0%, ED50 = 1.49 × 10-2). Dilation to Thromb was abolished with either hirudin or denudation but was not affected by PTX. Neither Nomega -nitro-L-arginine methyl ester (n = 7), indomethacin (n = 9), 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (n = 6), tetraethylammonium chloride (n = 5), nor iberiotoxin (n = 4) reduced dilation to Thromb. However, KCl (maximum dilation = 89 ± 5 vs. 20 ± 10%; P < 0.05; n = 7), tetrabutylammonium chloride (maximum dilation = 79 ± 7 vs. 21 ± 4%; P < 0.05; n = 5), and charybdotoxin (maximum dilation = 89 ± 4 vs. 10 ± 2%; P < 0.05; n = 4) attenuated dilation to Thromb. In contrast to animal models, Thromb-induced dilation in human arterioles is independent of Gi-protein activation and NO release. However, Thromb dilation is endothelium dependent, is maintained on consecutive applications, and involves activation of K+ channels. We speculate that an endothelium-derived hyperpolarizing factor contributes to Thromb-induced dilation in HCA.

coronary circulation; coronary disease; K+ channel; vasoactive agent


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THE SERINE PROTEASE THROMBIN (Thromb), a pivotal enzyme in the coagulation pathway, has nonhemostatic effects elicited by activation of Thromb receptors. These include the modification of vascular tone in a variety of species and vascular beds (6). The mechanism of the vasoactive effect involves Thromb binding to a specific, seven-transmembrane-domain receptor on endothelial cells and smooth muscle cells (16, 31). In the act of binding to the receptor, an amino terminus of the receptor is cleaved, the tethered ligand that is left then binds to the receptor itself, and activation occurs (31). One of the characteristics of the cellular response to Thromb is that receptor activation produces a state of homologous desensitization in which refractoriness occurs to dilation on subsequent application (11, 23). It has been reported that in endothelium-intact vessels, Thromb elicits dilation, whereas in denuded vessels constriction is seen (13, 14, 27). However, there is marked variability among species and vascular beds with regard to the vasoactive properties of Thromb (4, 13, 19, 27). This diverse response may be due to the complex nature of events leading to Thromb activation and dilation. In humans, it has been shown that Thromb elicits endothelium-dependent vasodilation in the coronary (7) and peripheral conduit arteries (9, 17, 33).

Endothelium-derived nitric oxide (NO) is responsible for Thromb-induced dilation in many vascular beds and in some human tissues (7, 14, 25, 29, 32). It is not known whether Thromb elicits vasodilation in the human coronary microvasculature or where it is released during acute coronary events, and it may achieve high local concentrations due to reduced flow distal to a stenosis at the site of release. Therefore, we applied Thromb to fresh, isolated coronary microvessels from patients with coronary artery disease to determine the nature and the mechanism of the vasoactive response.

The purpose of the present study was to test the following hypotheses: 1) Thromb-induced vasodilation in human coronary arterioles is mediated through activation of a pertussis toxin (PTX)-sensitive G protein, as suggested by others (3), and 2) Thromb-mediated dilation requires the production of NO. The results indicate that Thromb-induced relaxation of human coronary arterioles does not require activation of PTX-sensitive G proteins, nor does it require the production of NO. However, K+ channels appear to play an important role, implicating endothelium-derived hyperpolarizing factor (EDHF) as a possible mediator of the response to Thromb.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

General preparation. This investigation conforms to the principles outlined in the Declaration of Helsinki. Human coronary arterioles were dissected from the right atrial appendage and removed for cannulation during cardiopulmonary bypass at the time of cardiac surgery. Vessels ranging in size from 50 to 180 µm (means ± SE = 106 ± 7 µm) were cleaned of fat and connective tissue in a cold HEPES buffer. In a tissue chamber, both ends of each arteriole were secured to impedance-matched glass pipettes (internal tip diameter = 40 µm) using 10-0 Ethilon monofilament nylon suture (Ethicon). Vessels were bathed continuously with physiological saline solution (PSS) consisting of (in mmol/l): 123.0 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 16 NaHCO3, 1.2 KH2PO4, and 11 glucose. The preparation was then transferred to the stage of an inverted microscope (magnification = ×200; Olympus CK2). Attached to the microscope were a video camera (WV-BL200; Panasonic), a video monitor (Panasonic), and a calibrated video measurement system (VIA-100K; Boeckeler Instruments). Internal diameter (resolution = 2 µm) was measured by manually adjusting the video micrometer. The vessels were then pressurized (20 mmHg) by simultaneously adjusting the height of each reservoir attached to the pipettes. Vessels were incubated in oxygenated PSS (21% O2-5% CO2-74% N2) for 30 min at 20 mmHg pressure and 37°C. Pressure was slowly increased (to 60 mmHg), with a subsequent 30-min incubation period. A final pressure of 60 mmHg was selected on the basis of estimates of physiological pressure in 100-µm coronary arterioles (1). All drugs were added to a continuously circulating buffer except PTX, iberiotoxin (IBTX), and charybdotoxin (CTX), which were incubated in a 20-ml noncirculating vessel chamber. Intraluminal pressure was maintained at 60 mmHg, with no flow.

Patient profiles. Microvessels were obtained from 70 patients, ranging in age from <1 to 85 yr. The average age was 61 yr. Among these patients, 74% were male and 26% were female, 84% had coronary artery disease, 21% had myocardial infarctions, 36% had hypertension, 20% had diabetes mellitus, and 26% had hypercholesterolemia. Three patients were children with congenital heart disease. In 12 of the 70 patients studied, information about the surgical procedure was not available (Table 1).

                              
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  		Table 1.   Demographics

Protocol. Vessels were constricted with 75 mmol/l KCl to assess viability. Vessels that constricted >30% of resting internal diameter were used for subsequent experiments. After a vessel was washed with fresh buffer, endothelin-1 was added to constrict the vessel by 30-50% of its maximum diameter. Internal diameter readings were taken 5 min after each endothelin-1 dose until the desired diameter was obtained. Cumulative doses of Thromb, from 0.0001 to 1 U/ml, were then added to the bath, and steady-state diameter readings were taken 5 min after each dose. The tissue bath was then washed with fresh buffer for ~20 min and allowed 10-15 min for equilibration, and inhibitor(s) or vehicle was added. After incubation with inhibitors for 10-30 min (depending on inhibitor used), vessels were again constricted with endothelin-1 in the same manner, followed by a second dose-response curve to Thromb. At the end of each dose-response curve, a single dose of sodium nitroprusside (SNP, 10-4 mol/l) was added to determine the maximal internal diameter for normalization of dilator responses.

Specific antagonists were used to determine the mechanism of dilation to Thromb. Because PTX-sensitive G proteins are responsible for dilation to Thromb in arteries from animals (3), PTX (100 ng/ml) was used. To determine the involvement of NO, vessels were treated with Nomega -nitro-L-arginine methyl ester (L-NAME, 10-4 mol/l). Indomethacin (Indo, 10-5 mol/l) was used to inhibit the activity of cyclooxygenase, and 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ, 2 × 10-5 mol/l) was used to block the activity of guanylyl cyclase. KCl (50-75 mmol/l) was used to clamp membrane potential in a depolarized state. K+-channel blockers were tested, including tetraethylammonium chloride (TEA, 10-3 mol/l) to inhibit large-conductance (BKCa) and small-conductance (SKCa) Ca2+-activated K+ channels and IBTX (10-7 mol/) to inhibit BKCa channels (10). We also tested tetrabutylammonium chloride (TBA, 10-3 mol/l) and CTX (10-7 mol/l), which inhibit both BKCa and intermediate-conductance Ca2+-activated K+ channels (IMKCa) (18, 21). To test the role of ATP-sensitive K+ (KATP) channels, glibenclamide (10-6 mol/l) was used. We also used hirudin (2 U/ml), which selectively prevents Thromb-induced responses by binding to Thromb and thereby rendering it inactive. Finally, ouabain (0.5 µM) was used to block the Na+-K+-ATPase pump (2). Vessels were incubated with inhibitors for 15-30 min, except for PTX (60-90 min) and hirudin (10 min). PTX, Indo, L-NAME, TEA, TBA, ouabain, hirudin, IBTX, CTX, and glibenclamide were obtained from Sigma (St. Louis, MO). ODQ was obtained from Tocris (Ballwin, MO).

Denuding vessels tested the role of the endothelium in Thromb-induced vasodilation. Denudation was achieved by passing a hair through the vessel several times followed by injection of 0.3 ml of air (15).

Statistical analysis. All values are expressed as a percentage of the maximum dilation to SNP from the initially constricted diameter. Values are means ± SE. A two-factor repeated-measures analysis of variance with autoregressive covariance assumption (proc mixed program in SAS Windows 6.12) was used to analyze differences between groups compared (e.g., control vs. inhibitor) and respective dosages. When a significant difference was observed between dose-response curves (P < 0.05), specific effect slices were done comparing individual dosages between two treatment groups by using a Bonferroni-corrected Student's t-test. In assessing recorded clinical parameters on the dilation to Thromb, we used multiple stepwise regressions.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Repeated application of Thromb. We examined whether successive applications of Thromb result in desensitization, as would be expected with the traditional mechanism involving irreversible cleavage of the receptor. In vessels from eight patients, two successive applications of Thromb produced identical dilation, indicating reproducibility of the response and lack of desensitization (Fig. 1).


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  		Fig. 1.   Vasodilation to repeated application of thrombin (Thromb). In all graphs, values are expressed as a %maximum dilation to sodium nitroprusside (SNP) and are means ± SE. Thromb reproducibly induced dose-dependent dilation, indicating no tachyphylaxis. %Maximal dilation was 87 ± 3 vs. 79 ± 5% at 1 U/ml. Passive diameter was 89 ± 15 µm.

Effect of PTX. Figure 2A shows the effect of inhibiting Gi proteins, which is critical for Thromb-induced dilation in the porcine coronary artery (3). PTX did not affect baseline arteriolar diameter (80 ± 3 vs. 78 ± 6 µm after PTX). Dilation to Thromb was similar in the presence and absence of PTX. To confirm the effectiveness of the dose of PTX used in these experiments, we tested serotonin, which produces dilation that is mediated by Gi proteins (3). In contrast to Thromb, the same dose of PTX completely blocked dilation to serotonin (Fig. 2B). Together, these findings suggest that Thromb-induced vasodilation of human coronary arterioles is not mediated through a Gi protein pathway.


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  		Fig. 2.   Concentration response to Thromb after incubation with pertussis toxin (PTX). A: Thromb-induced vasodilation was not inhibited by PTX. %Maximum dilation was 80 ± 3 vs. 78 ± 6% at 1 U/ml. Passive diameter was 98 ± 20 µm; baseline diameter was not affected by PTX (4.7 ± 8%). B: serotonin-induced dilation was significantly attenuated by PTX, suggesting that Thromb-induced dilation is not mediated through a Gi protein pathway. %Maximum dilation was 60 ± 11 vs. 15 ± 15%. # P < 0.05.

Effect of hirudin. We next tested the specificity of the response to Thromb by using the selective Thromb-inactivating agent hirudin (5). Hirudin had no effect on baseline diameter. However, it abolished dilation to Thromb (Fig. 3). The same dose of hirudin did not affect dilation to ADP (10-4 M; 71 ± 13 vs. 71 ± 13%; n = 5) or SNP (10-4 mol/l; 82 ± 11 vs. 81 ± 11% after hirudin).


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  		Fig. 3.   Effect of hirudin on Thromb-induced dilation. Hirudin produced minor nonsignificant changes in baseline diameter (6 ± 2%); however, it completely blocked Thromb-induced dilation. %Maximum dilation was 71 ± 9 vs. -0.1 ± 1% at 1 U/ml. # P < 0.05.

Endothelium-dependent dilation. Because the endothelium can contribute importantly to vasodilation, we tested the effect of endothelial disruption on Thromb-induced relaxation. The progressive dilation to increasing doses of Thromb was completely abolished by mechanical disruption of the endothelium (Fig. 4). Vessel dilator capacity was intact because dilation to SNP, an endothelium-independent agonist, was not affected.


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  		Fig. 4.   Role of endothelium in Thromb-induced dilation. Vasodilation to Thromb was reduced by endothelial denudation, although dilation to SNP (10-4 M) was preserved. EC, endothelial cell. %Maximum dilation was 87 ± 3 vs. 6 ± 7% at 1 U/ml. # P < 0.05.

Involvement of the endothelium in human coronary arteriolar dilation suggests one of several mechanisms, including release of NO, prostacyclin, or EDHF. We examined these potential mechanisms of dilation to Thromb. After treatment with L-NAME (10-4 M) in a dose that impairs responses to adrenomedullin (30), dilation to Thromb was not affected (Fig. 5A). ODQ (2 × 10-5 M), an inhibitor of guanylyl cyclase (Fig. 5B), abolished vasodilation to SNP (26) but did not reduce relaxation to Thromb. This is consistent with the lack of involvement of NO as shown by others (20). In separate experiments, incubation of vessels with Indo did not reduce dilation to Thromb (Fig. 5C). Therefore, neither prostaglandins, NO, nor other cGMP dilator mechanisms are required for Thromb-induced vasodilation.


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  		Fig. 5.   Vasodilation to Thromb in the presence of either nitric oxide synthase inhibitor, soluble guanylate cyclase inhibitor, or cyclooxygenase inhibitor. A: Nomega -nitro-L-arginine methyl ester (L-NAME) did not affect dilation to Thromb. %Maximum dilation was 60 ± 9 vs. 81 ± 9% at 1 U/ml (not significant). B: 1H-[1,2,4]oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ), an inhibitor of guanylate cyclase, did not attenuate dilation to Thromb (maximal dilation = 77 ± 5 vs. 78 ± 8% at 1 U/ml; not significant). C: incubation of vessels with indomethacin (Indo) did not affect dilation to Thromb.

Hyperpolarization-dependent dilation. The constellation of findings that Thromb-induced dilation is endothelium dependent but does not involve NO synthase or cyclooxygenase implicates EDHF as a mediator of the dilation. Because EDHF acts by opening K+ channels, resulting in vascular smooth muscle hyperpolarization and vasodilation, we examined the effect of inhibiting these channels. High concentrations of external KCl prevent K+ channel-activated hyperpolarization. When vessels were constricted with KCl, rather than endothelin-1, dilation to Thromb was markedly reduced (Fig. 6A). TEA, an inhibitor primarily of BKCa and SKCa channels, had no effect on the ability of Thromb to dilate these coronary arterioles (Fig. 6B). Similarly, because mainly BKCa channels were inhibited by using IBTX, there was no change in dilation (Fig. 6C). However, TBA or CTX, each inhibitors of both BKCa and IMKCa, significantly reduced this dilation (Fig. 6, D and E, respectively). Glibenclamide, a KATP channel blocker, had no effect (Fig. 6F).


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  		Fig. 6.   Effect of K+ channels on human coronary arteriolar dilation to Thromb. A: Thromb-induced dilation was attenuated in the vessels preconstricted with KCl (61 ± 10 mM). The magnitude of constriction to endothelin-1 and KCl was similar (47 ± 5 vs. 47 ± 7%, respectively; not significant). B: tetraethylammonium chloride (TEA) did not affect baseline diameter (0.1 ± 0.5%) and did not affect the dilation to Thromb. C: iberiotoxin (IBTX) did not affect dilation to Thromb. %Maximum dilation was 77 ± 10 vs. 75 ± 11% at 1 U/ml. D: tetrabutylammonium chloride (TBA) significantly attenuated Thromb-induced dilation. E: charybdotoxin (CTX) also inhibited dilation to Thromb (89 ± 4 vs. 10 ± 2% at 1 U/ml; # P < 0.05). F: glibenclamide did not affect dilation to Thromb.

Effect of ouabain. Ouabain (0.5 µM), a Na+-K+-ATPase blocker, had no effect on the dilation to Thromb (maximal dilation = 89.6 ± 5 vs. 79.5 ± 9%, n = 4) (2).

Effect of cardiovascular risk factors. A multiple-regression analysis was done to detect whether age, gender, presence of coronary artery disease, hypertension, hypercholesterolemia, diabetes mellitus, myocardial infarction, congestive heart failure, and tobacco use were associated with impaired human coronary arteriolar dilation to Thromb. No significant effects were observed. Therefore, differences in the Thromb-induced dilations were due to the presence of the specific inhibitors or blockers.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The present study demonstrates that Thromb is a potent vasodilator in human coronary arterioles. This is the first direct evidence that Thromb causes endothelium-dependent vasodilation in the human coronary microcirculation. Because repeated applications of Thromb produced similar dose-dependent vasorelaxations, Thromb desensitization, which has been shown in conduit human (7) and pig (28) coronary arteries, is not seen in the human coronary microcirculation. There are at least four possible explanations for this finding. First, it may be that a substantial percentage of the surface population of Thromb receptors is not being activated by Thromb. Second, there may be mobilization of receptors to the cell surface after initial receptors are cleaved. Third, the classic cleavage mechanism may not be responsible for Thromb-induced dilation of human coronary arterioles. Finally, the dose and duration of incubation with Thromb may not have been sufficient to cause desensitization.

The results following denudation of the endothelium indicate an endothelium-dependent mechanism, which is consistent with other studies (7, 17). However, in contrast to some animal studies, we observed no vasoconstriction to Thromb in human coronary arterioles following denudation. This is consistent with findings in human conduit coronary arteries (7) and might be explained by localization of the Thromb receptor, a protease-activated receptor (PAR)-1, to endothelial cells in certain (22), but not all (33), human arteries. Four distinct PARs have been cloned; however, the differential role of these receptors in regulating of human coronary arteriolar tone remains to be established.

Thromb-induced relaxation does not require activation of PTX-sensitive Gi proteins, NO synthase, or cyclooxygenase. This contrasts with a previous report of NO-mediated vasodilation in human conduit coronary vessels (7) and could be due to well-known differences between the conduit and resistance vasculatures. In resistance arteries, EDHF generally plays a greater role in regulating vascular tone (12). The mechanism of EDHF-induced dilation involves activation of K+ channels in the vascular smooth muscle, as we observed. Our study also begins to identify the nature of the K+ channel involved. A prominent role for KATP channels or BKCa channels was not observed. Similarly, the KCl-sensitive Na+-K+-ATPase is not responsible for Thromb-induced dilation. However, the differential inhibitory effect of TEA (BKCa and SKCa channels) or IBTX (BKCa channels), compared with TBA or CTX, both inhibitors of BKCa and IMKCa channels, is consistent with a prominent role for IMKCa in Thromb-mediated dilation. Agonist-induced activation of IMKCa channels in human arteries has been described before (9), and IMKCa mRNA has been detected in human coronary vessels (24).

Limitations. All vessels used in this study were from patients who underwent heart surgery, 84% of whom had coronary artery disease. Thus our findings pertain to patients with heart disease and may reflect an adaptation to disease rather than a primary physiological process. Interestingly, we observed robust dilation to Thromb (with a maximum of nearly 80% of the dilation seen to SNP), whereas in animal models of vascular disease much less dilation is generally observed (8, 32). This could reflect chronicity of disease or different primary mechanisms of dilation between models. Nevertheless, this study highlights the importance of examining vascular function in humans, especially when assessing the effect of disease.

Despite the overall Thromb-induced dilation among patients, there was much variability among the control groups, in which the percent maximal diameter dilation to Thromb varied between 60.1 and 92.2%. The reason for this difference is not known, but interpretation of the data should not be affected by this variability, because vessels from each subject served as their own control. It is not possible to acquire cardiac tissue from normal subjects, but future studies could address this issue with vessels from large numbers of patients who have no coronary artery disease undergoing surgery for valve replacement.

In contrast to prior studies in animal models, we speculate that EDHF may contribute to Thromb-induced dilation in coronary arterioles from humans with coronary artery disease. The lack of inhibition of dilation with Indo and L-NAME indicates that cyclooxygenase and/or NO synthase products do not play a role in mediating the relaxation. The speculation that IMKCa channels are responsible for the dilation to Thromb is based on pharmacological data with relatively nonspecific blocking agents. When more specific pharmacological inhibitors are developed, these findings can be confirmed with greater specificity.

In conclusion, Thromb-induced vasodilation is maintained on consecutive applications and is dependent on IMKCa channels with an intact endothelium but is not dependent on NO or prostacyclin. The dilation involves membrane hyperpolarization, possibly as a result of endothelial release of EDHF.


    ACKNOWLEDGEMENTS

We acknowledge the expert statistical assistance of Dr. Fausto R. Loberiza. We also thank Timothy A. Boyle for critical review of this paper.


    FOOTNOTES

This study was supported by a Veterans Affairs Merit Award and by National Heart, Lung, and Blood Institute Grants P50-HL-65203 and RO1-HL-62852 to D. D. Gutterman.

Address for reprint requests and other correspondence: D. D. Gutterman, CVC Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: dgutt{at}mcw.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published December 19, 2002;10.1152/ajpheart.00465.2002

Received 10 June 2002; accepted in final form 10 December 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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