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J Thorac Cardiovasc Surg 1995;110:148-156
© 1995 Mosby, Inc.

GENERAL THORACIC SURGERY

Endothelin-1 focally constricts pulmonary veins in rats

Worcester, Mass.

Supported in part by a grant from the National Institutes of Health (No. DE-07444) (Sandy C. Marks, Jr.) and the James E. Liston Fund at the University of Illinois at Chicago.

Received for publication June 23, 1994. Accepted for publication Oct. 24, 1994. Address for reprints: Dean E. Schraufnagel, MD, Section of Respiratory and Critical Care Medicine, Department of Medicine M/C 787, University of Illinois at Chicago, 840 S. Wood St., Chicago, IL 60612-7323.

Abstract

Serum endothelin levels increase during sepsis, ischemia, reperfusion, pulmonary operations, and systemic hypertension after surgery. Despite extensive study, the site and extent of action of endothelin on the pulmonary microcirculation are not well established. To assess the effect of endothelin on the pulmonary vasculature, especially the veins, the circulation of the lung was cast with methyl methacrylate 10 minutes after endothelin-1 was given intravenously to rats. Endothelin-1, at concentrations of 0.1, 1.0, and 10.0µg/kg of body weight, increased the mean systemic arterial blood pressure 8%, 7%, and 17% (p < 0.01) and mean pulmonary arterial blood pressure 15%, 28%, and 53%, respectively (p < 0.01). The proportional increases in the pulmonary pressures were greater than those of the systemic pressures (p < 0.01). Scanning electron microscopy of cast blood vessels showed more contraction of the veins than the arteries. For doses of 0, 0.1, 1.0, and 10.0µg/kg, the respective focal contraction of small veins was 6.7% (±4.4), 15.4% (±9.1), 23.3% (±10.1), and 14.4% (±9.0) of the vessel diameter (p < 0.01). In addition, the diameters of capillaries increased (p < 0.01) and the capillary interspaces decreased (p < 0.01) after endothelin administration, but not in a linear dose-dependent manner. The dose of endothelin correlated with the change in the mean systemic (r = 0.82, p < 0.01) and the mean pulmonary (r = 0.80, p < 0.01) blood pressures. The mean pulmonary pressure change correlated with the focal venous contraction on the casts (r = 0.35, p < 0.01), capillary diameter (r = 0.64, p < 0.01), and capillary interspace distance (r = -0.34, p < 0.01). The venous contraction was related to the capillary diameter (r = 0.26, p < 0.01). The most notable effect of endothelin-1 in rat pulmonary microcirculation is focal constriction of small veins. Because this effect may lead to pulmonary edema, endothelin antagonists may be of benefit in a variety of clinical situations. (J THORAC CARDIOVASC SURG 1995;110:148-56)

Endothelin-1, a 21-residue peptide first isolated from endothelial cell cultures, ¹ has important effects on vascular smooth muscle. ² Endothelin controls regional perfusion of the lung ³ and its serum level increases during sepsis, ⁴ ischemia, ⁵ reperfusion, ⁶ and pulmonary operations. ⁷ Endothelin plays a role in vascular restenosis in patients undergoing angioplasty ⁸ and contracts bronchi in experimental lung transplantation in dogs. ⁹ It has been associated with systemic hypertension after liver transplantation. ¹⁰ Although its effects are largely vasoconstrictive, ¹¹ an initial vasodilatory effect of endothelin-1 occurs in certain young animal species. ^12,13 Endothelin-1 causes a biphasic response in the systemic vasculature and increases myocardial contractility in adult rabbits, although the reason for the initial dilation remains uncertain. ¹⁴ There is disagreement about the location of action and its magnitude in response to specific doses. ¹⁵ Fortes, de Nucci, and Garcia-Leme ¹⁶ found it constricts bothperipheral arteries and veins, but Brain ¹⁷ found that endothelin did not affect peripheral veins. Synthesized by the pulmonary vasculature, ¹⁸ endothelin increases pulmonary vascular resistance. ^19-22 Endothelin is increased in the alveoli of animals that have been experimentally injured ²³ and in the serum of patients who havepulmonary hypertension ^24-27 and those who undergo heart transplantation. ²⁸

Most studies of the effect of endothelin on the pulmonary vasculature have used physiologic measurements, such as the pressure generated by the shortening of smooth muscle or the resistance to pulmonary blood flow. Although these studies give important functional information they do not show the site of action, especially on the small pulmonary blood vessels. We were interested in the effect of endothelin-1 on the pulmonary vascular bed especially as concerns the veins, which we have studied earlier. ^29,30 We used vascular casts examined with scanning electron microscopy, which show changes in three dimensions in disease ³¹ and after the application of vasoactive drugs. ³² Understanding these effects contributes to our understanding of pulmonary vascular reactions in patients undergoing surgery.

METHODS

This experiment was approved by the Animal Care Committee at the University of Massachusetts Medical Center at Worcester. The animals were handled humanely according to the Public Health Service guidelines.

Blood pressure measurements.
We divided 24 male Wistar Kyoto rats (Charles River, Boston, Mass.) weighing 160 to 320 gm into four groups and anesthetized them with diethyl ether (Metofane; Fisher Chemicals, Chicago, Ill.). We opened the abdomen, cannulated the aorta, and connected the cannula to a transducer that recorded blood pressure on a Grass polygraph (Grass, Quincy, Mass.). We connected a 24-gauge Teflon catheter with an outer diameter of 0.99 mm, an inner diameter of 0.66 mm, and a tip shaped into an "R crook" to a transducer and placed it into a metal cannula. ³³ The cannula was inserted into the right jugular vein and advanced into the right ventricle until the typical right ventricular pressure waveform was obtained. ³³ After recording the pressure, we plied the catheter into the pulmonary artery and recorded the pressure again. Then, the caudal vena cava was cannulated at the level of the renal arteries with a 20-gauge catheter. The rats were given 0, 0.1, 1.0, or 10 µg of endothelin-1 per kilogram of body weight through the caudal vena cava and both systemic and pulmonary arterial pressures were again recorded. The different doses of endothelin-1 were selected on the basis of previous reports ^20,22,34 and correlated with pharmacologic doses. ³⁵ In pilot studies in a group of animals in which the lungs were not cast, the vasoconstrictor effect of endothelin-1 lasted 35 (±7) minutes before the blood pressure gradually decreased to the baseline level. The body temperature was maintained with use of a heat lamp. Animals recovered from the surgical procedure for 30 minutes before baseline blood pressures were recorded and any drug administered.

Cast preparation.
Ten minutes after the endothelin injection, the catheter in the jugular vein was clamped. The vasculature was flushed with 20% dextran 40 in 0.9% saline (Macrodex; Pharmacia, Piscataway, N.J.) with 5000 IU/L of heparin at 42º C through the caudal vena cava until the aortic efflux cleared. This required about 60 ml of solution. ³⁰ Then, 20 ml of methyl methacrylate (Mercox; Ladd Industries, Burlington, Vt.), mixed with 2 gm of catalyst, was injected over about 1 minute through the vena cava to cast the lungs. ³⁶ After hardening at room temperature for 2 hours, the lungs were dissected out and transferred to a 60º C water bath overnight. The tissue was macerated in a 5% potassium hydroxide solution at 40º C for 6 days. ³⁰ The specimens were rinsed with tap water for 30 minutes, with 5% formic acid for 10 minutes, and then with three rinses in distilled water for 2 minutes each. ³¹ The casts were frozen in distilled water, freeze-dried, cut with scissors into 1 to 2 mm thick slices, and mounted onto studs with silver paste and conductive bridges. ³⁷ The casts were sputter coated with palladium-gold for 3 minutes and examined with a JEOL JSM-35C scanning electron microscope (JEOL, Tokyo, Japan) at an accelerating voltage of 10 kV.

Specimens were coded so that the microscopist was unaware of the group to which they belonged. From each lung we mounted four slices on aluminum studs. On each stud we studied four arteries, four veins, and four alveolar fields. The fields containing the arteries and veins were selected randomly at 200-fold magnification. Those containing alveoli were also selected randomly at 1000-fold magnification. We looked for changes in the surface and caliber of the arteries and veins. ^31,38 Casts of arteries are distinguishable from those of veins because the nuclei of arterial endothelial cells imprint oval impressions that run with the long axis of the vessel. The nuclei of venous endothelial cells imprint round impressions that have no direction. ³⁹ Arteries track with the airways; veins lie apart. Veins have regular ring-shaped indentations; arteries do not. The depths of the contractions in the veins were measured by the method of Schraufnagel and Thakkar. ³² Briefly, the casts were fractured at the constricted sites of the blood vessels. The constricted sites were rotated perpendicular to the viewing plane of the scanning electron microscope. The constricted diameter and outer vessel diameter were measured at the same site. One minus the inner constricted segment divided by the outer diameter of the cast was the percentage of contraction.

Cast alveolar capillaries cover most of the alveolus but leave a small opening between spokes in their hub-and-spoke configuration. In each alveolar capillary basket, the horizontal distances of 10 capillary interspaces (scanning from top to bottom) were measured. In separate areas, we measured the diameters of the capillaries. A transparent plastic overlay with a test pattern ⁴⁰ was put on the cathode ray tube of the scanning electron microscope. Capillaries beneath the marked points were measured: 10 capillaries per field and 4 fields per stud at 1000-fold magnification.

Data analysis.
The variables analyzed were the animal's body weight and age; pulmonary and systemic arterial systolic, diastolic, and mean pressures; diameters of the veins; depths of venous contraction in percentage; diameters of the capillaries; and widths of the interspaces between alveolar capillary casts. The pressures were compared before and after endothelin administration (one dose for each animal) by paired t tests. We compared these factors with the dose of endothelin as the independent variable and with the focal venous contraction as the dependent variable by an analysis of variance and multivariate regression. We used the Student-Newman-Keuls multiple range procedure to show where the differences were. The dose of endothelin was evaluated both as a continuous and categoric variable. We concluded that differences were significant if the p value was <0.01. Because correlations included many comparisons, the p value was divided by the number of tests performed (Bonferroni p). ⁴¹ The standard deviation is displayed after the plus or minus sign. Statistics were done on a Dell 310 microcomputer (Dell Computer Corp., Austin, Tex.) running SAS statistical software for DOS, release 6.03. ⁴²

RESULTS

Endothelin-1, at concentrations of 0.1, 1.0, and 10.0 µg/kg body weight, increased the mean systemic blood pressure 10, 7, and 17 mm Hg and the mean pulmonary artery blood pressure 2, 4, and 7 mm Hg, respectively. All p values were <0.01 (Fig. 1). This represents an 8%, 7%, and 17% increase for the mean systemic blood pressure and a 15%, 28%, and 54% increase for the mean pulmonary blood pressure. The proportional increases in mean pulmonary arterial pressures are greater than the increases in the systemic arterial pressures (p < 0.01) (Table I).

View larger version (91K): [in this window] [in a new window]   Fig. 1. A, Stippled columns represent mean systemic arterial blood pressures before injection of endothelin. Solid columns represent mean systemic blood pressure after endothelin injection. B, Stippled columns represent mean pulmonary arterial blood pressures before injection of endothelin. Solid columns represent mean pulmonary blood pressures after endothelin injection. Endothelin-1 increases blood pressure in both circulations.

Arteries usually had a normal appearance, although many were contracted (Fig 2). The capillaries in both the tissue and casts appeared normal, but the veins regularly were contracted with focal constrictions (Figs. 3 and 4). The diameters of the veins studied ranged from 12 to 311 µm. Focal venous contraction increased with the increasing dosage of endothelin up to 1 µg/kg. For animals given 0, 0.1, 1.0, and 10.0 µg/kg of endothelin, the average contraction was 6.7% (±4.4), 15.4% (±9.1), 23.3% (±10.1), and 14.4% (±9.0), respectively (p < 0.01) (Fig. 5). For animals given 0, 0.1, 1.0, and 10.0 µg/kg of endothelin the average capillary diameters were 6.2 (±1.5) µm, 7.1 (±1.4) µm, 9.7 (±1.6) µm, and 9.0 (±1.2) µm, respectively (p < 0.01). For animals given 0, 0.1, 1.0, and 10.0 µg/kg of endothelin, the average capillary interspace was 5.9 (±3.6) µm, 5.2 (±3.1) µm, 4.9 (±2.9) µm, and 5.3 µm (±3.4), respectively (p < 0.01) (Figs. 6 and 7).

View larger version (118K): [in this window] [in a new window]   Fig. 2. Scanning electron micrograph shows cast of pulmonary artery with elongated imprints of its endothelial cell nuclei. Pulmonary arteries lack ring constrictions and were less often contracted. This lung cast was from rat given 1 µg/kg of endothelin-1. Bar represents 30 µm.

View larger version (168K): [in this window] [in a new window]   Fig. 3. Scanning electron micrograph of cast of pulmonary vein shows moderately deep ring constrictions in animal that received 0.1 µg/kg of endothelin-1. Bar represents 50 µm.

View larger version (155K): [in this window] [in a new window]   Fig. 4. This cast pulmonary vein with its round reliefs of endothelial cell nuclei has contraction of about 40% of its diameter at its constricted site. This lung cast was from rat that received 0.1 µg/kg of endothelin-1. Bar represents 20 µm.

View larger version (23K): [in this window] [in a new window]   Fig. 5. Graph shows that mean venous contraction (± standard deviation) at sphincters, expressed in percentage of diameter, was highest in animals receiving 1 µg/kg endothelin-1.

View larger version (166K): [in this window] [in a new window]   Fig. 6. Cast shows capillaries of alveolus and spaces between them. This lung cast was from rat that received 10 µg/kg endothelin-1. Bar represents 10 µm.

View larger version (54K): [in this window] [in a new window]   Fig. 7. Stippled bar shows mean capillary diameter (in microns) increased in rats given endothelin-1. Solid bars show that capillary interspaces (in microns) decreased. Error bars represent standard deviation.

The multivariate regression showed that the animal's body weight and age had an effect on venous contraction in addition to the blood pressure change caused by endothelin. When each variable was entered first into the regression, the change in blood pressure (F = 26.3, p < 0.01) had a greater effect than weight (F = 0.2, p was not significant) and age (F = 7.8, p < 0.01), but when the other variables were in the equation, the change in blood pressure (F = 11.6, p < 0.01) had a lesser effect than weight (F = 36.2, p < 0.01) and age (F = 41.9, p < 0.01). Not surprisingly, these variables were interactive so that the effect of the change in pulmonary blood pressure on venous contraction was greater in the older animals (F = 22.2, p < 0.01), although the interactive term of weight and change in blood pressure was not significant (F = 0.01). Older and heavier animals also had greater contraction (F = 14.8, p < 0.01 for the interactive term age times weight with the dependent variable contraction).

DISCUSSION

Endothelin-1 had proportionally a greater effect on the pulmonary blood pressure than on the systemic blood pressure and pulmonary veins appeared more constricted than pulmonary arteries in rats. Others have reported that pulmonary veins are more sensitive to endothelin-1 than arteries in sheep ^21,43 and rabbits. ³⁴ Small pulmonary veins contract with narrow ringlike constrictions that we have termed venous sphincters. ^29,30 By casting and fracturing the casts we can measure the contractions of the individual veins at specific constriction points. Endothelin caused more constriction of these structures than any other stimulus that we have studied so far. ^29,44 Although it clearly appeared that the veins contracted more than arteries, the comparison may not be fair because we could precisely measure the focal constriction of veins that pinch with ringlike narrowness. Arteries, with their thicker muscularis, contract by a broad narrowing on the cast, which makes their contraction less obvious and impossible to measure exactly.

We used corrosion casting to describe the effect of endothelin on the microvasculature. Scanning electron microscopy of corrosion casts allows direct observation in three dimensions and measurement of large segments of the microvasculature. We can visualize where and how frequently the small blood vessels contract and we can see associated structural changes. We can rather precisely measure the depth of an individual contraction of small veins. The methacrylate resin passes into all parts of the vascular tree. The pressure applied to the syringe to fill the vasculature with the resin depends on its state of polymerization and the amount of resistance encountered before the resin reaches the desired vascular bed. The pressure cannot be measured at the capillary bed, but when the methacrylate is injected through the caudal vena cava, the aortic (venting) pressure during the injection is nearly zero. ³⁶ Damage to the delicate pulmonary capillary bed, if it should occur, can be detected by electron microscopy. ^31,45 Although this technique gives useful information and is probably the only one that could answer the questions we asked, it has limitations. Like most other microscopic investigations it is static and requires familiarity with the normal and pathologic anatomy. Many landmarks of light microscopy are not present and it does not give the intracellular detail of transmission electron microscopy of tissue. We always use light microscopy of tissue in conjunction with the scanning electron microscopy of casts, but find new information more often studying the casts than the tissue. Appropriate controls are essential to determine the changes caused by any agent.

To account for the greater sensitivity to endothelin, veins could have more endothelin receptors or the receptors on veins could have greater affinity for endothelin-1. ²¹ The receptors in the pulmonary vessels for endothelin-1, 2, and 3 have different affinities for the different endothelins. ^46,47 Another explanation may be that endothelin can more easily reach venous than arterial smooth muscle because pulmonary veins lack the continuous internal elastic lamina that pulmonary arteries have. ⁴⁸ Endothelin may also act on adrenergic neural transmission in addition to its direct effect on smooth muscle cells, ⁴⁹ although our studies indicate that nerve endings are rarein the wall of rat pulmonary veins. ^30,31

The average capillary diameter may have increased because the capillaries were fuller as a result of venous contraction. The size of the capillary interspace may be decreased because of passive distension of the capillaries. The structural differences shown here were greater when the dose of endothelin was considered as a class variable in the multivariate analysis, which means that the structural changes in the capillaries do not respond in a linear, dose-dependent manner in the doses we used. This may be because the 10 µg/kg dose of endothelin was not more potent than the 1.0 µg/kg dose of endothelin, but more likely indicates that the expansion of capillaries is limited to about 9 µm and the intercapillary space will decrease only so far in response to an acute stimulus, which was reached with the 1 µg/kg dose.

We have associated contraction of pulmonary venous sphincters with pulmonary edema, ^29-31 and other workers have found thatendothelin-1 causes pulmonary edema in rats and dogs. ²⁰ Endothelin levels increase in the plasma of patients who receive cyclosporine after solid organ transplantation ⁵⁰ and in the pulmonary circulation of patients with mitral stenosis. ⁵¹ Other studies have shown that endothelin contracts liver sinusoids ⁵² and is involved in the pathogenesis of ischemia and reperfusion liver injury after transplantation. ⁵³ Although the postoperative pulmonary edema may have many causes, this study adds to the evidence that sharp focal venous contractions are caused by endothelin and could be associated with pulmonary edema. Application of endothelin antagonists may be a potential adjunctive therapy after operation, especially in lung transplantation, but needs further study. Recent reports have shown that endothelin receptor antagonists can lower blood pressure and block cardiac hypertrophy in experimental rat models of hypertension and circulatory overload. ^54,55 Additional studies on injured and transplanted lung should further define these effects and are planned.

Acknowledgments

We thank Mrs. Deborah Ellström for excellent technical assistance during blood pressure recording.

Footnotes

*From the Department of Thoracic and Cardiovascular Surgery, University of Vienna.

**From the Departments of Medicine and Pathology, the University of Illinois at Chicago.

***From St. Elisabeth Hospital, Vienna.

****From the University of Massachusetts Medical Center.

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