Journal of Cardiovascular Pharmacology:
Arteries and Veins Desensitize Differently to Endothelin
Thakali, Keshari; Fink, Gregory D. PhD; Watts, Stephanie W. PhD
From the Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI.
Received for publication September 30, 2003; accepted November 05, 2004.
Supported by a grant from the National Institutes of Health (PO1 HL70687).
Reprints: Keshari Thakali, B445 Life Sciences Building, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317. E-mail: firstname.lastname@example.org
Hypertension is accompanied by increased arterial endothelin-1 (ET-1) and decreased arterial contraction to ET-1. By contrast, veins remain responsive to ET-1 in hypertension. Isometric contraction was used to test the hypothesis that veins do not desensitize to ET-1 to the extent of arteries, possibly because of the presence of functional ETA and ETB receptors on veins and only functional ETA receptors on arteries. Contraction to ET-1 after exposure to ET-1 (100 nmol/L) was abolished in aortae, while in veins 36.3 ± 0.2% of maximal contraction to ET-1 remained. Aortae were unresponsive to the ETA receptor agonist ET-1(1-31) (100 nmol/L) after ET-1 exposure, while 21.9 ± 0.6% of maximum venous contraction to ET-1 (1-31) remained. In a similar manner, the venous ETB receptor did not lose responsiveness to the ETB receptor agonist sarafotoxin 6c (S6c, 100 nmol/L); aortae did not contract to S6c. In ET-1-desensitized veins, the ETB receptor antagonist BQ-788 (100 nmol/L) decreased maximum contraction to ET-1, but did not alter potency (-log EC50 control = 8.14 ± 0.01 mol/L; BQ-788 = 8.13 ± 0.04 mol/L). The ETA receptor antagonist atrasentan (100 nmol/L) blocked remaining venous contraction to ET-1 (control = 8.05 ± 0.05 mol/L; atrasentan = unmeasurable). Maintained responsiveness to ET-1 in veins occurs primarily via the ETA receptor, while in arteries the ETA receptor is responsible for desensitization to ET-1.
The endothelins are potent endogenous vasoconstrictor peptides, and arterial mRNA and peptide levels of ET-1 are elevated in rat models of mineralocorticoid hypertension. 1,2 Importantly, ET receptor antagonists reduce the elevated blood pressure of DOCA-salt rats, 3–6 suggesting that ET plays an important role in mineralocorticoid hypertension in rats. ET-1 exerts its physiological effects primarily through the ETA and ETB receptors on endothelial and smooth muscle cells of blood vessels. The endothelin receptors are G-protein-coupled receptors predicted to have 7 transmembrane domains and interact with several different G-proteins to activate multiple signaling effectors including phospholipase C, D, and A2, as well as MAP kinase. 5 Similar to other heptahelical receptors, the ET receptors are sensitive to mechanisms of desensitization. Specifically, the ETA and ETB receptors can undergo rapid desensitization through internalization. 7–9 While the ETA and ETB receptors are susceptible to desensitization, experiments pertaining to the mechanisms of desensitization have for the most part been performed in cell culture; thus, these data cannot be directly correlated to what occurs in whole tissues or in vivo.
Recent studies suggest that the ETA receptor is down-regulated in human and animal models of hypertension, leading to impaired ET-1-mediated arterial contraction, while physiological responses mediated by the ETB receptor remained intact. 10,11 Giulumian et al reported that decreased Ca2+ influx, but not reduced ET-1 binding to ETA and ETB receptors, could explain impaired contraction to ET-1 in the small coronary arteries of DOCA-salt rats, suggesting an uncoupling of the ET-1 signaling mechanism. 12 The question remains: if arteries are relatively unresponsive to elevated levels of ET-1 in mineralocorticoid hypertension, how does ET antagonism reduce the high blood pressure of the DOCA-salt rat, and which system physiologically mediates this reduction in blood pressure? We suggest that the venous system may play a role.
There are a number of important differences between arterial and venous responses to ET-1. ET-1 is more potent in contracting veins than it is in arteries, 13,14 and in many arterial vascular beds the ETA receptor appears to be predominant as ET-1 is more potent than ET-3 (ET-1 has higher affinity for the ETA receptor than ET-3, but ET-1 and ET-3 have similar affinities for the ETB receptor), and the ETB receptor agonist S6c does not contract most arteries. 15,16 In contrast, the ETB receptor plays an important role in contraction in most veins as ET-1 and ET-3 have similar potency and S6c contracts most veins. 17,18 Our group has previously shown that arteries from DOCA-salt hypertensive rats are less responsive to ET-1 than normotensive rats are, while venous contraction to ET-1 remained unchanged in DOCA-salt hypertension. 2 Mean circulatory filling pressure (MCFP), a measure of venomotor tone, is elevated in the DOCA-salt rat and is ET receptor–mediated. 19,20 We believe that maintained venous contractility to ET-1 could be responsible for the decrease in vascular capacitance that accompanies mineralocorticoid hypertension in the face of ET-1 desensitized arteries. Thus, we propose that maintained venous responsiveness to ET-1 occurs via a functional ETB receptor on veins. Here we test this basic hypothesis in vessels from normal rats.
Isolated Tissue Bath Protocol
Male Sprague-Dawley rats (0.225 kg, Charles River, Portage, MI) were euthanized [pentobarbital (60 mg kg−1, i.p.)] and thoracic aortae and/or thoracic vena cava were removed. Aortae and vena cava were dissected into rings (3–4 mm), cleaned of fat and connective tissue while keeping the endothelial layer intact, and were hung between 2 wire hooks with 1 end attached to a stationary glass rod and the other end attached to a force transducer to measure isometric contractile force. Tissues were placed in warmed (37°C) and oxygenated (95% O2, 5% CO2) physiologic salt solution (PSS) [(mmol/L): NaCl, 130; KCl, 4.7; KH2PO4, 1.18; MgSO4 7H2O, 1.17; CaCl2 2H2O, 1.6; NaHCO3, 14.9; dextrose, 5.5; and CaNa2EDTA, 0.03 (pH 7.2)] as previously described. 2 Aortae and vena cava were placed under optimum resting tension (aortae = 4000 mg, vena cava = 1000 mg) 2 and were equilibrated for 1 hour in PSS with frequent buffer changes prior to challenge with a maximal concentration of phenylephrine (PE, 10 μmol/L) or norepinephrine (NE, 10 μmol/L), respectively. The adrenergic agonist PE was not used in vena cava because veins did not respond to PE in a reproducible manner. PE was used in aortae to relate current findings to previous experiments done by our laboratory. Tissues were washed and contracted to an initial agonist challenge of vehicle (deionized water), ET-1 (100 nmol/L), ET-1 (1-31) (100 nmol/L), or S6c (100 nmol/L) until contraction plateaued, typically after 15 minutes. Tissues were washed every 3–5 minutes for at least 60 minutes until tone returned to baseline. After a 30-minute rest period without washing, cumulative response curves to agonists (10−11 to 10−7 mol/L) were performed. When investigating antagonists, either vehicle (deionized water) or antagonist was equilibrated with tissues during the 30-minute rest period prior to agonist addition.
Rat thoracic aortae and vena cava were cleaned of extraneous tissue and fixed overnight in 10% formalin. Tissues were paraffin embedded and 5-μm sections were collected onto clean glass slides. Sections were dried overnight at 37°C. Slides were dewaxed in xylenes (2 washes, 3 minutes each). Slides were rehydrated by passing through graded alcohols (2 changes 100% ethanol, 3 minutes each, followed by 2 changes 95% ethanol, 3 minutes each). Slides were rinsed in deionized water and air dried before use. Antigen unmasking was required for performing ETA receptor immunohistochemistry. Briefly, slides were immersed in Antigen Unmasking Reagent (Vector Laboratories, USA) and microwaved on high for 5-minute intervals 2–3 times and were then allowed to cool in the unmasking solution. Slides were rinsed twice in deionized water before proceeding. Endogenous peroxidases were blocked by incubating samples with 0.3% hydrogen peroxide (H2O2) in phosphate-buffered saline (PBS) for 30 minutes. Samples were then incubated in 1.5% blocking serum for 1 hour and incubated overnight with antibody (4°C, anti-ETA receptor or anti-ETB receptor, 5 μg/mL with 1.5% blocking serum in PBS, Alomone Labs Ltd., Israel) or antibody neutralized with an equivalent concentration of competing peptide. Then samples were washed 3 times with PBS and incubated with a peroxidase-conjugated secondary antibody (30 minutes, room temperature). Samples were washed and incubated with Vectastain Elite™ for 30 minutes and then incubated with 3,3-diaminobenzidine/H2O2. Reactions were stopped with washing, counterstained with Vector hematoxylin, and slides were air dried, mounted, cover-slipped, and photographed using a Spot 2 digital camera on a Leica light microscope.
Data are presented as means ± SEM and as a percentage of the initial response to phenylephrine (10−5 mol/L for arteries) or norepinephrine (10−5 mol/L for veins) for the number of animals indicated in parentheses. Agonist EC50 values were calculated using a nonlinear regression analysis using the algorithm [effect = maximum response /1+(EC50/agonist concentration)] (GraphPad Prism, San Diego, CA, U.S.A.). When comparing two groups, the appropriate Student's t test was used. In all cases, a P value less than or equal to 0.05 was considered statistically significant.
Phenylephrine and norepinephrine were solubilized in water and purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). ET-1 and S6c were obtained from Peninsula Laboratories (Belmont, CA, U.S.A.). ET-1(1-31) was obtained from Peptide International (Lexington, KY, U.S.A.). These peptides were solubilized in deionized water or 0.1% acetic acid. BQ-788 was purchased from Peninsula Laboratories (Belmont, CA, U.S.A.) and was solubilized in dimethylsulfoxide (DMSO). Atrasentan (DMSO) was a gift from Abbott Laboratories.
ETA and ETB Receptors Are Present on the Smooth Muscle of Rat Thoracic Aortae and Vena Cava
Figures 1 and 2 show localization of the ETA and ETB receptors to the smooth muscle and adventitial layer of rat thoracic aortae and vena cava. In aortae, incubation of the ETA receptor primary antibody with an equivalent concentration of competing peptide for the ETB receptor did not appear to reduce primary antibody binding (Fig. 1A, right panel), while incubation with the ETA receptor competing peptide reduced primary antibody binding (Fig. 1A, middle panel), suggesting that this binding was specific for the ETA receptor. Similar results were observed with the ETB receptor primary antibody (Fig. 1B). Staining for both the ETA and ETB receptor was present in the smooth muscle of rat thoracic aortae and was present throughout the vessel wall. There was also notable ETB receptor staining in the adventitia of rat thoracic aortae. The antigen unmasking procedure appeared to damage the adventitia of the aortae, making it difficult to discern ETA receptor antibody staining in the adventitia.
In vena cava, ETA and ETB receptor antibody staining similar to that in aortae was observed (Fig. 2). In vena cava, there did not appear to be a thick adventitial layer as was pres-ent in aortae. ETA and ETB receptor staining occurred diffusely throughout the smooth muscle of the vessel. In both aortae and vena cava, ETA receptor visualization required unmasking to reveal ETA receptor antibody binding, while ETB receptor staining occurred without unmasking, even though the same concentration of antibody was used (5 μg/mL), suggesting that the fixative procedure alters the ETA receptor antigen.
ETA Receptor Desensitization in Arteries and Veins
Figure 3A displays complete arterial desensitization yet partially maintained venous responses to ET-1. Contraction to ET-1 after exposure to a maximal concentration of ET-1 (100 nmol/L) was abolished in the aortae (Fig. 3A, left), while in veins 36.3 ± 0.2% of maximal contraction to ET-1 remained (Fig. 3A, right). Figure 3B displays desensitization of the ETA receptor in rat thoracic aortae and vena cava determined using the ETA receptor specific agonist, ET-1(1-31). Aortae were unresponsive to the ETA receptor agonist ET-1(1-31) after ET-1 exposure (Fig. 3B, left), while 21.9 ± −0.6% of maximum venous contraction to ET-1(1-31) remained after ET-1 exposure (Fig. 3B, right).
ETB Receptor Desensitization in Veins
While the ETA receptor on arteries and veins desensitizes in a qualitatively similar manner, the ETB receptor on veins does not desensitize to ET-1 (Fig. 4A) or the ETB agonist, S6c (Fig. 4B). A bolus concentration of S6c (100 nmol/L) was administered because cumulative concentration response curves to S6c were not reproducible. Contraction to a maximal concentration of ETB receptor agonist S6c (100 nmol/L) after ET-1 (100 nmol/L) was not altered in veins (117 ± 7% of norepinephrine contraction in control tissue versus 118 ± 6% in ET-1 desensitized tissues, P > 0.05). Moreover, maximal venous contraction to S6c after S6c pre-exposure (100 nmol/L) was not altered (80 ± 15% of norepinephrine contraction in control tissues versus 87 ± 12% in S6c desensitized tissues, P > 0.05). Contraction to S6c (10−11 to 10−7 mol/L) was not observed in aortae. These data suggest that the ETB receptor may be responsible for maintained venous responsiveness to additional ET challenges, as the ETB receptor remains functional and responsive to ET-1 in the desensitization time frame used.
Desensitization of ET Receptors Is Specific for ET Agonists
Desensitization of the ET receptors after tissue exposure to ET-1 is specific to the ET system. Contraction to the α-adrenergic agonist norepinephrine was not reduced or rightward-shifted in control or ET-1 treated aortae (Table 1).
Venous Contraction to ET-1 After Desensitization
Veins were exposed to a maximal concentration of ET-1 as described above and incubated with either vehicle, an ETA receptor antagonist (atrasentan, 100 nmol/L) or an ETB receptor antagonist (BQ-788, 100 nmol/L) 21 for the 30-minute rest period prior to performing an ET-1 concentration response curve. The ETB receptor antagonist BQ-788 was unable to shift the remaining contraction to ET-1 (-log EC50 = 8.14 ± 0.01 mol/L in control tissues versus -log EC50 = 8.13 ± 0.04 mol/L in BQ-788 incubated tissues), but did reduce maximal contraction to ET-1 (Fig. 5A). However, the ETA receptor antagonist atrasentan was able to rightward shift and reduce the remaining contraction to ET-1 (-log EC50 = 8.05 ± 0.05 mol/L in control tissues versus unmeasurable in atrasentan-incubated tissues, Fig. 5B). These data suggest that the ETA receptor, along with small contributions by the ETB receptor, is primarily responsible for continued venous responsiveness to ET-1.
We have previously identified the presence of both the ETA and ETB receptors in rat thoracic aortae and vena cava through Western analysis and RT-PCR. 2 Immunohistochemical results demonstrate that ETA and ETB receptors are present on the smooth muscle of rat thoracic aortae and vena cava. We found it interesting that the ETA and ETB receptors were present in the adventitia of aortae, not just the smooth muscle of the aortae. Rey and Pagano reported that the adventitia is a site for superoxide production, thus modulating smooth muscle vascular tone and growth. 22 Adventitial endothelin receptors may play a role in endothelin-induced smooth muscle contraction. With this knowledge, we hypothesized that the ETA receptor was susceptible to desensitization by ET-1 in veins and arteries while the ETB receptor in veins does not desensitize to either ET-1 or ETB agonists, allowing for continued venous contraction to ET-1.
Conduit arteries from normotensive rats were used to develop the desensitization protocol to test our hypothesis. Responses to a bolus of S6c were determined because we were unable to perform reproducible concentration response curves to S6c. While we did not observe a diminished response to S6c after ET-1 exposure or previous S6c exposure, we cannot determine whether there was any change in the sensitivity of the ETB receptor by measuring EC50 values. Our hypothesis is supported by previous work in hypertensive rats where aortae from DOCA-salt rats was less responsive to ET-1 and ET-1(1-31), while contraction to ET-1, ET-1(1-31) and S6c in vena cava from DOCA-salt rats was not diminished. 2 Thus, it was surprising to find that BQ-788, a selective ETB receptor antagonist, reduced maximum contraction to ET-1 after previous ET-1 challenge but was not able to act as a competitive inhibitor of ET-1 contraction by rightward shifting the concentration response curve of ET-1. Interestingly, atrasentan, a selective ETA antagonist, was able to block this remaining venous contraction to ET-1, suggesting that the ETA receptor plays a more significant role in maintaining venous responsiveness to ET-1 than the ETB receptor. Previously our group observed a leftward shift in ET-1-induced contraction in aortae and vena cava after incubation with an ETB antagonist, while the ETA antagonist rightward shifted ET-1-induced contraction in these tissues. 2 This is consistent with previous findings that the ETB receptor depresses ET-1-induced contraction, as it is involved in endothelium-dependent vasodilation and tissue clearance of ET-1. 23 However, during desensitizing conditions detailed here, ETB receptor blockade did not leftward shift ET-1-induced contraction in this desensitization paradigm. These results suggest that under desensitizing conditions, the ETB receptor no longer plays a vasodilatory role in response to ET-1, but may play a role in ET-1 contraction while the ETA receptor is primarily responsible for maintained venous contraction to ET-1.
Differences in receptor handling and trafficking in veins and arteries could explain the differences observed in ET-1 desensitization. The ETA and ETB receptors are rapidly desensitized and internalized in cell cultures expressing these receptors when exposed to ET-1. 7–9 In Chinese hamster ovary cells, ETA and ETB receptors appear to follow different pathways once they are internalized; ETA receptors tagged with green fluorescent protein (GFP) follow a recycling pathway, while ETB-GFP was targeted to lysosomes. 9 If the ETA receptor was recycled and reinserted into the plasma membrane of venous smooth muscle, while the ETB receptor was degraded in lysosomes, this could explain why maintained venous contraction to ET-1 is ETA receptor-dependent and not ETB receptor-dependent. However, lysosomal degradation of the ETB receptor does not explain the apparent lack of degradation of the ETB receptor in veins. The recycling of ETA receptors and lysosomal targeting of ETB receptors may highlight characteristics of different expression systems, but could possibly explain differences in arterial and venous handling of the ETA and ETB receptors observed in whole tissues and in vivo.
Arteries and veins differ in their structure and may differ in their plasma membrane composition, affecting signaling. One possible explanation for differences in desensitization to ET-1 between the two vessel types could be the presence of spare ETA receptors in veins. Another explanation may be differences in the lipid environment of the plasma membrane of arteries and veins. The ETA receptor has been localized to caveolae and immunoprecipitated with caveolin-1, a distinctive protein of caveolae, in the monkey kidney cells (COS-7 cells). 24 Yamaguchi et al have recently shown that the ETB receptor associates with caveolin-1 in an ET-1-sensitive manner. 25 Disruption of caveolae in rat tail arteries through cholesterol depletion impaired arterial contraction to serotonin, ET-1, and vasopressin, suggesting that caveolae may play an important role in signaling of these vasoactive agonists. 26 Another study by Zeidan et al suggests that the ET receptors are linked to caveolae as they observed that caveolar disruption through cholesterol depletion reduced ET-1-induced ERK1/2 activation in rat portal vein. 27 Variable organization of caveolae in arteries and veins may explain different signaling mechanisms for the ET receptors in each tissue.
In conclusion, the present study shows that the ETA receptor is primarily responsible for desensitization to ET-1 in aortae and vena cava. Our studies suggest that tissue-specific handling may occur with the ETA receptor, allowing veins to continue to respond in an ETA-dependent manner after desensitization. The nature of ETA and ETB receptor desensitization in arteries and veins may provide further insight on whether such desensitization occurs in vivo. Our ultimate goal is to apply these studies in the normotensive rat to the hypertensive rat to understand fully whether receptor desensitization or altered drug trafficking can explain reduced arterial responsiveness to ET-1 and maintained venous responsiveness in mineralocorticoid hypertension.
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