The observation that levels of the mitogenic peptide endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide endothelin receptor antagonist SB 209670. In vitro, endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [3Hlthymidine incorporation. This endothelin A receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2±2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic pressor action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by '50% relative to control animals. Thus, the data indicate for the first time that (1) endothelin-1 promotes neointimal formation in vivo and (2) tensin II and norepinephrine, endothelin-1 is now recognized as playing an intrinsic role in the endogenous control of systemic hemodynamics.3 Since levels of endothelin-1 are elevated in the human coronary sinus after PTCA, it has been suggested that endothelin-1 is involved in the pathogenesis of vascular restenosis.4In addition to its actions on vascular smooth muscle tonus, endothelin-1 is also a potent mitogen in several cultured cell lines of both cardiovascular and noncarReceived February 1, 1994; accepted March 21, 1994.

Endothelins (ETs) are potent vasoconstrictors known to play a role in tissue remodeling after vascular wall injury. The molecular mechanisms for the expression and functions of ETs and their receptors after carotid artery angioplasty are not fully understood. Using quantitative reverse transcription and polymerase chain reaction, the present study demonstrates the temporal mRNA expression of ET-converting enzyme-1 (ECE-1), preproET-1, preproET-3, and both ETA and ETB receptors after rat carotid artery balloon angioplasty. A significant increase in ECE-1 mRNA was observed at 6 hours (1.8-fold increase over control, P < .01) and 24 hours (1.7-fold increase, P < .01) in carotid arteries after angioplasty. In contrast, a significant increase in preproET-1 mRNA levels was not observed until 3 days (1.9-fold increase, P < .05) and 7 days (2.1-fold increase, P < .05). A similarly delayed increase in preproET-3 mRNA was observed at 7 days (2.8-fold increase, P < .05) and 14 days (2.6-fold increase, P < .05) after angioplasty. A parallel but marked increase in ETA and ETB receptor mRNAs compared with preproET-1 and -3 messages was observed after angioplasty. The levels of ETA receptor mRNA were elevated 29.3-fold (P < .001) and 24.3-fold (P < .01) at 3 and 7 days, respectively, after angioplasty. The increase in ETB receptor mRNA occurred slightly earlier than the increase in ETA receptor mRNA, showing 15.1-fold increase at 1 day (P < .001) and 11.3-fold increase at 3 days (P < .01) after angioplasty. Immunohistochemical studies using anti-ET antibodies demonstrated a corresponding increase in ET immunoactivity, which was distributed mainly in the neointimal cells 14 days after angioplasty. The increases in ECE-1, ET-1, and ET-3 and their receptor expression after balloon angioplasty suggest that these proteins play an active role in the pathogenesis of neointimal formation.

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1 The role of endothelin-1 in mediating the phenomenon of hypoxic vasoconstriction was examined in canine, isolated pulmonary, circumflex coronary and femoral arterial rings. 2 In tissues with an intact endothelium, the exogenous application of endothelin-1 (0.1-300nM) caused concentration-dependent increases in canine, isolated pulmonary artery tone.

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Neither acute nor chronic ETA receptor blockade is sufficient to inhibit angioplasty induced neointima formation in the rat. Since it was previously shown that the ETA/B antagonist SB 209670 was effective in this model, while the ETA selective antagonist BQ-123 is now found to be ineffective, the data implicate the ETB receptor subtype in the pathogenesis of neointima formation.