Effect of an Angiotensin Ii Receptor Antagonist, Tcv‐116, on Neointimal Formation Following Balloon Injury in the SHR Carotid Artery

Abstract

1. In the present study, we examined the effect of a novel angiotensin I1 type I receptor antagonist, TCV-116, on carotid neointimal formation after balloon injury in SHR and WKY rats.2. Oral administration of TCV-116 at a dose of 10mg/kg per day reduced not only systolic blood pressure but also neointimal formation after carotid balloon injury. TCV-116 also suppressed cardiac hypertrophy. An angiotensin-converting enzyme inhibitor, lisinopril (20 mg/kg per day), had a similar effect to that of 3. In the WKY experiment, both TCV-116 and lisinopril suppressed neointimal formation as well as systolic blood pressure, but did not suppress cardiac hypertrophy. 4.Although SHR showed markedly enhanced neointimal formation after balloon injury compared with age-matched WKY rat, both TCV-116 and lisinopril showed similar suppressive effects on neointimal formation in both SHR and WKY rats.5. These results confirm the important role of angiotensin I1 in neointimal formation following balloon injury. Further studies are needed to clarify the mechanism of the difference between SHR and WKY rats in the response of vascular smooth muscle cells.

Hypertension Induces Compensatory Arterial Remodeling Following Arteriotomy

“…The stimulation of AT1 mRNA synthesis we observed in WKY injured carotids ( Fig. 2A) is in agreement with other studies [19,20] and can stimulate vascular cell proliferation and migration, as well as SMC contraction and the production of extracellular matrix. The behavior of AT1 and AT2 mRNAs after carotid arteriotomy could indicate a different regulation of vascular RAS in hypertensive strains compared with normotensive rats.…”

Adrenomedullin Overexpression to Inhibit Cuff-Induced Arterial Intimal Formation

“…Actually, both ACE inhibitors and angiotensin type 1 (AT1) receptor antagonists reduce intimal lesion formation after balloon injury. 25,26 Thus, the importance of the local renin-angiotensin system in SMC proliferation and migration after both balloon injury and cuff injury is widely accepted. Whereas AngII stimulates the migration of rat aortic SMCs, AM has an antagonistic action against AngII-induced cell proliferation and migration in VSMCs and mesangial cells.…”

Strain Differences in Neointimal Hyperplasia in the Rat

“…21 Also, several studies have shown that different rat strains differ in vascular cell apoptosis, 5,8,9,26 vascular wall fragility, 18 the amount of elastase and lysyl oxidase in the elastin fiber networks of their vessel walls, 19 and the amount of neointimal production after a standard vascular injury. 22,23 Presumably, these strain differences are due to genetic factors. To our knowledge, the current work is the first systematic study of representative rat strains to eventually allow a total genome scan to determine which genes are responsible for neointimal hyperplasia and was based on the following principles: Because all animals within an inbred rat strain are homozygous at essentially all genetic loci, the variance in neointimal hyperplasia and/or vessel wall constriction after vascular injury among different animals of the same strain must be attributable to environmental factors that cause somatic differences among individual animals; subtle variations in the surgical technique used to produce the vascular injury from animal to animal; or lack of precision in the measurement of neointimal hyperplasia.…”

“…21 Also, experimental studies have shown that the carotid arteries and thoracic aortas of spontaneously hypertensive rats (SHR) have an increased neointimal hyperplasia response 2 weeks after a standard injury when compared with Wistar-Kyoto and Sprague-Dawley (SD) rat vessels. 22,23 Although these studies have shown that genetic elements may contribute to vascular restenosis, the preparative work for a formal genetic analysis to identify the genes responsible for these observed differences has not been performed.…”