The effects of L-arginine on neointimal formation and vascular function following balloon injury in heritable hyperlipidaemic rabbits.
OBJECTIVE
The aims of this study were to determine the morphological and functional consequences of balloon angioplasty of the left subclavian artery of Froxfield heritable hyperlipidaemic (FHHL) rabbits and the influence of oral L-arginine therapy on these changes.


METHODS
Sixteen-week-old FHHL rabbits were subjected to balloon injury of the left subclavian artery under halothane anaesthesia. Control rabbits (n = 7) were given free access to food and normal tap water. L-Arginine-treated rabbits were given L-arginine (5 g.l-1 in the drinking water for 2 days prior to angioplasty and then for either 2 weeks (n = 7) or 4 weeks (n = 7) after surgery. All rabbits were euthanised 28-30 days after surgery and blood and tissue removed for quantification of neointimal size and determination of endothelial function using isolated vessel tension studies. The ability of the endothelium to prevent platelet aggregation was determined by challenging a vessel ring with carbachol when incorporated into a whole blood sample in which platelet aggregation was induced with collagen.


RESULTS
Balloon injury in non-treated rabbits resulted in the development of marked intimal hyperplasia (18.8[3.6]% of the area within the internal elastic lamina) while endothelial function remained intact. Maximum responses to carbachol and calcimycin were, respectively, a 66.6[14.7]% and 46.9[12.9]% relaxation of 5HT-induced tone, compared to 58.0[3.2]% and 39.8[9.4]% in non-injured vessels. Maximum contractile responses to 5HT and KCl were unaffected by injury. L-Arginine therapy alone had no effect on the vasodilator function of the endothelium, but reduced the endothelium-dependent inhibition of platelet aggregation (68.4[7.8] vs 109[10]% of the maximum extent of platelet aggregation in non-treated and 2-week L-arginine-treated non-injured vessels, respectively). L-Arginine significantly reduced the extent of neointimal formation (7.2[3.9]% of the area within the IEL; P < 0.05 vs. non-treated group). However, L-arginine significantly attenuated the relaxant responses to both carbachol (26.5[10.4]% and 31.4[9.4]% for 2- and 4-week L-arginine groups) and calcimycin (38.7[15.4]% and 16.4[10.7]%) in the injured artery (P < 0.05 compared to non-treated controls).


CONCLUSIONS
L-Arginine reduces neointimal formation following balloon catheter injury in heritable hypercholesterolaemic rabbits, which is consistent with previous findings in normocholesterolaemic models. However, in the presence of hypercholesterolaemia, L-arginine has a detrimental effect on endothelial function following injury. This may be a consequence of the presence of lipids in the vascular wall on nitric oxide synthase activity.
Greenlees
C
C
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, UK.
Wadsworth
R M
RM
Martorana
P A
PA
Wainwright
C L
CL
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001120:Arginine / Q000627:therapeutic use*; D000001:Calcimycin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006949:Hyperlipidemias / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D012701:Serotonin; D000001:Calcimycin; C002385:linsidomine; D011189:Potassium Chloride; D002217:Carbachol; D001120:Arginine; D008981:Molsidomine