Serotonin receptor blockade improves distal perfusion after lower limb ischemia in the fatty Zucker rat.
OBJECTIVE
Lower limb perfusion following arterial occlusion depends on the recruitment of collateral vessels. Blood flow through these collateral vessels may be jeopardized by hypersensitivity to vasoconstriction by serotonin (5-HT), as has been reported during hyperlipidemia and diabetes. Therefore the aim of this study was to determine the benefits of chronic treatment with SL65.0472, a mixed 5-HT(1B)/5-HT(2A) receptor antagonist, on lower limb ischemia in fatty fa/fa Zucker rats, a strain characterized by obesity, diabetes and hyperlipidemia. Comparison was made with lean control fa/+ Zucker rats.


METHODS
SL65.0472 (3 mg/kg/day, n=16) or its vehicle (n=20) were administered orally for 13 days to male fatty fa/fa Zucker rats submitted to lower limb ischemia. Hindlimb ischemia was induced unilaterally by resection of the left femoral and external iliac arteries and embolization of the left internal iliac artery with microspheres. Distal perfusion was measured under mild anesthesia by laser Doppler imaging of both feet. The perfusion deficit (Delta%) was calculated before and 3, 7 and 14 days after induction of hindlimb ischemia. Twenty-four hours after the last administration of SL65.0472, muscular partial oxygen pressure, iliac blood flows, maximal vasodilatory reserve and the vasoreactivity to 5-HT were measured in both limbs.


RESULTS
Chronic administration of SL65.0472 improved the distal perfusion from day 3. At day 14, the deficit of perfusion was limited to -36+/-7% in SL65.0472-treated animals vs. -70+/-6% in the vehicle-treated group (P<0.001) and was accompanied by a significant improvement of partial oxygen pressure in the ischemic limb (SL65.0472: 10.4+/-3.9 mmHg vs. vehicle: 3.5+/-1.1 mmHg, P<0.05). Maximal vasodilatory reserve tended to increase from 2.2+/-0.4 ml/min in the vehicle-treated group to 3.8+/-0.6 ml/min after SL65.0472. SL65.0472 markedly reduced 5-HT-mediated vasoconstriction, which was enhanced in the hypoperfused limb, without altering arterial pressure. Induction of hindlimb ischemia led to the overexpression of both 5-HT(1B) and 5-HT(2A) receptors only in the hypoperfused skeletal muscle as assessed by semi-quantitative RT-PCR.


CONCLUSIONS
These results suggest that the recruitment of collateral vessels after the induction of hindlimb ischemia is significantly impaired in obese fa/fa Zucker rats due to a persistent vasoconstriction mediated by 5-HT and involving stimulation of 5-HT(1B) and/or 5-HT(2A) receptors.
Janiak
Philip
P
Cardiovascular-Thrombosis Department, Sanofi-Synthélabo Research, 1 Avenue Pierre Brossolette, 91385 Cedex, Chilly-Mazarin, France. philip.janiak@sanofi-synthelabo.com
Lainée
Pierre
P
Grataloup
Yoann
Y
Luyt
Charles-Edouard
CE
Bidouard
Jean-Pierre
JP
Michel
Jean-Baptiste
JB
O'Connor
Steve E
SE
Herbert
Jean-Marc
JM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply*; D007085:Ilium / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D009765:Obesity / Q000503:physiopathology; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010879:Piperazines / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects
C416534:7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide; D010879:Piperazines; D011804:Quinolines; D012702:Serotonin Antagonists; D012701:Serotonin; D010100:Oxygen