TY - JOUR
T1 - CGP12177-induced haemodynamic and vascular effects in normotensive and hypertensive rats
AU - Holopherne, Delphine
AU - Mallem, Mohamed Yassine
AU - Le Strat, Erwan
AU - de Chantemèle, Eric J.Belin
AU - Gogny, Marc
AU - Henrion, Daniel
AU - Noireaud, Jacques
AU - Desfontis, Jean Claude
N1 - Funding Information:
This work was supported by a grant from “la Société Française d'Hypertension Artérielle”. The authors are grateful to Véronique Bucas for the expert technical assistance and Francis Prual and Patrick Guyot for the skilled animal care. The authors are indebted to Dr. D. Ellis (University of Edinburgh, Scotland) for his help in writing the article in English.
PY - 2008/9/4
Y1 - 2008/9/4
N2 - CGP12177 is a non-conventional partial agonist, known to have cardiostimulating and vasorelaxant properties related to its agonist action on the low affinity state of the β1-adrenoceptor (β1LA-adrenoceptor). In normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), CGP12177-induced vasorelaxant effects were analysed in hindquarter vessels to assess modifications in hind limb vascular resistance, and in femoral artery rings. The global haemodynamic effects induced by CGP12177 were also investigated using telemetry in conscious animals. In hindquarters vasculature precontracted with 5-hydroxytryptamine, CGP12177 (0.16 to 475 μg) produced a similar dose-dependent decrease in hindquarters perfusion pressure in both strains. Vasorelaxation was not modified by nadolol, a β1 and β2-adrenoreceptor antagonist, nor by L748337, a β3-adrenoceptor antagonist, but was concentration dependently inhibited by bupranolol, a β1LA-adrenoceptor antagonist at high concentrations. In femoral artery rings from WKY rats and SHR, CGP12177 produced a concentration-dependent relaxation, which was unaffected by nitric oxide synthases inhibition but was significantly reduced in the presence of bupranolol. With double cardiac autonomic blockade (atropine plus atenolol) in conscious WKY rats and SHR, CGP12177 greatly increased heart rate with minor changes in mean arterial pressure in both strains. Conversely, in the absence of double cardiac autonomic blockade, the amplitude of CGP12177-induced heart rate increase was less pronounced and had an hypotensive effect. The reduction in tachycardia and the hypotension were significantly greater in SHR compared to WKY rats. In conclusion, in both strains, CGP12177 produced vasodilating effects in hindquarter vessels and femoral arteries that can be attributed to a β1LA-adrenoceptor stimulation. In conscious WKY rats and SHR, CGP12177-induced cardiostimulation and hypotension were not significantly different after baroreflex blockade, but were decreased and increased respectively, in the presence of baroreflex activity.
AB - CGP12177 is a non-conventional partial agonist, known to have cardiostimulating and vasorelaxant properties related to its agonist action on the low affinity state of the β1-adrenoceptor (β1LA-adrenoceptor). In normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), CGP12177-induced vasorelaxant effects were analysed in hindquarter vessels to assess modifications in hind limb vascular resistance, and in femoral artery rings. The global haemodynamic effects induced by CGP12177 were also investigated using telemetry in conscious animals. In hindquarters vasculature precontracted with 5-hydroxytryptamine, CGP12177 (0.16 to 475 μg) produced a similar dose-dependent decrease in hindquarters perfusion pressure in both strains. Vasorelaxation was not modified by nadolol, a β1 and β2-adrenoreceptor antagonist, nor by L748337, a β3-adrenoceptor antagonist, but was concentration dependently inhibited by bupranolol, a β1LA-adrenoceptor antagonist at high concentrations. In femoral artery rings from WKY rats and SHR, CGP12177 produced a concentration-dependent relaxation, which was unaffected by nitric oxide synthases inhibition but was significantly reduced in the presence of bupranolol. With double cardiac autonomic blockade (atropine plus atenolol) in conscious WKY rats and SHR, CGP12177 greatly increased heart rate with minor changes in mean arterial pressure in both strains. Conversely, in the absence of double cardiac autonomic blockade, the amplitude of CGP12177-induced heart rate increase was less pronounced and had an hypotensive effect. The reduction in tachycardia and the hypotension were significantly greater in SHR compared to WKY rats. In conclusion, in both strains, CGP12177 produced vasodilating effects in hindquarter vessels and femoral arteries that can be attributed to a β1LA-adrenoceptor stimulation. In conscious WKY rats and SHR, CGP12177-induced cardiostimulation and hypotension were not significantly different after baroreflex blockade, but were decreased and increased respectively, in the presence of baroreflex activity.
KW - CGP12177
KW - Femoral artery
KW - Haemodynamic effects
KW - Hypertension
KW - Isolated perfused hindquarters
KW - Low affinity β-adrenoceptor
KW - Telemetry
UR - http://www.scopus.com/inward/record.url?scp=48949099307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48949099307&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2008.06.060
DO - 10.1016/j.ejphar.2008.06.060
M3 - Article
C2 - 18601917
AN - SCOPUS:48949099307
SN - 0014-2999
VL - 591
SP - 196
EP - 202
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -