Article date: January 1998
By: Hiroko Toyoshima, Yoshihisa Nasa, Yumi Kohsaka, Yoko Isayama, Fuminari Yamaguchi, Atsushi Sanbe, Satoshi Takeo, in Volume 123, Issue 2, pages 344-352
Characteristics of cyclic GMP‐ and cyclic AMP‐mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation.
Cardiac output indices of coronary artery‐ligated and sham‐operated rats were 125±8 and 189±10 ml min−1 kg−1, respectively (P<0.05), indicating the development of CHF at this period.
The maximal relaxant response of aortic segments to 10 μM acetylcholine in rats with CHF and sham‐operated rats was 64.0±5.7 and 86.9±1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham‐operated rats.
In endothelium‐intact segments of rats with CHF, the maximal relaxant response to 10 μM isoprenaline (44.5±6.7%) was lower that sham‐operated rats (81.3±2.5%, P<0.05) and the concentration‐response curve for NKH477, a water‐soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline‐induced relaxation of aortic segments was attenuated by NG‐nitro‐L‐arginine methyl ester (L‐NAME) in sham‐operated rats, but not in rats with CHF. Relaxation to 30 μM dibutyryl cyclic AMP in rats with CHF (26.8±2.7%) was lower than that in sham‐operated rats (63.4±11.8%, P<0.05).
Trandolapril (3 mg kg−1 day−1) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5±3.6 ml min−1) was lower than that of sham‐operated rats (55.0±3.0 ml min−1), and this reduction was reversed (54.1±3.4 ml min−1) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril‐treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7±1.0%; that to isoprenaline, 80.5±2.8%; that to dibutyryl cyclic AMP, 54.7±6.2%). However, aortic segments of trandolapril‐treated rats with CHF, L‐NAME did not attenuate isoprenaline‐induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged.
The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP‐mediated signal transduction, was partially restored by long‐term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF‐induced endothelial dysfunction.
Characteristics of cyclic GMP‐ and cyclic AMP‐mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation.
Cardiac output indices of coronary artery‐ligated and sham‐operated rats were 125±8 and 189±10 ml min−1 kg−1, respectively (P<0.05), indicating the development of CHF at this period.
The maximal relaxant response of aortic segments to 10 μM acetylcholine in rats with CHF and sham‐operated rats was 64.0±5.7 and 86.9±1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham‐operated rats.
In endothelium‐intact segments of rats with CHF, the maximal relaxant response to 10 μM isoprenaline (44.5±6.7%) was lower that sham‐operated rats (81.3±2.5%, P<0.05) and the concentration‐response curve for NKH477, a water‐soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline‐induced relaxation of aortic segments was attenuated by NG‐nitro‐L‐arginine methyl ester (L‐NAME) in sham‐operated rats, but not in rats with CHF. Relaxation to 30 μM dibutyryl cyclic AMP in rats with CHF (26.8±2.7%) was lower than that in sham‐operated rats (63.4±11.8%, P<0.05).
Trandolapril (3 mg kg−1 day−1) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5±3.6 ml min−1) was lower than that of sham‐operated rats (55.0±3.0 ml min−1), and this reduction was reversed (54.1±3.4 ml min−1) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril‐treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7±1.0%; that to isoprenaline, 80.5±2.8%; that to dibutyryl cyclic AMP, 54.7±6.2%). However, aortic segments of trandolapril‐treated rats with CHF, L‐NAME did not attenuate isoprenaline‐induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged.
The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP‐mediated signal transduction, was partially restored by long‐term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF‐induced endothelial dysfunction.
British Journal of Pharmacology (1998) 123, 344–352; doi:10.1038/sj.bjp.0701635
DOI: 10.1038/sj.bjp.0701635
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