Cardiovascular effects of substituted tetrahydroisoquinolines in rats.
1. A series of substituted tetrahydroisoquinolins derived from the cleavage products of tetrandrine were found to inhibit [3H]-nitrendipine binding to rat cerebral cortical membranes. Those compounds which displaced [3H]-nitrendipine binding were also able to inhibit high KCl-induced contraction of rat aorta in vitro. 2. There was a significant correlation between the ability of these tetrahydroisoquinolines to inhibit [3H]-nitrendipine binding and KCl-induced contraction (r = 0.99, P less than 0.001). 3. CPU-23 (1-(1-[(6-methoxy)-naphth-2-yl])-propyl-2-(1-piperidine)-acetyl- 6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline), one of the most potent compounds identified in this series, behaved as a simple competitive inhibitor at the [3H]-nitrendipine binding site and reduced the apparent affinity but not the maximal number of binding sites in saturation analysis. 4. In contrast to nifedipine which caused hypotension and tachycardia, CPU-23 induced both hypotension and bradycardia in a dose-dependent manner in pentobarbitone-anaesthetized Sprague-Dawley rats, spontaneously hypertensive and age-matched normotensive WKY rats. 5. It is suggested that CPU-23 may exert its cardiovascular effects via interaction with the dihydropyridine binding site on the L-type calcium channel.
Dong
H
H
Chinese Medicinal Material Research Centre, Chinese University of Hong Kong, Shatin, N.T.
Lee
C M
CM
Huang
W L
WL
Peng
S X
SX
D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D044182:Benzylisoquinolines; D001794:Blood Pressure / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009568:Nitrendipine / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines; D014661:Vasoconstriction / Q000187:drug effects
D000470:Alkaloids; D044182:Benzylisoquinolines; D015220:Calcium Channels; D007546:Isoquinolines; D010880:Piperidines; D044005:Tetrahydroisoquinolines; C077683:CPU 23; C009438:tetrandrine; D011189:Potassium Chloride; D009568:Nitrendipine