Cardiovascular effects of CPU-23, a novel L-type calcium channel blocker with a unique molecular structure.
1. The cardiovascular effects of CPU-23 (1-[1-[(6-methoxy)-naphth-2-yl]]-ethyl-2-(1-piperidinyl)-acetyl-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline), a cleavage product of tetrandrine, were investigated using the whole cell perforated patch-clamp technique, in vitro tension measurements and in vivo haemodynamic recordings. 2. CPU-23 (1 and 10 microM) dose-dependently reduced concentration-response curves for KCl and phenylephrine (PE) in the rat tail artery; inhibition of KCl-induced contraction was much more potent than for PE. At the same concentrations, CPU-23 inhibited the inward Ba2+ currents in single smooth muscle cells isolated from the rat tail artery, while CPU-23 (10 microM) produced 95% vasorelaxation of the rat middle cerebral artery preconstricted with BayK 8644. 3. CPU-23 (10 and 30 microM) inhibited the noradrenaline-induced phasic contraction of the rat tail artery in the absence of extracellular Ca2+ from 40% of control to 23% and 14%, respectively (P<0.01) and tonic contraction of the artery after addition of Ca2+ (2 mM) from 100% of control to 83% and 75%, respectively (P<0.01). In the presence of extracellular Ca2+ the PE-induced contraction was reduced by CPU-23 (30 and 100 microM) to 27% and 37%, respectively. 4. The haemodynamic profile of CPU-23 in the rat was very similar to diltiazem. At 5 mg kg(-1) CPU-23 induced a rapid onset and long-lasting decrease in left ventricular systolic pressure (LVSP), maximal velocity of pressure increase (dP/dt(max)), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). When haemodynamic actions of CPU-23, verapamil, diltiazem and nifedipine were compared at equidepressor doses, the order of potency for reducing LVSP and dP/dt(max) was verapamil > CPU-23 = diltiazem > nifedipine and the order of potency for decreasing HR was verapamil = CPU-23 = diltiazem > nifedipine. 5. These data indicate that CPU-23 is a novel calcium channel blocker with unique molecular structure, which exerts antihypertensive and cardiac depressant effects due primarily to its action on L-type voltage-gated calcium channels.
Dong
H
H
Faculty of Medicine, University of Calgary, Alberta, Canada.
Earle
M L
ML
Jiang
Y
Y
Loutzenhiser
K A
KA
Triggle
C R
CR
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines; D014664:Vasodilation / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D007546:Isoquinolines; D010880:Piperidines; D044005:Tetrahydroisoquinolines; C077683:CPU 23; D010656:Phenylephrine; D011189:Potassium Chloride; D002118:Calcium; D009638:Norepinephrine