Pharmacology of TA-3090 (8-chloro diltiazem) related to its cerebrovascular protective properties.
TA-3090 (8-chloro diltiazem) has been shown in three experimental circumstances to have cerebrovascular protective properties. In vitro investigation of its pharmacology was undertaken to determine the foundation of this effect. Based on contractile responses of rabbit arteries to high potassium and norepinephrine, TA-3090 has some selectivity for cerebral and renal artery potential-sensitive and cerebral receptor-operated calcium-dependent mechanisms. It has no effect on arterial contraction to sympathetic nerve stimulation. It prevents the increase in uptake of 45Ca2+ in response to K+ (80 mM) in rabbit thoracic aorta and antagonizes the contractile effect of the putative cerebrovascular spasmogen alpha-thrombin on the femoral artery. All these effects take place in concentrations below those that significantly depress the action of the rabbit atrium. TA-3090 has little or no effect on other factors known to regulate cerebral blood flow (e.g., stretch-induced contraction and flow-induced contraction and dilation). This spectrum of pharmacologic activity suggests that TA-3090 would selectively block Ca2+ entry into cerebrovascular smooth muscle through potential-sensitive and receptor-operated Ca2+ channels that would be expected to increase in subarachnoid hemorrhage and cerebral ischemia. The action would occur using doses that have little effect on other factors that contribute to the control of cerebral blood flow.
Bevan
J A
JA
University of Vermont, Department of Pharmacology, Burlington 05405.
Kaminow
L
L
Laher
I
I
Thompson
L P
LP
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004110:Diltiazem / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D012077:Renal Artery / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D013841:Thiazepines; C056595:clentiazem; D013917:Thrombin; D004110:Diltiazem; D011188:Potassium; D009638:Norepinephrine