Diltiazem and autoregulation of canine cerebral blood flow.
Recent in vitro evidence suggests the existence of stretch-activated calcium channels in cerebrovascular smooth muscle. These channels, which may play a role in cerebral autoregulation, also appear resistant to antagonism by the benzothiazepine calcium antagonist diltiazem, an agent known to block potential-sensitive and receptor-operated calcium channels. If cerebral autoregulation involves stretch-sensitive diltiazem-resistant calcium channels, then autoregulation should remain intact during vasodilatation produced by diltiazem. The present study was conducted to test this hypothesis. Using a canine cerebral venous outflow preparation, experiments were first performed to determine the optimum dose and route of administration for diltiazem. Although continuous i.v. diltiazem (1-100 micrograms/kg/min) did not increase cerebral perfusion at any normotensive dose, i.a. (lingual artery) diltiazem at 10.0 micrograms/kg/min increased cerebral blood flow by 36% and decreased cerebrovascular resistance by 31% without significant effects on blood gas levels, cerebral oxygen uptake, cardiac output or mean arterial pressure. In autoregulation experiments, 10.0 micrograms/kg/min of diltiazem significantly attenuated but did not eliminate autoregulatory responses to increases (inflation of an aortic balloon) and decreases (hemorrhage) in cerebral perfusion pressure. Autoregulatory responses to increases and decreases in perfusion pressure were equally affected by diltiazem, but both were unaffected by i.a. saline. These data support the view that cerebral autoregulation involves both diltiazem-sensitive and diltiazem-resistant mechanisms. The diltiazem-resistant mechanisms, which may include the proposed population of stretch-sensitive calcium channels appear to account for up to one-half of the autoregulatory capacity in the cerebral circulation.
Pearce
W J
WJ
Macpherson Laboratory, White Memorial Medical Center, Los Angeles, California.
Bevan
J A
JA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004110:Diltiazem / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D014664:Vasodilation / Q000187:drug effects
D004110:Diltiazem