Cerebral blood flow effects of the nitric oxide donor, nitroglycerin and its drug combinations in the non-human primate model.
Nitroglycerin (CAS 55-63-0, Nitrocene) has successfully been used in the management of angina during the last several decades. Although important information on the pharmacological actions and efficacy of nitroglycerin have been extracted, to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur under treatment of a wide variet of drugs. Illucidation of the pharmacological mode of action of nitroglycerin has gained momentum with the discovery of nitric oxide (NO) as an endogenous mediator and with the knowledge that nitroglycerin acts as a NO donor. The present study investigated the effects of nitroglycerin (0.25 microgram/kg/min over 10 min) on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amine oxime) and SPECT, in an anaesthetised primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The present study with nitroglycerin indicates that the response time to measure cerebral blood flow effects seems to be present and an important factor as the transient is relatively short. The current treatment regime with nitroglycerin indicates a slight increase, when compared with control control results, although not significant, except for regional significant increases in particular the occipital regions of the brain. Drug interaction between nitroglycerin and nimodipine may occur as a reduction of 20% in cerebral blood flow from the control control was observed in this case. The results for the combination of nitroglycerin with sumatriptan showed a further increase of the cerebral blood flow to near significance, when compared with the control results and is significantly increased (+27%) when compared with sumatriptan treatment alone. Effective treatment with sumatriptan may therefore be compromised with simultaneous administration of nitroglycerin or NO donor drugs. The combination of nitroglycerin and acetazolamide suggested that the increase in cerebral blood flow is primarily attributed to the influence of acetazolamide. The cerebral blood flow effects of these drugs and possible interactions during an angina attack need to be investigated.
Oliver
D W
DW
Faculty Pharmacy, Pharmacology, Potchefstroom University for Christian Higher Education, South Africa. fkldwo@puknet.puk.ac.za
Dormehl
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IC
D000086:Acetazolamide / Q000008:administration & dosage / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009553:Nimodipine / Q000008:administration & dosage / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D010215:Papio; D011877:Radionuclide Imaging; D018170:Sumatriptan / Q000008:administration & dosage / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D002257:Carbonic Anhydrase Inhibitors; D004338:Drug Combinations; D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009553:Nimodipine; D018170:Sumatriptan; D005996:Nitroglycerin; D000086:Acetazolamide