Pharmacological profile of a novel neuronal calcium channel blocker includes reduced cerebral damage and neurological deficits in rat focal ischemia.
Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage following ischemia. Therefore, blocking voltage-operated calcium channels on nerve cells should provide significant neuroprotection in ischemia. We now report on a novel neuronal calcium channel blocker, NNC 09-0026, in terms of its selective effects on neuronal calcium current and its efficacy in reducing infarct size and neurological deficits in a rat model of focal stroke. In the present studies, the effects of NNC 09-0026 on neuronal calcium influx, calcium channel binding, and cardiovascular parameters were determined. Also, phencyclidine, NNC 09-0026, or vehicle were administered i.v. to rats subjected to permanent middle cerebral and common carotid artery occlusions. Infarct volumes and contralateral forepaw and hindlimb neurological deficits were assessed at 24 and 48 h after onset of stroke. NNC 09-0026 exhibited a pharmacological profile suggesting selectivity at neuronal calcium channels. It inhibited potassium-stimulated calcium uptake into rat synaptosomes with an IC50 of 13 microM. Voltage-operated calcium currents measured from cultured rat dorsal root ganglion cells using the patch clamp technique were blocked by 43% at 10 microM (p < 0.05). The compound showed only weak effects on smooth muscle from the guinea pig taenia coli and was relatively inactive at displacing nitrendipine and omega-conotoxin in receptor-binding studies. Single, bolus injections of NNC 09-0026 as high as 10 mg/kg i.v. produced only 12% reduction in heart rate and a 28% decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Barone
F C
FC
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Price
W J
WJ
Jakobsen
P
P
Sheardown
M J
MJ
Feuerstein
G
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002132:Calcium Radioisotopes; D002544:Cerebral Infarction / Q000517:prevention & control / Q000523:psychology; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D010880:Piperidines; C088314:NNC 09-0026; D010622:Phencyclidine