On the mechanism underlying spasmogenic actions of oxy-hemoglobin on the cerebral artery, analyzed from the inhibitory effects of nicardipine, procaine and indomethacin
Doi, M.
No Shinkei Geka. Neurological Surgery 16(2): 123-130
1988
ISSN/ISBN: 0301-2603 PMID: 3368031 Document Number: 309324
The present study was to analyze the basic mechanism underlying spasmogenic actions of Oxy-hemoglobin (Oxy-Hb) on the bovine cerebral arteries. Using helical strips of the middle cerebral arteries (M2), the changes in muscular tension during an isometric contraction induced by either Oxy-Hb, hydrogen peroxide (H2O2), high potassium-ion-Tyrode (30 mM K+), prostaglandin F2.alpha. (PGF2.alpha.), or carbocyclic thromboxane A2 (cTXA2) were recorded on the polygraph. Blocking effects of nicardipine, procaine indomethacin were compared on the contractions produced by each reagent described above. The results obtained are summarized as follows. 1) H2O2 dissolved in different concentrations produced arterial contractions similar to those by equimolar Oxy-Hb, showing similar dose-response curves. In contrast, equimolar met-hemoglobin (Met-Hb) always produced much weaker contractions. When the equimolar H2O2 was applied during an Oxy-Hb-induced contraction, the response to H2O2 was completely occluded. When H2O2 was applied during a Met-Hb-induced contraction, the response to H2O2 was not occluded and always additive to the response to Met-Hb. Indomethacin blocked both responses to Oxy-Hb and H2O2 showing similar dose dependence. 2) The above results suggested that Oxy-Hb induced contraction consisted of two components; a strong contraction by active oxygen within Hb molecule, and a weak contraction by Hb molecule itself. The former may be mediated by some PG's which are produced inside the muscle cells as the results of arachidonic acid release and subsequent cyclooxygenase activation. 3) Oxy-Hb of 10-6 M and 30 mM K+ produced the contractions of similar strength. The response to Oxy-Hb was partially (40%) inhibited, while the response to 30 mM K+ was blocked completely (100%) by 10-9 M nicardipine. The inhibitory effect of nicardipine on the Oxy-Hb response was not augmented by the increase in nicardipine concentration up 10-7 M, but was augmented by 10-6 M to inhibit 70% of the control. Similar dose dependent effect (i.e., biphasic inhibition) of nicardipine was observed in the PGF2.alpha.-induced contraction but not in the cTXA2-induced contraction, the latter exhibiting monophasic inhibitory effect only by nicardipine higher than 10-6 M. 4) The above results suggested that nicardipine of 10-10 M to 10-7 M would block only the Ca++-influx through the voltage dependent Ca++-channels whereas nicardipine of 10-6 M or above might antagonize the Ca++-influx through the receptor-operated Ca++-channels (for example PG's receptors) as well. This could explain our clinical experience that local application of high dose nicardipine is fairly protective from occurrence of vasospasm. 5) Procaine of 10-8 M depressed both responses to 10-6 M Oxy-Hb and 30 mM high K+ as much as 20% of the control. This effect was dose-dependent but even 10-6 M procaine could depress only 40% of the control response to 10-6 M Oxy-Hb. In contrast, the depressing power of procaine markedly increased to 80% of the control when applied together with 10-9 M nicardipine. 6) The above results suggested that procaine inhibited the Ca++-induced Ca++-release from the intracellular Ca++-store, thus blocking the positive feed back mechanism for the steep increase in intracellular Ca++-concentration. The local application of nicardipine mixed with appropriate concentration of procaine may be clinically useful for preventing the vasospasm.