Effect of desmethyl tirilazad, dizocilpine maleate and nimodipine on brain nitric oxide synthase activity and cyclic guanosine monophosphate during cerebral ischemia in rats.

The present study was designed to evaluate the effects of pretreatment with a combination of desmethyl tirilazad (21-aminosteroid) plus dizocilpine maleate (N-methyl-D-aspartate receptor antagonist) and nimodipine (calcium channel antagonist) on constitutive nitric oxide synthase (cNOS) activity and cyclic guanosine monophosphate (cGMP) levels in brain homogenates of rats subjected to global cerebral transient ischemia induced by bilateral clamping of the carotids for 30 min and reduction of arterial pressure (to 50-60 mm Hg) by intravenous infusion of trimethaphan (30 mg/kg). Our results show that cerebral ischemia produced an increase in cNOS activity and cGMP levels in brain homogenates. Pretreatment with desmethyl tirilazad or dizocilpine maleate or nimodipine individually significantly suppressed (p < 0.01) the increase in cNOS activity and cGMP levels induced by cerebral ischemia, which may be related to their neuroprotective effect. Similar results were obtained with pretreatment by a combination of desmethyl tirilazad plus dizocilpine maleate plus nimodipine.

Effect of tirilazad on brain nitric oxide synthase activity during cerebral ischemia in rats.

The effect of the 21-aminosteroid tirilazad mesylate (10 mg/kg, i.p.) on nitric oxide synthase (NOS) activity in the brain cortex was studied in male Wistar rats subjected to cerebral global transient ischemia induced by bilateral clamping of the carotids for 10 min and reduction of arterial pressure (to 50 mm Hg) by intravenous infusion of 1.5 ml of a solution of trimethaphan (5 mg/ml). NOS activity was determined by measuring the rate of conversion of [3H]arginine to [3H]citrulline in brain cortex. Our results show for the first time that tirilazad suppresses the increase of NOS activity in brain cortex induced by cerebral ischemia (136 +/- 16 vs. 60 +/- 9 pmol [3H]citrulline/min per mg protein) and also suppresses the increase in K(m) of NOS (5.7 +/- 0.1 vs. 1.2 +/- 0.2 mumol/l). These effects are attributed to the fact that tirilazad acts as a scavenger of oxygen free radicals formed during cerebral ischemia. These results document the neuroprotective efficacy of tirilazad mesylate in cerebral ischemia.

Desmethyl tirilazad reduces brain nitric oxide synthase activity and cyclic guanosine monophosphate during cerebral global transient ischemia in rats.

Experiments were conducted to evaluate the effects of desmethyl tirilazad (10 mg/kg, i.p.), a 21-aminosteroid, on constitutive nitric oxide synthase (cNOS) activity and cyclic guanosine monophosphate (cGMP) levels in brain homogenates of rats subjected to cerebral global transient ischemia induced by bilateral clamping of the carotids for 30 minutes and reduction of arterial pressure (to 50-60 mmHg) by intravenous infusion of 1.5 ml of a solution of trimethaphan (5 mg/ml). Our results show that ischemia induces a rise in cNOS activity (from 62.0 +/- 6.1 to 133.3 +/- 13.3 pmol/min/mg protein) and cGMP levels (from 459.3 +/- 49.6 to 1074.1 +/- 132.1 fmol/mg protein). Pretreatment with desmethyl tirilazad abolishes these increases. These results are in agreement with the neuroprotective efficacy of desmethyl tirilazad in cerebral ischemia.

[Effects of transcutaneous nerve stimulation on the plasma and CSF concentrations of beta-endorphin and the plasma concentrations of ACTH, cortisol and prolactin in hysterectomized women with postoperative pain]. / Efectos de la estimulación nerviosa transcutánea sobre las concentraciones en plasma y en el LCR de betaendorfina y plasmáticas de ACTH, cortisol y prolactina en mujeres histerectomizadas con dolor postoperatorio.

Plasmatic and cerebrospinal fluid levels of beta-endorphin and plasmatic concentration of ACTH, cortisol, and prolactin were investigated in 10 healthy volunteers free of pain and in a group of 38 patients who presented moderate or intense postoperative pain. The analgesic technique was transcutaneous neural stimulation. In 28 patients the stimulation was delivered at 40-80 Hz (high frequency) whereas in the remaining 10 patients it was administered in a placebo form. Measurements of hormone concentrations were performed using radioimmunoassay techniques. In patients free of pain hormone analysis was done at once, whereas in patients with pain this analysis was performed before and one hour after transcutaneous neural stimulation. We compared data obtained in control subjects with data collected in patients before and one hour after high frequency and placebo transcutaneous neural stimulation. Levels of beta-endorphin were comparable in patients with and without pain. However, ACTH, cortisol, and prolactin were increased in patients with pain. High frequency stimulation induced greater beta-endorphin levels than placebo neural stimulation and slightly lower concentration of prolactin. There were no significant differences in ACTH and cortisol levels.