Burton M. Altura^1,2,3, Asefa Gebrewold¹, Bella T. Altura^1,3, And Raj K. Gupta⁴

Departments of Physiology¹ and Medicine², and The Center for Cardiovascular and Muscle Research³, State University of New York, Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, New York 11203 and Department of Physiology and Biophysics⁴, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461

Received 4/2/97; Accepted 5/5/97; On-line 5/15/97

4. RESULTS AND DISCUSSION

Continuous intravenous infusion of 10 µmol/min of MgCl₂, in normal control rats, lowered mean arterial blood pressure (5-25 mmHg), but failed to alter the brain [Mg²⁺]i, pHi, [PCr], [PCr]/[ATP] or [P_i] up to 2 hr (Table 1). The regimen of MgCl₂ increased the plasma ionized Mg²⁺ 300% and total plasma Mg threefold over normal; plasma Ca²⁺, Na⁺, H⁺ and K⁺ were not altered, even after 2 hr of continuous Mg²⁺ infusion.

40% (8 out of 20) of animals died in the absence of Mg²⁺ infusion following cocaine administration. However, only 13% (4 out of 30, p<0.05) died with Mg²⁺ infusion, suggesting a better than 3-fold protection of Mg²⁺. All animals which died, upon autopsy, exhibited intracranial and/or intracerebral bleeding (1-3 ml). Table 2 demonstrates that in protected animals neither [Mg²⁺]_i, pH_i, [PCr]/[ATP], nor [P_i]/[ATP] fall when toxic and lethal doses of cocaine are administered 45 min after constant infusion of 10 µmol/min MgCl₂. However, animals that receive similar toxic doses of cocaine, in the absence of Mg²⁺ infusion, demonstrated initially a fall in the brain [Mg²⁺]_i, followed by progressive falls in pH_i and [PCr]/[ATP] and an increase in [P_i]/[ATP] (Table 2).

Low basal brain [Mg²⁺]_i (275 ± 24 vs. 466 ± 35 µM) and low basal brain [PCr] (3.36 ± 0.35 vs. 4.26 ± 0.25 mM) were found to result in a three-fold increased incidence of stroke (p<0.01). A positive correlation (r = 0.31, p<0.03) between brain [Mg²⁺]_i and [PCr]/[ATP] was found. In view of such new data, it is possible that brain [Mg²⁺]_i and [PCr] may be useful as important predictors of susceptibility to hemorrhagic strokes.

These findings point to a vasospastic response in cerebral microvessels in response to cocaine, leading to vascular occlusion and intracerebral, as well as subarachnoid, bleeding set into motion by loss of cerebral vascular smooth muscle and neuronal [Mg²⁺]_i. The associated loss of [PCr] and rise in [Pi] and [H⁺]_i, indicating severe ischemia, would be consistent with this hypothesis. Mg²⁺ therapy prevents these events from taking place. It is known that Mg²⁺ normally either gates or has an action on Ca²⁺ entry and intracellular release of Ca²⁺ (12-14). Thus, depletion of [Mg²⁺]_i by cocaine would allow entry and intracellular release of Ca²⁺ causing contraction. Recently, we have shown that treatment of cerebral vascular smooth muscle cells with cocaine HCl (10^-9 to 10^-5 M) induces concentration-dependent rapid rises in free cytosolic Ca²⁺ (8). Loss of [Mg²⁺]_i appears to precede the rapid rise in [Ca²⁺]_i (7,8).

The fact that significant levels of [PCr] remain in the stroked animals, associated with subarachnoid bleeds, immediately following death, suggests that cocaine exerts differential effects and actions on various regions of the brain.