Summary

Background and objective: The cyclic guanosine monophosphate level, which causes an antinociception, is increased in cells as a direct result of phosphodiesterase inhibition. This study used a nociceptive test to examine the nature of the pharmacological interaction between intrathecal zaprinast, a phosphodiesterase inhibitor, and morphine. Methods: Catheters were inserted into the intrathecal space through an incision in the atlantooccipital membrane of male Sprague–Dawley rats. As a nociceptive model, 50 μL of a 5% formalin solution was injected into the hind paw. After observing the effect of zaprinast (37, 111, 369 nmol) and morphine (1, 4, 10, 40 nmol) alone, the interactions of their combination were examined by an isobolographic analysis. Results: Intrathecal zaprinast (P < 0.05) and morphine (P < 0.05) dose-dependently suppressed the flinching observed during phase 1 and phase 2 in the formalin test. The ED50 values (95% confidence intervals) of zaprinast and morphine in phase 1 were 161.9 (87.9–298.3) and 11.6 nmol (4.8–27.9 nmol), respectively. The phase 2 ED50 values (95% confidence intervals) of zaprinast and morphine were 229.9 (142.5–370.9) and 3.9 nmol (1.9–7.6 nmol), respectively. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery a zaprinast–morphine mixture in both phases. The ED50 values of (95% confidence intervals) zaprinast in the combination of zaprinast with morphine in phase 1 and phase 2 were 14.2 (4.9–40.6) and 10.4 nmol (3–35.9 nmol), respectively. Conclusions: Intrathecal zaprinast and morphine are effective against acute pain and facilitated pain state. Zaprinast interacts synergistically with morphine.

Summary

Background and objective: Acute isovolaemic haemodilution increases local and mean cerebral blood flow. It is not known whether a single haemodilution has a short-term effect only or whether it affects cerebral perfusion over a longer time period. In the present study, local and mean cerebral blood flow were determined in conscious rats after a 4, 24 and 48 h period following one-time haemodilution.

Methods: Thirty-six rats were randomized to three untreated sham groups and three groups of haemodilution (4, 24 or 48 h, n = 6 for each group). Isovolaemic haemodilution with albumin 5% aimed to a target haematocrit of 0.2. Local cerebral blood flow was measured in 38 brain regions by the iodo-[14C]antipyrine method in conscious normothermic rats.

Results: Isovolaemic haemodilution reduced haematocrit from 0.44 to 0.20. During the following 24 and 48 h periods, haematocrit remained low (0.22 and 0.21). Mean cerebral blood flow was similar in untreated sham groups (88 ± 12 after 4 h, 92 ± 11 after 24 h, 96 ± 10 mL 100 g−1 min−1 after 48 h). Haemodilution increased mean cerebral blood flow after 4 h (184 ± 11 mL 100 g−1 min−1), after 24 h (153 ± 13 mL 100 g−1 min−1) and 48 h (149 ± 15 mL 100 g−1 min−1) (P ≤ 0.05). Local cerebral blood flow increased in all 38 structures after 4 h haemodilution but decreased with time in six of 38 brain structures after 24 h and in 15 regions after 48 h (P ≤ 0.05).

Conclusions: A single one-time haemodilution increased mean cerebral blood flow for 2 days. However, local adaptation of cerebral blood flow to a chronic low haematocrit occurred but was heterogeneous within the brain.