Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats

Abstract

Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide (EP) 2 or 4 receptors attenuated the exercise pressor reflex in decerebrated rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100 μg in 10 μl), a COX-2-specific inhibitor Celecoxib (100 μg in 10 μl), an EP2 antagonist PF-04418948 (10 μg in 10 μl), and an EP4 antagonist L-161,982 (4 μg in 10 μl) effectively attenuated the pressor responses to intrathecal injections of arachidonic acid (100 μg in 10 μl), EP2 agonist Butaprost (4 ng in 10 μl), and EP4 agonist TCS 2510 (6.25 μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hind limb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23 ± 5 mmHg, after Ketorolac 14 ± 5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8 μg of L-161,982, but not 4 μg of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21 ± 4 mmHg, after L-161,982 12 ± 3 mmHg; p<0.05), whereas PF-04418948 (10 μg) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors.

Keywords: cyclooxygenase; endoperoxide receptors; static contraction; sympathetic nervous system; thin fiber muscle afferents.

Figure 1

Effects of intrathecal injection of Ketorolac (100μg in 10μl) or Celecoxib (100μg in 10μl) on the pressor (A and C) and cardioaccelerator (B and D) responses evoked by intrathecal injection of Arachidonic Acid (100μg in 10μl). Baseline values are given within mean bars for their corresponding conditions. Asterisks (*) denotes significantly smaller pressor response after Ketorolac or Celecoxib than before, p<0.05.

Figure 2

Peak pressor and cardioaccelerator responses to static contraction before and after intrathecal injection of Ketorolac (A and B) or Celecoxib (D and E). Developed tension was similar before and after Ketorolac and Celecoxib (C and F). Baseline values are given within mean bars for their corresponding conditions. Asterisks (*) denotes significantly smaller pressor response after Ketorolac than before.

Figure 3

Effects of intrathecal injection of PF-04418948 (10μg in 10μl) or L-161,982 (4μg in 10μl) on the pressor (A and C) and cardioaccelerator (B and D) responses evoked by intrathecal injection of Butaprost (4ng in 10μl) or TCS 2510 (6.25μ in 2.5 μl), respectively. Baseline values are given within mean bars for their corresponding conditions. Asterisks (*) denotes significantly smaller pressor response after PF-04418948 or L-161,982 than before, p<0.05.

Figure 4

Peak pressor (A) and cardioaccelerator (B) responses to static contraction before and after intrathecal injection of PF-04418948 (10μg in 10μl). Developed tension was similar before and after PF-04418948 (C). Baseline values are given within mean bars for their corresponding conditions. Asterisks (*) above mean bars denotes significantly smaller cardioaccelerator response after PF-04418948 than before, p<0.05. Cross (†) following baseline values within mean bars denotes significantly different baseline values after drug or vehicle than before, p<0.05.

Figure 5

Peak pressor (A) and cardioaccelerator (B) responses to static contraction before and after intrathecal injection of L-161,982 (4μg in 10μl). Peak pressor (D) and cardioaccelerator (E) responses to static contraction before and after intrathecal injection of L-161,982 (8μg in 20μl). Developed tension was similar before and after L-161,982 (C and F). Baseline values are given within mean bars for their corresponding conditions. Asterisks (*) denotes significantly smaller pressor response after L-161,982 than before.