Post-hypoxic frequency decline does not depend on alpha2-adrenergic receptors in the adult rat.

The aim of this study was to determine whether post-hypoxic frequency decline (PHFD) requires central activation of alpha2-adrenergic receptors. PHFD is defined as the undershoot in respiratory frequency that occurs immediately following brief hypoxic periods. Adult anesthetized, vagotomized rats were exposed to hypoxia (8% O2, mean=45 s) before and after intracerebroventricular (i.c.v.) infusion of vehicle or alpha2-antagonist. The efficacy of the i.c.v. antagonist was assessed by recording the response to intravenous injection of alpha2-agonist before and after the infusion. We compared breathing frequencies before, during, and after hypoxia, both before and after treatments. The decline in breathing frequency after hypoxia was not prevented by the alpha2-antagonists, RX 821002 or SK&F-86466. Guanabenz, an alpha2-agonist, prolonged baseline expiration and potentiated PHFD. Prior treatment with SK&F-86466 blocked the agonist-evoked response which was also reversed by subsequent administration of SK&F-86466. We conclude that PHFD does not require the activation of alpha2-adrenergic receptors, but that alpha2-adrenergic receptors can modulate resting and post-hypoxic respiratory frequency.

Effect of chronic hypertension on the blood-brain barrier permeability of libenzapril.

Very little information is available on the permeability of the blood-brain barrier (BBB) to small polar drugs in chronic hypertension. The blood and cerebrospinal fluid (CSF) pharmacokinetics of libenzapril (LZP), a potent angiotensin converting enzyme inhibitor, were investigated in hypertensive (SH) and normotensive (SD) rats. Following intravenous bolus administration of this hydrophilic drug, the terminal rate constant for elimination (beta), steady-state volume of distribution (Vdss), and systemic clearance (CL) were similar in these two animal groups. Other pharmacokinetic parameters (Cpo, alpha, k12, and k21) were significantly (P less than 0.05) greater in the hypertensive group, except for the volume of the central compartment (Vc) and ratio of Vc to Vdss, which were smaller in SH rats. The ratio of area under the concentration-time curve (AUC) in CSF to blood was about twofold higher in SH rats compared to normotensive rats, showing increased BBB permeability in hypertensive rats. An acute brain uptake study was also performed in SH, SD, and WK rats by intracarotid administration of 14C-LZP along with 3H2O as a reference marker. Both LZP and water transport was found to be significantly higher (about two- to five-fold) in six of the seven different brain regions in SH rats as compared to the normotensive (SD and WK) controls. Because of this simultaneous increase in concentrations of both the drug and the reference marker, BUI values were not affected. Regional brain concentrations in SH rats were also linearly correlated with the mean arterial pressure (MAP) values, providing further evidence of the systemic pressure related increase in BBB permeability.

Penetration into and elimination from the cerebrospinal fluid of diltiazem, a calcium antagonist, in anesthetized rabbits.

Penetration into and elimination from the cerebrospinal fluid (CSF) of diltiazem were studied following intravenous (i.v.) or intra-cisternal (i.c.) administration of 14C-diltiazem to anesthetized rabbits. 14C-Diltiazem rapidly penetrated into the CSF through the blood-CSF barrier after i.v. injection (1 mg/kg). A CSF level of the radioactivity attained the peak (0.13 microgram eq./ml) 5 min after i.v. injection and declined bi-exponentially with rapid initial half-life of 3.8 min (5-15 min) and second half-life of 2.7 h (15 min-8 h). A CSF/plasma ratio was 0.05-0.2 throughout the observation period. After i.c. administration (100 micrograms/body), the CSF level of the radioactivity decreased with a half-life of 7.5 min up to 1 h. The CSF level was maintained above 10(-7) mol/l until 2-3 h. Elimination half-life of 14C-diltiazem after i.c. injection was much more similar to that of 3H2O than 14C-inulin, indicating that the main elimination route of this compound from the CSF is diffusion into the brain, followed by rapid diffusion into the cerebral capillary, rather than filtration from the sub-arachnoid villi. An autoradiographic investigation supported the above route of elimination.