To gain a better understanding of the metabolic properties between the open acid and lactone form of HMG-CoA reductase inhibitors (statins), the paper focused primarily on characterizing the metabolic properties of statins. We compared the metabolism of the acid and lactone forms of several statins, including atrovastatin, simvastatin, cerivastatin fluvastatin, pitavastatin and rosuvastatin with respect to metabolic clearance, CYP enzymes involved and drug-drug interactions. A remarkable increase in metabolic clearance was noted for all lactones compared with all acids except for pitavastatin lactone. The metabolic clearances of the atrovastatin, simvastatin, cerivastatin, fluvastatin and rosuvastatin lactones were 73-, 70-, 30-, 7- and 64-fold higher, respectively, than those of the corresponding acids. CYP2Cs were critically involved in the metabolism of cerivastatin, fluvastatin and pitavastatin acids. In contrast, CYP2Cs were not involved in the metabolism of the corresponding lactones and CYP3A4 was mainly involved. Moreover, a substantial difference in the metabolic inhibition of statins was found between acids and lactones. Overall, the study demonstrates that CYP-mediated metabolism of lactones is also a common metabolic pathway for statins and that the CYP3A4-mediated metabolism of the lactone forms clearly will need to be taken into account in assessing mechanistic aspects of drug-drug interaction involving statins.

Cells, Cultured↗

PubMedDate not supplied

Faulty induction of blood-brain barrier functions by astrocytes isolated from stroke-prone spontaneously hypertensive rats.

1. It has been suggested that astrocytes prompt the induction of blood-brain barrier (BBB) functions in cerebrovascular endothelial cells. 2. In the present study we have tried to elucidate the genetic differences between astrocytes isolated from Wistar-Kyoto (WKY) control rats and astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP). 3. We show that endothelial cells develop tight junction-like structures, a reduction in vesicular transport and high electrical resistance when they are co-cultured with astrocytes isolated from WKY rats. In contrast, SHRSP astrocytes have less of an ability to induce BBB functions than do WKY astrocytes. 4. In addition, we demonstrate that SHRSP astrocytes produce enormous quantities of lactic acid when cerebral ischaemia develops. The decrease in pH causes astrocyte swelling and damages BBB functions. 5. Consequently, we reason that genetically weak functions in astrocytes cause disruptions of BBB function and result in widespread cerebral lesions in SHRSP.

Animals↗

PubMedDate not supplied

Astrocyte-conditioned medium induces blood-brain barrier properties in endothelial cells.

1. We evaluated the induction of endothelial barrier functions by the type 1 astrocyte-derived supernatant in culture using horseradish peroxidase (HRP) as a parameter. 2. A gel filtration fraction (molecular weight 16-20 kDa) of type 1 astrocyte-derived supernatant reduced plasmalemmal vesicles and induced tight junctions in endothelial cells. 3. In addition, this fraction promoted the uptake of [3H]-glucosamine by endothelial cells. This cell activity disappeared after heating at 95 degrees C for 10 min and was sensitive to trypsin. 4. These results suggest that a type 1 astrocyte-derived protein factor(s) promotes proteoglycan synthesis with a resultant increase in charge selectivity in endothelial cells and plays an important role in the induction of blood-brain barrier functions.

Animals↗

PubMedDate not supplied

Permeability of intracranial extracerebral vessels in stroke-prone SHR.

Permeability of intracranial extracerebral arteries of stroke-prone spontaneously hypertensive rats (SHRSP) was studied using labeling techniques (ferritin and horseradish peroxidase), at the cellular level. In the arterial endothelial cells, the tracer molecules were slowly but constantly transported by the plasmalemmal vesicles to the subendothelial space. This endothelial transportation of the tracers into these cerebral arteries did not seem to be significantly influenced by aging, increased blood pressure, hyperlipidemia or the existence of cerebral bleeding and infarction. Around the adventitia, there were a great number of periadventitial capillaries, especially near bifurcations. In the periadventitial capillaries, the tracer molecules were readily trapped by endothelial cells and were quickly transported to pericapillary spaces. The tracer molecules were then detected in the phagocytes adjacent to the deeper layers of the media, and further in the medial smooth muscle cells. The possibility that large amounts of plasma components are supplied to the media from periadventitial capillaries in the intracranial extracerebral arteries has to be considered in the pathogenic mechanisms of cerebrovascular lesions.

Animals↗

PubMedDate not supplied

Increased transendothelial channel transport of cerebral capillary endothelium in stroke-prone SHR.

Permeability of brain capillaries of stroke-prone spontaneously hypertensive rats (SHRSP) was studied using labelling (horseradish peroxidase) and cytochemical techniques at the cellular level. In the cerebral capillary endothelium the tracer molecules were quickly transported by abundant transendothelial channels which directly connected the capillary lumen to the subendothelial space. Transendothelial channels are abundant and should be postulated as structural formations engaged in the increased transport of proteins across the capillary endothelium. Ultracytochemical studies revealed that the channels, bounded by indistinct delimiting membranes, initially had no acid phosphatase activity. With the passage of time, however, the channels showed acid phosphatase activity and were lined with distinct membranes. These observations suggested that the lysosomes might fuse with the transendothelial channels and might play an important part in the transport of macromolecules.

Acid Phosphatase↗

PubMedDate not supplied

Ultrastructural characteristics of occluded perforating arteries in stroke-prone spontaneously hypertensive rats.

We studied ultrastructurally cerebral perforating arteries in 60 stroke-prone spontaneously hypertensive rats (SHRSP), which were sequentially killed at 4-52 weeks of age before showing symptoms of stroke. Another 24 SHRSP were killed soon after they showed symptoms of cerebral infarction. The initial vascular lesions observed in the asymptomatic group included focal cytoplasmic necrosis in the outer layers of the media. This change progressed to widespread medial necrosis with time. In the infarction group, numerous monocytes were seen adhering to the endothelium of the arteries having advanced medial damage. Following the adherence of monocytes to the endothelium, large amounts of plasma components were visible in the arterial wall. The accumulation of the plasma components (especially fibrin) thickened the wall, narrowed the lumen, and resulted in occlusion. These results suggest that monocytes may affect the endothelium, perhaps disturbing the so-called blood-brain barrier to proteins. The monocytes may therefore be closely related to the occurrence of arterial occlusion with resultant cerebral infarction.

Animals↗