Cyclooxygenase-1 and cyclooxygenase-2 expression in rat kidney and adrenal gland after stimulation with systemic lipopolysaccharide: in situ hybridization and immunocytochemical studies.

Cyclooxygenase-2 (COX-2) is a recently discovered isoform of cyclooxygenase that is inducible by various types of inflammatory stimuli. Although this enzyme is considered to play a major role in inflammation processes by catalyzing the production of prostaglandins, the precise location, distribution, and regulation of prostaglandin synthesis remains unclear in several tissues. Using in situ hybridization histochemistry, we investigated the induction of COX-1 and COX-2 mRNA expression after systemic administration of a pyrogen, lipopolysaccharide (LPS), in kidney and adrenal gland in the rat. The COX-2 mRNA signals dramatically increased 1 h after LPS treatment in the kidney outer medulla and adrenal cortex, where almost no or little expression was observed in nontreated animals, and returned to control levels within 24 h. COX-2 mRNA levels increased in the kidney inner medulla 6 h after treatment. There was also a significant increase in mRNA levels in the kidney cortex and adrenal medulla. On the other hand, COX-1 mRNA levels did not show any detectable changes except in the kidney inner medulla, where a significant downregulation of mRNA expression was observed after LPS treatment. Light and electron immunocytochemistry using COX-2 antibodies showed that strong COX-2 immunoreactivity was localized to certain cortical cells of the thick ascending limb of Henle. In addition, based on double-staining with antiserum to nitric oxide synthase (NOS) four further cell populations could be identified in kidney cortex, including weakly COX-2-positive, NOS-positive macula densa cells. After LPS treatment, changes in COX-2 immunoreactivity could be observed in interstitial cells in the kidney medulla and in inner cortical cells in the adrenal gland. These results show that COX-2 is a highly induced enzyme that can be up-regulated in specific cell populations in kidney and adrenal gland in response to inflammation, leading to the elevated levels of prostaglandins seen during fever. In contrast COX-1 mRNA levels remained unchanged in this experimental situation, except for a decrease in kidney inner medulla.

Long-term effects of nimodipine on pial microvasculature and systemic circulation in conscious rats.

The chronic cranial window preparation allows repeated measurements of the same pial vessels in unanesthetized rats for several weeks and correlation with 24-h monitoring of hemodynamic variables. Nimodipine (20 mg) or placebo was given via two subcutaneous pellets. Large arterioles dilated 26 and 16%, at hour 1 and days 6-13, respectively (P less than 0.02). There was an increase in number of small arterioles throughout the whole observation period with the maximal increment of 47% (P less than 0.05) at days 6-13. Maximal vasodilation with 10% CO2 indicated that the increase in number of small arterioles after administering nimodipine was not caused by the opening of previously closed vessels. The total length of small arterioles and venules increased 47 and 23% at days 6-13, respectively (P less than 0.001). These increases seem to be caused by the increases in the numbers of vessels, because the average length of the small vessels did not appear to change. This suggests that nimodipine reduces cerebral vascular resistance by causing cerebral microvessel neovascularization. Our data demonstrate that the administration of nimodipine (20 mg) is potent in dilating pial arterioles in the short-term without affecting systemic arterial pressure, and that its long-term effect results in new vessel growth.