1. Pharmacological inhibition of nitric oxide (NO) synthesis is known to produce acute and chronic hypertension in many animal species, but the underlying mechanisms mediating the hypertension are not completely understood. In particular, the pathogenetic roles of sodium sensitivity and the sympathetic nervous system in this model of hypertension are controversial. The present study was designed to test the hypothesis that long-term administration of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to male Sprague-Dawley rats would produce a sodium-sensitive hypertension and that the enhanced activity of the sympathetic nervous system in this type of hypertension contributes to the sodium sensitivity. 2. NG-Nitro-L-arginine methyl ester was added to drinking fluid for 8 weeks at a concentration of 16 mg/dL. Rats received tap water for the first 4 weeks of the study and were then divided into two groups and placed on either a normal or high sodium intake (ingestion of either tap water or 0.9% NaCl, respectively). Awake systolic blood pressure was measured by the tail-cuff method every week. Urinary excretion rates of the stable NO metabolites and catecholamines during NO synthesis inhibition were examined. 3. Long-term administration of L-NAME produced a marked and sustained elevation in arterial pressure without altering urine flow, or sodium excretion rate. NG-Nitro-L-arginine methyl ester-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites NO2- and NO3- and was aggravated when rats drank 0.9% NaCl in place of tap water. Urinary excretion of adrenaline and noradrenaline, but not dopamine, in L-NAME-treated rats increased significantly within the first week of the study compared with control rats. L-Arginine (2 g/dL in drinking fluid) completely reversed the elevation of arterial pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment by 3 weeks of concomitant administration. 4. These results suggest that long-term inhibition of NO synthesis produces a sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.

Animals↗

PubMedDate not supplied

Studies on the minimum requirements for in vitro "cure" of tumor cells by cytotoxic T lymphocytes.

DBA/2-derived P815 tumor cells form progressively growing tumors when injected into the anterior chamber (AC) of normal BALB/c eyes. By contrast, P815 cells injected into the subconjunctival (SCon) space of BALB/c mice are promptly rejected. Despite these very different outcomes, both AC and SCon tumors elicit an equal clonal expansion of tumor-specific precursor cytotoxic T cells (pTc) within the draining cervical lymph nodes. Moreover, tumor-specific pTc migrate systemically and infiltrate both AC and SCon tumor-containing eyes. The present study explores the hypothesis that pTc generated in response to AC P815 tumors are less efficient "killers" than their SCon counterparts. To address this issue pTc were restimulated in vitro in the presence of exogenous lymphokines to initiate the terminal differentiation of pTc into fully functional cytotoxic T cells (Tc). Then an assay was developed to evaluate the capacity of AC and SCon CD8+ Tc to eliminate P815 tumor cells growing in vitro, i.e., achieve a "cure." This assay established the day tumor cells were completely eliminated (cure), as well as the rate of tumor cell removal. Using this approach it has been learned that pTc harvested from AC and SCon tumor-bearing mice have the same potential for eliminating P815 tumor cells in vitro. Moreover, the efficiency of achieving an in vitro tumor "cure" was found to be remarkably enhanced if exogenous lymphokines, as a surrogate source of T cell "help," were included in the cultures at the time effector lymphocytes were added to the proliferating tumor target cells. This latter finding emphasizes the need for sustained availability of helper factors in order to maximize the efficiency with which Tc can eliminate tumor cells. We interpret the results to mean that successful rejection of tumors in vivo is likely to turn upon (a) arrival of tumor-specific pTc at the tumor site, (b) delivery of "help" that promotes the terminal conversion of these cells into Tc, and (c) sustained presence of "help" which promotes the efficiency of immune elimination of tumor cells. Since equally large numbers of P815-specific pTc enter AC and SCon tumor sites in BALB/c mice, the failure of rejection in the former may be due to an inability of the host to provide immediate and sustained local T cell help. Implications of these studies for the development of immunotherapies for intraocular tumors are discussed.

Animals↗

PubMedDate not supplied

Differential effects of propentofylline on the production of cytokines by peripheral blood mononuclear cells in vitro.

The effects of the xanthine derivative propentofylline on the production of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) by human peripheral blood mononuclear cells (PBMCs) were studied. When PBMCs were cultured with propentofylline in vitro, the production of IL-6 was markedly increased at concentrations of 0.1 to 3.0 mmol/L of propentofylline and the production of IL-1 beta was slightly increased at concentrations of 1.0 to 3.0 mmol/L. However, an insignificant increase in TNF-alpha production was observed. When the effects of propentofylline on the production of IL-6, IL-1 beta, and TNF-alpha by OK-432-stimulated PBMCs were examined, IL-6 secretion was not significantly increased, whereas production of IL-1 beta and TNF-alpha were significantly suppressed in a dose-dependent manner. The results demonstrate that propentofylline has a differential effect on the production of IL-6, IL-1 beta, and TNF-alpha by PBMCs, and it is proposed that propentofylline may exert pharmacologic actions on the regulation of the production of cytokines in the central nervous system.

Adult↗

PubMedDate not supplied

Surgical treatment of aneurysm or dissection involving the ascending aorta and aortic arch, utilizing circulatory arrest and retrograde cerebral perfusion.

Recently we replaced the ascending aorta and aortic arch in 8 patients with aneurysm or dissection, using profound hypothermic circulatory arrest with retrograde cerebral perfusion. There were no operative deaths. Open aortic anastomosis facilitated repair of the aortic arch without clamping the arch tributaries, and embolism due to particulate debris from clamping of the arch vessels was eliminated. Retrograde cerebral perfusion during profound hypothermic circulatory arrest is a simplified technique that may protect the brain. This method offers advantages over previously described methods, particularly in obviating dissection of the arch tributaries and the clamping thereof, and in protecting the central nervous system.

Aged↗