1. The threshold for any detectable rise of systemic arterial pressure during the prolonged intravenous administration of angiotensin to conscious rabbits was observed to be an infusion rate of 0.003-0.006 mug.kg(-1).min(-1).2. At infusion rates between threshold and 0.04 mug.kg(-1).min(-1) the systemic arterial pressure rose progressively over a 3- to 7-day period to a plateau.3. On stopping the angiotensin infusion the blood pressure fell rapidly back to its base line much faster than it rose during the infusion. The time taken to reach control values was approximately related to the duration of the infusion.4. At infusion rates of about 0.05 mug.kg(-1).min(-1) the full rise of blood pressure developed within a few minutes, and could be sustained without change for many days. At higher rates the blood pressure diminished with time.5. Diurnal fluctuations of blood pressure were often seen during prolonged infusions of angiotensin at low rates; and more rapid fluctuations of blood pressure over an hour or two were frequently encountered immediately after an infusion was turned off.6. The possible role of angiotensin in producing chronic renal hypertension is discussed in the light of these observations.

Angiotensin II↗

PubMed1967

Mechanisms involved in the progressive pressor response to very small amounts of angiotensin in conscious rabbits.

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Adrenal Glands↗

PubMed1965

Neurogenic effects of angiotensin.

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Angiotensin II↗

PubMedDate not supplied

Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE).

Cellular responses to xenobiotic-induced stress can signal proliferation, differentiation, homeostasis, apoptosis, or necrosis. To better understand the underlying molecular mechanisms after exposure to xenobiotics or drugs, we studied the signal transduction pathways, the mitogen-activated protein kinase (MAPK), and the basic leucine zipper transcription factor Nrf2, activated by different agents in the induction of Phase II drug metabolizing enzymes (DMEs). The MAPKs, characterized as proline-directed serine/threonine kinases, are essential components of signaling pathways that convert various extracellular signals into intracellular responses through serial phosphorylation cascades. Once activated, MAPKs can phosphorylate many transcription factors, such as c-Jun, ATF-2, and ultimately lead to changes in gene expression. Two classes of Phase II gene inducers, which are also cancer chemopreventive agents, were studied: (1) the phenolic antioxidants, namely butylated hydroxyanisole (BHA) and its active de-methylated metabolite t-butylhydroquinone (tBHQ), and phenolic flavonoids such as green tea polyphenols (GTP) and (-)-epigallocatechin-3-gallate (EGCG); and (2) the naturally occurring isothiocyanates, namely phenethyl isothiocyanate (PEITC), and sulforaphane. BHA and tBHQ are both well-known phenolic antioxidants used as food preservatives, and strongly activate c-Jun N-terminal kinase 1 (JNK1), extracellular signal-regulated protein kinase 2 (ERK2), or p38, in a time- and dose-dependent fashion. Free radical scavengers N-acetyl-L-cysteine (NAC), or glutathione (GSH), inhibited ERK2 activation and, to a much lesser extent, JNK1 activation by BHA/tBHQ, implicating the role of oxidative stress. Under conditions where MAPKs were activated, BHA or GTP also activated ARE/EpRE (antioxidant/electrophile response element), with the induction of Phase II genes such as NQO. Transfection studies with various cDNAs encoding wild-type or dominant-negative mutants of MAPKs and/or transcription factor Nrf2, substantially modulated ARE-mediated luciferase reporter activity in the presence or absence of phenolic compounds. Other phytochemicals including PEITC, and sulforaphane, also differentially regulated the activities of MAPKs, Nrf2, and ARE-mediated luciferase reporter gene activity and Phase II enzyme induction. A model is proposed where these xenobiotics (BHA, tBHQ, GTP, EGCG, PEITC, sulforaphane) activate the MAPK pathway via an electrophilic-mediated stress response, leading to the transcription activation of Nrf2/Maf heterodimers on ARE/EpRE enhancers, with the subsequent induction of cellular defense/detoxifying genes including Phase II DMEs, which may protect the cells against toxic environmental insults and thereby enhance cell survival. The studies of these signaling pathways may yield insights into the fate of cells upon exposure to xenobiotics.

Animals↗

PubMedDate not supplied

Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340.

The practical synthesis of a mixed phenoxy-amidate derivative of PMPA with high oral bioavailability and favorable pharmacokinetics is described. The non-stereoselective synthetic route produces a 1:1 mixture of two diastereomers at phosphorous. Simulated moving bed chromatography using Chiralpak AS enabled kilo-scale isolation of the more potent diastereomer (GS-7340). The GS-7340 phosphorous chiral center was found to be (S) by X-ray crystallography.

Adenine↗

PubMedDate not supplied

Successful treatment of chromoblastomycosis with itraconazole.

An unusual severe case of chromoblastomycosis due to Cladosporium carrionii unresponsive to 5-FC and some azoles is reported. With oral itraconazole at a dosage of 100 mg d(-1) for 15 months (total dose 45.5 g) the patient had a complete clinical and mycological recovery without any side-effects.

Chromoblastomycosis↗

PubMedDate not supplied

Color stability of elastomers for maxillofacial appliances.

The color stability of polyvinyl chloride, polyurethane, and silicone polymers for maxillofacial applications was determined after accelerated aging using reflectance spectrophotometry. On the basis of color stability after accelerated aging, and ease of processing, several silicone materials were the most promising.

Color↗

PubMedDate not supplied

Measurement of benzene in human breath associated with an environmental exposure.

The concentration of benzene in breath was measured after exposure to environmental benzene. Five volunteers were exposed to environmental tobacco smoke at different exposure levels and for different exposure durations. The breath samples were collected before, during, and postexposure for up to three hours. Benzene in breath was confirmed as a short-term biomarker of environmental benzene exposure at the sub-ppm level. Less than 10% of the inhaled benzene was expired within three hours following two-hour inhalation exposures, with a greater percentage expired following shorter exposures. An average of 64% percent of the inhaled benzene was absorbed through the lung barrier, with the percentage absorbed decreasing with continued exposure. Benzene biological half-lives of 7.6 and 68 minutes were calculated empirically using a two-compartment model based on the exponential benzene decay curve after correcting the breath concentrations for background breath concentrations. The breath concentration calculated at the end of the exposure by extrapolation of the postexposure breath samples demonstrates a discontinuity with the breath concentration collected during exposure, consistent with equilibrium exchange between blood and breath.

Adult↗