Angiotensin-(1–7) causes endothelium-dependent relaxation in canine middle cerebral artery

The heptapeptide, angiotensin-(1–7), is an active member of the renin–angiotensin system. The present study was designed to characterize the role of endothelium in relaxations of large cerebral arteries to angiotensin-(1–7). Rings of canine middle cerebral arteries were suspended in organ chambers for isometric force recording. The levels of cyclic guanosine 3′,5′-monophosphate (cGMP) were assessed by radioimmunoassay. During contraction to uridine 5′-triphosphate (UTP, 3×10⁻⁶ to 10⁻⁵ mol/l), angiotensin-(1–7) (10⁻⁹ to 3×10⁻⁵ mol/l) caused concentration-dependent relaxations in arteries with endothelium, but not in endothelium-denuded vessels. Angiotensin-(1–7) significantly increased formation of cGMP. Nitric oxide synthase inhibitor, N-ω-nitro- -arginine methyl ester ( -NAME, 3×10⁻⁴ mol/l), and selective soluble guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one (ODQ, 3×10⁻⁶ mol/l), abolished angiotensin-(1–7)-induced relaxations. Angiotensin receptor antagonists, losartan (10⁻⁵ mol/l), PD 123 319 (10⁻⁵ mol/l), [Sar¹,Thr⁸]-angiotensin II (10⁻⁵ mol/l) [Sar¹,Val⁵,Ala⁸]-angiotensin II (10⁻⁵ mol/l) or [7- -Ala]-angiotensin 1–7 (10⁻⁶ mol/l) did not affect these relaxations. However, angiotensin-converting enzyme inhibitor, captopril (10⁻⁵ mol/l) augmented relaxations to angiotensin-(1–7). Finally, bradykinin B₂ receptor antagonist, [ -Arg⁰,Hyp³,Thi⁵, -Tic⁷,Oic⁸]-bradykinin (HOE 140, 5×10⁻⁸ mol/l) significantly reduced the effect of angiotensin-(1–7), while bradykinin B₁ receptor antagonist, des-Arg⁹, [Leu⁸]-bradykinin (6×10⁻⁹ mol/l) did not influence the vascular response to the heptapeptide. These findings indicate that (1) angiotensin-(1–7) produces relaxation of canine middle cerebral arteries by the release of nitric oxide from endothelial cells, (2) angiotensin receptors do not mediate endothelium-dependent relaxations to the heptapeptide, and (3) this effect appears to be dependent on activation of local production of kinins. Our studies support the concept that angiotensin-(1–7), as a natural vasodilator hormone, may counterbalance the hemodynamic actions of angiotensin II.     

REGRESSION OF LIVER METASTASES FOLLOWING TREATMENT WITH YTTRIUM-90 MICROSPHERES

Book reviews in this article: Selective internal radiation (SIR) therapy is a technique developed by our group for concentration of Yttrium-90 microspheres into liver metastases. The technique involves laparotomy, insertion of the catheter into the hepatic artery, redistribution of liver blood flow with vaso-active agents and incremental embolization of Yttrium-90 containing microspheres (SIR spheres) into the liver. Twenty-nine patients with non-resectable liver metastases from primary adenocarcinoma of the large bowel were treated by this technique and followed for a minimum of three months to assess evidence of tumour regression. Response to treatment was measured by serial estimations of carcino-embryonic antigen (CEA) and tumour volumes measured from serial computerized tomography (CT) scanning of the liver. There was a fall in the serum CEA level in all 26 patients in whom the serial estimations of CEA were performed following SIR therapy. The overall mean fall in CEA was 70% of pre-treatment levels with 88% of patients (23 of 26) experiencing more than a 50% fall in pre-treatment CEA levels. In 18 of 22 evaluable patients CT measured tumour volumes decreased following SIR therapy. In 48% of patients (10 of 22 patients) the decrease in tumour volume was more than 50%. SIR therapy results in a high rate of tumour regression in patients with liver metastases secondary to large bowel cancer.     

Pharmacological studies of ricin in mice and humans

Summary A highly sensitive enzyme-linked immunosorbent assay (ELISA) for determination of ricin in serum is presented. Using this method it was found that IV-injected ricin disappeared from the plasma of mice and cancer patients according to first-order kinetics.DBA mice were found to be more sensitive to ricin than C3H and B6D2 mice. When mice of the different strains were given the same dose of ricin, the concentrations found in liver, spleen, and kidneys were highest in the most sensitive mice. Ricin disappeared most rapidly from serum of the mice with the highest sensitivity. The inverse correlation between the rate of disappearance of ricin from serum and the tissue concentrations reached may be due to the fact that ricin is rapidly and firmly bound to cell surface receptors.Whole-body autoradiography after IV injection of ¹²⁵I-labeled ricin showed the highest amount of radioactivity in liver, spleen, and adrenal cortex. Considerable amounts of radioactivity were also present in bone marrow, showing that the lack of myelosuppressive activity of ricin previously found in mice and dogs cannot be accounted for by the failure of ricin to reach the bone marrow.Part of the ricin in the tissues was present in the form of free chains, the highest fraction being present in the liver.In this tissue both the free A-chains and those present in whole ricin were found to be modified. However, the modified A-chains had retained their full capacity to inhibit protein synthesis in vitro.In cancer patients, toxicity appeared at about the same initial serum levels as in the mice, supporting the view that mouse data have a good predictive value for man. At each dose level the individual variations were modest, a finding that is important for eventual clinical use of this potent drug.     

Selective internal radiation therapy: validation of intraoperative dosimetry

In selective internal radiation (SIR) therapy of hepatic metastases, tumor vasculature is preferentially embolized with high-energy beta-emitting yttrium-90-labeled microspheres. To enable accurate estimation of the resultant absorbed radiation doses to tissues, an intraoperative beta detection probe is used to scan the liver surface. The validity of the response of this probe to Y-90 and its clinical application were assessed with a phantom containing varying activities and with biopsy samples obtained from patients being treated with SIR therapy. A linear relationship was found between the probe counts taken from the biopsy samples and the calculated tissue radiation doses from the specific activities of each sample. This relationship was repeated with probe counts determined against a water phantom containing various activities of Y-90. The probe was shown to respond minimally to bremsstrahlung. The use of the probe in measuring tissue radiation doses at laparotomy provides the opportunity to control dose administration during SIR therapy. In this way, subtherapeutic exposure of normal tissue can be assured while tumor tissue receives maximal radiation levels.     

T-cell receptor γδ-positive peripheral T-cell lymphomas presenting in the skin:

Examination of biopsy samples from 62 patients with--or with suspected--cutaneous T-cell lymphoma (CTCL) revealed 2 cases in which the neoplastic cells were positive for the T-cell receptor (TCR) gamma delta complex. One patient had mycosis fungoides and 1 patient had a pleomorphic lymphoma of medium and large-cell type. Both cases showed aggressive courses with dissemination to internal organs and short survival times. The phenotypic examination showed that the neoplastic cells were positive with TCR delta 1, CD3, CD25, CD29, CD45R0 and CD54. No staining was seen with antibodies against framework determinants or variable regions on the TCR alpha beta heterodimer. Negative reactions were also seen with CD4, CD8, CD5, CD7, CD16, CD30 and CD57. It is concluded that rare CTCL express TCR gamma delta chains. These malignancies may originate from the TCR gamma delta-positive T cells seen in normal skin, and it is possible that their recognition may be important for clinical reasons.     

Intestinal Metabolism of DNOC and DNBP in the Rat

Abstract The metabolism of the dinitrophenols DNOC and DNBP and their respective monoamino derivatives, 6-ANOC and 6-ANBP, was studied in rat caecal incubates. All of the compounds were reduced to their corresponding diamino metabolites. The results are discussed in relation to the comparative toxicology of the dinitrophenols with special regard to a possible significance of the intestinal metabolites.     

The Presence of an Androgen Controlled Phospholipase A in Rat Epididymis

The presence of a phospholipase A (EC 3.1.1.4) and a lysophospholipase (EC 3.1.1.5) has been demonstrated in a postmitochondrial preparation from rat epididymis. Three different enzyme assays using both endogenous and exogenous substrates were employed. Phospholipase A was the rate limiting enzyme in the hydrolysis of lecithin to sn -3-glycerophosphorylcholine which also was the main product of the hydrolysis. The enzyme preparation did not show any phospholipase D (EC 3.1.4.4) nor glycerophosphinicocholine glycerophosphohydrolase (EC 3.1.4.2) activity. A small amount of phosphorylcholine was liberated during the hydrolysis indicating the presence of a glycerophosphinicocholine cholinephosphohydrolase (EC 3.1.4.38).
The phospholipase A activity per mg of protein was 10 times higher in the cauda than in the caput epididymidis, while the corpus epididymidis possessed an intermediate specific activity. Castration reduced the specific activity of the enzyme with about 50% in the caput and with about 95% in the cauda epididymidis. Testosterone supplementation restored the enzyme activity nearly to normal in the castrated animals.
This work suggests that the androgen control of the epididymal concen tration of sn-3-glycerophosphorylcholine is exerted via a control of the phospholipase A activity in the epididymal epithelial cells. It is suggested that this enzyme controls the concentration of epididymal glycerophosphorylcholine and the supply of long chain fatty acids to epididymal spermatozoa.     

A prospective study of parotid metastases from head and neck cancer

A prospective study of eighty-eight patients with cutaneous head and neck cancer was undertaken to define patients at high risk for parotid lymph node metastases. Over a three year period, twenty-one patients with highly malignant primary melanoma or squamous carcinoma of the eyelid, frontal, temporal, posterior cheek, or anterior ear skin underwent either initial wide primary excision and superficial parotidectomy with radical neck dissection (16 patients) or secondary parotidectomy after initial treatment elsewhere (5 patients).