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Biomedical subjects

R W Alexander

Publications and source records attributed to R W Alexander.

At least 199 records · Page 11Linked to original sources
PubMed1983

Characterization of the rabbit ventricular myocardial receptor for angiotensin II. Evidence for two sites of different affinities and specificities.

Angiotensin II binding sites in a rabbit ventricular myocardial particulate fraction were identified and characterized with the radioligand 125I-angiotensin II. The order of potency in competing with 125I-angiotensin II for these sites was similar to that observed in physiological studies. Computer-assisted analysis of the competition of binding sites for 0.3 nM 125I-angiotensin II by unlabeled angiotensin II (3 X 10(-11) M to 1 X 10(-5) M) demonstrated that optimal fitting of the competition curves was attained with a two-site model having one site of high affinity (KA1 = 2.4 +/- 0.6 X 10(9) M-1), low capacity (N1 = 7.8 +/- 0.8 fmoles/mg of protein) and a second site low affinity (KA2 = 9.6 +/- 0.6 X 10(6) M-1) and high capacity (N2 = 219 +/- 128 fmoles/mg of protein). Analysis of competition by Sar1-Ile8 angiotensin II for 125I-angiotensin II binding sites indicated that the antagonist interacted with the first site with high affinity (KA1 = 8 X 10(9) M-1), but interacted minimally with the second site (KA2 = 10(5) M-1). Monovalent cations (Na+, K+, Li+, NH4+) were roughly equipotent in decreasing 125I-angiotensin II binding by reducing the number of high-affinity sites (N1 = 2.6 +/- 0.7 fmoles/mg of protein with 100 mM Na+) without changing the affinity of either site or the number of low-affinity sites. The number of high-affinity sites was increased to 14.4 +/- 1.5 fmoles/mg of protein by 5 mM Mg2+. In the presence of divalent cations, nucleotides reduced binding of 125I-angiotensin II with the potency order guanosyl-5'-yl-imidodiphosphate greater than GTP greater than GDP greater than ATP greater than GMP. Guanosyl-5'yl-imidodiphosphate significantly reduced the affinity of the high-affinity site (KA1 = 1.0 +/- 0.2 X 10(9) M-1) and perhaps of the low-affinity site (KA2 = 1.0 +/- 2.2 X 10(6) M-1). Computer-assisted assessment of dissociation of 0.3 nM 125I-angiotensin II from rabbit myocardial membranes corroborated the equilibrium data: dissociation was biphasic (K-1 = 0.19 +/- 0.2 min-1 for a rapidly dissociating site, k-1 = 2.5 +/- 2.1 X 10(-3) min-1 for a slowly dissociating site); 5 mM Mg2+ did not significantly change either dissociation rate; but guanosyl-5'-yl-imidodiphosphate significantly increased dissociation rates from both sites. Despite the indirect evidence that these angiotensin II receptors interact with guanine nucleotide regulatory proteins, angiotensin II (10(-6) M) failed to influence adenylate cyclase activity. The physiological implications of the presence in ventricular myocardium of two distinct angiotensin II receptors and in particular the implications of a receptor-associated guanine nucleotide regulatory protein which does not couple to adenylate cyclase require further investigation.

Adenylyl Cyclases↗
PubMed1982

Nutritional myopathy in a cat.

A case of nutritional myopathy in a cat primarily caused by vitamin E deficiency is described. The animal which had been fed a diet consisting almost entirely of boiled Norwegian coley, was presented with swollen muscles in both the hind and fore legs. Sections of biopsy material revealed chronic, severe myositis, with normal muscle tissue undergoing a series of degenerative changes. Correct dietary management, with multivitamin and mineral supplementation, led to a complete clinical recovery, the cat regaining full use of its legs within 14 days.

Animals↗
PubMed1982

Non-co-ordinate development of beta-adrenergic receptors and adenylate cyclase in chick heart.

We have studied the properties of beta-adrenergic receptors and of their interaction with adenylate cyclase in the chick myocardium during embryogenesis. Between 4.5 and 7.5 days in ovo the number of receptors determined by (-)-[3H]dihydroalprenolol ([3H]DHA) binding is constant at approx. 0.36 pmol of receptor/mg of protein. By day 9 the density decreases significantly to 0.22 pmol of receptor/mg of protein. At day 12.5--13.5 the number was 0.14--0.18 pmol of receptor/mg of protein. This number did not change further up to day 16. The same results were obtained with guanosine 5'-[beta, gamma-imido]triphosphate (p[NH]ppG) added to the assay mixtures. There was no significant change in receptor affinity for the antagonist [3H]DHA between days 5.5 and 13. Despite the decrease in numbers of beta-adrenergic receptors, there was no change in basal, p[NH]ppG-, isoprenaline- or isoprenaline-plus-p[NH]ppG-stimulated adenylate cyclase activity between days 3 and 12 of development. We conclude that beta-adrenergic receptors and adenylate cyclase are not co-ordinately regulated during early embryonic development of the chick heart. Some of the beta-adrenergic receptors present very early in the ontogeny of cardiac tissue appear not to be coupled to adenylate cyclase since their loss is not reflected in decreased activation of the enzyme.

Adenylyl Cyclases↗
PubMed1982

Functional angiotensin II receptors in cultured vascular smooth muscle cells.

To study cellular mechanisms influencing vascular reactivity, vascular smooth muscle cells (VSMC) were obtained by enzymatic dissociation of the rat mesenteric artery, a highly reactive, resistance-type blood vessel, and established in primary culture. Cellular binding sites for the vasoconstrictor hormone angiotensin II (AII) were identified and characterized using the radioligand 125I-angiotensin II. Freshly isolated VSMC, and VSMC maintained in primary culture for up to 3 wk, exhibited rapid, saturable, and specific 125I-AII binding similar to that seen with homogenates of the intact rat mesenteric artery. In 7-d primary cultures, Scatchard analysis indicated a single class of high-affinity binding sites with an equilibrium dissociation constant (Kd) of 2.8 +/- 0.2 nM and a total binding capacity of 81.5 +/- 5.0 fmol/mg protein (equivalent to 4.5 x 10(4) sites per cell). Angiotensin analogues and antagonists inhibited 125I-AII binding to cultured VSMC in a potency series similar to that observed for the vascular AII receptor in vivo. Nanomolar concentrations of native AII elicited a rapid, reversible, contractile response, in a variable proportion of cells, that was inhibited by pretreatment with the competitive antagonist Sar1,Ile8-AII. Transmission electron microscopy showed an apparent loss of thick (12-18 nm Diam) myofilaments and increased synthetic activity, but these manifestations of phenotypic modulation were not correlated with loss of 125I-AII binding sites or hormonal responsiveness. Primary cultures of enzymatically dissociated rat mesenteric artery VSMC thus may provide a useful in vitro system to study cellular mechanisms involved in receptor activation-response coupling, receptor regulation, and the maintenance of differentiation in vascular smooth muscle.

Angiotensin II↗
PubMed1982

Segmental membranous glomerulonephritis.

Each of the four stages of membranous glomerulonephritis (MGN) has a characteristic ultrastructural appearance. This report described four children with another distinctive pattern of MGN, which we propose to call segmental membranous glomerulonephritis (SMGN). In all cases there were segmentally distributed subepithelial or intramembranous electron-dense or electron-lucent deposits and prominent spikes. Less than 50% of capillary loops per glomerulus were affected. Granula deposits of IgG were identified by immunofluorescence microscopy, but deposits were either absent or less intensely fluorescent in repeated biopsies. All four patients had proteinuria. Three patients have normal creatinine clearances with either diminished proteinuria (one patient) or no proteinuria (two patients) after a mean follow-up of ten years. The fourth patient died of an unrelated cause. The evolution of MGN and SMGN is discussed and it is proposed that SMGN represents partial resolution of MGN.

Adolescent↗
PubMed1982

Myoelectric effects of Clostridium difficile: motility-altering factors distinct from its cytotoxin and enterotoxin in rabbits.

Clostridium difficile is a bacterium that causes antibiotic-associated pseudomembraneous enterocolitis. This bacterium produces a cytotoxin that induces tissue culture assay positivity and an enterotoxin that causes in vivo mucosal injury. In previous studies we have described two altered myoelectric patterns in response to certain diarrheagenic organisms in an in vivo rabbit model. The first pattern was called the migrating action potential complex and is associated with noninvasive agents; the second pattern was called repetitive bursts of action potentials and is characteristic of invasive or cytolytic agents. In this study, we evaluated the effects of purified cytotoxin (2.5-3.75 micrograms) and enterotoxin (140 micrograms) from C. difficile on the myoelectric activity in isolated ileal loops in New Zealand White rabbits. These observations in myoelectric activity were correlated with the results of similar studies by using the crude culture filtrates from C. difficile, or the products of Amicon XM50 filtration of its culture supernatant resulting in a high molecular weight product (0.3 mg protein/ml) and a low molecular weight product (0.57 mg protein/ml). Monopolar silver-silver chloride electrodes were used to record all myoelectric activity for an 8-h period. The animals were then killed, and tissue obtained from the ileal loops was histologically evaluated. Crude culture filtrates of C. difficile induced 7.0 migrating action potential complexes/hour and 6.8 repetitive bursts of action potentials/hour. Saline controls induced no migrating action potential complexes and 0.1 repetitive bursts of action potentials/hour. The high molecular weight filtration product obtained from the culture supernatant of C. difficile induced significantly more repetitive bursts of action potentials (41.1/h) than all agents studied. The purified cytotoxin or enterotoxin induced no migrating action potential complex activity and minimal repetitive bursts of action potential activity (0.9/h and 0.6/h, respectively). These values were not different from the saline controls; however, only the enterotoxin and the high molecular weight filtration product caused mucosal damage. These studies suggest that C. difficile produces a heat-labile substance or substances that alter the motility of the small intestine independent of the proteins responsible for in vivo tissue damage and cytotoxin assay positivity.

Action Potentials↗
PubMed1981

Intramural papilloma of the vagina: evidence of Müllerian histogenesis.

A papillary tumor occurred in the posterior-superior vaginal wall of a 5-year-old girl who was free of recurrence one year following surgical excision. The light microscopic features included papillae lined by eosinophilic cells with uniform, bland nuclei, solid areas of identical cells, and scattered glandular lumina which contained mucopolysaccharides. Foci of eosinophilic hyaline globules were another distinctive feature. Electron microscopy of the tumor demonstrated features associated with müllerian neoplasms including projecting microvilli, whorls of perinuclear cytoplasmic microfilaments, conspicuous lysosomes, squamous metaplasia, complex cytoplasmic interdigitations, and pseudoinclusions of "cytoplasmic" collagen. Previously described "mesonephric papillomas" of the vagina and cervix are compared with the tumor of the authors' patient. The previously described tumors share some histologic and clinical features, although they were superficial rather than intramural proliferations. The authors conclude that the ultrastructure, location, and documented presence of müllerian structures in the vagina favor a müllerian origin for this vaginal tumor. A number of other vaginal tumors that occur in children and young women show different light microscopic features.

Child, Preschool↗
PubMed1981

Coronary vasoconstrictor effect of indomethacin in patients with coronary-artery disease.

Prostaglandins may be important regulators of coronary blood flow. To investigate this possibility, we studied the effect of blockade of prostaglandin synthesis by indomethacin in nine patients with coronary-artery disease. Coronary-sinus blood flow (determined with the thermodilution technique) was recorded, together with mean arterial blood pressure and the myocardial arteriovenous oxygen difference from simultaneously obtained arterial and coronary-sinus blood samples, before and 20 minutes after an intravenous dose of indomethacin (0.5 mg per kilogram of body weight). There were significant increases (P less than 0.05) in mean arterial pressure (from 99 +/- 4 to 118 +/- 5 mm Hg [+/- S.E.M.]), coronary vascular resistance (+73 per cent), and myocardial arteriovenous oxygen difference (from 107 +/- 5 to 138 +/- 4 ml per liter) after indomethacin, but coronary blood flow fell significantly, from 181 +/- 29 to 111 +/- 14 ml per minute (P less than 0.05). Thus, despite an increase in myocardial oxygen demand, coronary blood flow fell and coronary vascular resistance increased. This coronary vasoconstrictor effect may have been due to blockade of vasodilatory prostaglandin synthesis or to a direct drug effect. Whatever the mechanism, indomethacin should be used with caution in patients with severe coronary-artery disease.

Blood Pressure↗
PubMed1981

Cushing's syndrome secondary to a neuroendocrine tumor: relapse after bilateral adrenalectomy.

Bilateral adrenalectomy results in the removal of the site of glucocorticosteroid production thereby eliminating the signs and symptoms of Cushing's syndrome. A case is reported of a middle-aged man with Cushing's syndrome due to an ACTH-producing tumor. The patient initially responded to adrenalectomy but had a fatal relapse. Autopsy showed that the right adrenal bed containing remnants of adrenal tissue. An islet cell carcinoma of the pancreas was thought to be the primary tumor.

ACTH Syndrome, Ectopic↗
PubMed1981

Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol.

We compared the initial and long-term effects of the beta-adrenergic agonist pirbuterol in 12 patients with chronic congestive heart failure. The drug's initial effect was a 35 per cent increase in cardiac index, but there was no significant change in heart rate or mean arterial pressure. After one month of therapy, the mean cardiac index and ejection fraction had returned to base-line values, and no clinical effect was evident in most patients. This apparent tolerance was not accompanied by changes in heart rate, blood pressure, or body weight, and it occurred in the presence of therapeutic drug levels during long-term therapy. The density of beta-adrenergic receptors on lymphocytes from patients treated with pirbuterol was significantly depressed as compared with that of patients with heart failure of comparable severity but not treated with pirbuterol. We conclude that tolerance to the hemodynamic and clinical effects of pirbuterol develops during long-term administration; this tolerance may be related to a decrease in myocardial or vascular beta-adrenergic receptors or both.

Adrenergic beta-Agonists↗