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Biomedical subjects

S A Atlas

Publications and source records attributed to S A Atlas.

125 records · Page 7Linked to original sources
PubMed1976

Genetic control of interindividual variations in the inducibility of aryl hydrocarbon hydroxylase in cultured human lymphocytes.

Interindividual and intraindividual variations in aryl hydrocarbon hydroxylase (AHH) induction by 3-methylcholanthrene were studied in cultured lymphocytes from normal adult volunteers. Using eight pairs of monozygotic and eight pairs of dizygotic twins, we examined to what extent these variations are controlled by heritable factors and whether AHH inducibility correlations in an individual with the plasma half-lives of three drugs. Substantial overestimation of the induction ratio (fold inducibility) may occur if the nonlinearity of the assay standard curve is not considered. Fold inducibility remains relatively constant for an individual, but large intraindividual variations occur in absolute "control" and "induced" AHH activities. Fetal calf serum may contain inducers of AHH activity that vary with the particular lot of serum, thereby rendering the apparent induction ratio an imprecise indicator of genetic susceptibility to induction by 3-methylcholanthrene. The index of heritability for AHH fold inducibility in twins studied with different lots of fetal calf serum (0.80) or with a single lot of fetal calf serum (0.77) suggests nonetheless that genetic rather than environmental factors are mainly responsible for interindividual variations in AHH inducibility by 3-methylcholanthrene in human lymphocytes. In these twins a significant but poor correlation (r=-0.551; 0.03 less than p less than 0.05) occurs between AHH inducibility in culture and the plasma antipyring half-life, but not between AHH inducibility and phenylbutazone or bishdroxycoumarin half-lives.

Adolescent↗
PubMed1976

Inducible monooxygenase activities and 3-methyl-cholanthrene-initiated tumorigenesis in mouse recombinant inbred sublines.

The induction of a certain group of hepatic monooxygenase activities by polycyclic aromatic compounds is regulated by the same locus or gene cluster controlling the formation of cytochrome P1-450 (P-448) in mice. Certain inbred strains of mice are "responsive" (Ahb) to such induction, whereas others are "nonresponsive" (Ahd). A pair of closely related sublines that differ with respect to the Ah locus (for aromatic hydrocarbon responsiveness) were used to identify or confirm the pleiotropic effects of this gene. The lines were derived by sibling-mating without selection from (C57L/J x AKR/J)F2 mice; the two sublines were separated at the F12 generation. Ten microsomal monooxygenase activities and one cytosol enzyme activity known to be associated with the Ah locus were similarly associated with cytochrome P1-450 formation in these recombinant inbred sublines as well. Nine additional hepatic monooxygenase activities studied were found not to be associated with the Ah locus; certain of these activities were increased slightly, following treatment of nonresponsive as well as responsive mice with polycyclic aromatic compounds. The Ahb-containing subline was highly susceptible to 3-methylcholanthrene-induced subcutaneous sarcomas, whereas the Ah-d-containing subline was relatively resistant. These results emphasize the potential importance of this particular enzyme for the study of coordinated regulation in mammals.

Animals↗
PubMedDate not supplied

Purification, sequencing and synthesis of natriuretic and vasoactive rat atrial peptide.

Mammalian atria contain potent natriuretic and diuretic substances which exist in high- and low-molecular-weight forms and which appear to be associated with atrium-specific granules. The natriuretic effect of atrial extract is largely accountable for by its renal haemodynamic effects; atrial extracts also antagonize hormone- and non-hormone-induced contraction of the isolated rabbit aorta and isolated rat kidney vasculature. We have completely purified a low-molecular-weight natriuretic and vasoactive substance from rat atria and characterized it as a 24-amino acid peptide. Synthetic peptide, produced by solid-phase synthesis, mimics biological effects of crude atrial extract and purified peptide; its activity is enhanced by slow oxidation, suggesting a disulphide (Cys 4-Cys 20) configuration for the native peptide. If secreted into blood, this atrial natriuretic peptide (' auriculin B') could be a novel peptide hormone of considerable importance to renal and cardiovascular homeostasis.

Amino Acid Sequence↗
PubMedDate not supplied

Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: identification of triphasic pattern of blood pressure response.

A triphasic pattern of blood pressure response was observed in 13 of 26 patients treated with captopril. Pressure fell after the first dose in all but 3 patients, reaching a minimum by 90 min. Over the next several days, pressure either remained at this level (n = 13) or returned towards control levels (n = 13) even with increased dosage. Blood pressure then fell gradually, usually reaching a level by 10 days that was equal to or slightly lower than that after the first dose. The secondary rise in blood pressure was more frequent and pronounced in patients who had larger initial responses and higher renin levels. The transient increase in pressure could not be explained by failure of blockade of the renin system, since aldosterone excretion was maximally suppressed by the second day of treatment. The data indicate that both the blood pressure response to the first dose and the renin level can be used to predict the long-term response to captopril.

Aldosterone↗
PubMedDate not supplied

Detection and isolation of inactive, large molecular weight renin in human kidney and plasma.

Estimation of apparent molecular weight (mw) of inactive renin by gel filtration of human plasma was found to be inaccurate when "acid activation" or "cryoactivation" was used for detection; recoveries were only 5% to 20%. Trypsin activation produced greater recoveries, but the apparent elution volume of inactive renin varied with the concentration of trypsin used; the presence of trypsin inhibitors increased trypsin requirements to 100 to 200 micrograms/ml in the 60,000 dalton region, while low protein concentration in the 50,000 dalton region resulted in destruction of renin by as little as 10 microgram/ml trypsin. A composite trypsin-activated inactive renin peak corresponded to a mw of 56,000 +/- 1500 daltons (104% to 120% recovery), while active plasma renin was 48,000 +/- 2000 daltons. When this prorenin-like substance was isolated by affinity chromatography, it was found to be completely inactive. It was also nearly free of trypsin inhibitors, so that a single trypsin concentration correctly identified and confirmed the elution characteristics of inactive renin peak following gel filtration. The apparent mw of trypsin-activated inactive renin was slightly lower (52,000 daltons) than that of inactive renin. Human renal cortex was also found to contain a trypsin-activable form of renin. Like plasma inactive renin, it could be isolated by chromatography on Cibacron blue-agarose (Affi-Gel blue). It was found to be completely inactive following passage over a pepstatin affinity column. This inactive renal renin, as well as a similar substance in perfusate of normal human kidney, had a mw of 49,500 +/- 1000, while active renal renin was 39,500 +/- 500. Trypsin-activated inactive renal renin had a mw of 46,500 +/- 500; its pH optimum was identical with that of active renal renin, and it no longer bound to Cibacron blue-agarose. We conclude that both human plasma and kidney contain an inactive, prorenin-like substance that can be detected reliably by trypsin activation. There appear to be slight differences in the apparent mw of plasma renins and kidney renin, but the similarity of other characteristics suggests that the inactive, prorenin-like substances in renal cortex, renal perfusate, and plasma may be one and the same substance.

Chromatography, Gel↗
PubMedDate not supplied

Renin system activity as a determinant of response to treatment in hypertension and heart failure.

In hypertension, irrespective of its underlying etiology, the baseline pretreatment renin-sodium profile predicts the antihypertensive action or the lack of it for five major types of antihypertensive drugs: 1) diuretic agents; 2) beta-receptor blockers; 3) converting-enzyme inhibitors; 4) the alpha 1 postsynaptic blocker, prazosin; and 5) the calcium channel blockers, verapamil and nifedipine. Moreover, vigorous compensatory activation of the renin-angiotensin system in response to therapy often explains initial drug ineffectiveness or resistance to treatment by diuretics and nonspecific vasodilators. This correlation between renin system behavior and antihypertensive drug efficacy likely reflect basic pharmacologic-physiologic interactions. This correlation is also observed in congestive heart failure without hypertension, where operant renin-aldosterone profiles may help to explain both drug efficacy and drug resistance to commonly administered therapeutic agents. Accordingly, a control system analysis of the renin axis has broad applications in therapy. The analysis is also conceptually significant since it exposes the operation of fundamentally different mechanisms of increased vascular resistance to flow occurring in different patients with hypertension or heart failure. One form is renin-angiotensin-mediated whereas the other, in the absence of renin, is associated with sodium-volume excess and/or abnormal alpha-adrenergic and calcium channel activity. Further definition of these two mechanisms of increased peripheral resistance could lead to a better understanding of the pathogenesis of some forms of essential hypertension and congestive heart failure.

Antihypertensive Agents↗
PubMedDate not supplied

Atrial natriuretic factor inhibits angiotensin-, norepinephrine-, and potassium-induced vascular contractility.

We have previously shown that the natriuretic effect of rat atrial extract (AE) may be due, perhaps entirely, to its powerful renal hemodynamic actions. The present study was undertaken to test the hypothesis that mammalian atria contain a substance that behaves as a functional antagonist of endogenous vasoconstrictors, by examining the direct effects of AE and extensively purified atrial "natriuretic" factor on the contractile response of rabbit aortic rings to angiotensin II (AII), norepinephrine (NE), and K+-induced depolarization. Dose-response curves to AII and NE (i.e., change in tension vs log hormone concentration) were determined in the absence or presence of boiled AE or ventricular extracts (VE). Increasing concentrations of boiled AE caused a progressive right-ward shift of the AII and NE dose-response curves, whereas VE was without effect. A similar inhibitory effect was produced after extensive purification of atrial natriuretic factor by gel filtration and reversed-phase high performance liquid chromatography (HPLC). It appeared that this factor antagonized AII-induced contractility to a greater degree than that of NE. Moreover, the partially purified factor also inhibited the contraction induced by depolarization with 15 mM KCl in a concentration-dependent manner. These studies show that a substance present in the atria, but not ventricles, blocks both hormone- (receptor) and depolarization- (nonreceptor) induced vasoconstriction in aortic rings. Moreover, this antagonism is retained following extensive purification of an atrial factor that induces natriuresis in the intact rat and isolated rat kidney, suggesting that both the vasoactive and natriuretic properties of AE may reside in a single substance.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMedDate not supplied

Effect of atrial natriuretic factor on blood pressure, renin, and aldosterone in Goldblatt hypertension.

We previously provided evidence that atrial natriuretic factor (ANF) antagonizes angiotensin II-induced vascular contractility and angiotensin II-stimulated aldosterone production by isolated adrenal cells. To examine the importance of these effects in vivo, synthetic ANF (auriculin A) was administered intravenously (2 micrograms/kg bolus followed by 0.3 microgram/kg/min constant infusion) to conscious, unrestrained two-kidney, one-clip and one-kidney, one-clip rats on normal sodium intake and their sham-operated controls. The one-kidney, one-clip rats also were studied on a sodium-deficient diet. Mean blood pressure, plasma renin activity, and plasma aldosterone levels were measured before and after 60-minute infusion. In saralasin-responsive two-kidney, one-clip rats (n = 10), ANF administration reduced blood pressure (from 187 +/- 11 [SE] to 153 +/- 11 mm Hg; p less than 0.001) and plasma aldosterone levels (from 182 +/- 61 to 125 +/- 60 ng/dl; p less than 0.05), while plasma renin activity increased (from 59 +/- 16 to 82 +/- 20 ng/ml/hr; p less than 0.05). Lesser changes in blood pressure occurred in saralasin-nonresponsive two-kidney, one-clip rats (149 +/- 10 to 143 +/- 8 mm Hg; n = 5), sodium-replete one-kidney, one-clip rats (183 +/- 9 to 170 +/- 11 mm Hg; n = 9), two-kidney sham-operated rats (122 +/- 3 to 115 +/- 4 mm Hg; n = 8), and one-kidney sham-operated rats (117 +/- 3 to 112 +/- 3 mm Hg; n = 7). Control plasma renin and aldosterone levels were not elevated in these latter groups and did not change significantly with ANF administration. In sodium-depleted one-kidney, one-clip rats, which became saralasin responsive, ANF administration significantly reduced blood pressure (from 184 +/- 11 to 156 +/- 12 mm Hg; n = 8), plasma aldosterone levels (from 286 +/- 41 to 179 +/- 36 ng/dl), and plasma renin activity (from 69 +/- 19 to 44 +/- 13 ng/ml/hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMedDate not supplied

Biochemical similarity of partially purified inactive renins from human plasma and kidney.

Inactive renin was partially purified from 4.5 liters of human plasma (502-fold, specific activity 0.8 X 10(-3) Goldblatt units/mg protein) and from 207 g renal cortex (103-fold, 52 X 10(-3) Goldblatt units/mg). In contrast to active renin, inactive renin from each source bound to Cibacron blue-agarose and was unable to bind to pepstatin-Sepharose. Both plasma and renal inactive renin had weaker affinity for anion-exchange resins than the active form, both bound to concanavalin A-Sepharose and were eluted with carbohydrate, and both bound tightly to hydrophobic gels. Each substance could be isolated in a completely inactive form during small-scale pilot studies, but "spontaneous" activation did occur, to a limited degree, during large-scale purification; this was possibly due to a plasma serine protease that fractionated with inactive renin during the initial purification steps. Both plasma and renal inactive renin were activated irreversibly by trypsin. Following activation, each substance lost it ability to bind to Cibacron blue-agarose. Each could be activated fully by acidification at 4 degrees C, but this activation was reversed during subsequent incubation at higher temperature and pH. There was no evidence of acid protease activity in either preparation. Activated inactive renin from both plasma and kidney were identical to partially-purified active renal renin in terms of pH optimum (pH 5.5-6.0) and reaction kinetics (Km 0.8-1.3 microM) with homologous angiotensinogen, noncompetitive inhibition by pepstatin (ki 2.5-3.5 microM), and an identical inhibition profile by monospecific antirenin antibodies. These results suggest that inactive renin from plasma and kidney may be the same substance and that their activated forms are similar to the endogenously produced active enzyme, consistent with the possibility that inactive renin is a precursor of circulating active renin.

Chromatography, Affinity↗