PubMed Health⌕ Search

Biomedical subjects

F M Bumpus

Publications and source records attributed to F M Bumpus.

At least 37 records · Page 2Linked to original sources
PubMed1977

Angiotensinase activity in red blood cell membranes and intact adrenal cells.

The present study was undertaken to characterize angiotensinase activity in human red blood cells (RBCs), RBC ghosts and rabbit adrenal cells. It was found, by the use of paper chromatography, that each of these preparations possess enzymes capable of converting angiotensin II to its heptapeptide derivative, [des=Asp1] angiotensin II (angiotensin III). Further characterization of these enzymes by the use of a chromogenic assay indicates that although intact RBCs do not split sarcosine-beta-naphthylamide, RBC ghosts do. Intact rabbit adrenal cells from the zona glomerulosa, however, do show activity against sarcosine-beta-naphthylamide. This is interpreted to indicate the presence of non-specific angiotensinases on the inside of the RBC membrane and the outside of the adrenal cell membrane.

Adrenal Cortex↗
PubMed1977

Pathogenic factors involved in renovascular hypertension. State of the art.

The complex hormonal action of angiotensin II in the long-term control of blood pressure or sodium metabolism, or in renal hypertension, is not completely understood. Structure-activity relations with analogues of angiotensin II gave information about the functions responsible for pressor and myotropic response in the molecule that led to the synthesis of competitive antagonists of this hormone. These antagonists, however, show variable agonist/antagonist ratios in different species or different tissues of the same species. This fact necessitates further work to induce tissue specificity. Although des-Asp1-angiotensin II ("angiotensin III") has been recognized as a hormone, its exact role in the biosynthesis of aldosterone is yet to be discovered. The antagonists such as des-Asp1-[Ile8]-angiotensin II or des-Asp1-[Thr8]-angiotensin II have provided important leads in this direction. Many of the biologic effects of angiotensin I have been attributed to its conversion to angiotensin II by the converting enzyme. Recent investigations indicate that angiotensin I itself may play a direct role; however, most of these studies were carried out by inhibiting the converting enzyme activity with peptides obtained from the venom of Bothrops jararaca. Since these peptides also potentiate bradykinin action, the observed biologic activities could be caused by either angiotensin I or bradykinin. Bsides, converting enzyme is no longer thought to be a single enzyme and its nature varies from species to species and from tissue to tissue in the same species. Renin inhibitors related to renin substrate or pepstatin are not freely soluble in plasma and are not effective under physiologic conditions. This points to the importance of renin inhibitors isolated from kidney or other natural sources. Thus, although the renin-angiotensin system appears to be an integral part of the problem of hypertension, characterization of various converting enzymes, roles of extrarenal renin, isorenin, tonin, and brain-renin, and the involvement of other humoral, neurogenic, and immunogenic factors should be pieced together to get a clear picture of the hypertension problem.

Aldosterone↗
PubMed1977

Isolation of a hypertension-producing compound from normal human urine.

A protein fraction has been isolated from normal human urine which, when injected over a period of 10-15 days in normal rats, produced sustained hypertension. On cessation of injection, the blood pressure fell to normal level within 7-10 days. The hypertension was accompanied by expansion of plasma volume, retention of sodium, and alteration in urinary Na/K ratio. Further, it led to hypertrophy of the adrenal cortex and increased circulating aldosterone without a change in plasma corticosterone values. These results suggest that the protein fraction increased arterial pressure in rats through direct stimulation of aldosterone production resulting in sodium retention and volume expansion.

Aldosterone↗
PubMed1977

New aspects of aldosterone regulation.

Evidence is presented that points to an important role of the COOH-terminal heptapeptide fragment of angiotensin II, (Des-Asp) angiotensin II, in the regulation of aldosterone biosynthesis. In favor of this view are the demonstrations that (1) the heptapeptide is as effective as angiotensin II in stimulating aldosterone secretion, (2) heptapeptide antagonists are potent and specific inhibitors of angiotensin II-induced steroidogenesis, and (3) the heptapeptide can be generated readily in plasma and locally in tissues. The concept of specific adrenal cortical receptors for the heptapeptide also allows a possible explanation for the observation that arterial pressure-angiotensin II-aldosterone inter-relations often are inconsistent.

Adrenal Cortex↗
PubMed1977

New approaches to the study of angiotensin tachyphylaxis.

Of the various mechanisms proposed to explain the development of tachyphylaxis, the initial step of drug-receptor interaction has received the most attention. The present study suggests that the affinity of angiotensin II itself or an angiotensin analogue for the angiotensin receptor is a determing factor in the development of tachyphylaxis. The concept of negative cooperativity is introduced as a consequence of the observed correlation in the present study between slopes of less than unity as determined in Hill plots and the development of tachyphylaxis.

Angiotensin II↗
PubMed1976

Circular-dichroism spectra of truncated and other analogs of angiotensin II.

Circular dichroism spectra on angiotensin II and analogs, and its truncated N-terminal and C-terminal peptides were determined in fluroinated alcohols under several conditions in the peptide or aromatic spectral regions. The following conclusions were suggested: (a) evidence for a beta structure for angiotensin II; (b) evidence for a folding at the N-terminal and C-terminal part of the molecule; (c) an interaction involving the C-terminal residue which decreases progressively when phenylalanine is replaced by isoleucine and then by alanine; (d) the N-terminal amino acid seems to play an important role in the overall conformation of the molecule possibly by interacting with the C-terminus, its absence in the 2 -- 8 heptapeptide giving rise to a more pronounced signal than angiotensin II; (e) in trifluoroethanol the conformation of these peptides is well defined and fits well with observed structure-activity relationships and observed binding data. There is a loss of this relationship when these solvents are diluted with water.

Amino Acid Sequence↗
PubMed1976

Synthesis of angiotensin II antagonists containing N- and O-methylated and other amino acid residues.

[1-N-Methylisoasparagine,8-isoleucine]- (I), [1-sarcosine,4-N-methyltyrosine,8-isoleucine]- (II), [1-sarcosine,5-N-methylisoleucine,8-isoleucine]- (III), [1-sarcosine,8-N-methylisoleucine]- (IV), [1-sarcosine8k-N-methylisoleucine,8-N-methylisoleucine]- (V), [1-sarcosine,8-O-methylthreonine]- (VI), [1-sarcosine,8-methionine]- (VII), and [1-sarcosine,8-serine]angiotensin II (VIII), synthesized by Merrifield's solid-phase procedure, possess respectively 0.8, 0.3, 0.5, 1.0, 0.0, 0.5, 3.7, and 0.7% pressor activity of angiotensin II (vagotomized, ganglion-blocked rats). They caused an initial rise in blood pressure (30 min of infusion, 250 ng/kg/min in vagotomized, ganglion-blocked rats) of 16.57, 9.80, 22.80, 32.00, 7.00, 15.06, 32.50, and 11.42 mmHg and showed secretory activity (isolated cat adrenal medulla) of 1.0, 0.1, 0.01, 0.1, less than 0.01, 0.1, less than 0.01, and 0.05% of angiotensin II. On isolated organs pA2 values (rabbit aortic strips) of 8.74, 7.44, 7.64, 7.85, 7.89, 8.76, 8.63, and 8.08, and pA2 values (cat adrenal medulla of 8.16, 9.16, 9.31, 8.00, 8.00, 7.00, 9.16, and 9.33 were obtained. Dose ratios (ratio of ED20 of angiotensin II during infusion of the antagonist and before infusion of the antagonist) in vagotomized, ganglion-blocked rats, infused at 250 ng/kg/min, were 33.43, 2.14, 3.26, 2.99, 0.62, 62.52, incalculable, and 11.15, respectively. The results obtained suggest that (a) analogs I and VI are potent antagonists of the pressor response of angiotensin II in normal rat, VI being the most potent antagonist thus far synthesized; (b) replacement of position 4 (Tyr) with MeTyr or position 5 and/or 8 (Ile) with Melle in [1-sarcosine,8-isoleucine]angiotensin II reduced the antagonist activity of this peptide (rabbit aortic strips and rats), indicating that steric hindrance imposed due to N-methylation in positions 4, 5, or 8 was not favorable in eliminating the initial pressor activity or prolonging the duration of action of [Sar1, Ile8]angiotensin II without reducing its antagonistic properties; (c) except II, none of the analogs showed any enhanced duration of action, suggesting that N-methylation in positions 5 or 8 did not afford protection against proteolytic enzymes; and (d) perfusion studies in cat adrenals indicated that all of these analogs are only very weak secretagogues. With the exception of [Sar1,Thr(ObetaMe)8]angiotensin II, which gave lower antagonistic properties, all other analogs had either similar antagonistic properties or were better antagonists in adrenal medulla than in smooth muscle.

Adrenal Glands↗
PubMed1976

Differential effects of Asp-angiotensin II and Sar-angiotensin II on vascular and adrenal receptors in the dog.

1. Adrenocorticotrophic hormone-suppressed, bilaterally nephrectomized male mongrel dogs (n = 12) were infused with Sar1-angiotensin II and Asp1-angiotensin II, the naturally occurring octapeptide. 2. Sar1-angiotensin II was found to be almost twice as potent as Asp1-angiotensin II in elevating blood pressure but its aldosterone-stimulating activity was not higher than that of the naturally occurring peptide. 3. A specific competitive antagonist of angiotensin II, Sar1-Ile8-angiotensin II, blocked the pressor but not the aldosterone-stimulating activity of Sar1-angiotensin II. 4. These results suggest functional differences in receptors for angiotensin II in vascular smooth muscle and in adrenal cortex.

Adrenal Cortex↗
PubMed1976

Biochemical changes associated with development and reversal of cardiac hypertrophy in spontaneously hypertensive rats.

This study is the first report describing the sequence of biochemical alterations of myocardium during the progression of naturally occurring hypertrophy in spontaneously hypertensive rats (SHRs) and then with its reversal by alpha-methyldopa therapy. Changes in DNA, RNA, hydroxyproline, as well as incorporation of 14C lysine into cardiac myosin, were compared with the pattern found in suitably matched controls. A significant increase in RNA, hydroxyproline, and 14C incorporation was observed in SHRs. Antihypertensive treatment caused reversal of hypertrophy and normalization of all biochemical parameters except hydroxyproline, the concentration of which increased significantly as myocardial weight decreased. These compositional changes may help explain the conflicting result of the haemodynamic effects of cardiac hypertrophy.

Animals↗
PubMed1976

The role of angiotensins in aldosterone production.

The hypothesis that the COOH-terminal heptapeptide mediates the aldosterone-stimulating activity of angiotensin II was evaluated by comparing the relative effects on aldosterone production of angiotensin II and the heptapeptide to angiotensin analogues that are poorly metabolized to the heptapeptide and to a nonapeptide, des-Asp-1-angiotensin I, that is directly converted to the heptapeptide. In in vivo studies utilizing the adrenocorticotropic hormone-suppressed bilaterally nephrectomized dog, angiotensin II and the heptapeptide produced statistically significant increases in both aldosterone and cortisol secretory rates (P less than 0.001 for both relations). Sar-1-angiotensin II stimulated the production of both steroids to the same extent, but had much longer duration of action. [Poly(oAc)Seryl]angiotensin II was a weak agonist, having only about 30% of the steroidogenic potency of either angiotensin II or the heptapeptide. In equimolar concentrations des-Asp-1-angiotensin I had about one-half of the aldosterone-stimulating activity of the hepatpeptide. In in vitro studies, employing the trypsin-dispersed cat adrenal zona glomerulosa cells, the steroidogenic potency of angiotensin II and the heptapeptide was identical to maximal aldosterone production of 10(-8) M peptide concentration. By contrast, the response to Sar-1-angiotensin II was approximately a 10-fold increase in relative potency, while the response to [poly(oAc)Seryl]angiotensin II demonstrated a 10-fold decrease. These findings suggest that, although the heptapeptide may play an important role in the regulation of aldosterone production, the possibility remains open that angiotensin II could stimulate aldosterone biosynthesis without prior conversion to the heptapeptide.

Adrenal Cortex↗
PubMed1976

Comparative studies of the humoral and arterial pressure responses to Sar1-Ala8-, Sar1-Ile8 and Sar1-Thr8-angiotensin II in the trained unanaesthetized dog.

The humoral and arterial blood pressure responses to Sar1-Ala8-, Sar1-Ile8- and Sar1-Thr8-angiotensin II were studied in sodium-depleted, trained, unanaesthetized dogs. Of the three angiotensin antagonists, Sar1-Thr8-angiotensin II appeared to be the best suited for clinical use. In the smallest amount that was found to be effective in reducing arterial pressure, it was devoid of agonist activity. Also, in marked contrast to Sar1-Ala8- and Sar1-Ile8-angiotensin II, Sar1-Thr8-angiotensin II was not shown to stimulate either catecholamine or aldosterone secretion.

Aldosterone↗
PubMed1976

Effects of angiotensin antagonists in various forms of experimental arterial hypertension.

The dependence of renal hypertension on increased levels of angiotensin II was investigated in conscious dogs at various stages of hypertension of four different types. Two of the most potent angiotensin inhibitors, Sar1-Ile8- and Sar1-Thr8-angiotensin II, were infused separately in various doses and at different times throughout the evolution of renal hypertension. The results of these experiments are consistent with the view that the renin-angiotensin system may participate in the acute and malignant phases of renal hypertension; they do not provide evidence for its participation when hypertension enters the chronic phase.

Angiotensin II↗
PubMed1976

In vitro and in vivo studies of (1-sarcosine, 8-threonine) angiotensin II.

The capacity of (1-Sarcosine, 8-Threonine) angiotensin II to block the contractile and pressor effects of exogenous and endogenous angiotensin II was examined. In isolated rabbit aorta, the pA2 value (from pA2 plots) for the analog was 8.75 +/- 0.11. Both the maximum response and the slope of the dose-response curve to angiotensin II were unchanged by the analog. In ganglion-blocked vagotomized rats, infusion of the analog produced a dose-dependent blockage of the angiotensin II pressor effect. In these rats, the analog displayed less agonistic activity than that of (1-Sarcosine, 8-Isoleucine) and (1-Sarcosine, 8-Alanine) angiotensin II. In two-kidney hypertensive rats, the angiotensin II antagonist significantly reduced the arterial blood pressure. The results indicate that (1-Sar, 8-Thr) angiotensin II is a potent antagonist of angiotensin II with less inherent agonistic activity than previously reported analogs.

Adrenal Glands↗
PubMed1975

Influence of the adrenal gland on the pressor effect and antagonistic potency of angiotensin II analogs.

In ganglion blocked vagotomized rats, several 1,8-substituted angiotensin II analogs (250 ng/kg/min, i.v.) antagonized the pressor effect of angiotensin II. Dose ratios measured at the ED20 levels were: [Sar1,Ile8]-28; [Gac1,Ile8]- 19;[MeAla1,Ile8i1- 16;[MeIle1,Ile8]- 10;[sar1,Ala8]- 9;[me2Gly1,Ile8]- 4. Elimination of aspajtic acid in position 1 of [Ile8]-angiotensin II significantly reduced the antagonistic potency of the analog. No antagonistic effect was observed with [Phe4,Ile8] and [Ala4,Ile8]-angiotensin II even when infused at 6 mug/kg/min. During infusion, a partial rise in blood pressure was observed with all the above 1,8-substituted angiotensin II analogs. Phentolamine (100 mug/rat) injected 30 min after the start of the analog infusion reduced and sometimes abolished the pressor effect. However, phenoxybenzamine )Pbz, 2 mg/kg) injected 30 min prior to the analog infusion diminished but did not completely abolish the initial pressor effect. In adrenalectomized rats, the pressor effect was reduced by approximately 50 percent and disappeared completely 15-30 min after start of the infusion. Under these conditions, dose ratios of [Sar1,Ile8]-,[MeAla1,Ile8]- and [Gac1,Ile8]-angiotensin II were significantly reduced. Noradrenaline, 83 ng/kg/min. increased the ED20 value of angiotensin II(ratio 1.79) in normal rats but did not do so in adrenalectomized rats. In these rats no regular correlation was found between the angiotensin II ED20 values and initial blood pressure. These data indicate that under the present experimental conditions, the low pressor effect observed with these angiotensin II antagonists appears to be due to both adrenal catecholamine release and a direct vasoconstrictor effect. Variations in antagonistic activity of angiotensin II analogs, apart from changes introduced in the molecule, may be the manifestation of a complex interaction between angiotensin II, its antagonists, and the sympathoadrenal system.

Adrenal Glands↗
PubMed1975

Synthesis and evaluation of (Des-Asp1)angiotensin I as a precursor for (Des-Asp1)angiotensin II ("Angiotensin III").

The nonapeptide [des-Asp1]angiotensin I (IV), synthesized by Merrifield's solid-phase procedure, was tested as a possible substrate for the converting enzymes from porcine lung and plasma. IV, [des-Asp1]angiotensin II (III), [des-(Asp1,Arg2)]angiotensin II (V), [des-(Asp1,Arg2,Val3)]angiotensin II (VI), [Sar1,Ile8]angiotensin II (VII), and [des-Asp1,Ile8]angiotensin II (VIII) possessed 0.5, 20, 2, 0 less than 0.1, and less than 0.01% of the inotropic activity (rabbit atria), 1, 15, 5, 0, 3, and 0% secretory activity of the cat adrenal medulla, and 0.0, 150, 0.5, 3, and 10% of the adrenal steroidogenic activity of angiotensin II, respectively. When tested for their antagonistic activity in the above tissues, only VII and VIII were found to inhibit responses to angiotensin II. The pA2 values for VII and VIII were 8.31 and 10.0 in the adrenal cortex and 9.31 and 9.16 in the adrenal medulla, respectively. All these peptides were also tested as product inhibitors for the plasma and lung converting enzymes. With the plasma enzyme, the ID50 values were II, 1.6 X 10(-4) M; III, 5 X 10(-5) M; V, 1.2 X 10(-4) M; VI 5 X 10(-4) M; VII 5 X 10(-5) M; VIII, 5 X 10(-4) M. Thus, IV is a good substrate for converting enzymes from lung and plasma while all other compounds were inhibitors of these enzymes. The most potent inhibitors of converting enzyme were III followed by VII and VIII. With the exception of II and III, all the other analogs had very low intrinsic activities, per se. These results suggest (a) an alternate pathway for the formation of heptapeptide III, viz., by the action of converting enzyme on the nonapeptide IV, and (b) that III may also be acting as inhibitor of the converting enzyme by the feedback mechanism.

Angiotensin II↗
PubMed1975

Inhibition of the pressor and aldosterone-releasing effects of angiotensin II.

1. Competitive or non-competitive inhibition of the myotropic and pressor response of angiotensin II is dependent on the nature of the substituent in position 8 of the antagonist peptide analogue. Substituents in other positions of the molecule, particularly position 1, contribute greatly to the potency of these antagonists. 2. As is evidenced after adrenalectomy or after blockade with phentolamine and phenoxybenzamine, the initial pressor activity observed with all the antagonistic peptides is partially due to the release of catecholamines and partially to a direct myotropic effect. 3. [Sar1, Thr8]angiotensin II has been found to possess the lowest agonist to antagonist ratio of all antagonists tested. 4. [Des-Asp1, Ile8]angiotensin II selectively and specifically inhibits the release of aldosterone from adrenal cortex. Thus, unlike angiotensin II, this heptapeptide has pronounced organ specificity, suggesting that the heptapeptide (angiotensin III) is the aldosterone-releasing hormone.

Adrenal Glands↗