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Biomedical subjects

F M Bumpus

Publications and source records attributed to F M Bumpus.

At least 19 recordsLinked to original sources
PubMed1979

Synthesis of angiotensin II analogues by incorporating beta-homotyrosine or beta-homoisoleucine residues.

[1-Sarcosine,4-beta-homotyrosine]-(I), [5-beta-homoisoleucine]-(II), and [1-sarcosine,5-beta-homoisoleucine]angiotensin II (III) were synthesized by Merrifield's solid-phase procedure to study the effect of pressor activity and duration of action. The analogues I--III possessed, respectively, 1.98, 2.82, and 29.2% pressor activity of angiotensin II (vagotomized, ganglion-blocked rats by single-injection procedure) and duration of action of 5.5, 6.7, and 4.7 min; the comparative duration of action of an equipressor dose of angiotensin II was 5.2, 6.3, and 5.3 min, respectively. When incubated with leucine aminopeptidase, degradation of II was as fast as that of angiotensin II; this degradation became considerably slower when position 1 was replaced with sarcosine. Incubation of all these analogues with chymotrypsin showed very little or no degradation up to 3 h. The results indicate that an increase in the chain length by one carbon atom in position 4 or 5 of angiotensin II increased resistance to degradation by chymotrypsin without any increase in in vivo duration of action. Further, all analogues showed low pressor activity.

Angiotensin II↗
PubMed1979

Cardiac effects of angiotensin antagonists in normotensive rats.

1. Angiotensin II (AII) antagonists, namely Sar1,Ile8-AII, Sar1,Ala8-AII and Sar1,Thr8-AII, were administered daily for 4 weeks to normotensive rats to study their effect on cardiac hypertrophy. 2. None of the antagonists altered blood pressure significantly but Sar1,Ile8-AII and Sar1,Ala8-AII produced a significant increase in heart weight, as compared with untreated age-matched control rats. Administration of Sar1,Thr8-AII did not produce cardiac hypertrophy. 3. A significant increase in catecholamine concentration was observed in the ventricles of rats treated with Sar1,Ile8-AII and Sar1,Ala8-AII but no change was found in the group treated with the Sar1,Thr8-AII analogue. The production of cardiac hypertrophy by Sar1,Ile8-AII was prevented by bilateral adrenalectomy, suggesting an important role for catecholamines in modulating cardiac hypertrophy.

Angiotensin II↗
PubMed1979

Comparative studies of receptor binding and steroidogenic properties of angiotensins in the rat adrenal glomerulosa.

Angiotensin and analogs were tested in isolated rat adrenal zona glomerulosa cells to find if there was a correlation between receptor affinity and steroidogenic potency. Comparative receptor-binding affinities and corresponding aldosterone-releasing effects obtained for each analog were: [Asp1, Ile5]angiotensin II, 1.0 and 1.0: [Asp1, Val5]angiotensin II, 0.69 and 1.65; [Asn1, Val5]angiotensin II, 1.18 and 0.68; [Sar1]angiotensin II, 2.07 and 1.7; [Me2Gly1]angiotensin II, 0.63 and 0.72; [Ile5]angiotensin III, 0.72 and 0.59; [Val5]angiotensin III, 0.92 and 0.34; [Ile5]angiotensin I, 0.007 and 0.051; des-Asp1-[Ile5]-angiotensin I, 0.004 and 0.03; and [Val5, Ser9]angiotensin I, 0.03 and 0.098. Taken as a group, these agonist analogs demonstrated good correlations between these two variables (r = 0.76; P less than 0.001). There was parallelism between binding inhibition and aldosterone-releasing effect when position 5 was substituted with isoleucine, regardless of the substituent in position 1 of the angiotensins. This parallelism was lost when analogs of angiotensin II or III contained valine in position 5. In addition, angiotensin III was found to be less potent than angiotensin II, regardless of the substituent in position 5 (valine or isoleucine).

Aldosterone↗
PubMed1978

Steroidogenic and pressor activity of angiotensin analogues in the rat.

1. A classical 6 point assay in vitro for measuring aldosterone stimulating activity has been developed. 2. The steroidogenic potency of Ile5-angiotensin II was 62% of that given by Val5-angiotensin II. Ile5-angiotensin III (Des-Asp1-Ile5-angiotensin II) was likewise 50% as active as Val5-angiotensin III (Des-Asp1-Val5-angiotensin II). Similar results were obtained in the pressor and myotropic assays. 3. Ile5-angiotensin III and Val5-angiotensin III had only 7% and 16% respectively of the steroidogenic activity of Val5-angiotensin II. 4. Sar1-Ile5-angiotensin II was 2.3 times as potent as Val5-angiotensin II in aldosterone-stimulating activity. The corresponding activities of Me2-Gly1-angiotensin II, Pro1-angiotensin II and Pro31-angiotensin II were 71%, 15% and 3% of Val5-angiotensin II respectively.

Adrenal Glands↗
PubMed1978

Hypotensive effect of [Sar1,Thr8]angiotensin II in spontaneously hypertensive sodium-depleted rats.

Under inactin anesthesia, intravenous infusion of [Sar1,Thr8]angiotensin II produced a hypotensive effect in young spontaneously hypertensive rats (SHR) treated with furosemide and in mature SH rats fed a low-sodium diet. The angiotensin antagonist also lowered blood pressure of young and mature SH rats receiving a normal diet. Deoxycorticosterone acetate (DOCA) plus saline reversed the hypotensive effect of [Saru,Thr8]angiotensin II in young SH rats, but did not do so in mature SH rats. Plasma renin activity (PRA) was not significantly changed by anesthesia. Furosemide or the low-sodium diet significantly increased PRA in young and mature SH rats. In contrast, DOCA plus saline significantly reduced PRA in both young and mature SH rats. However, there was no correlation between PRA and the action of the angiotensin II antagonist. These data suggest that the renin-angiotensin system is involved in genetic hypertension.

Aging↗
PubMed1978

Lack of specific inhibition of angiotensin II in eels by angiotensin antagonists.

Synthetic angiotensins I and II (AI and AII) and natural eel angiotensin were injected with angiotensin antagonists into freshwater-adapted, unanesthetized American eels, Anguilla rostrata, in an attempt to characterize the vasopressor properties of angiotensins in a primitive vertebrate. A converting enzyme inhibitor, SQ 20,881, inhibited vasopressor responses to eel angiotensin (presumably AI) and [Val5,Ser9]AI, but not those to [Asn1,Val5]AII, suggesting that a converting enzyme-like substance may exist in eels. [Sar1,Thr8]AII (10 microgram/kg per min) and [Sar1,Ile8]AII (1 microgram/kg per min), which antagonize angiotensin's action in mammals, showed neither agonistic vasopressor nor antagonistic effects in eels against [Asn1,Val5]AII or eel angiotensin. [Tal8]AII ([8-thienylalanine]AII) and a higher dose of [Sar1,Ile8]AII increased eel aortic pressure themselves and reduced vasopressor responses to [Asn1,Val5]AII. This is presumably a nonspecific decrease in response during the agonistic phase of the analogs. Angiotensin receptors in the blood vessels of eels may differ from those in mammals. Alpha-adrenergic blocking drugs and reserpine partially inhibited the pressor effect of [Asn1,Val5]AII in eels.

Angiotensin I↗
PubMed1978

Cutaneous tubeless ureterostomy as a procedure to study renal function in conscious dogs.

We describe the results obtained with a modified technique for single-side cutaneous ureterostomy in awake mongrel dogs. The success of this surgical procedure was evaluated by intravenous pyelography and urinary cultures that ruled out infection. In addition, we investigated the effects of this procedure on the excretory capacity of the kidney with a diverted ureter. Average values for effective renal plasma flow and glomerular filtration rate were comparable to those obtained in the literature and in the constralateral untouched kidney of the same dogs. The results indicate that cutaneous ureterostomy can be used successfully to monitor renal function in awake dogs over periods of weeks or months.

Animals↗
PubMed1977

Circular dichroism studies of angiotensin II and analogues: effects of primary sequence, solvent, and pH on the side-chain conformation.

Conformational aspects of the pressor hormone angiotensin II and 11 of its structural analogues were studied by circular dichroism. Each position of the peptide was singly substituted with an aliphatic residue and alterations of the CD spectra of the resulting analogues in the peptide and aromatic spectral regions (320-250 nm, 250-190 nm) were examined. The spectra of these peptides in 2,2,2-trifluoroethanol solution permit estimation of the relative importance of the various side chains in maintaining the backbone conformation of the hormone. The evolution of the CD spectra in both spectral regions of the peptides in aqueous solution during a titration from pH 1 to pH 12 makes it possible to elucidate further the role of ionizable groups and their interaction with aromatic amino acids such as tyrosine. The results obtained indicate that substitutions in aspartic acid 1, proline 7, and phenylalanine 8 of angiotensin II entail changes in the backbone conformation. On the other hand, the side chains of valine 3, isoleucine 5, and the biologically essential histidine 6 serve mainly to correctly align the phenolic ring of tyrosine in position 4.

Amino Acid Sequence↗
PubMed1977

Synthesis of [1-sarcosine, 8-O-methylserine]angiotensin II and 1-substituted analogues of [8-threonine]angiotensin II as antagonists of angiotensin II.

[1-N-methylisoleucine,8-threonine]-(I), [1-dimethylglycine,8-threonine]-(II), [1-guanidineacetic acid,8-threonine]-(III), des-1-aspartic acid-[8-threonine]-(IV), and [1-sarcosine,8-O-methylserine]angiotensin II (V) were synthesized by Merrifield's solid-phase procedure to study the effect of (a) substituents in position 1 on the antagonistic activity of [1-sarcosine,8-threonine]angiotensin II, and (b) a change in size and branching in position 8 of [1-sarcosine,-8-O-methylthreonine]angiotensin II. The analogues I-V caused an initial rise in blood pressure (30 min of infusion, 250 ng/kg/min in vagotomized ganglion-blocked rats) of 8.05, 11.7, 3.50, 4.5, and 11.16 mmHg. The pA2 values (rabbit aortic strips) obtained were 7.68, 7.53, 7.23, 7.53, and 9.66, and the dose ratios (in vagotomized ganglion-blocked rats infused at 250 ng/kg/min) obtained were 2.37, 4.49, 1.02, 1.47, and 24.04, respectively. The results obtained indicate that (a) the nature of the substituent in position 1 has an important influence on the biological activity of these peptides, and (b) the potency of antagonists I-IV (all less potent antagonists than [1-sarcosine,8-threonine]angiotensin II) is very much influenced by the length and branching of the side chain in position 8. The in vivo antagonistic activity of [1-sarcosine,8-O-methylthreonine]angiotensin II is reduced considerably by shortening the chain length by one carbon atom as is in V.

Angiotensin II↗
PubMed1977

Synthesis and specific pressor activity of [1-aspartic acid,5-valine,9-serine]angiotensin I ("fowl angiotensin I").

[Asp1, Val5, Ser9]angiotensin I was synthesized by Merrifield's solid-phase procedure. The dansylated derivative of this angiotensin was cochromatographed on the TLC with the dansylated angiotensin decapeptide isolated from white leghorn fowl. Either angiotensin showed identical behavior. The per mole pressor activity of the synthetic decapeptide (in rats anesthetized with pentobarbital and treated with pentolinium) as compared to mammalian angiotensins, namely, [Ile5]angiotensin I, [Val5]angiotensin I, [Ile5]angiotensin II, and [Val5]angiotensin II, was 157, 181, 114, and 85%, respectively.

Angiotensin II↗
PubMed1977

The course of arterial pressure and the effect of Sar1-Thr8-angiotensin II in a new model of two-kidney hypertension in conscious dogs.

1. We describe a new method of producing two-kidney hypertension in dogs by a two-step procedure with complete occlusion of a renal artery 2 weeks after it was partially constricted. 2. Control mean arterial pressure (96 +/- 3 mmHg) of nine conscious, trained dogs rose to 107 +/- 3 mmHg 2 weeks after partial constriction of a renal artery, and it stabilized at a sustained hypertensive plateau (124 +/- 7 mmHg) 3 weeks after complete occlusion. 3. Intravenous infusion of an angiotensin II antagonist (Sar1-Thr8-angiotensin II) caused arterial pressure to fall during the acute but not the chronic phase of renal hypertension. In this latter phase plasma renin activity had returned to control values. 4. We conclude that the renin-angiotensin system appears not to be directly involved in the chronic phase of two-kidney hypertension in the dog.

Angiotensin II↗
PubMed1977

Specific receptors for des-Asp1-angiotensin II (("angiotensin III") in rat adrenals.

The specific binding of angiotensin II and des-Asp1-angiotensin II ("angiotensin III") III") to rat adrenals was studied with the use of the tritiated peptides. The binding sites having maximal affinity for angiotensin II were characterized by an equilibrium dissociation constant of 3.3 to 5.2 X 10(-9) M. Angiotensin III was able to interact with these sites, and also with a class of sites with very high affinity, characterized by an equilibrium dissociation constant of 1 to 2 X 10(-10) M. These sites exhibited a greater affinity for the heptapeptide angiotensin III than for the octapeptide angiotensin II. These findings, together with the known potent aldosterone stimulating effect of angiotensin III and its presence in rat plasma, suggest that this heptapeptide could be the physiologically important steroidogenic angiotensin in this species.

Adrenal Glands↗
PubMed1977

Cardiac hypertrophy and antihypertensive therapy.

Biochemical (myocardial DNA, RNA, and hydroxyproline) and humoral (plasma [PRA] and kidney [KRA] renin activity) factors were determined in spontaneously hypertensive rats (SHR) and normotensive Wistar controls (NR) before and following treatment with minoxidil or propranolol. Minoxidil (150 mg.litre-1 drinking water) effectively controlled blood pressure (17.3 kPa vs 24.9 kPa [130 mmHg vs 187 mmHg], P less than 0.001) despite marked and sustained increases in both PRA and KRA ventricular weight which were not reduced and myocardial DNA, RNA, and hyperdroxyproline which were increased by minoxidil (P less than 0.01). In contrast propranolol did not reduce blood pressure in SHR but ventricular weight was reduced somewhat (3.1 +/- 0.4 mg.g-1 vs 3.4 +/- 0.09 mg.g-1, P less than 0.05); in both SHR and NR, KRA, and PRA were lowered by pranolol. Methyldopa which controlled blood pressure and lowered PRA led to a reversal of hypertrophy. Thus, although blood pressure control is obviously important for reversing cardiac hypertrophy, it may not be the sole factor for the development and reversal of cardiac hypertrophy.

Animals↗
PubMed1977

Mechanisms and sites of action of newer angiotensin agonists and antagonists in terms of activity and receptor.

From the myotropic and vasopressor activities of the numerous analogs of angiotensin II, it has been determined that the phenyl group of position 8 possesses the information for biologic response while the aromatic side groups in positions 4 and 6, the guanido group in position 2 and the C-terminal carboxyl are involved in binding to the receptor site. Removal of a side group of the C-terminal phenyalanine yields peptides that bind to the receptor. While many of these have low agonist properties, all have antagonist properties. Modifications in the aromatic side groups affect conformation of the octapeptide. This change may relate to receptor binding but sufficient data are not yet available to determine a correlation pattern. A proposed conformation for angiotensin is given as well as an artist's concept of angiotensin II binding to its membrane receptor utilizing the groups known to be involved in binding. Both angiotensin II and III [des-Asp] angiotensin II stimulate the biosynthesis and release of aldosterone from adrenal glomerulosa cells. Sufficient data are not yet available to determine whether the conversion of angiotensin II to angiotensin III is neccessary for the steroidogenesis activity.

Adrenal Glands↗