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M Manning

Publications and source records attributed to M Manning.

At least 127 records · Page 7Linked to original sources
PubMed1983

Partial blockade of neurotensin-induced hypotension in rats by nephrectomy captopril and saralasin. Possible mechanisms.

We have assessed the influence of acute bilateral nephrectomy, of captopril and saralasin, on the hypotensive activity of neurotensin (NT) and of various hypotensive drugs in pentobarbital-anesthetized rats. The results show that the hypotensive activity of NT and of compound 48/80 (C48/80), in contrast to that of histamine, of 5-hydroxytryptamine and of hexamethonium, is markedly reduced, especially for NT, in nephrectomized as compared to sham operated rats. The pretreatment of rats with captopril (10 mg kg-1, i.v.) or with saralasin (20 micrograms kg-1 min-1, i.v.) was found to inhibit significantly the hypotensive activity of NT and of C48/80. Adrenalectomy restored partially the hypotensive activity of NT in nephrectomized rats. The potent vasopressin antagonist [d(CH2)5 Tyr(Me)AVP] did not alter the refractoriness of nephrectomized rats to the hypotensive activity of NT. Neither nephrectomy nor saralasin were found to interfere with the ability of NT or of C48/80 to evoke an increase of plasma histamine level or of the hematocrit. The results were interpreted as an indication that NT produces part of its hypotensive effect in anesthetized rats by reducing the activity of the renin angiotensin system. The results also suggest that part of the refractoriness of nephrectomized rats to the hypotensive activity of NT could be due to the release of catecholamines from adrenal glands by NT. Endogenous vasopressin does not appear to contribute to the refractoriness of nephrectomized rats to the hypotensive action of NT.

Angiotensin II↗
PubMed1983

Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D- phenylalanine,4-valine]arginine-vasopressin at position 4.

As part of a program in which we are attempting (a) to delineate the structural features at positions 1-9 in our previously reported antidiuretic antagonists required for antidiuretic antagonism and (b) to obtain analogues with enhanced antiantidiuretic potency and/or selectivity, we have synthesized 14 new analogues of the antidiuretic antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D-phenylalanine,4-valine]arginine-vasopressin [d-(CH2)5-D-Phe2VAVP), in which the valine residue at position 4 was replaced by the following L-amino acids and glycine: Ile, Abu, Thr, Ala, Gln, Lys, Cha, Nle, Nva, Phe, Leu, Gly, Tyr, and Pro. These analogues are 1, d-(CH2)5-D-Phe2,Ile4AVP; 2, d(CH2)5-D-Phe2,Abu4AVP; 3, d(CH2)5-D-Phe2,Thr4AVP; 4, d(CH2)5-D-Phe2,Ala4AVP;5, d(CH2)5-D-Phe2AVP; 6, d(CH2)5-D-Phe2,Lys4AVP; 7, d(CH2)5-D-Phe2,Cha4AVP; 8, d(CH2)5-D-Phe2,Nle4AVP; 9, d(CH2)5-D-Phe2,Nva4AVP; 10, d(CH2)5-D-Phe2,Phe4AVP; 11, d(CH2)5-D-Phe2,Leu4AVP; 12, d(CH2)5-D-Phe2,Gly4AVP; 13, d(CH2)5-D-Phe2,Tyr4AVP; 14, d(CH2)5-D-Phe2,Pro4AVP. The protected intermediates required for the synthesis of all of these peptides were prepared by the solid-phase method and cleaved from the resin by ammonolysis. Following deblocking with Na in NH3 and oxidizing with K3[Fe(CN)6], each peptide was purified on Sephadex G-15 in a two-step procedure using 50% HOAc and 0.2 M HOAc as eluants. Analogues 1-14 were tested for agonistic and antagonistic activities by antidiuretic, vasopressor, and oxytocic assays in rats. Analogues 1, 2, and 4-6 exhibit no detectable antidiuretic agonistic activity. All analogues, with the exception of the Pro4-containing analogue, are antidiuretic antagonists. Their antiantidiuretic pA2 values are as follows: 1, 8.24 +/- 0.08; 2, 7.96 +/- 0.07; 3, 7.62 +/- 0.09; 4, 7.52 +/- 0.03; 5, 7.21 +/- 0.07; 6, 7.22 +/- 0.12; 7, 7.19 +/- 0.08; 8, 7.12 +/- 0.09; 9, 6.99 +/- 0.06; 10, 6.07 +/- 0.11; 11, 6.07 +/- 0.11; 12, 5.85 +/- 0.05; 13, approximately 5.57; 14, a weak agonist (0.004 U/mg). Analogues 1-14 also antagonize the vascular responses to arginine-vasopressin (AVP) and the in vitro oxytocic responses to oxytocin. Analogues 1, 2, 3, and 5 have also been shown to antagonize the in vivo oxytocic responses to oxytocin. Five of these analogues (1, 2, 3, 6, and 7) exhibit enhanced antiantidiuretic/antivasopressor selectivity. d(CH2)5-D-Phe2,Lys4AVP and other position-4 analogues with side-chain functional groups may be useful covalent ligands with which to probe the structural characteristics of AVP renal and vascular receptors. With an antiantidiuretic "effective dose" of 0.46 +/- 0.07 nmol/kg and a pA2 value of 8.24 +/- 0.08, d(CH2)5-D-Phe2,Ile4AVP (1) appears to be the most potent antidiuretic antagonist reported to date.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Relative contribution of vasopressin and angiotensin II to the altered renal microcirculatory dynamics in two-kidney Goldblatt hypertension.

The renal microcirculation was assessed in non-clipped kidneys of 23 Munich-Wistar rats with two-kidney one-clip Goldblatt hypertension. Four weeks after placement of a renal arterial clip, mean systemic arterial pressure averaged 163 +/- 5 mm Hg in hypertensive rats as compared to 108 +/- 2 in sham-operated controls (n = 6 rats). Non-clipped kidneys in hypertensive rats were characterized by higher glomerular capillary hydraulic pressures, single nephron glomerular filtration rate, and afferent arteriolar resistance. The glomerular capillary ultrafiltration coefficient was significantly reduced in hypertensive rats. In 10 of these rats, intravenous infusion of the angiotensin antagonist, saralasin, or the converting enzyme inhibitor, SQ20881, led to significant reductions in systemic arterial pressure and in afferent and efferent arteriolar resistance, on average by 8 +/- 3%, 15 +/- 4%, 28 +/- 5%, respectively. These changes were associated with significant increase in glomerular plasma flow, while ultrafiltration coefficient remained unaffected. In the presence of saralasin or SQ20881, infusion of a specific antagonist of the vascular action of arginine vasopressin led to significant systemic but not renal vasodilation. Thus, whereas systemic arterial pressure fell further, on average by 23 +/- 2%, renal arteriolar resistance remained constant, resulting in marked reduction in glomerular capillary hydraulic pressures (by 18 +/- 2%) and glomerular plasma flow rate (by 28 +/- 10%). Because of these pronounced reductions in glomerular pressures and flows induced by vasopressin antagonist, single nephron glomerular filtration rate fell markedly in hypertensive rats (by 34 +/- 6%) despite normalization of ultrafiltration coefficient. When hypertensive rats (n = 7) were treated with vasopressin antagonist alone, a modest fall in systemic arterial pressure was again observed in the absence of changes in renal arteriolar resistance. Due to this selective extrarenal vasodilatory action of vasopressin antagonist, glomerular capillary hydraulic pressure, plasma flow rate, and single nephron glomerular filtration rate again fell markedly. When these vasopressin antagonist pre-treated hypertensive rats were given saralasin or SQ20881, marked reductions in renal arteriolar resistance were observed in association with a significant increase in glomerular plasma flow rate. These observations made during acute inhibition of angiotensin II and vasopressin indicate that both of these vasopressin hormones may play important roles in maintaining systemic hypertension in hypertensive rat. By virtue of its preferential constrictor effects on extrarenal rather than renal vasculature vasopressin serves to maintain high glomerular pressures and flows in the non-clipped kidney of Goldblatt hypertensive rats.

Angiotensin II↗
PubMed1982

Design of more potent antagonists of the antidiuretic responses to arginine-vasopressin.

As part of a program aimed at designing more potent and selective antagonists of the antidiuretic responses to arginine-vasopressin (AVP), we substituted O-alkyl-D-tyrosine (where alkyl = methyl, ethyl, isopropyl, or n-propyl) at position 2 in our eight previously reported O-alkyl-L-tyrosine antagonists of antidiuretic and vasopressor responses to AVP. We also substituted D-tyrosine for L-tyrosine in two vasopressor antagonists with weak antidiuretic agonistic activity, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid),4-valine,8-D-arginine]vasopressin [d(CH2)5VDAVP] and its L-arginine isomer [d(CH2)5VAVP]. The ten analogues, synthesized by the solid-phase method, are as follows: 1, d(CH2)5-D-Tyr(Me)VDAVP; 2, d(CH2)5-D-Tyr(Et)VDAVP; 3, d(CH2)5-D-Tyr(i-Pr)VDAVP; 4, d(CH2)5-D-Tyr(n-Pr)VDAVP; 5, d(CH2)5-D-Tyr(Me)VAVP; 6, d(CH2)5-D-Tyr(Et)VAVP; 7, d(CH2)5-D-Tyr(n-Pr)VAVP; 8, d-(CH2)5-D-Tyr(i-PR)VAVP; 9, d(CH2)5-D-TyrVDAVP; 10, d(CH2)5-D-TyrVAVP. These analogues were tested for agonistic and antagonistic activities in rat antidiuretic and rat vasopressor systems. All ten D-tyrosine analogues possess transient weak antidiuretic activities (0.004--0.05 U/mg). Subsequent doses of AVP are reversibly antagonized for 1--3 h, depending on the dose of the antagonist. They exhibit the following antiantidiuretic pA2 values: 1, 7.19 +/- 0.11; 2, 7.59 +/- 0.04; 3, 7.51 +/- 0.06; 4, 7.60 +/- 0.05; 5, 7.77 +/- 0.07; 6, 7.81 +/- 0.07; 7, 7.66 +/- 0.11; 8, 7.61 +/- 0.06; 9, 7.03 +/- 0.05; 10, 7.51 +/- 0.08. They are all effective antagonists of vasopressor responses to AVP. Analogues 1--8 are two to ten times more potent than their respective O-alkyl-L-tyrosine isomers as antidiuretic antagonists. Since the vasopressor potencies of the O-alkyl-L-tyrosine analogues have either diminished or remained virtually unchanged, these analogues exhibit a selective increase in their antiantidiuretic/antivasopressor ratios with respect to their respective O-alkyl-L-tyrosine analogues. The finding that the substitution of an unalkylated D-tyrosine for L-tyrosine in d(CH2)5VDAVP and d(CH2)5VAVP converts these weak antidiuretic agonists into potent antagonists of antidiuretic responses to AVP is highly significant, especially in view of the relative ease of synthesis and much higher yields of unalkylated vs. alkylated tyrosine analogues. These ten new analogues are potentially useful as pharmacological tools and as therapeutic agents. The findings presented here have also obvious potential for the design of even more potent and selective antidiuretic antagonists.

Animals↗
PubMed1981

Light-dependent pupation site preferences in Drosophila. II. Drosophila melanogaster and Drosophila simulans.

Drosophila melanogaster prefers to pupate in the dark, while its sibling species, D. simulans, prefers the light when the species are tested in isolation and when cultured and tested together. Reciprocal interspecific hybridizations were carried out and the F1 individuals were tested. Progeny from the cross of D. melanogaster females with D. simulans males chose pupations sites exactly intermediate between those of the two parental species, while the reciprocal-cross offspring preferred light pupation sites. The pupation site preferences (PSPs) of the hybrids are compatible with a sex-linked locus or loci influencing light-dependent PSP in this pair of species. Examination of light preferences of larvae prior to the late third instar demonstrates that these preferences are highly specific, being restricted to the time just before pupation. During the first two larval instars D. melanogaster is quite photopositive while D. simulans is comparatively photoneutral. These differences in light-dependent behaviour could aid in reducing competition between the two species.

Animals↗
PubMed1981

Filamentous bacteriophage contract into hollow spherical particles upon exposure to a chloroform-water interface.

The bacteriophage M13 is a 1 micrometer long filament consisting of a circular single-stranded DNA loop firmly held within a tubular protein and capsid. We report here that exposure to a chloroform-water interface initiates a 20 fold contraction of each filament into a hollow protein sphere. In these 0.04 micrometer diameter particles, termed M13 "spheroids," two thirds of the DNA is apparently extruded through a hole in the wall of the spheroid; the portion of DNA remaining inside the shell centers about the origins of M13 DNA replication. These results suggest that the filament, upon exposure to a membrane environment, undergoes an ordered change whereby the DNA is released into the cell and the coat protein is changed to a form more easily solubilized by the membrane lipids.

Binding Sites↗
PubMed1981

Arginine vasopressin and a vasopressin antagonist peptide: opposite effects on extinction of active avoidance in rats.

Systemic injection or arginine vasopressin (AVP) (1 micrograms/rat) significantly prolonged extinction of a pole-jump, active avoidance response in rats; lateral ventricular injection of 1000-fold less AVP (1 ng/rat) produced similar results. A new AVP analogue, [1-deaminopenicillamine-2-(O-methyl)tyrosine]arginine vasopressin (dPTyr-(Me)AVP), is known to antagonize behavioral and vascular effects of exogenous AVP at molar ratios of 5 : 1. At a dose of 100 micrograms/rat (subcutaneously) dPTyr-(Me)AVP produces, by itself, a behavioral effect opposite to that of exogenous AVP, namely a facilitation of extinction. Injections of dPTyr-(Me)AVP into the lateral ventricle were ineffective except at a dose of 10 micrograms/rat. These results confirm previous reports of the effect of vasopressin on delaying extinction of avoidance behavior, but suggest a site of action distant from the lateral ventricle.

Animals↗