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Biomedical subjects

M H Humphreys

Publications and source records attributed to M H Humphreys.

At least 55 records · Page 3Linked to original sources
PubMed1993

Natriuretic properties of melanocyte-stimulating hormones.

Proopiomelanocortin (POMC) is a protein that contains the amino acid sequences of numerous peptide hormones, including the melanocyte-stimulating hormones (MSH). MSH peptides of alpha, beta, and gamma primary structure are present in plasma, and all exhibit natriuretic activity. Intravenous infusion of alpha or beta-MSH leads to a time- and dose-dependent natriuresis, whereas gamma-MSH is reported to be natriuretic at low doses but antinatriuretic at high doses. The natriuretic activity of MSH peptides occurs without change in arterial pressure or renal hemodynamics, suggesting a possible direct tubular inhibition of sodium reabsorption. Intravenously infused gamma-MSH is associated with an increase in the plasma concentration of atrial natriuretic peptide. In addition, gamma-MSH also has a direct intrarenal natriuretic action that is dependent on the renal nerves. In rats, gamma-MSH-related peptides are involved in the reflex control of sodium excretion in situations such as the natriuresis that occurs (a) from the remaining kidney after acute unilateral nephrectomy, (b) from the contralateral kidney shortly after unilateral ureteral pressure elevation, and (c) after unilateral carotid artery traction. POMC-derived peptides (including MSH) are modulated in response to salt loading, and alterations in POMC metabolism and plasma peptide concentrations have been observed in genetically hypertensive rats and during the development of adrenal regeneration hypertension. In addition, plasma gamma-MSH levels are elevated in patients with severe congestive heart failure, and in primary hyperaldosteronism. These observations suggest a possible involvement of MSH-related peptides in sodium homeostasis as well as in certain forms of hypertension.

Animals↗
PubMed1992

Inhibition of neutral endopeptidase amplifies the effects of endogenous atrial natriuretic peptide on blood pressure and fluid partition.

Neutral endopeptidase (EC 3.4.24.11) is a wide-spread enzyme that degrades atrial natriuretic peptide (ANP). We studied the effects of a potent neutral endopeptidase inhibitor, SQ 28,603, given intravenously (30 mg/kg over 45 min) to anesthetized, bilaterally nephrectomized Sprague-Dawley rats. Infusion of vehicle alone was accompanied by a modest increase, 3.2 +/- 2.2% (mean +/- SE), in mean arterial blood pressure (MAP) and a slight rise in hematocrit (Hct) of 0.9 +/- 0.7%. After administration of SQ 28,603, MAP fell 3.2 +/- 0.5%, and Hct rose 4.9 +/- 0.5%, both significantly different from the changes with vehicle alone; the lesser increase in plasma protein concentration (2.5 +/- 0.4%) suggested an increase in vascular permeability to both plasma protein and fluid similar to that caused by ANP. When SQ 28,603 was given to rats pretreated with rabbit antirat ANP antiserum, blood pressure rose by 3.8 +/- 0.5%, and Hct increased by 1.0 +/- 0.4%, values very similar to those observed with vehicle alone. Inhibition of neutral endopeptidase therefore amplifies the actions of endogenous ANP on blood pressure and fluid partition.

Alanine↗
PubMed1992

Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome.

Experimental nephrotic syndrome results in sodium retention, reflecting, at least in part, an intrinsic defect in renal sodium handling in the distal nephron. We studied the relationships among plasma atrial natriuretic peptide (ANP) concentration, sodium excretion (UNaV), and urinary cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP in vitro, in rats with adriamycin nephrosis (6-7 mg/kg body weight, intravenously). 3-5 wk after injection, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline, 2% body weight given over 5 min. 30 min after onset of the infusion, plasma ANP concentrations were elevated in normals and were even higher in nephrotics. Despite this, nephrotic animals had a reduced rate of UcGMPV after the saline infusion, and accumulation of cGMP by isolated glomeruli and IMCD cells from nephrotic rats after incubation with ANP was significantly reduced compared to normals. This difference was not related to differences in binding of 125I-ANP to IMCD cells, but was abolished when cGMP accumulation was measured in the presence of 10(-3) M isobutylmethylxanthine or zaprinast (M&B 22,948), two different inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Infusion of zaprinast (10 micrograms/min) into one renal artery of nephrotic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. These results show that, in adriamycin nephrosis, blunted volume expansion natriuresis is associated with renal resistance to ANP, demonstrated both in vivo and in target tissues in vitro. The resistance does not appear related to a defect in binding of the peptide, but is blocked by PDE inhibitors, suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1992

Acute unilateral nephrectomy elicits a specific increase in plasma of peptides derived from the N-terminal region of proopiomelanocortin.

Acute unilateral nephrectomy (AUN) causes natriuresis from the contralateral kidney through neurohumoral reflex pathways that involve an increase in the plasma of peptides derived from the N-terminal region of the adrenocorticotropic hormone (ACTH)/beta-endorphin precursor proopiomelanocortin (POMC). To determine the specificity of these humoral changes, the concentrations in plasma of ACTH and two peptides arising from the N-terminal fragment (NTF) of POMC, NTF32-49 and gamma-melanocyte-stimulating hormone (gamma-MSH), and of another natriuretic peptide, atrial natriuretic peptide (ANP), were measured by RIA with highly specific antisera to these epitopes. Group I experiments followed the course of sodium excretion (UNaV) for 120 min after AUN or sham nephrectomy. UNaV more than doubled within 60 min of AUN, and this natriuresis was maintained for the remainder of the experiment, whereas UNaV in sham rats did not change. There was no difference in plasma immunoreactive (ir) ACTH or ir-ANP concentrations between sham and AUN rats 120 min after the procedure, but plasma ir-NTF concentration was double in AUN rats compared with sham (P < 0.03). In Group II experiments, animals were killed 30, 60, 90, or 120 min after AUN and the urinary response related to peptide concentrations in plasma. UNaV rose rapidly after AUN, reaching a maximum value within 45 min that again was double the control value and remained stable for the duration of the experiment, up to 120 min after AUN. There was no significant change in ir-ACTH or ir-ANP at any point after AUN compared with values in sham AUN rats. However, plasma concentrations of both ir-NTF and ir-gamma-MSH were elevated 30 min after AUN and reached values at 120 min that were again double the values in sham rats (P < 0.05 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1992

[Modulating effects of atrial natriuretic peptide on vascular permeability and blood pressure by inhibition of cyclic phosphodiesterase GMP in the rat].

Atrial natriuretic peptide lowers arterial pressure and increases hematocrit through reduction in plasma volume caused by a transcapillary shift of plasma fluid and protein toward the interstitium. Cyclic GMP, the second messenger of atrial natriuretic peptide is catabolized by cGMP-phosphodiesterase; therefore we examined the consequences of inhibition of the phosphodiesterase on these responses using the specific cGMP inhibitor M&B 22.948. In anesthetized, bilaterally nephrectomized rats, a 45-min infusion of atrial natriuretic peptide (1 microgram/kg/min) reduced arterial pressure by 7.6 +/- 1.5% and increased hematocrit by 9 +/- 0.6% (both p < 0.01), leading to a calculated decrease in plasma volume of 14.4 +/- 0.9%. Infusion of M&B 22.948 (0.68 mg/kg/min) did not affect hematocrit and lowered arterial pressure by 8.1 +/- 0.5% (p < 0.01), an effect similar to that observed following administration of sodium nitroprusside (10 micrograms/kg/min). Simultaneous infusion of atrial natriuretic peptide and M&B 22.948 had additive arterial pressure lowering effects (-15.9 +/- 1.1%; p < 0.01 vs atrial natriuretic peptide or M&B 22.948 alone), while the increase in hematocrit of 9.4 +/- 0.7% was identical to that seen with atrial natriuretic peptide alone. Thus, M&B 22.948 amplified atrial natriuretic peptide effects on arterial pressure, but not on vascular permeability. These findings indicate differential regulation of atrial natriuretic peptide effects by inhibition of the cGMP-phosphodiesterase.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1991

Increasing incidence of human immunodeficiency virus-associated nephropathy at San Francisco General Hospital.

A survey of consultations to the Division of Nephrology at San Francisco General Hospital from 1982 to 1988 found only seven cases of proven or possible renal disease matching that described for human immunodeficiency virus (HIV)-associated nephropathy (nephrotic proteinuria, rapidly progressive renal insufficiency, and focal and segmental glomerulosclerosis [FSGS] histologically). In the period from April 1, 1988 (the conclusion of the original survey) through December 31, 1990, a roughly 11-fold increase in the incidence of such cases among referrals of HIV-infected patients to the Division occurred compared with the initial experience. The patients were nearly exclusively black men, only about half of whom had intravenous drug abuse (IVDA) as an HIV risk factor. This striking increase was associated with a progressive increase in the number of black patients with acquired immunodeficiency syndrome (AIDS) in San Francisco, and in the percentage of patients with an AIDS diagnosis discharged from San Francisco General Hospital (SFGH) who were black. These data support other evidence indicating a particular vulnerability of blacks to this form of renal disease and help to reconcile data from our division with the experience reported from other centers.

AIDS-Associated Nephropathy↗
PubMed1991

Renal nerves and the natriuresis following unilateral renal exclusion in the rat.

Both acute unilateral nephrectomy (AUN) and acute ureteral pressure elevation (UPE) stimulate sodium excretion (UNaV) from the contralateral kidney, a response which in each case is interrupted by prior denervation of either kidney. Yet the natriuresis after AUN is known to be related to an increase in the plasma concentration of a gamma-melanocyte stimulating hormone (gamma-MSH)-like peptide. In anesthetized rats, sham AUN had no effect on contralateral UNaV, and plasma immunoreactive (IR) gamma-MSH concentration was 10.6 +/- 3.0 (SD) fmol/ml. In rats with intact renal innervation, UNaV more than doubled after AUN (P less than 0.001), and IR-gamma-MSH was increased to 14.9 +/- 4.6 fmol/ml (P less than 0.025). Unilateral renal denervation led to the expected increase in ipsilateral and decrease in contralateral UNaV, and neither sham AUN nor AUN of the denervated of innervated kidney influenced UNaV. In all three of these groups, IR-gamma-MSH concentration was reduced below the sham or post-AUN values seen in rats with innervated kidneys, to 4.9 +/- 3.3, 3.8 +/- 3.4, and 2.8 +/- 3.5 fmol/ml, respectively (P less than 0.001 for all). These results suggested that removal of renal afferent nerve input by renal denervation lowered basal IR-gamma-MSH activity and prevented the stimulated level normally seen after AUN. To examine the effect of stimulating afferent renal nerve activity, we carried out UPE, a maneuver known to increase ipsilateral afferent renal nerve traffic through activation of renal mechanoreceptors, as well as cause a natriuresis from the contralateral kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Modulation of endothelin effects on blood pressure and hematocrit by atrial natriuretic peptide.

Infusion of endothelin has been observed to increase hematocrit, and the peptide also stimulates release of atrial natriuretic peptide (ANP) both in vitro and in vivo. We studied the relation of these two actions of endothelin in anesthetized, bilaterally nephrectomized Sprague-Dawley rats. Infusion of endothelin (25 ng/kg/min) for 45 minutes produced a modest increase in blood pressure of 12% from a baseline of 99 +/- 5 mm Hg and an increase in hematocrit of 8.0 +/- 0.6%, reflecting a reduction in plasma volume of 13.1 +/- 0.9%. These changes each exceeded greatly those observed after 45 minutes of vehicle infusion. Plasma protein concentration, however, increased only by 4.2 +/- 0.6%, suggesting protein extravasation, which was confirmed by finding an endothelin-dependent increase in the accumulation of Evans blue dye in heart, skeletal muscle, and intestine, but not liver, lung, brain, or testis. Endothelin infusion increased plasma immunoreactive ANP concentration from 196 +/- 50 to 722 +/- 203 pg/ml (p less than 0.02), and a close correlation existed between the increase in plasma immunoreactive ANP and immunoreactive endothelin concentrations as a result of the infusion (r = 0.84, p less than 0.01). Pretreatment of rats with rabbit anti-rat ANP antiserum did not affect baseline variables but led to an exaggerated increase in blood pressure (25.3 +/- 2.9%, p less than 0.002 versus endothelin alone). No change in hematocrit occurred. Thus, the increase in plasma immunoreactive ANP concentration resulting from endothelin infusion mediates the increase in hematocrit through an increase in vascular permeability to whole plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[Extravascular transfer of fluids and proteins induced by endothelin in the binephrectomized rat].

To test the possibility that endothelin affects extracellular fluid partition between plasma and interstitium, we compared the effects of endothelin and vehicule in euvolemic binephrectomized anesthetized rats by measuring changes in hematocrit and plasma protein concentration. Forty-five minutes infusion of endothelin (25 ng/kg/min) induced a progressive increase in blood pressure by 1.7 +/- 1.3, 6.8 +/- 1.5 and 12.1 +/- 2.1% at 15, 30 and 45 min respectively from a basal value of 99 +/- 5 mmHg. Hematocrit increased by 8.0 +/- 0.6% (p less than 0.001) after 45 min of infusion, while the vehicle had no significant effect (+ 1.7 +/- 0.7%). The same increase in hematocrit was observed in binephrectomized and splenectomized rats. The calculated loss of plasma volume during endothelin infusion was 13.1 +/- 0.9% as compared to 2.1 +/- 1.2% in rats receiving the vehicle. Plasma protein concentration increased by only 4.2 +/- 0.6% suggesting an extravasation of proteins. To document and localize an alteration in vascular leak of proteins induced by endothelin, albumin-bound Evans Blue (EB) extravasation was measured spectrophotometrically in different tissues after extraction by formamide. Endothelin increased vascular permeation of EB-albumin in skeletal and cardiac muscle, intestine and mesentery. No change was observed in brain, liver, spleen as compared to rats receiving the vehicle. In addition, endothelin infusion elicits a three fold increase of the plasma immunoreactive atrial natriuretic peptide (ir-ANP) concentration (from 196 +/- 50 to 722 +/- 203 pg/ml; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Renal involvement in patients infected with HIV: experience at San Francisco General Hospital.

A spectrum of renal abnormalities has been described in patients infected with the human immunodeficiency virus (HIV) with or without signs of the acquired immunodeficiency syndrome (AIDS). In particular, attention has been focused on a nephropathy characterized clinically by nephrotic proteinuria and rapidly advancing renal insufficiency, and histologically by focal and segmental glomerulosclerosis (FSGS). To evaluate the relationship between HIV infection and structural renal disease, we reviewed all consultations between January 1982 and March 1988 to the Division of Nephrology at San Francisco General Hospital (SFGH), a municipal hospital treating approximately one-third of AIDS cases in San Francisco. Seventy-three consultation requests were received during this period regarding patients with AIDS (48), AIDS-Related Complex (23), or asymptomatic HIV infection (2). Of these, 27 gave evidence of structural renal disease (Group I): 14 had chronic renal insufficiency, in 10 of whom nephrotic proteinuria was also present. However, progression of renal insufficiency to end-stage renal disease (ESRD) in this group did not follow the rapid course described for HIV-associated nephropathy. Renal tissue was examined in 11 Group I patients and showed FSGS in four and a variety of acute and chronic glomerular and tubulointerstitial changes in the others. In 46 Group II patients, consultation was requested for acute renal failure or fluid, electrolyte, and acid-base disturbances. We also reviewed 91 consecutive autopsies performed in patients dying with AIDS at SFGH between 1981 and 1986.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1990

Mechanism of the natriuretic effect of unilateral carotid artery traction in the rat.

Unilateral traction on a carotid artery is known to activate the carotid baroreceptor reflex. This maneuver increases sodium excretion in a manner not completely dependent on the renal nerves, suggesting that a humoral factor(s) could be involved. We measured sodium excretion before and after unilateral carotid artery traction or sham traction in anesthetized rats and related the results to the plasma concentration of immunoreactive (IR)-gamma-melanocyte stimulating hormone (gamma-MSH), a peptide known to be natriuretic in other circumstances. In 12 rats undergoing sham traction, sodium excretion did not change and plasma IR-gamma-MSH activity at the end of the experiment was 10.5 +/- 5.4 (SD) fmol/mL. Carotid artery fraction in 20 other rats caused a transient dip in mean arterial pressure of 20.1 +/- 13.2 mm Hg, and sodium excretion increased from 746 +/- 431 to 1,739 +/- 1,436 nEq/min (P less than 0.005). Plasma IR-gamma-MSH was increased to 21.1 +/- 7.1 fmol/mL (P less than 0.001 versus sham). Prior ipsilateral carotid sinus denervation markedly attenuated the carotid artery traction-related dip in blood pressure and prevented both the natriuresis and the increase in IR-gamma-MSH activity seen after this maneuver in intact rats. Pretreatment with anti-gamma-MSH antiserum also blocked the natriuretic response to carotid artery traction, despite a similar transient dip in blood pressure of 18.3 +/- 9.9 mm Hg. These observations suggest that activation of the carotid baroreceptor reflex by unilateral carotid artery traction causes natriuresis that is mediated largely by an increase in the plasma concentration of a peptide or peptides closely related to the gamma-MSH sequence.

Animals↗
PubMed1988

Renal ornithine decarboxylase activity, polyamines, and compensatory renal hypertrophy in the rat.

We determined the role of ornithine decarboxylase (ODC) in compensatory renal hypertrophy (CRH) by relating renal ODC activity and polyamine content to kidney size, expressed as a percent of body weight, 1 wk after unilateral nephrectomy (UN). In normal rats, renal ODC activity increased from 11.0 +/- 7.4 (SD) to 36.7 +/- 15.4 pmol 14CO2.min-1.g wet wt-1 3 h after UN (P less than 0.002); 1 wk later the remaining kidney weight had increased from 0.38 to 0.46% body weight (P less than 0.001). Renal concentration of putrescine, the product of ODC's decarboxylation of ornithine, was increased 3, 8, and 48 h after UN, but concentrations of polyamines synthesized later in the pathway, spermidine and spermine, were not appreciably affected. Pretreatment with difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, as a 1% drinking water solution inhibited both base-line renal ODC activity and putrescine concentration as well as increases stimulated by UN, although concentrations of spermidine and spermine were not decreased. In these rats, CRH still occurred, since kidney weight increased from 0.36 to 0.46% (P less than 0.001). A 2% DFMO solution caused depletion of all three polyamines, but CRH took place nevertheless. In hypophysectomized rats, both increased renal ODC activity and CRH occurred as well, indicating that these two consequences of UN do not require intact pituitary function. Although increased renal ODC activity and CRH after UN are correlated in normal and hypophysectomized rats, CRH takes place in rats treated with DFMO despite inhibition of ODC activity and depletion of polyamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗