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M H Humphreys

Publications and source records attributed to M H Humphreys.

At least 37 records · Page 2Linked to original sources
PubMed1997

Long-term captopril treatment restores natriuresis after carotid baroreceptor activation in the SHR.

In anesthetized Sprague-Dawley rats, intermittent bilateral carotid artery traction (BilCAT) caused a transient decrease in mean arterial pressure (MAP) of 28 +/- 3 mmHg and led to a progressive increase in sodium excretion (UNaV) that nearly doubled 45-90 min after initiation of the repetitive application of BilCAT (P < 0.001). This natriuresis was accompanied by an increase in glomerular filtration rate (GFR) from 2.70 +/- 0.3 to 3.2 +/- 0.3 ml/min (P < 0.001), no change in renal plasma flow [clearance of p-aminohippurate (PAH)], and an increase in the fractional excretion of lithium. Rats with bilateral renal denervation exhibited neither natriuresis nor an increase in GFR in response to BilCAT despite similar vasodepression caused by the maneuver. Normotensive Wistar-Kyoto (WKY) rats responded to BilCAT like Sprague-Dawley rats, whereas spontaneously hypertensive rats (SHR) exhibited an exaggerated vasodepressor response to BilCAT (-51 +/- 3 mmHg) without increasing either UNaV or GFR. Separate groups of WKY and SHR were treated from 4 wk of age with captopril added to the drinking water at a concentration of 1 g/l. At 12-14 wk, both groups had lower MAP compared with untreated animals. Captopril treatment did not alter either the natriuretic response or the increase in GFR seen in untreated WKY after BilCAT, and the maneuver produced equivalent degrees of vasodepression as in controls. However, treated SHR now responded to BilCAT with increases in both UNaV and GFR that closely resembled the responses seen in Sprague-Dawley and WKY rats. These results suggest that BilCAT produces natriuresis through a pathway dependent on the renal nerves. This pathway does not function in untreated SHR despite similar vasodepression. Long-term treatment with captopril restores this reflex pathway in SHR, lending support to the concept that angiotensin II is critically linked to heightened sympathetic nerve activity and abnormal sodium metabolism in this strain.

Analysis of Variance↗
PubMed1997

The renin-angiotensin system and compensatory renal hypertrophy in the rat.

Angiotensin II (Ang II) may act as an angiogenic and growth promoting factor in different tissues. To assess the role of Ang II in compensatory renal growth following unilateral nephrectomy (UNX), we measured renin, angiotensinogen, and Ang II type 1 (AT1) receptor mRNA levels, as well as Ang II receptor density, in two groups of Sprague-Dawley rats 7 days after either sham operation or UNX. Half of each group received either no treatment or an angiotensin-converting enzyme inhibitor (100 mg/dL captopril in the drinking water, initiated at the time of the intervention). Following UNX, the ratio of kidney weight to body weight (KW/BW) in untreated animals was greater than in rats undergoing sham UNX (0.46 +/- 0.01 v 0.37 +/- 0.01%, P < .01). Neither renal renin, nor renal or hepatic angiotensinogen mRNA levels, determined by slot blot hybridization, changed significantly after UNX. Ang II receptor density in glomeruli, determined using an 125I-Sar1-Ile8 Ang II in situ receptor binding assay on frozen kidney sections, did not change significantly after UNX, nor did renal AT1 receptor mRNA. In captopril-treated rats, KW/BW was greater in UNX than in sham operated rats (0.44 +/- 0.01 v 0.37 +/- 0.01%, P < .01), similar to results in untreated animals. Renal and hepatic angiotensinogen mRNA levels were not affected by captopril treatment and did not change further in response to UNX. Captopril treatment increased renin mRNA in both sham operated and UNX rats as compared with untreated controls, but had no significant effect on Ang II receptor density and AT1 receptor mRNA; and no change was observed in either variable as a consequence of UNX. Thus, compensatory renal hypertrophy following UNX occurred in the absence of measurable changes in components of the renin-angiotensin system, and despite functionally significant inhibition of this system by captopril. These data do not support a critical role for Ang II in compensatory renal hypertrophy.

Animals↗
PubMed1996

Phosphodiesterase activity as a mediator of renal resistance to ANP in pathological salt retention.

Resistance to the natriuretic action of atrial natriuretic peptide (ANP) is a hallmark of states of pathological sodium retention including congestive heart failure, cirrhosis of the liver, and nephrotic syndrome. A variety of mechanisms including reduced delivery of filtrate to ANP-sensitive sites in the inner medullary collecting duct and diminished receptor density in this tubular segment have been offered to account for this resistance. Recent studies in experimental nephrotic syndrome and in liver disease produced by ligation of the common bile duct in rats suggest that increased activity of cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase may be an important mediator of renal resistance to ANP. Such increased enzyme activity rapidly catabolizes the second messenger cGMP, normally formed when ANP interacts with its biologically active natriuretic peptide A receptors, thereby leading to blunted ANP responsiveness. This increased phosphodiesterase activity offers a novel approach to the management of clinical conditions associated with sodium retention and edema formation.

Animals↗
PubMed1996

Dietary sodium intake modulates pituitary proopiomelanocortin mRNA abundance.

The pituitary prohormone proopiomelanocortin gives rise to melanocortins of alpha, beta, and gamma primary structure in addition to corticotropin. Melanocortins have a variety of actions in mammals, and each is natriuretic. In particular, gamma-melanocyte-stimulating hormone has been shown to mediate reflex natriuresis after acute unilateral nephrectomy. We examined whether this peptide could play a role in longer term adjustments in sodium balance by measuring plasma gamma-melanocyte-stimulating hormone and corticotropin concentrations, as well as pituitary proopiomelanocortin mRNA abundance, in Sprague-Dawley rats ingesting either a low (0.07% NaCl) or high (7.5% NaCl) sodium diet. One week after the high sodium diet, plasma gamma-melanocyte-stimulating hormone concentration was double the value seen in rats on the low sodium diet (158 +/- 5 [SE] versus 76 +/- 9 fmol/mL, P < .001), a change that was accompanied by a fivefold increase in plasma atrial natriuretic peptide concentration but no change in plasma corticotropin. Whole pituitary proopiomelanocortin mRNA abundance, measured with a probe to exon 3 of the rat proopiomelanocortin gene, was significantly increased after 1 week of the high sodium diet compared with the low sodium diet and increased further at 2 and 3 weeks. This increase occurred primarily in the neurointermediate lobe as demonstrated by in situ hybridization; the content of gamma-melanocyte-stimulating hormone immunoreactivity was also increased in this lobe, but not the anterior lobe, after 1 week of the high sodium diet. These results demonstrate that high dietary sodium intake increases neurointermediate lobe proopiomelanocortin mRNA abundance compared with a very low sodium diet and also suggest that proopiomelanocortin is preferentially processed into gamma-melanocyte-stimulating hormone rather than corticotropin. These observations consequently raise the possibility of a role for this peptide hormone system in the adjustments to a high salt diet.

Animals↗
PubMed1996

Mechanisms contributing to renal resistance to atrial natriuretic peptide in rats with common bile-duct ligation.

Blunted volume expansion (VE) natriuresis and renal resistance to atrial natriuretic peptide (ANP) characterize states of pathological sodium retention. This study examined rats 1 to 3 wk after common bile-duct ligation (CBDL), at which time they had hyperbilirubinemia and hypoalbuminemia. Sham-operated normal rats (Sham) showed an increased sodium excretion rate (UNaV) from 1.0 +/- 0.1 to 16.3 +/- 3.9 muEq/min in response to acute VE (iv saline, 2 mL/100 g body wt over 5 min), whereas CBDL rats had a blunted response that was apparent after 1 wk and became maximal at 2 and 3 wk (0.3 +/- 0.1 to 3.2 +/- 0.4 muEq/min at 3 wk, P < 0.01 versus Sham response). The peak urinary cGMP excretion rate (UcGMPV) was also blunted (37.9 +/- 3.6 versus 87.5 +/- 8.3 pmol/min, P < 0.01) despite an even greater increase in plasma ANP concentration (Sham, 9.6 +/- 0.4 pg/mL in hydropenia to 22.8 +/- 2.6 pg/mL after VE; CBDL, 15.3 +/- 2.3 to 41.8 +/- 6.8 pg/mL). ANP-dependent cGMP accumulation by isolated inner medullary collecting duct (IMCD) cells from both Sham and CBDL rat kidneys was dose-dependent; however, at higher concentrations of ANP (> 10(-8) M), accumulation by cells from CBDL rats was significantly blunted, indicating resistance to ANP. Binding of 125I-ANP to IMCD cells was not different in CBDL rats compared with Sham control rats. Renal denervation improved but did not completely reverse the blunted natriuresis, and ANP resistance persisted in IMCD cells from denervated kidneys of CBDL rats. Incubation of IMCD cells with the phosphodiesterase inhibitors isomethylbutylxanthine or Zaprinast (each at 10(-3) M) restored ANP responsiveness in both innervated and denervated kidneys from CBDL rats, and intrarenal infusion of Zaprinast (10 micrograms/min) corrected the blunted increase in UNaV and UcGMPV after VE in rats with CBDL. These results suggest that ANP resistance in a model of abnormal sodium metabolism devoid of intrinsic renal disease may be related to increased activity of phosphodiesterase in renal target cells for ANP as well as to heightened renal nerve activity.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis.

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus 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.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Human immunodeficiency virus-associated glomerulosclerosis.

The constellation of nephrotic proteinuria, FSGS, and rapid loss of renal function in a patient infected with HIV-1 has been sufficiently widespread and well documented to justify identification as a specific renal syndrome, HIV-associated nephropathy. The position paper of the National Kidney Foundation-National Institutes of Health task force estimated in 1990 that 10,000 to 15,000 persons will develop renal disease in association with AIDS [94]. Management of these patients is complex, and many will reach ESRD and require dialysis treatment, posing additional care problems. Greater understanding of the pathogenesis of the renal disease should lead to treatments which will forestall the development of HIVAN and possibly other forms of fibrotic renal disease. The ultimate eradication of AIDS will consign this renal syndrome to an interesting footnote in the history of nephrology. Since that time is still far in the future, nephrologists will continue to be faced with the need to diagnose and treat HIV-1-infected patients with renal involvement.

AIDS-Associated Nephropathy↗
PubMed1995

Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus.

To determine whether decreased renal responsiveness to atrial natriuretic peptide (ANP) in diabetes is mediated by alterations in the renal ANP receptor, ANP receptor density and affinity were measured 17-20 d after streptozotocin injection and compared with values in vehicle-treated controls and streptozotocin-treated rats made euglycemic with insulin. Plasma ANP concentration was significantly greater in hyperglycemic diabetic rats than in control or euglycemic diabetic rats. Both in glomeruli and inner medulla, ANP receptor dissociation constant did not differ among the three study groups, whereas the maximum binding capacity was decreased significantly in hyperglycemic diabetics in comparison with controls and euglycemic diabetics. Glomerular clearance receptors were also decreased significantly in hyperglycemic diabetic rats in comparison with control and euglycemic diabetic rats. To determine whether the decreased number of renal ANP receptors in diabetic rats was associated with a decreased biological response, we measured ANP-dependent cyclic GMP (cGMP) accumulation by isolated glomeruli and inner medullary collecting duct cells in vitro. cGMP accumulation was significantly less in hyperglycemic diabetic rats than in controls or euglycemic diabetic rats both in the presence or absence of the phosphodiesterase inhibitor zaprinast. cGMP phosphodiesterase activity in inner medullary collecting duct cells obtained from control and hyperglycemic diabetic rats did not differ. Thus, the decreased number of biologically active ANP receptors in the kidneys of diabetic rats is accompanied by decreased biological responsiveness in vitro and provides a potential explanation for the reduction in renal sensitivity to ANP in this condition.

Animals↗
PubMed1995

Modulation of ANP-dependent effects of endothelin by inhibitors of neutral endopeptidase and cGMP phosphodiesterase.

Endothelin 3 (ET3) infusion increases the concentration of atrial natriuretic peptide (ANP) in plasma, which in turn raises hematocrit (Hct) through a transcapillary shift of plasma fluid and proteins into the interstitium, thereby reducing plasma volume (PV). The level of ANP bioactivity in peripheral target tissues is a function of ANP secretory rate and the turnover rate of ANP and its intracellular effector mechanisms. Neutral endopeptidase (NEP) is a widely distributed enzyme that participates in ANP catabolism, whereas cGMP-phosphodiesterase (PDE) degrades the intracellular second messenger of ANP. Therefore, we examined the consequences of inhibition of NEP and PDE on the ANP-dependent activity described above using the NEP inhibitor SQ 28,603 and the cGMP-PDE inhibitor zaprinast (M&B 22,948). In anesthetized, bilaterally nephrectomized rats, infusion of SQ 28,603 alone reduced mean arterial pressure (MAP) by 2.5 +/- 0.5% and increased Hct by 4.6 +/- 0.3% (P < .01 for both), leading to a calculated decrease in PV of 7.5 +/- 0.6%. These changes were prevented by pretreatment with rabbit anti-rat ANP antiserum. Simultaneous infusion of ET3 (25 ng/kg/min) and SQ 28,603 caused MAP to increase by 12.8 +/- 2.2%, an effect identical with that observed after ET3 alone (12.7 +/- 2.3%), whereas the increase in Hct of 9.4 +/- 0.4% was greater (P < .05) than the 7.5 +/- 0.4% increase seen with ET3 alone. ET3 increased plasma ANP concentration (599 +/- 135 vs. 108 +/- 13 pg/ml in vehicle-infused rats; P < .0001); ET3 and SQ 28,603 infused simultaneously increased plasma ANP even further (810 +/- 166 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

Blunted effect of ANP on hematocrit and plasma volume in streptozotocin-induced diabetes mellitus in rats.

Atrial natriuretic peptide (ANP) infusion increases hematocrit and decreases plasma volume by inducing a transfer of plasma fluid from the vascular to the interstitial compartment. Diabetes mellitus is associated with resistance to the renal actions of ANP. We explored the possibility that the extrarenal responses to ANP may also be altered in the diabetic state by measuring changes in arterial pressure and hematocrit during infusion of ANP (1 microgram.kg-1 x min-1 for 45 min) into anesthetized, acutely nephrectomized rats 2-3 wk after induction of diabetes from intravenous streptozotocin (STZ) injection (60 mg/kg). Blood glucose was significantly elevated in diabetic rats when compared with control and insulin-treated diabetic rats. Arterial pressure during ANP infusion decreased similarly in control; diabetic, and insulin-treated diabetic rats (by 7.6 +/- 1.6, 9.6 +/- 1.9, and 8.2 +/- 2% respectively; all P < 0.002). In control rats, hematocrit increased progressively to a maximum value of 9.5 +/- 0.9% as a result of the infusion, corresponding to a decrease in plasma volume of 16.3 +/- 1.3%. In contrast, the ANP-induced increase in hematocrit was markedly blunted in diabetic rats (1.6 +/- 0.8%; P < 0.0001 vs. ANP infusion in control rats). Reducing the hyperglycemia in diabetic rats by insulin therapy restored the increase in hematocrit in response to ANP (8.5 +/- 1.1%; P < 0.0001 vs. ANP infusion in diabetic rats and P = NS vs. control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate (cGMP) was significantly less in diabetic as compared with control and insulin-treated diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[Gene expression of the renin-angiotensin system in compensatory renal hypertrophy secondary to contralateral nephrectomy].

Angiotensin II may act as an angiogenic and growth promoting factor on different cell types. To assess the role of angiotensin II on the compensatory renal response of the remnant kidney to unilateral nephrectomy (UNX), we measured renin, angiotensinogen, and angiotensin II type 1 receptor (AT1) mRNA levels as well as angiotensin II receptor density in 2 groups of 7 Sprague-Dawley rats 7 days after either shamp operation or UNX, Following UNX, the ratio of kidney weight to body weight (KW/BW) increased from 0.38 +/- 0.01 to 0.46 +/- 0.01% (p < 0.01). Neither renin (kidney) or angiotensiongen (kidney and liver) mRNA levels, determined by slot blot hybridization, changed after UNX. Angiotensin II receptor density was determined using an 125I-Sar1-Ile8 Ang II in situ receptor binding assay on fixed kidney sections. Binding specificity was verified using unlabeled Sar1-Ang II. Glomerular angiotensin II receptor density did not change significantly after UNX, nor did AT1 receptor mRNA. Thus, these data do not support a critical role for angiotensin II in the compensatory renal growth following uninephrectomy.

Animals↗
PubMed1994

[Resistance to hemoconcentration but non hypotensive action of atrial natriuretic peptide in diabetes mellitus induced by streptozocin in the rat].

ANP infusion increased hematocrit and decreased plasma volume (PV) by inducing a shift of plasma fluid from the vascular towards the interstitial compartment. Rats with experimental diabetes mellitus resulting from streptozotocin (STZ) treatment exhibit renal resistance to infused ANP. To determine if resistance to the extrarenal actions of ANP also occurs in these conditions, changes in arterial pressure and hematocrit were measured during infusion of ANP (1 microgram/kg/min for 45 min) in anesthetized binephrectomized rats 2-3 weeks after induction of diabetes. Blood glucose was significantly elevated in diabetic when compared to control and insulin-treated diabetic rats. Arterial pressure decreased similarly in control, diabetic and insulin-treated diabetic rats (by 7.6 +/- 1.6, 9.6 +/- 1.9 and 8.2 +/- 2% respectively; all p < 0.0002). In control rats, hematocrit increased progressively to a maximal value of 9.5 +/- 0.9% corresponding to a decrease in PV of 16 +/- 1%. In contrast, the ANP-induced increase in hematocrit was markedly blunted in diabetic rats (1.6 +/- 0.8%; p < 0.0001 vs ANP infusion in control rats), corresponding to a decrease in PV of only 2.2 +/- 1%. In addition, reducing the hyperglycemia in diabetic rats by insulin therapy restored the increase in hematocrit to ANP (8.5 +/- 1.1%; p < 0.0001 and p = NS vs ANP infusion in diabetic and control rats respectively). PV, measured at the end of the infusion period, did not differ between control and insulin-treated diabetic rats infused with ANP (21.3 +/- 1.4 and 22.5 +/- 1.4 ml/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[Resistance to the action of atrial natriuretic peptide and urodilatin in Heymann nephritis in vitro].

We examined renal sodium handling in rats with Hymann nephritis (HEN), an immunologically mediated model of nephrotic syndrome. Rats were studied 9-14 days following i.p. injection of anti-Fx1A antiserum. We previously demonstrated that HEN had a blunted volume expansion natriuresis (2% body weight isotonic saline infused over 5 min), excreting sodium at only half the rate of normal controls (CTL) despite similar increase in plasma atrial natriuretic peptide (ANP) concentration. Urinary excretion of cGMP accumulation by isolate glomeruli and inner medullary collecting duct (IMCD) cells in response to increasing concentration of ANP, and RNP (also called urodilatin). Results (fmol/mg prot/10 min) are means +/- SEM: [table: see text]. Basal accumulation of cGMP was not different among the groups, HEN rats hd reduced cGMP accumulation in response to ANP, and RNP. In binding studies using 125I-ANP, no difference in either density or affinity was found between CTL and HEN rats. Thus, there is a renal resistance to ANP in rats with HEN, which can be extended to other agents acting through the cGMP pathway. This resistance is not due to impaired binding of ANP, but to impaired accumulation of cGMP in responsive tissues, reflecting perhaps increased cGMP catabolism by phosphodiesterase. Such an observation may account for the altered sodium handling in nephrotic rats.

Animals↗
PubMed1993

Urodilatin binds to and activates renal receptors for atrial natriuretic peptide.

Urodilatin is a recently described member of the atrial natriuretic peptide family, thought possibly to be synthesized in the kidney. To determine if urodilatin binding sites are present in rat and human kidney, we evaluated the effect of urodilatin on iodine-125-labeled atrial natriuretic peptide (ANP) (100 pM) binding to tissue sections using an in situ autoradiographic technique. 125I-ANP binding occurred primarily in glomeruli and medullary structures of both rat and human kidney. Increasing concentrations of urodilatin yielded a monophasic displacement of 125I-ANP binding with an IC50 of 4.2 nM, a value nearly identical to that achieved with unlabeled ANP (7.2 nM). In additional experiments, rat glomeruli and inner medullary collecting duct cells were isolated and incubated in vitro with either ANP or urodilatin (10(-11) to 10(-6) M) and cyclic guanosine-3',5'-monophosphate accumulation measured by radioimmunoassay. Dose-response curves for the two peptides were superimposable in each tissue; at 10(-6) M, ANP generated 613 +/- 41 and urodilatin 603 +/- 55 fmol cyclic guanosine monophosphate per 10 minutes per milligram protein in inner medullary collecting duct cells (p = NS). Thus, urodilatin is as effective as ANP in displacing 125I-ANP binding to both rat and human renal tissue and in generating cyclic guanosine monophosphate in renal target cells in the rat, suggesting that its physiological effects may occur through the same receptors and signaling pathways that mediate the actions of ANP.

Animals↗