Biomedical subjects

W R Fitzgibbon

Publications and source records attributed to W R Fitzgibbon.

13 recordsLinked to original sources

PubMed2000

Role of citrate synthase in aldosterone-mediated sodium reabsorption.

Aldosterone and other mineralocorticoids increase citrate synthase activity in the kidney and enhance renal sodium reabsorption, but it is unclear whether the increased citrate synthase activity is involved in renal sodium transport. We used the Wistar-Furth rat, an inbred strain found to be deficient in renal citrate synthase activity, as an experimental model to investigate this issue. We confirmed that renal citrate synthase activity from adrenalectomized Wistar-Furth rats was decreased compared with that from control Wistar rats (by 28%). Similarly, urinary citrate excretion was 23% lower in Wistar-Furth rats. Subnormal citrate formation in Wistar-Furth rats could not be accounted for by differences in systemic pH or circulating potassium levels. Because renal citrate synthase activity was reduced in Wistar-Furth rats, we hypothesized that renal sodium excretory responses to mineralocorticoids would be reduced as well. Four-hour sodium excretion after intraperitoneal injection of 5 microg of aldosterone was reduced by 56% in adrenalectomized Wistar rats and by 52% in adrenalectomized Wistar-Furth rats (both P<0.01 compared with vehicle injection). Similarly, the pattern of urinary sodium excretion in response to subcutaneous injections of deoxycorticosterone acetate over a 2-week period was similar in adrenalectomized Wistar and Wistar-Furth rats. In summary, acute and chronic antinatriuretic responses to mineralocorticoids are maintained in Wistar-Furth rats at the level of Wistar rats, despite the marked reduction in citrate synthase activity. These findings are not consistent with an important role for citrate synthase activity in mineralocorticoid-mediated renal sodium transport.

Adrenalectomy↗

PubMed1999

Resistance to remnant nephropathy in the Wistar-Furth rat.

The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164+/-5 [Wistar-Furth] versus 184+/-7 [Wistar] mm Hg mean arterial pressure), with sham animals remaining normotensive (134+/-6 mm Hg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7+/-4.2 [Wistar-Furth] versus 97.4+/-22.6 [Wistar] mg/d per 100 g body wt, P<0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats (P<0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144+/-8 mm Hg [Wistar] versus 157+/-7 mm Hg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction.

Albuminuria↗

PubMed1998

Effect of chronic bradykinin B2 receptor blockade on blood pressure of conscious Dahl salt-resistant rats.

1. In this study 3 protocols were utilized to determine the role of endogenous kinins in the resistance of the inbred Dahl (Rapp) salt-resistant (SR/Jr) rats to high salt diet-induced blood pressure elevation. 2. The bradykinin B2 receptor antagonist, Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) at doses of either 10-20 or 20-40 nmol day(-1) (subcutaneously (s.c), via osmotic minipumps, for either 1 or 3 weeks during a high (8%) salt diet) effectively blocked or attenuated the hypotensive responses to 100-1000 ng of bradykinin. 3. In the first protocol, 5 week old SR/Jr rats treated with Hoe 140 (10-20 nmol day(-1), n = 9, s.c., via osmotic minipumps) for 3 weeks and concomitantly fed high (8%) NaCl diet had significantly higher conscious tail cuff blood pressures (BPc) at 1 and 3 weeks when compared with rats treated with vehicle (0.9% NaCl, n = 6). The differences in BPc between the 2 groups were 13 mmHg (P < 0.001) after 1 week and 8 mmHg (P < 0.05) after 3 weeks of treatment. 4. In the second protocol, 5 week old SR/Jr rats were treated with Hoe 140 (20-40 nmol day(-1), n = 8, s.c., via osmotic minipumps) or vehicle (n = 8) for 3 weeks. During the first week of treatment the rats were fed normal (0.8%) NaCl diet. The rats were then switched to 8% NaCl for 2 remaining weeks of the protocol. The mean BPc of Hoe 140-treated rats was not significantly different from that of the vehicle-treated rats when fed 0.8% NaCl diet. In contrast, rats treated with Hoe 140 and concomitantly fed high (8%) NaCl diet had significantly increased BPc (123+/-2 vs 111 +/- 1 mmHg, P < 0.001 for the Hoe 140- and vehicle-treated rats, respectively). 5. In the third protocol, treatment with Hoe 140 (20 40 nmol day(-1), s.c., via osmotic minipumps) during high salt diet did not increase BPc in rats that were pre-exposed to the high salt diet for 2 weeks. 6. At the end of 3 weeks of study, blood pressure was measured via an arterial catheter during pentobarbitone-induced anaesthesia. Rats treated with Hoe 140 for 1 or 3 weeks had significantly lower mean arterial blood pressures than the vehicle-treated rats. 7. Our findings suggest that in SR/Jr rats, kinin activation of bradykinin B2 receptors at least partially contributes to early regulatory mechanisms that resist an increase in blood pressure following exposure to a high salt diet. The mechanism underlying the decreased blood pressure during pentobarbitone anaesthesia of SR/Jr rats chronically treated with Hoe 140 has yet to be elucidated.

Animals↗

PubMed1997

Resistance to mineralocorticoids in Wistar-Furth rats.

Wistar-Furth rats (WF) do not develop hypertension when treated with salt and mineralocorticoids and therefore may be useful for investigating the mechanisms of mineralocorticoid action and hypertension. In the present studies, we determined vascular and renal responses of WF to mineralocorticoids. Control Wistar rats (W) developed deoxycorticosterone acetate (DOCA)-NaCl and dexamethasone hypertension, whereas WF rats developed dexamethasone hypertension only. Aldosterone treatment of vascular smooth muscle cells cultured from WF resulted in 82% less upregulation of angiotensin II radioligand binding, 50% less induction of angiotensin II AT1a receptor mRNA, and 76% less potentiation of angiotensin II-stimulated inositol phosphates than did aldosterone treatment of cells from W. Similarly, DOCA-NaCl potentiated angiotensin II- and phenylephrine-stimulated contractions in aortic rings from W but not from WF. Although DOCA-NaCl treatment affected hypokalemia to an equal degree in WF and W, increases in renal citrate synthase activity (a specific renal mineralocorticoid response) were greater in W than in WF. WF manifest a partial defect in mineralocorticoid responsiveness in vascular smooth muscle and, possibly, in the kidney.

Aldosterone↗

PubMed1996

Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting duct.

This study tested the hypothesis that intrarenal kinins play a regulatory role in electrolyte excretion by altering Cl- absorption in the collecting duct. We measured Cl- and insulin concentrations in tubular fluid samples obtained from medullary collecting ducts (MCD) of Dahl/Rapp salt-resistant (SR/ Jr) rats by microcatheterization of ducts of Bellini before and after treatment with the bradykinin receptor antagonist HOE-140. Tubular fluid was obtained from paired terminal inner medullary (t-IMCD) and outer medullary (OMCD) collecting duct sites of the left kidney. HOE-140 (n = 7) or vehicle (n = 5) was infused intravenously, and the collections were repeated. HOE-140 did not alter glomerular filtration rate but decreased urine flow rate (P < 0.05) and absolute and fractional Cl- excretion (P < 0.01). HOE-140 did not alter the fraction of filtered Cl- delivered (FDCl) to the OMCD but decreased FDCl to the t-IMCD from 2.3 +/- 0.3 to 1.3 +/- 0.3% (P < 0.05). The fraction of filtered Cl- absorbed per millimeter between the collection sites was increased from 0.2 +/- 0.1 to 0.6 +/- 0.1% (P < 0.05). Fractional absorption of water along the MCD was also increased (P < 0.05). No changes in excretory function or tubular Cl- or water absorption were observed in vehicle-treated rats. These studies show that kinin B2 receptor blockade enhances Cl- and water absorption in the MCD, a finding that supports a role of renal kinins in the regulation of NaCl and water excretion.

Absorption↗

PubMed1996

Effect of dietary protein and enalapril on proximal tubular delivery and absorption of albumin in nephrotic rats.

In passive Heymann nephritis (PHN), angiotensin-converting enzyme inhibition (ACEI) or a low dietary protein intake decreases albuminuria (UAlbV). Although this reduction in albuminuria appears to result from an improvement in glomerular permselectivity, the effect of these treatments on albumin permeation and absorption by the nephron has not been clarified. This study used micropuncture techniques to examine the effect of these two treatments on albumin permeation (by measuring the delivery of albumin to the proximal tubule) and the tubular absorption of albumin. PHN rats (12-18 days after injection of FX1A) were switched from 23% to either 40% protein diet (HP), 40% protein diet and concomitantly treated with enalapril (40 mg.kg-1.day-1) (HPE), or to 8% (LP) protein diet for 4-6 days. Although left kidney glomerular filtration rate (GFR) did not differ among the groups, UAlbV from the left kidney in LP and HPE was only 20-40% of that observed for the HP group. In protocol 1, the fractional recovery of albumin (FRAlb) in urine was calculated following injection of artificial tubular fluid containing [14C]inulin and 125I-labeled albumin into the earliest identifiable proximal loops. There were no differences in FRAlb among the three groups. In protocol 2, timed quantitative collections of tubular fluid were obtained from proximal tubular loops. The rate of albumin delivery to the earliest accessible loops of the proximal tubule was significantly lower for the LP and HPE groups compared with the HP group. For each group, albumin concentration corrected for water absorption was not altered along the proximal tubule. The data indicate that alterations of dietary protein intake or ACEI treatment results in large changes in the delivery of albumin at the proximal tubule that could singularly account for the changes in urinary albumin excretion.

Absorption↗

PubMed1996

Role of kinins in the renal response to enalaprilat in normotensive and hypertensive rats.

This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B2 receptor antagonist (D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin, 1 or 10 micrograms.kg-1.min-1) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg.kg-1.h-1 increased renal blood flow (P < .01) and decreased renal vascular resistance (P < .01). The superimposition of the kinin antagonist at 1 micrograms.kg.min-1 during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist--the "mean effect of enalaprilat." The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (P < .025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Effects of chronic treatment with angiotensin converting enzyme inhibitor or an angiotensin receptor antagonist in two-kidney, one-clip hypertensive rats.

The effects of chronic angiotensin II (Ang II) receptor blockade (losartan) or converting enzyme inhibition (enalapril) on blood pressure (BP), urinary albumin excretion (Ualb V), renal histology and the hemodynamic and excretory function of the clipped and nonclipped kidneys were studied in two-kidney, one-clip (2-K 1-C) rats. One day after clipping the right renal artery, male Wistar rats were divided into three groups receiving: (1) losartan, 20 mg/kg/day (N = 7), (2) enalapril, 20 mg/kg/day (N = 8), or (3) no treatment (controls, N = 9) for three weeks. Both losartan and enalapril treatments maintained conscious BP at comparably lowered levels compared to control animals (116 +/- 6 mm Hg and 113 +/- 2 mm Hg vs. 188 +/- 11 mm Hg, respectively, P < 0.01). Treatment also prevented the increase in Ualb V, observed for the untreated group, three weeks after clipping (1.7 +/- 0.5 and 0.7 +/- 0.1 mg/24 hr vs. 17.8 +/- 7 mg/24 hr, respectively, P < 0.01). After three weeks of treatment, acute study of renal function during pentobarbital anesthesia revealed higher values of GFR and RPF and lowered vascular resistance for nonclipped kidneys from the losartan and enalapril groups compared to the corresponding kidneys from control animals. Despite the lower BP of both treated groups, clipped kidney GFR and RPF were unchanged compared to the control group. Ualb V for nonclipped kidneys from untreated rats was approximately 5- to 10-fold higher than in the nonclipped kidneys from the treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗

PubMed1993

Kinins as vasoactive peptides.

During the past year, a number of significant publications have provided data that clearly establish the basis for the important role of the tissue kallikrein-kinin system in cardiovascular control and renal function. These publications include a report of advances in techniques for system component measurement, reports of the localization of central bradykinin receptors and an alteration in the sensitivity of the central bradykinin system in hypertension, and a description of the effects of new kinin receptor antagonists on our understanding of endogenous and exogenous kinin-induced vasorelaxation and its possible alteration in hypertension. Several significant reports describe the potentiation of endogenous kinin action by kininase inhibitors and establish the important interaction between kininase activity and kinin control of blood pressure.

Amino Acid Sequence↗

PubMed1993

Urodilatin: binding properties and stimulation of cGMP generation in rat kidney cells.

Urodilatin (URO) [ANP-(95-126)] is an analogue of atrial natriuretic peptide (alpha-ANP) [ANP-(99-126)] that was first isolated from human urine. In rat mesangial cells, URO competed with high affinity for non-guanylate cyclase-coupled ANPR-C receptors [concentration at which 50% labeled ligand is displaced (IC50) approximately 70 pM], but with lesser affinity to the guanylate cyclase-linked ANPR-A receptors (IC50 approximately 800 pM). alpha-ANP bound to both receptors with similar affinity [dissociation constant (Kd) approximately 150 pM]. In papillary collecting duct homogenates, which possess only ANPR-A receptors, the apparent Kd value averaged 229 pM for alpha-ANP and 2.7 nM for URO. Intravenous URO was at least as potent and effective as alpha-ANP in inducing diuresis and natriuresis in anesthetized rats, but URO was approximately 10-fold less potent in stimulating guanosine 3',5'-cyclic monophosphate generation in mesangial and inner medullary collecting duct cells. We conclude that URO has a lesser affinity than alpha-ANP for guanylate cyclase-coupled ANP receptors in the kidney and that the relative natriuretic potency of URO in vivo cannot be directly attributed to its binding characteristics with ANPR-A receptors.

Animals↗

PubMed1981

Effect of acute and chronic salt loading on erythrocyte 22Na efflux in males with essential hypertension.

1. Present results confirm our previous work which showed that a sodium intake over 3 mmol day-1 kg-1 decreased the total erythrocyte efflux rate constant in untreated males with essential hypertension. 2. The infusion of saline (2.25 mmol of Na+/kg) over 30 min decreased the efflux rate constant. 3. The change after chronic sodium loading and the intravenous infusion of saline is in the ouabain-sensitive component (ouabain-sensitive Na+, K+ aTPase pump activity) of total efflux. 4. The reduction in efflux by an acute sodium load occurred only when chronic sodium intake was low. 5. Posture did not affect the efflux rate constant whether sodium intake was high or low. 6. The reduction in efflux after chronic ingestion and acute administration of sodium occurred only when erythrocytes were incubated in plasma. It did not occur in artificial medium, which suggested that a plasma factor mediated the effect of added sodium on cell sodium efflux. 7. The effect of sodium on cell sodium transport by a plasma factor with ouabain-like properties (which may be a natriuretic hormone) constitutes a regulatory system. This system, the sodium--ouabain-sensitive cell sodium-transport pathway system, has important implications for the understanding of blood pressure control and sodium homeostasis.

Adult↗

PubMed1980

Erythrocyte 22Na efflux and urinary sodium excretion in essential hypertension.

1. The rate constant for total 22Na efflux from erythrocytes was examined in patients with mild to moderate hypertension and in normotensive controls. No difference in 22Na efflux rate constant was found when the cells from both groups were incubated in artificial medium. When the cells from both groups were incubated in their own plasma, the rate constant for Na efflux was significantly elevated for hypertensive patients compared with controls (0.40 +/- 0.02, 0.36 +/- 0.01 respectively; P < 0.05). 2. In hypertensive patients sodium efflux rate constant varied inversely with 24 h urinary sodium excretion when erythrocytes were incubated in artificial medium (r = -0.34, P < 0.05) or in plasma (r = -0.42, P < 0.05). No association between sodium efflux rate constant and urinary sodium excretion occurred in normotensive subjects. 3. These findings provide further evidence that sodium is an important aetiological factor in hypertension. In 'salt-sensitive' individuals dietary sodium may interact with the regulation of cellular sodium transport via both humoral and cellular mechanisms to elevate blood pressure.

Erythrocytes↗

PubMedDate not supplied

"Salt sensitivity' of normotensives: interactions between changes in red blood cell 22Na efflux rate constant, dietary sodium intake and changes in blood pressure.

1. In normotensive people who altered dietary sodium intake there was no overall difference in blood pressure or efflux rate constant when on a low or high sodium intake. 2. Many individuals studied had changes in blood pressure or efflux rate constant greater than the expected variation. 3. Subjects were classified into three groups depending on the change in efflux rate constant. Seven subjects who had a fall in the efflux rate constant greater than 0.02 h when they changed from a low to a high sodium intake had a significant rise in diastolic blood pressure (73, s.e.m. = 4; to 80, s.e.m. = 3 mmHg). 4. Eight subjects who had a rise in the efflux rate constant greater than 0.02 h when they changed from a low to a high sodium intake had a significant fall in diastolic pressure (82, s.e.m. = 4; to 76, s.e.m. = 4 mmHg). 5. Eight subjects who had no change in efflux rate constant when they changed from a low to a high sodium intake had no significant change in blood pressure. 6. The above associations were found when the red blood cells were incubated in plasma. No association was found when the cells were incubated in artificial medium. 7. The data supports the hypothesis that changes in membrane Na transport have a role in the control of blood pressure. 8. It is postulated that normotensive subjects who had a decreased efflux rate constant when exposed to a high sodium intake may develop essential hypertension.

Adolescent↗