PubMed Health⌕ Search

Biomedical subjects

L D Dworkin

Publications and source records attributed to L D Dworkin.

17 recordsLinked to original sources
PubMed1992

Effects of salt restriction on renal growth and glomerular injury in rats with remnant kidneys.

Male Munich-Wistar rats underwent right nephrectomy and infarction of two thirds of the left kidney. Rats were randomly assigned to ingest standard chow (REM) or a moderately salt restricted chow (LS). A third group of rats were fed the low salt diet and were injected with an androgen (LSA). Eight weeks after ablation, glomerular volume and glomerular capillary radius were markedly increased in REM. This increase was prevented by the low salt diet, however, the antihypertrophic effect of the diet was overcome by androgen. Values for glomerular volume and capillary radius were similar in LSA and REM. Morphologic studies revealed that approximately 25% of glomeruli were abnormal in REM. Much less injury was observed in salt restricted rats, however, the protective effect of the low salt diet was significantly abrogated when renal growth was stimulated in salt restricted rats by androgen. Micropuncture studies revealed that glomerular pressure was elevated in all three groups and not affected by diet or androgen. Serum cholesterol was also similar in the three groups. These findings indicate that renal and glomerular hypertrophy are correlated with the development of glomerular injury after reduction in renal mass and suggest that dietary salt restriction lessens renal damage, at least in part, by inhibiting compensatory renal growth.

Adaptation, Physiological↗
PubMed1992

Does essential hypertension cause end-stage renal disease?

The number of patients developing end-stage renal disease (ESRD) as a consequence of hypertension is increasing and accounts for 25% of new cases of ESRD in the United States. However, the diagnosis of hypertensive ESRD is one of exclusion and no pathologic data corroborate this classification. Undoubtedly, these patients suffer from a variety of diseases, including accelerated hypertension and atherosclerotic disease of the large arteries. Also included are patients with an undiagnosed primary renal disease. The prevalence of these conditions in the hypertensive population is unknown. It is also proposed that mild to moderate hypertension can lead to ESRD. In support of this view, early investigators noted that nephrosclerosis was correlated with hypertension and/or left ventricular hypertrophy. More recently, in the Hypertension Detection and Follow-up Program, renal function was found to decline in some patients despite treatment. Data from the Baltimore Longitudinal Study of Aging indicate that the rate at which creatinine clearance declines with aging is correlated with blood pressure. A recent retrospective study reported that serum creatinine increased significantly in approximately 15% of treated hypertensive patients. However, in none of these studies was the presence of intrinsic renal disease definitively excluded. Furthermore, although an increase in serum creatinine or decline in clearance has been reported, progression to end-stage renal disease has not been documented. Therefore, additional studies are necessary to determine the frequency with which essential hypertension leads to end-stage renal disease.

Humans↗
PubMed1991

Effects of nifedipine and enalapril on glomerular structure and function in uninephrectomized SHR.

Spontaneously hypertensive rats (SHR) that underwent uninephrectomy (UNX) at six weeks of age were randomly assigned to receive no treatment, the calcium channel blocker, nifedipine, or the angiotensin converting enzyme inhibitor, enalapril. Both drugs reduced systemic blood pressure, however, blood pressure tended to be greater in rats given nifedipine than in those on enalapril. After six months, proteinuria and the relevance of glomerula sclerosis were significantly reduced in the two treated groups compared to values observed in untreated SHR. Kidney weight was also reduced by therapy, suggesting that both enalapril and nifedipine inhibited compensatory kidney growth. Micropuncture studies performed in similarly treated groups of rats, but at 11 weeks of age, revealed that PGC was elevated in untreated UNX SHR and reduced by both nifedipine and enalapril. These findings support the hypothesis that glomerular hypertension and renal hypertrophy are important risk factors for glomerular injury. They suggest that calcium blockers are as effective as angiotensin converting enzyme inhibitors in preventing progressive kidney damage.

Animals↗
PubMed1991

Effects of calcium antagonists on glomerular hemodynamics and structure in experimental hypertension.

The RK, DS, and UNX SHR rats are related models of progressive renal disease characterized by the presence of severe systemic hypertension and reduction in renal mass. In these models, glomerular injury is related to increased glomerular pressure and to kidney and glomerular hypertrophy. As summarized in Table 1, administration of a calcium antagonist reduces the prevalence of glomerular sclerosis in all three models. Calcium antagonists have many effects that might tend to reduce renal injury. Similar to the ACE inhibitors, they may reduce PGC, although a protective effect has been observed in some models despite persistence of marked glomerular capillary hypertension. Calcium antagonists also appear to inhibit compensatory renal growth. The observation that these drugs lessen injury in experimental hypertension has important implications for the treatment of patients with hypertension and renal disease. However, widespread use of calcium antagonists specifically to prevent kidney damage should await the results of controlled clinical trials.

Animals↗
PubMed1990

Impact of calcium entry blockers on glomerular injury in experimental hypertension.

A major problem for patients with kidney disease and their physicians is that most chronic renal diseases progress to global glomerular sclerosis and end-stage renal failure. Studies in experimental models of hypertension and renal insufficiency have advanced our understanding of the pathogenesis of progressive kidney damage. In a number of settings, sclerosis has been related to the presence of intrarenal hypertension, a consequence of the hemodynamic adaptation to a reduction in the number of functioning nephrons. A growing body of evidence also supports the hypothesis that kidney and glomerular hypertrophy constitute an independent risk factor for glomerular sclerosis. Recent studies suggest that calcium antagonists can reduce glomerular injury in experimental hypertension. Renal protection may be related to the ability of these agents to inhibit compensatory renal growth.

Animals↗
PubMed1990

Calcium carbonate exacerbates glomerular capillary hypertension and injury in rats with desoxycorticosterone-salt hypertension.

To examine the effects of dietary calcium supplementation on systemic and renal hemodynamics and glomerular injury in experimental hypertension, rats with desoxycorticosterone-salt hypertension were fed either standard chow, containing 1% calcium by weight, or chow supplemented with calcium carbonate to achieve a calcium content of 2% by weight. Ingestion of calcium carbonate failed to reduce systemic blood pressure, but was associated with increased proteinuria and morphologic evidence of glomerular injury. Micropuncture studies revealed that afferent arteriolar resistance was reduced and glomerular capillary pressure further increased in the high calcium group. Thus, calcium carbonate, in moderate amounts, not only failed to ameliorate systemic hypertension but, paradoxically, worsened intrarenal hypertension and injury in rats with mineralocorticoid-induced hypertension.

Animals↗
PubMed1990

Superiority of salt restriction over diuretics in reducing renal hypertrophy and injury in uninephrectomized SHR.

Spontaneously hypertensive rats (SHR) were uninephrectomized (UNX) at 6 wk of age and given either standard chow (CON), low-sodium chow (LSC), or standard chow and hydrochlorothiazide (HCTZ) added to the drinking water. Severe hypertension developed in all three groups. Forty-two weeks after UNX, proteinuria and glomerular sclerosis were significantly lower in LSC than in CON or HCTZ. The protective effect of salt restriction did not depend upon alterations in plasma renin concentration or glomerular hemodynamics. Micropuncture revealed that glomerular pressure was high in all three groups. Renal hypertrophy assessed by kidney weight, kidney-to-body weight ratio, glomerular volume, and glomerular capillary radius were reduced by salt restriction. These findings suggest that, in the setting of glomerular hypertension, hypertrophy promotes sclerosis. Salt restriction inhibits compensatory kidney growth and protects the kidney.

Animals↗
PubMed1990

Effects of nifedipine and enalapril on glomerular injury in rats with deoxycorticosterone-salt hypertension.

Male Munich-Wistar rats underwent right nephrectomy and were given weekly injections of deoxycorticosterone acetate (DOCA) and 1% saline (salt) to drink. Two studies were performed. In the first, rats given enalapril (ENP) were compared with controls. In the second, rats ingested either standard chow or chow to which the calcium-entry blocker nifedipine (NIF) had been added. Six to eight weeks after nephrectomy, both control DOCA-salt rats and those given ENP had severe hypertension and significant proteinuria. Rats given NIF excreted less protein, and glomerular lesions were not observed in this group. The effects of NIF on several parameters that have been associated with glomerular injury were examined. Micropuncture studies revealed that glomerular capillary pressure was increased in DOCA-salt rats and was not reduced by NIF. Platelet aggregation was also similar in NIF-treated and control rats. Morphometric studies revealed a tendency toward lower glomerular volume of NIF-treated rats; however, kidney weight and glomerular capillary radius were unaffected by therapy. Thus NIF, but not ENP, prevents DOCA-salt rats from developing hypertension and glomerular injury. This effect does not depend on reduction in glomerular pressure or inhibition of platelet aggregation.

Animals↗
PubMed1990

Renal vascular effects of calcium channel blockers in hypertension.

Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro, their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high, glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension, calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease, calcium channel blockers slow the progression of renal damage; however, variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage, including compensatory renal hypertrophy, platelet aggregation, and calcium deposition, may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.

Calcium Channel Blockers↗
PubMed1989

Renal vascular effects of antihypertensive therapy in uninephrectomized SHR.

Serial determinations of protein excretion rate and systolic blood pressure (SBP) were made in spontaneously hypertensive rats (SHR) uninephrectomized (UNX) at six weeks of age and given tap water (CON), or water with hydrochlorthiazide, hydralazine and reserpine (HHR), captopril (CAP) or enalapril (ENP). Compared to CON, significant hypertension was prevented, kidney weight was lower and there was less proteinuria in HHR, CAP and ENP rats followed for 30 weeks after UNX. Morphologic studies of these four groups revealed that antihypertensive therapy reduced the incidence of glomerular sclerosis in UNX SHR by 50%. Despite complete absence of systemic hypertension, there was striking medial thickening of lobular arteries and arterioles of rats given the angiotensin converting enzyme (ACE) inhibitor, captopril. These vascular abnormalities were present to a lesser degree in rats given ENP, but were entirely absent in untreated animals or in those ingesting the HHR combination. Micropuncture studies performed five weeks after UNX in four additional groups of CON, HHR, CAP and ENP rats revealed that glomerular capillary pressure was elevated in CON and reduced by all three drug regimens. These studies support the hypothesis that glomerular capillary hypertension and/or nephron hypertrophy predispose to glomerular injury in this model of hypertension and reduced renal mass. ACE inhibitors and HHR are equivalent in their ability to prevent glomerular hypertension and damage in these rats, but the former, and in particular captopril, produce abnormalities of cortical vessels via a mechanism not dependent on the presence of systemic hypertension.

Animals↗
PubMed1989

Impact of antihypertensive therapy on progressive kidney damage.

Our ability to measure precisely the pressures and flows within the glomerular microcirculation has enabled us to begin to unravel the complex relationship between systemic hypertension and kidney disease. Although a number of factors have been implicated in the development of glomerular sclerosis, one consistent finding has been that glomerular injury occurs when elevated pressures are transmitted to the glomerular capillaries. Intrarenal hypertension, in conjunction with renal hypertrophy, and, possibly, disturbances in lipid metabolism and blood coagulation constitute secondary processes through which those nephrons not severely injured by the primary renal disease are eventually destroyed. Ultimately, all renal function is lost. Clinically, increased glomerular pressure is likely to contribute to glomerular injury in those patients in whom hypertension and renal insufficiency coexist. In patients with diabetes, as yet unidentified factors cause preglomerular resistance to fall so that glomerular hypertension develops even in the absence of elevation in systemic blood pressure. Although no therapy has been proven to slow the rate of progression to end stage renal failure in humans, a number of promising interventions have been identified. These include dietary protein or salt restriction, and medication, with either converting enzyme inhibitors or calcium channel blockers.

Animals↗
PubMed1988

Glomerular size-selective barrier dysfunction in nephrotoxic serum nephritis.

We have previously reported amelioration of heavy proteinuria, vascular sclerosis and glomerular structural damage by antihypertensive therapy in nephrotoxic serum nephritis (NSN). In the present study, we examine glomerular permselectivity in this hypertensive form of NSN and the effect of hypertension treatment on size-selective barrier function. Mean arterial pressure was maintained at normotensive levels (mean 123 +/- 3 mm Hg) with a combination of hydralazine, hydrochlorthiazide and reserpine in 7 nephritic rats, while 10 untreated rats remained hypertensive (mean 165 +/- 4 mm Hg). At six weeks, glomerular filtration rate was reduced in untreated rats (mean 0.54 ml/min) but was preserved in those rendered normotensive (mean 1.71 ml/min), P less than 0.02). Twenty-four-hour urinary protein excretion, mean 371 +/- 74 mg in hypertensive nephritic rats, was markedly reduced in rats on the antihypertensive regimen to a mean of 120 +/- 17 mg (P less than 0.02), as was 24-hour urinary gamma-globulin excretion (mean 35 +/- 9 mg in untreated vs. 16 +/- 2 mg in treated). Fractional clearances of tritiated polydisperse neutral dextrans were significantly enhanced for molecular radii exceeding 50 angstroms in hypertensive animals, indicative of a loss of glomerular size permselectivity. Rats on antihypertensive therapy did not develop such a size selective defect. Thus, hypertensive rats with nephrotoxic serum nephritis develop "gaps" in the glomerular basement membrane which allow the excretion of large molecular weight neutral dextrans and gamma-globulin. This defect in glomerular permselectivity can be averted with antihypertensive therapy.

Animals↗
PubMed1987

Pathogenesis of systemic hypertension and glomerular injury in the spontaneously hypertensive rat.

Weanling and young spontaneously hypertensive rats (SHRs) demonstrate higher plasma renin activity and plasma aldosterone concentration than age-matched normotensive Wistar-Kyoto (WKY) control rats. In addition, this age group exhibits a salt-retaining tendency not seen in WKYs. Nevertheless, when they reach adulthood, these differences between SHRs and WKYs are all but abolished, yet hypertension persists in SHRs. The possible mechanisms leading to these changes in SHRs and to the differences seen with advancing age are discussed. Results of micropuncture studies that help elucidate the glomerular hemodynamic adaptations to elevation in systemic blood pressure in young SHRs are also presented. Evidence is advanced suggesting that increased intraglomerular pressure is responsible for the histologic lesions characteristic of untreated severe hypertension. The salutary effects of treatment with vasodilator drugs that reduce intraglomerular pressure are emphasized.

Aldosterone↗
PubMed1987

Glomerular hypertension and injury in desoxycorticosterone-salt rats on antihypertensive therapy.

Uninephrectomized male Munich-Wistar rats received either weekly subcutaneous injections of vehicle and water for drinking; injections of desoxycorticosterone (DOC) and 1% saline (SALT) for drinking; or DOC and SALT with hydrochlorthiazide, hydralazine, reserpine and KCl added. All studies were performed six weeks after UNX. At that time, rats receiving DOC and SALT alone were hypertensive and had significantly more proteinuria and morphologic evidence of glomerular injury than rats given vehicle and tap water which were normotensive. Antihypertensive therapy normalized mean arterial pressure in DOC-SALT rats, but failed to prevent proteinuria, mesangial expansion or focal segmental glomerular lesions. Micropuncture studies revealed that glomerular capillary pressure was elevated in both untreated and treated DOC-SALT animals. We conclude that drugs which successfully reduce systemic blood pressure may fail to correct glomerular capillary hypertension in DOC-SALT rats. As persistence of intrarenal hypertension is associated with significant glomerular injury, normalization of glomerular capillary pressure rather than systemic arterial pressure is crucial to the prevention of glomerular injury in this model.

Animals↗
PubMed1986

Glomerular injury in uninephrectomized spontaneously hypertensive rats. A consequence of glomerular capillary hypertension.

Micropuncture and/or morphologic studies were performed in intact Wistar-Kyoto rats (WKY) (group 0), intact spontaneously hypertensive rats (SHR) (groups 1 and 5), uninephrectomized (UNX) WKY (groups 2 and 6), and UNX SHR (groups 3 and 4, 7 and 8). UNX was performed when rats were 5 wk of age. Groups 0-4 were observed for 34 wk after which whole kidney clearance and morphologic studies were performed. Groups 5-8 underwent micropuncture study at 10 wk of age. Groups 4 and 8 were fed a diet containing 6% protein. All other rats ingested standard laboratory diet. 5 wk after UNX, normotensive group 6 had higher single nephron glomerular filtration rate (SNGFR) and initial glomerular plasma flow rate (QA) than intact, hypertensive group 5. Glomerular transcapillary hydraulic pressure difference (delta P) was similar in these two groups. Hypertensive group 7 exhibited less elevation in SNGFR and QA than group 6, but delta P was significantly increased. The presence of glomerular capillary hypertension in UNX SHR at 10 wk was associated with the development of significant proteinuria and an increased incidence of mesangial expansion and glomerular sclerosis at 7 mo (group 3) as compared with groups 0, 1, and 2. Protein restriction prevented the development of increased delta P in UNX SHR (group 8) and also conferred long-term protection from increased urinary protein excretion and glomerular injury (group 4). These studies suggest that glomerular capillary hypertension predisposes to glomerular injury in this model of hypertension with reduced renal mass.

Animals↗
PubMed1976

Small intestinal mass of the rat is partially determined by indirect effects of intraluminal nutrition.

Although intraluminal nutrition presumably maintains small intestinal mass by direct contact with the epithelial cells, hormonal or neurovascular elicited by feeding may play an indirect role. In order to test for the presence of indirect factors, Thiry- Vella fistulae were created from the proximal small intestine of two groups of rats. The bypassed gut of a group of rats receiving an elemental diet intravenously was compared to a second group receiving the same diet by intragastric infusion. After 1 week, there was significantly greater (P less than 0.01) gut weight, mucosal weight, DNA content, and protein content of both the gut in continuity and tje bypassed gut of intragastric infused rats. Total sucrase activity was also greater (P less than 0.01) in intragastric fed rats, and this was due to both a greater protein content and specific activity (P is less than 0.05) of the gut in continuity and to the greater protein content of the bypassed gut. Serum gastrin levels were similar (P less than 0.05) in both groups, suggesting that gastrin may not play a role in initiating the differences reported. This study suggests that intraluminal nutrition maintains the small intestinal epithelial population in part, indirectly, by unidentified hormonal or neurovascular stimuli.

Animals↗