Biomedical subjects

G Navis

Publications and source records attributed to G Navis.

45 records · Page 3Linked to original sources

PubMed1996

Does the renin-angiotensin system determine the renal and systemic hemodynamic response to sodium in patients with essential hypertension?

Many patients with essential hypertension respond to a high dietary sodium intake with a rise in blood pressure. Experimental evidence suggests that the renal hemodynamic response to sodium determines, at least partially, this rise in blood pressure. Our aim was to clarify the role of the renin-angiotensin system in the renal and systemic adaptation to a change in dietary sodium. We studied changes in mean arterial pressure (MAP) (millimeters of mercury), effective renal plasma flow (ERPF), body weight, and immunoreactive renin in 17 patients with essential hypertension and 15 normotensive control subjects, randomly crossing over between a 3-week sodium-restricted (50 mmol/24 h) and a sodium-replete (200 mmol/24 h) diet period. In addition, the effects of renin inhibition by remikiren (600 mg, single oral dose) were studied during the high sodium period. In normotensive control subjects, high sodium intake had no effect on MAP or body weight, whereas ERPF increased (490 +/- 19 to 535 +/- 21 mL/min, P < .05) and immunoreactive renin decreased (32 +/- 6 to 14 +/- 1 pg/mL). In hypertensive subjects, high sodium intake induced a heterogeneous response of MAP (median change, 2.6 mm Hg; range, -4.7 to +21.2; P = NS) and ERPF (median change, 21 mL/min; range, -33 to +98; P = NS). Body weight increased from 81.3 +/- 1.9 to 82.5 +/- 2.0 kg (P < .05), and immunoreactive renin decreased from 18 +/- 3 to 10 +/- 1 pg/mL (P < .05). Interestingly, the patients with a distinct rise in MAP showed a blunted ERPF response to high sodium intake (r = -.70, P < .01) and an increase in body weight (r = .76, P < .001). Moreover, the increase of ERPF was more pronounced in patients with a larger fall in immunoreactive renin (r = .77, P < .001). After administration of remikiren, a heterogeneous response in ERPF was observed: the patients with the blunted ERPF response to high sodium intake showed the largest ERPF rise (r = .70, P < .01). The remikiren-induced rise in ERPF correlated (r = .68, P < .01) with the fall in MAP (114 +/- 2 to 110 +/- 2 mm Hg). In conclusion, in patients with essential hypertension a rise in blood pressure in response to high sodium intake appears to partially be the result of insufficient renal vasodilatation. This seems to be due to an inadequate (intrarenal?) renin-angiotensin system response to increased sodium intake.

Adult↗

PubMed1996

ACE inhibitors and the kidney. A risk-benefit assessment.

ACE inhibitors effectively reduce systemic vascular resistance in patients with hypertension, heart failure or chronic renal disease. This antihypertensive efficacy probably accounts for an important part of their long term renoprotective effects in patients with diabetic and non-diabetic renal disease. The renal mechanisms underlying the renal adverse effects of ACE inhibitors--intrarenal efferent vasodilation with a consequent fall in filtration pressure--are held to be involved in their renoprotective effects as well. The fall in filtration pressure presumably contributes to the antiproteinuric effect as well as to long term renoprotection. The former is suggested by the positive correlation between the fall in filtration fraction and the reduction in proteinuria found during ACE inhibition. The latter is suggested by the correlation between the (slight) reduction in glomerular filtration rate at onset of therapy and a more favourable course of renal function in the long term. Such a fall in filtration rate at the onset of ACE inhibitor treatment is reversible after withdrawal, and can be considered the trade-off for long term renal protection in patients with diabetic and nondiabetic chronic renal disease. In conditions in which glomerular filtration is critically dependent on angiotensin II-mediated efferent vascular tone (such as a post-stenotic kidney, or patients with heart failure and severe depletion of circulating volume), ACE inhibition can induce acute renal failure, which is reversible after withdrawal of the drug. Systemic and renal haemodynamic effects of ACE inhibition, both beneficial and adverse, are potentiated by sodium depletion. Consequently, sodium repletion contributes to the restoration of renal function in patients with ACE inhibitor-induced acute renal failure. Our the other hand, co-treatment with diuretics and sodium restriction can improve therapeutic efficacy in patients in whom the therapeutic response of blood pressure or proteinuria is insufficient. Patients at the greatest risk for renal adverse effects (those with heart failure, diabetes mellitus and/or chronic renal failure) also can expect the greatest benefit. Therefore, ACE inhibitors should not be withheld in these patients, but dosages should be carefully titrated, with monitoring of renal function and serum potassium levels.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Prognostic value of the short-term antiproteinuric response to ACE inhibition for prediction of GFR decline in patients with nondiabetic renal disease.

In chronic renal disease, the severity of proteinuria is associated with the rate of renal function loss. Proteinuria, therefore, was postulated to play a role in the final common pathway of chronic renal function loss. If so, reduction of proteinuria would improve long-term renal outcome. Improvement of long-term renal function outcome has been obtained in several intervention trials; in these studies; regimens providing better renoprotection were associated with more effective reduction of poteinuria than control regimens. As the reduction of proteinuria is mostly associated with a fall in blood pressure, however, it is difficult to delineate the respective roles of the lowering of blood pressure and of proteinuria. Interestingly, the initial reduction of proteinuria (but not of blood pressure) by antihypertensive treatment appears to predict long-term renal outcome in man as well as in experimental renal disease. This suggests that an intervention strategy aimed not only at the normalization of blood pressure, but also specifically at elimination of proteinuria, might be able to improve long-term renal outcome in proteinuric patients. If so, this would provide further evidence in support of the hypothesis that proteinuria is causally involved in the progression of long-term renal function loss.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Titrating for antiproteinuric effect: the clue to renoprotection?

Proteinuria may be involved in the final common pathway of progressive renal function loss. If so, intervention treatment that reduces proteinuria might prevent or retard long-term renal function loss. In renal patients and in experimental renal disease the severity of proteinuria is associated with the rate of long-term renal function loss. Several large trials on the prevention of long-term renal function loss by antihypertensive treatment with ACE inhibitors (ACEi), were recently completed in diabetic and in non-diabetic renal disease. In those studies long-term renal function loss could indeed be retarded by ACEi; these ACEi regimens were associated with a more effective reduction of proteinuria than control regimens. In studies with a single treatment regimen (drug treatment or a protein restricted diet) a more effective reduction of proteinuria is associated with a more favourable long-term course of renal function as well. As reduction of proteinuria is mostly associated with a lower blood pressure (BP) the respective contributions of the fall in BP and in proteinuria are hard to dissect. Remarkably, however, the efficacy of the reduction of proteinuria (but not of BP) at onset of antihypertensive treatment is predictive of long-term renal outcome. Albeit consistent with a causal role of proteinuria reduction in renoprotection these data cannot distinguish between proteinuria as a marker or a mediator of renal damage. In view of the consistent association of antiproteinuric efficacy with long-term renal outcome we suggest that it would be worthwhile to attempt to improve long-term renoprotection by a strategy aimed at enhancing antiproteinuric efficacy. This approach is feasible as antiproteinuric efficacy of ACEi can be enhanced in several ways, ie, by dietary sodium and protein restriction and by adding a diuretic or indomethacin. Such a strategy would require that titration for adequate BP control is followed by titration for a maximal antiproteinuric effect. If this treatment strategy would improve long-term renal outcome, it would not only be a step forward in the clinical treatment of chronic renal failure, but it would also provide compelling evidence for a causal role of proteinuria in the progression of renal disease.

Humans↗

PubMed1987

Moderate sodium restriction in hypertensive subjects: renal effects of ACE-inhibition.

It has been suggested that AII-mediated renal mechanisms limit the efficacy of moderate sodium restriction in the lowering of blood pressure (BP) in hypertension. We therefore studied renal hemodynamics and sodium handling in nine essential hypertensives in balance on 200 and on a 50 mmol sodium diet, before and during ACE-inhibition (enalapril 10 mg bid for 8 days) in a cross-over fashion. BP was similar on 50 and 200 mmol Na before enalapril, the fall in BP during enalapril was significantly more pronounced on 50 mmol Na. On 50 mmol Na, GFR and filtered Na were significantly lower, and tubular reabsorption was significantly higher than on 200 mmol Na. GFR increased during enalapril in 50 but not on 200 mmol Na. Consequently, the differences in GFR and filtered load elicited by sodium restriction were no longer present during ACE-inhibition. In contrast, the differences in tubular reabsorption between 50 and 200 mmol Na persisted during enalapril. In conclusion, moderate sodium restriction, not affecting BP, can elicit a renal hemodynamic response. As this response is blunted by ACE-inhibition it is probably mediated by AII. This blunting may contribute to the increased sodium sensitivity of BP during ACE-inhibition. The adaptation of tubular sodium reabsorption is not affected by ACE-inhibition.

Adult↗

PubMed1987

Diuretic effects of angiotensin-converting enzyme inhibition: comparison of low and liberal sodium diet in hypertensive patients.

Inhibitors of the angiotensin-converting enzyme (ACE) acutely increase sodium excretion. Whether or not continued treatment induces net negative sodium balance is not clear, and may depend on initial sodium balance. We therefore investigated the effects of 8 days of treatment with enalapril, 10 mg b.i.d., on sodium balance in 10 subjects with uncomplicated essential hypertension, in balance on a low (50 mmol sodium/24 h) and a liberal (200 mmol sodium/24 h) sodium intake. Sodium excretion exceeded intake during the first days of treatment, amounting to sodium losses of 101 +/- 24 and 112 +/- 15 mmol in the low and the liberal sodium diets, respectively. The sodium loss was accompanied by a fall in body weight with both regimens. The blood pressure response to enalapril was potentiated by the sodium-restricted diet. The net increase in sodium excretion after enalapril administration, however, was similar for both diets. This was particularly true for individual patients, suggesting an individual response pattern to ACE inhibition.

Adult↗

PubMed1986

Renal effects of ketanserin in essential hypertension.

The effects of maintenance treatment with ketanserin 40 mg twice daily on renal haemodynamics were studied in 13 essential hypertensives. To establish whether activation of the renin system modifies the response to ketanserin the patients were studied under three conditions: on a sodium restricted diet combined with hydrochlorothiazide, on a sodium restricted diet without hydrochlorothiazide and on a liberal sodium diet. Blood pressure fell in a proportion of the patients on all three regimens. Neither effective renal plasma flow (ERPF; clearance of 131I-hippuran) nor glomerular filtration rate (GFR; clearance of 125I-iothalamate) was significantly altered by ketanserin on either regimen. Neither the blood pressure response nor the renal response was modified by renin stimulation. The renal response was not related to the fall in blood pressure observed in some patients. Therefore ketanserin probably does not affect renal autoregulation.

Adult↗

PubMed1985

Effects of enalaprilic acid on sodium excretion and renal hemodynamics in essential hypertension.

The effects of MK 422 (enalaprilic acid) on renal function and electrolyte excretion were assessed in 14 patients with essential hypertension on a sodium intake of 100 mmol/day. Injection of MK 422 led to a prompt fall in blood pressure (p less than 0.01). Effective renal plasma flow increased by 9 +/- 4% (p less than 0.01) within 1 hour, an increase that persisted for a least 5 hours. Glomerular filtration rate did not change, so filtration fraction decreased by 6 +/- 2% (p less than 0.01). Sodium excretion increased with a maximum of 61 +/- 17% (p less than 0.01) after 5 hours, and potassium excretion fell (p less than 0.01). The log of the initial plasma renin activity correlated with the changes in blood pressure (r = 0.59, p less than 0.05) in effective renal plasma flow (r = 0.59, p less than 0.05) and in sodium excretion (r = 0.65, p less than 0.01). All the renal effects of MK 422 could be reversed by infusion with angiotensin II.

Blood Pressure↗

PubMedDate not supplied

Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis.

Nephrosis induced by doxorubicin (adriamycin) is an experimental model of glomerulosclerosis with relative stable proteinuria which is commonly used for pharmacological intervention studies. It is induced by a single or a double dose of doxorubicin, with doses that vary considerably among investigators from 2 to 7.5 mg/kg. Intervention studies with ACE-inhibitors in this model have provided conflicting results. We hypothesized that these discrepancies might be due to different properties of the doxorubicin model, related to the dose of doxorubicin used to induce proteinuria. We tested this hypothesis by inducing doxorubicin nephrosis with 1, 2 and 3 mg/kg, and evaluating the response to intervention with lisinopril. The 1-mg/kg doxorubicin dose did not induce significant proteinuria. The 2- and the 3-mg/ kg dose resulted in a proteinuria of 684+/-215 mg/24 h and 736+/-277 mg/24 h 6 weeks after induction, respectively (Mean+/-SD). Treatment with lisinopril 2 mg/kg/day reduced proteinuria to 160+/-170 mg/24 h(p<0.01) in the 2-mg/kg doxorubicin group, whereas in the 3-mg/kg doxorubicin group, proteinuria did not respond to lisinopril (529+/-264 mg/24 h). In time control rats, proteinuria remained stable. Renal damage developed in both time control groups, with a glomerulosclerosis score of 29+/-22 in the 2-mg/kg group and 84+/-41 in the 3-mg/kg doxorubicin group. Lisinopril resulted in a significantly lower glomerulosclerosis score in the 2-mg/kg doxorubicin group only (16+/-15, p<0.05), whereas the 3-mg/kg group showed no significant reduction (56+/-29, NS). In conclusion, the dose of doxorubicin used to induce nephrosis is an important determinant not only of the severity of the ensuring renal damage, but also of the response to intervention by ACE-inhibition. These findings have an impact on the interpretation of intervention studies in this model.

Angiotensin-Converting Enzyme Inhibitors↗