Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology may also be an important determinant of progressive renal dysfunction in diabetic nephropathy. In the present study, we investigated tubulointerstitial injury, TGF-beta1 expression, and the effect of blocking the RAS by inhibition of ACE. We randomized 36 male SD rats to control and diabetic groups. Diabetes was induced in 24 rats by administration of streptozotocin; 12 diabetic rats were further randomized to receive the ACE inhibitor ramipril (3 mg/l drinking water). At 6 months, experimental diabetes was associated with tubulointerstitial damage, a 70% increase in expression of TGF-beta1 (P < 0.05 vs. control), and a 120% increase in alpha1 (IV) collagen gene expression (P < 0.01 vs. control). In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and alpha1 (IV) collagen mRNA in renal tubules. In addition, intense expression of both transcripts was noted in regions of focal tubular dilatation. Administration of the ACE inhibitor ramipril prevented tubulointerstitial injury and the overexpression of TGF-beta1 and alpha1 (IV) collagen mRNA. Changes in gene expression were accompanied by parallel changes in immunostaining for TGF-beta1 and type IV collagen. The observed beneficial effects of ramipril on the tubulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy.

We conclude that ambulatory blood pressure, in particular at night, seems better than office blood pressure to capture the heritable part of blood pressure, suggesting that ambulatory blood pressure may be a more exact estimate of an individual's true blood pressure. Genetic studies using ambulatory blood pressure as the phenotype are likely to be more powerful than those using office blood pressure. The high heritability of pulse pressure ambulatory blood pressure indicates that variation in arterial stiffness in subjects free from antihypertensive medication is strongly affected by genetic factors.

Abstract-Gitelman's syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazidesensitive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman's syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C1420T variants, found in the mutation screening of subjects without Gitelman's syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264; Pϭ0.03). In conclusion, we confirm that Gitelman's syndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension. (Hypertension. 2000;36:389-394.)

SUMMARY Calcium entry blockers are potent vasodilators and may be suitable for antihypertensive therapy. We investigated hemodynamic responses together with changes of plasma catecholamines and renin activity (PRA) in 11 men (38.2 ± 5 . 1 years) with essential hypertension (EHT, WHO I-II) after administration of nifedipine 10 mg sublingually (s.l.) and after 6 weeks treatment with nifedipine 20 mg three times daily. Acutely, nifedipine 10 mg s.l. decreased intraarterial blood pressure (BP, 156.2 ± 5.3/83.1 ± 4.6 mm Hg) significantly after 15 minutes (p < 0.05) averaging 147.3 ± 5.4/76.5 ± 4.5 mm Hg after 30 minutes (p < 0.01) and 135.5 ± 4.4/69.7 ± 2.9 mm Hg after 6 weeks (p < 0.01). Acutely increased heart rate and cardiac index (CI), plasma norepinephrine (PNE), and PRA as a consequence of baroreflex activation due to markedly reduced systemic vascular resistance index (SVRI, 39.3 ± 4.3 vs 30.3 ± 3.0 units m 2 , p < 0.01). There was a direct correlation between acute changes of PNE and CI (r = 0.72, p < 0.05) suggesting an important role of acute sympathetic stimulation in the regulation of acute BP responses to nifedipine. Signs of sympathetic activation were absent at 6 weeks while SVRI decreased further (28.1 ± 1 . 5 units • m 2 ), a pattern suggestive of resetting of baroreflexes. Forearm hemodynamic changes paralleled the systemic circulation and blood volume did not change. Chronic changes in mean blood pressure and SVRI were significantly related to pretreatment values (r = 0.65 and r = 0.95, p < 0.05 and < 0.01, respectively). Changes in blood pressure were inversely related to pretreatment PRA (r = -0.71 and 0.67, p < 0.05, acute and chronic effects, respectively). Our findings are compatible with the reduction by nifedipine of a calcium-dependent vasoconstrictor mechanism in EHT. The depressor response to nifedipine is acutely, but not chronically, counteracted by baroreflex activation, and its magnitude is inversely related to the activity of the renin-angiotensin system. The lack of volume retention or chronic sympathetic stimulation suggests the potential by nifedipine for effective antihypertensive monotherapy. ( 1 Calcium entry blockers which decrease the intracellular free calcium concentration mainly by a reduction of the transmembranous calcium influx into muscle cells 2 and thereby reduce