Long-term effects of intensive blood-pressure lowering on arterial wall stiffness in hypertensive patients.

BACKGROUND: Aortic stiffness is assessed by pulse wave velocity (PWV) and predicts the cardiovascular morbidity and mortality of hypertensive patients. To determine the long-term effects of intensive blood pressure (BP) lowering by antihypertensive drug therapy on aortic stiffness assessed by PWV, a single-blind randomized prospective study was performed. METHODS: One hundred forty nondiabetic hypertensive patients (67.6 +/- 0.9 years old; systolic/diastolic BP: 177 +/- 1/101 +/- 1 mm Hg) were assigned to an intensive control group (IC) with a target BP of <130/85 mm Hg (n = 71) or a moderate control group (MC) with a target BP of <140/90 mm Hg (n = 69), and aortic stiffness was assessed every 3 months by measuring aortic PWV with a pulse pressure analyzer. RESULTS: During the 12-month treatment period, BP significantly decreased to 129 +/- 1/78 +/- 1 mm Hg and 152 +/- 2/87 +/- 1 mm Hg in the IC and MC, respectively. At the beginning of the study, PWV in the IC and MC was similar, averaging 1779 +/- 41 and 1885 +/- 50 cm/sec, respectively. By the end of the treatment period, however, PWV had decreased to 1621 +/- 34 cm/sec in the IC, but had not changed significantly in the MC. In the IC, the ratio of the change in PWV to the change in BP increased with the duration of BP lowering. Clinical and biological parameters were similar in both groups, except that higher doses of amlodipine were used in the IC. CONCLUSIONS: Long-term intensive BP lowering in the hypertensive patients was associated with a significant reduction in aortic stiffness distinct from its acute depressor effect.

Transmural pressure control of prorenin processing and secretion in diabetic rat juxtaglomerular cells.

In diabetic patients, the elevation of plasma prorenin levels or arterial pressure is correlated with the severity of diabetic nephropathy. This study was designed to assess the effects of transmural pressure on prorenin regulation in juxtaglomerular (JG) cells from diabetes rats. The JG cells, harvested from rats intraperitoneally injected with streptozotocin 7 (early-diabetic) or 28 (late-diabetic) days previously, were exposed to atmospheric pressure (AP) and AP+40 mmHg for 12 h, and the renin secretion rate (RSR), prorenin secretion rate (PRSR), active renin content (ARC), prorenin content (PRC), and total renin content (TRC) were determined. Exposure of control JG cells to AP+40-mmHg significantly decreased RSR, PRSR, and ARC and significantly increased PRC without affecting TRC, suggesting the occurrence of pressure-mediated inhibition of prorenin processing and secretion. Exposure of early-diabetic and late-diabetic cells to AP+40-mmHg significantly decreased ARC and significantly increased PRC without affecting RSR, PRSR, or TRC. The changes in ARC and PRC were similar in the control and early-diabetic cells, but greater changes were observed in late-diabetic cells. However, when streptozotocin-treated rats were continuously treated with insulin (9 U/kg/day), the transmural pressure control of prorenin in JG cells was similar to that observed in the JG cells from control rats. In late-diabetic cells, treatment with a phospholipase C inhibitor did not alter the pressure control of ARC or PRC; however, treatment with a phospholipase D inhibitor did inhibit the changes in ARC and PRC with transmural pressure. Thus, pressure-mediated inhibition of prorenin secretion from JG cells has already been impaired in early diabetes. Pressure-induced inhibition of prorenin processing in JG cells via phospholipase D-dependent pathways is enhanced in late diabetes.

Angiotensin II type 2 receptor inhibits prorenin processing in juxtaglomerular cells.

Long-term treatment with an angiotensin II type 1 receptor blocker (ARB) has been shown to decrease the plasma renin activity (PRA) of hypertensive patients, whereas PRA remains elevated during angiotensin-converting enzyme inhibitor (ACEI) treatment. In the present study, we used rat juxtaglomerular (JG) cells to elucidate the mechanism(s) involved in the differential regulation of PRA between ARB and ACEI treatment. Addition of 100 nmol/l angiotensinogen (Aogen) to JG cells (n=6 primary cultures) significantly increased the medium angiotensin (Ang) II levels from 14 +/- 2 to 440 +/- 9 pg/ml and suppressed the renin secretion rate (RSR) from 39.6 +/- 5.4% to 6.3 +/- 1.8% without affecting active renin content (ARC) or total renin content (TRC). In the Aogen-treated cells, the ACEI, delapril hydrochloride (CV3317, 10 micromol/l), significantly decreased the medium Ang II levels to 58 +/- 14 pg/ml and increased RSR to 39.8 +/- 4.1% without affecting ARC or TRC. The ARB, an active metabolite of candesartan cilexetil (CV11974, 10 micromol/l), however, significantly increased the medium Ang II levels and RSR to 486 +/- 15 pg/ml and 40.9 +/- 9.8%, respectively, and decreased ARC from 63.2 +/- 6.8 to 21.6 +/- 3.6 ng of Ang l x h(-1) x million cells(-1) without affecting TRC. The decreases in ARC of the Aogen+CV11974-treated cells (n=6 primary cultures) were inhibited by an Ang II type 2 receptor blocker, PD123319 (10 micromol/l). JG cells (n=6 primary cultures) were also treated with an Ang II type 2 receptor agonist, CGP42212A (0.1 micromol/l). CGP42212A significantly increased RSR from 38.2 +/- 1.6% to 49.7 +/- 4.7% and decreased ARC from 60.8 +/- 3.0 to 25.3 +/- 2.8 ng of Ang l x h(-1) million cells(-1) without affecting TRC. Addition of CV11974 did not alter the RSR, ARC, or TRC of the CGP42212A-treated cells; however, PD123319 abolished the effects of CGP42212A. These results indicate that, distinct from ACEIs, ARBs inhibit prorenin processing of JG cells through Ang II type 2 receptors. Long-term treatment with an ARB may decrease PRA in part by diminishing the storage of active renin in JG cells.

Blunted tubuloglomerular feedback by absence of angiotensin type 1A receptor involves neuronal NOS.

To define the role of angiotensin type 1A (AT1A) receptor in modulating tubuloglomerular feedback signals and to determine its relationship to neuronal NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT1A receptor-deficient mice was measured by the blood-perfused juxtamedullary nephron technique. The afferent arteriolar diameter of wild-type and AT1A receptor-deficient mice averaged 16.7+/-0.6 (n=9) and 16.8+/-0.7 micro m (n=9), respectively. In the wild-type mice, addition of 10 micro mol/L acetazolamide to the blood perfusate exerted a biphasic afferent arteriolar constriction, with the initial response and sustained response averaging 47.2+/-3.8% and 33.9+/-3.3%, respectively. In AT1A receptor-deficient mice, the initial response and sustained response averaged 51.6+/-3.6% and 9.5+/-1.3%, respectively, and the sustained response was significantly attenuated compared with that of wild-type mice. Inhibition of nNOS with 10 micro mol/L S-methyl-L-thiocitrulline significantly decreased the afferent arteriolar diameter of AT1A receptor-deficient mice, from 15.1+/-1.2 to 5.0+/-0.3 micro m (n=7), and the decrease was significantly greater than that observed in wild-type mice (from 15.9+/-1.2 to 10.6+/-1.3 micro m; n=8). During nNOS inhibition, the initial and sustained afferent arteriolar constrictor responses to acetazolamide in wild-type mice averaged 54.4+/-6.4% and 44.8+/-11.3%; respectively, and were similar to those in AT1A receptor-deficient mice (53.2+/-6.4% and 59.5+/-4.4%, respectively). These results suggest that AT1A receptors enhance tubuloglomerular feedback-mediated afferent arteriolar constriction, at least in part, through reducing the counteracting modulation by nNOS.

Phospholipase D contributes to transmural pressure control of prorenin processing in juxtaglomerular cell.

This study was designed to delineate the involvement of phospholipase C (PLC) and phospholipase D (PLD) in transmural pressure control of renin synthesis and secretion. Primary cultures of rat juxtaglomerular (JG) cells were applied to a transmural pressure-loading apparatus for 12 hours, and the renin secretion rate (RSR), active renin content (ARC), and total (active + inactive) renin content (TRC) were determined. Under control conditions (n=5), transmural pressure decreased RSR (78.1 +/- 3.0 and 64.6 +/- 4.4% for 0 or 40 mm Hg, respectively; P<0.05) and ARC (42.8 +/- 3.3 and 26.0 +/- 3.9 ng of angiotensin I per hour per million cells for 0 or 40 mm Hg, respectively; P<0.05) but did not have a significant effect on TRC (99.5 +/- 6.7 and 89.2 +/- 4.6 ng of angiotensin I per hour per million cells for 0 or 40 mm Hg, respectively). Treatment with PLC inhibitors, 2-nitro-4-carboxyphenyl-N,N-diphenyl-carbamate (200 micromol/L) and U73122 (10 micromol/L) did not alter RSR but prevented the RSR decrease with transmural pressure, whereas neither 2-nitro-4-carboxyphenyl-N,N-diphenyl-carbamate nor U73122 altered ARC, TRC, or the decrease in ARC with transmural pressure. Experiments were also performed using JG cells (n=5) treated with a PLD inhibitor, 4-(2-aminoethyl)-benzensulfonyl fluoride (AEBSF, 100 micromol/L). Treatment with AEBSF did not influence basal levels of RSR, ARC, and TRC or the RSR decrease with transmural pressure. However, AEBSF did inhibit the decrease in ARC with transmural pressure. These results indicate that transmural pressure inhibits renin secretion via PLC-dependent pathways and prevents conversion of inactive renin to active renin via PLD-dependent mechanisms in JG cells.