Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans.

Healthy skin is protected from pressure-induced ischemic damage because of the presence of pressure-induced vasodilation (PIV). PIV relies on small sensory nerve fibers and endothelial function. Since aging alters both nervous and vascular functions, we hypothesized that PIV is altered with aging. We compared PIV in non-neuropathic and neuropathic older subjects (60-75 years) with that of young subjects (20-35 years). Laser Doppler flowmetry was used to evaluate the cutaneous responses to local pressure application, acetylcholine, and local heating. Quantitative sensory tests were used to evaluate sensory-nerve-fiber function. The non-neuropathic older subjects had an impaired PIV (12+/-7% increase in blood flow with pressure) compared with young subjects (62+/-4%, P<0.001). In the presence of peripheral neuropathy, the older subjects were totally deprived of PIV, leading to early pressure-induced cutaneous ischemia (-31+/-10%, P<0.001). This inability of the skin to adapt to localized pressure in older subjects is related to the severity of the sensory-fiber dysfunction rather than to endothelial dysfunction, which was comparable between the non-neuropathic (141+/-19% increased blood flow with acetylcholine, P<0.05) and neuropathic older subjects (145+/-28% increase, P<0.05) compared with young subjects (234+/-25% increase).

Effect of perindopril on renal medullary blood flow: comparison with other antihypertensive treatments.

Early and chronic angiotensin-converting enzyme (ACE) inhibition in Lyfon hypertensive (LH) rats improves their blunted vasodilator response of renal medullary blood flow (MBF) to angiotensin II (AngII). This study examined the specificity of this effect and the possible involvement of nitric oxide (NO). The renal response to AngII (from 7.5 to 480 ng/kg, IV) and acetylcholine (Ach, from 3 to 192 microg/kg, IV) were examined in 12-week-old anesthetized LH rats treated orally from 3 weeks of age with perindopril (1.5 mg/kg/d), nifedipine (50 mg/kg/d), or a triple therapy with hydralazine, hydrochlorothiazide, and reserpine (75, 15, and 0.75 mg/kg/d, respectively). After 9 weeks of therapy, perindopril lowered systolic blood pressure to 113 +/- 3 mm Hg, nifedipine to 144 +/- 4 mm Hg, and triple therapy to 133 +/- 2 mm Hg compared with 160 +/- 3 mm Hg in untreated LH rats. Despite a significant reduction in blood pressure, only the treatment with perindopril significantly increased the vasodilator response of MBF to AngII. However, the vasodilator response of MBF to Ach was similar among the groups. In conclusion, a renal medullary protection is conferred in LH rats by ACE inhibition, an effect that is not obtained with other antihypertensive treatments and is not explained by Ach-induced NO release.

Effect of perindopril on renal medullary hemodynamics in genetically hypertensive rats.

BACKGROUND: Early and chronic angiotensin converting enzyme (ACE) inhibition prevents hypertension and improves the pressure natriuresis in Lyon hypertensive (LH) rats. The effect of this treatment on the responses of renal medullary blood flow (MBF) to angiotensin II (Ang II) was studied. METHODS: In chronic experiments, Ang II (7.5 to 480 ng/kg, intravenous) was injected in 15-week-old anesthetized LH and normotensive (LL) control rats treated orally since weaning with perindopril (0.4 or 1.5 mg/kg/day) with or without pretreatment with indomethacin (5 mg/kg intravenous). In acute experiment, Ang II (30 to 480 ng/kg intravenous) was given in LH rats treated acutely with perindopril (1.5 mg/kg, intravenous bolus). RESULTS: Administration of Ang II induced dose-dependent decreases in MBF, which were greater in LH than in LL rats. In LL rats, the initial and short-lasting (<1 min) medullary vasoconstriction evoked by Ang II was followed by a long-lasting (>2 min) and dose-dependent medullary vasodilation, which was blunted in LH rats. Chronic perindopril treatment normalized the blood pressure level in LH rats and corrected their blunted medullary vasodilation, whereas the same treatment had no significant effect in LL rats. In chronically perindopril-treated LH rats, indomethacin decreased by 90% the medullary vasodilation induced by Ang II. Acute perindopril treatment did not modify the medullary responses to Ang II in LH rats. CONCLUSIONS: Chronic ACE inhibition restores the vasodilator response of MBF to Ang II in LH rats. This effect, which is not observed after acute inhibition, is mainly mediated through the release of prostaglandins.

Acute pressure-natriuresis function shows early impairment in Lyon hypertensive rats.

OBJECTIVE: This study aimed to determine whether the alteration of the pressure natriuresis seen in Lyon genetically hypertensive (LH) rats occurs early, and the possible involvement in this alteration of the most important extra-renal factors that influence natriuresis. METHODS: In LH rats and their normotensive (LL) controls, acute pressure natriuresis was studied in denervated kidneys with or without controlling extra-renal influence; that is, adrenalectomy and an intravenous infusion of vasopressin, norepinephrine, hydrocortisone and aldosterone. RESULTS: With controlling the cited extra-renal influence, LH rats already exhibited, at 5 weeks of age, a slightly higher blood pressure (+9%) and a markedly reduced renal blood flow (-33%) compared with LL rats; their pressure-diuresis and pressure-natriuresis curves were significantly blunted. Between 16 and 50 weeks of age, although BP levels did not change, renal blood flow and glomerular filtration rate declined in LH rats while their pressure-diuresis and pressure-natriuresis curves continued to shift to higher pressures. When studied without controlling extra-renal influence, the values of pressure diuresis and natriuresis were significantly higher than in controlled conditions both in LH and LL rats. However, in 16-week-old rats, the LH/LL ratios for sodium and water excretion remained close under the two experimental conditions. CONCLUSIONS: The pressure-natriuresis function in LH rat shows early impairment and aggravates with age. This alteration is observed with, as well as without, controlling the influence of the main extra-renal factors that affect natriuresis.

Function of renal angiotensin AT2 receptors is not enhanced in Lyon hypertensive rats.

1. Because we previously observed that angiotensin AT2 receptor stimulation decreased pressure-natriuresis, in the present study we examined the possible involvement of these receptors in altered sodium excretion shown by Lyon hypertensive (LH) rats. 2. In 9-week-old male anaesthetized LH rats and normotensive (LL) controls pretreated with an angiotensin-converting enzyme inhibitor (quinapril; 10 mg/kg) and an AT1 receptor antagonist (losartan; 10 mg/kg), angiotensin (Ang) II was infused (30 ng/kg per min) to stimulate AT2 receptors. In other groups of rats, an AT2 receptor antagonist (PD123319; 50 micro g/kg per min) was added before AngII infusion. 3. During AT2 receptor stimulation, LH differed from LL rats by significantly reduced renal blood flow (RBF), glomerular filtration rate and pressure diuresis and natriuresis. The addition of PD123319 did not change total RBF, whereas it did increase pressure diuresis and natriuresis in both strains. However, the effects of PD123319 were less marked in LH rats than in LL rats. 4. These findings confirm that, under the present experimental conditions, AT2 receptors are antinatriuretic and are not of greater functional importance in hypertensive animals of the Lyon strain.

Angiotensin II and renal medullary blood flow in Lyon rats.

The present study evaluated the acute effects of ANG II (5-480 ng/kg iv) and phenylephrine (PE; 0.2-146 microg/kg iv) on total renal (RBF) and medullary blood flow (MBF) in anesthetized Lyon hypertensive (LH) and low-blood-pressure (LL) rats. ANG II and PE induced dose-dependent decreases in both RBF and MBF, which were greater in LH than in LL rats. Interestingly, after ANG II, but not after PE, the initial medullary vasoconstriction was followed by a long-lasting and dose-dependent vasodilation that was significantly blunted in LH compared with LL rats. The mechanisms of the MBF effects of ANG II were studied in LL rats only. Blockade of AT(1) receptors with losartan (10 mg/kg) abolished all the effects of ANG II, whereas AT(2) receptor blockade with PD-123319 (50 microg x kg(-1) x min(-1) iv) did not change these effects. Indomethacin (5 mg/kg) decreased by approximately 90% the medullary vasodilation induced by the lowest doses of ANG II (from 15 ng/kg). In contrast, N(G)-nitro-l-arginine methyl ester (10 mg/kg and 0.1 mg. kg(-1). min(-1) iv) and the bradykinin B(2)-receptor antagonist HOE-140 (20 microg/kg and 10 microg x kg(-1) x min(-1) iv) markedly lowered the medullary vasodilation at the highest doses of ANG II only. In conclusion, this study shows that LH rats exhibit an altered MBF response to ANG II compared with LL rats and indicates that the AT(1) receptor-mediated medullary vasodilator response to low doses of ANG II is mainly due to the release of PGs, whereas the dilator response to high doses of ANG II has additional nitric oxide- and kinin-dependent components.

Renal medullary blood flow and salt load in Lyon hypertensive rats.

The present work studied renal medullary blood flow (MBF) and its response to salt load in Lyon hypertensive (LH) rats to understand the mechanisms underlying the abnormal renal sodium excretion exhibited by LH rats. Experiments were conducted in uninephrectomized, anesthetized, and volume-expanded 15-week-old male LH and their normotensive (LL) controls. Under standard diet, LH rats exhibited a blunted pressure diuresis and natriuresis associated with an absence of pressure-induced increase in MBF compared to LL rats. One week of salt load (2% NaCl as drinking water) induced a significant increase in blood pressure (BP) in LH (+11 mm Hg) than in LL (+6 mm Hg) rats associated with a decrease in MBF in LH rats only (from 182 +/- 25 to 122 +/- 20 perfusion units, P < .001). Finally, despite the salt load-induced increase in pressure natriuresis, it remained significantly lower in LH than in LL rats. The results show an alteration in MBF regulation in LH rats and suggest that this abnormality may be involved in their blunted pressure natriuresis and their enhanced salt sensitivity.

Vascular reactivity to angiotensin II alone or combined with a thromboxane A2 mimetic in the isolated perfused kidney of Lyon hypertensive rats.

The aim of this study was to evaluate whether thromboxane A2-prostaglandin H2 (TP) receptor activation potentiates the renal vasoconstrictor effect of Angiotensin II (Ang II) in genetically hypertensive rats of the Lyon strain (LH). Concentration-response curves (CRCs) to Ang II (5 pM to 10 nM), to the specific TP receptor agonist U46619 (7.5-960 nM) and to a mixture of Ang II + U46619 (fixed molar ratio of 1 : 9) were obtained in single-pass perfused kidneys isolated from 8 week-old LH and low blood pressure (LL) control rats. Baseline vascular resistance was significantly increased in LH compared to LL kidneys. Comparison of the CRCs obtained for Ang II and U46619 showed that, in both strains, Ang II was about 100 times more potent than U46619. For both drugs, the pD2 or slope values did not differ among the two strains. Co-activation of TP receptors, analyzed with the method of Pöch and Holzmann, tended to potentiate the effects of Ang II in LH but not in LL kidneys. In conclusion, isolated perfused kidneys of LH rat did not exhibit an increased vascular sensitivity to acute infusion of Ang II or U46619 compared to control LL ones. In addition, the results suggest that the interactions between Ang II and TP receptor agonist may differ among the two strains.