Kiao Ling Liu

The subtype 2 of angiotensin II receptors and pressure-natriuresis in adult rat kidneys

The present work examined the effects of the subtype 2 of angiotensin II (AT2) receptors on the pressure‐natriuresis using a new peptide agonist, and the possible involvement of cyclic guanosine 3′, 5′ monophosphate (cyclic GMP) in these effects. In adult anaesthetized rats (Inactin, 100 mg kg−1, i.p.) deprived of endogenous angiotensin II by angiotensin converting enzyme inhibition (quinapril, 10 mg kg−1, i.v.), T2‐(Ang II 4–8)2 (TA), a highly specific AT2 receptor agonist (5, 10 and 30 μg kg−1 min−1, i.v.) or its solvent was infused in four groups. Renal functions were studied at renal perfusion pressures (RPP) of 90, 110 and 130 mmHg and urinary cyclic GMP excretion when RPP was at 130 mmHg. The effects of TA (10 μg kg−1 min−1) were reassessed in animals pretreated with PD 123319 (PD, 50 μg kg−1 min−1, i.v.), an AT2 receptor antagonist and the action of the same dose of PD alone was also determined. Increases in RPP from 90 to 130 mmHg did not change renal blood flow (RBF) but induced 8 and 15 fold increases in urinary flow and sodium excretion respectively. The 5 μg kg−1 min−1 dose of TA was devoid of action. The 10 and 30 μg kg−1 min−1 doses did not alter total RBF and glomerular filtration rate, but blunted pressure‐diuresis and natriuresis relationships. These effects were abolished by PD. TA decreased urinary cyclic GMP excretion. After pretreatment with PD, this decrease was reversed to an increase which was also observed in animals receiving PD alone. In conclusion, renal AT2 receptors oppose the sodium and water excretion induced by acute increases in blood pressure and this action cannot be directly explained by changes in cyclic GMP.

Adrenergic stimulation of renal prostanoids in the Lyon hypertensive rat.

Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover ofnorepinephrine and an elevated urinary excretion of thromboxane B2 when compared withnonnotensive (LN) and low blood pressure (LL) controls. Therefore, the effects of norepinephrine(1.2 xlO−8 to 9.6 lO−7 M) and of phenylephrine (5xlO−8 to 1.9x10−6 M) on renal functionand the urinary excretion of prostanoids were assessed in isolated perfused kidneys of8-week-old LH, LN, and LL rats. In addition, the effects of norepinephrine were assessed beforeand during thromboxane A2/prostaglandin H2 receptor blockade by AH23848 (4xlO−6 M).Before drug infusion, LH kidneys differed from those of LN and LL controls by having anelevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate;the urinary output of prostaglandin E2 and F2a, of 6-ketoprostaglandin Fla, and of thromboxaneB2 was similar in the three strains. The constrictor effects of norepinephrine andphenylephrine were significantly increased in LH rat kidneys compared with LL but not withLN controls, and their pressure‐natriuresis was markedly reduced. Norepinephrine andphenylephrine induced a 10- to 20-fold dose-dependent increase in the synthesis of the fourprostanoids, which was more pronounced in LH than in LN and LL rats for thromboxane B2only. AH23848 infusion significantly reduced the vascular effects of norepinephrine andincreased the natriuretic response of LH but not of LN and LL rat kidneys. In conclusion,isolated perfused kidneys from LH rats exhibit an increased production of thromboxane A2,which enhances the renal effects of norepinephrine and therefore could participate in thedevelopment of hypertension of the Lyon model.

Renal medullary blood flow and saltload 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.

Effect of Perindopril on Renal Medullary Blood Flow : Comparison With Other Antihypertensive Treatments

Early and chronic angiotensin-converting enzyme (ACE) inhibition in Lyon 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 μg/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.

Renal thromboxane A2 synthesis in the Lyon hypertensive rat

Summary— The aim of the present study was to assess the mechanisms by which norepinephrine (NE) increased the synthesis of prostanoids and revealed a hyperactivity of the Thromboxane (Tx) A2 synthase in the Lyon genetically hypertensive (LH) rat kidney. To this purpose, the effects of NE (1.2 times 10−8 to 9.6 times 10−7 M) on renal function and prostanoid synthesis were assessed in isolated perfused kidneys following β‐adrenoceptor blockade by sotalol (10−5M) and compared to those of equipressor concentration of an α2‐adrenoceptor agonist, BHT 933 (3.5 times 10−4 M) and angiotensin II (AII) (7.7 times 10−9 M). Kidneys were isolated from eight week‐old male LH rats and from their normotensive (LN) and low blood pressure (LL) controls and perfused in a single pass system. In baseline conditions, sotalol did not modify renal function or urinary prostanoids in any of the three strains. Following NE stimulation, it potentiated the increase in renal vascular resistance of LL and LN controls but not that of LH rats. The pressure‐natriuresis and the urinary prostanoids remained unchanged. BHT 933 elicited a weak stimulation of prostanoid release while AII markedly increased it and revealed, as did NE, the hyperactivity of the TxA2 synthase. It is concluded that the NE‐induced stimulation of prostanoid synthesis does not involve β‐adrenoceptors and is unrelated to the associated hemodynamic changes. These results also demonstrate that the increased renal synthesis of TxA2 observed in LH rat kidney is not a specific response to α‐adrenoceptor stimulation and is likely to involve activation of the phosphoinositide pathway.

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.

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.

Cutaneous and renal vasodilatory response to local pressure application: A comparative study in mice

BACKGROUND AND AIM We have reported a novel relationship involving mechanical stimulation and vasodilation in rodent and human skin, referred to as pressure-induced vasodilation (PIV). It is unknown whether this mechanism exists in kidney and reflects the microcirculation in deep organs. Therefore, we compared the skin and kidney PIV to determine whether their changes were similar. METHODS In anesthetized mice fed a normal salt-diet, laser Doppler flux (LDF) signals were measured when an increase in local pressure was applied to the surface of the head skin with the rate of 2.2Pa/s (1mmHg/min) and to the left kidney with a rate of 4.4Pa/s (2mmHg/min). The mechanism underlying renal PIV was also investigated. The skin and kidney PIV were also compared during salt load (4% NaCl diet). RESULTS The kidney had higher baseline LDF and vascular conductance compared to those of the skin. Pressure application increased the LDF in the kidney as well as in the skin with a comparable maximal magnitude (about 25% from baseline value), despite different kinetics of PIV evolution. As we previously reported in the skin, the kidney PIV response was mediated by the activation of transient receptor potential vanilloid type 1 channels, the release of calcitonin gene-related peptide, and the participation of prostaglandins and nitric oxide. In the absence of hypertension, high salt intake abolished the cutaneous PIV response and markedly impaired the renal one. CONCLUSION PIV response in the mouse kidney results from a neuro-vascular interaction. Despite some differences between the skin and the kidney PIV, the similarities in their response and signaling mechanisms suggest that the cutaneous microcirculation could reflect, in part, the microcirculation of the renal cortex.

Thyroid hormone receptor-α deletion decreases heart function and exercise performance in apolipoprotein E-deficient mice

The deletion of thyroid hormone receptor-α (TRα) in atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice (ApoE(-/-)TRα(0/0)) accelerates the formation of atherosclerotic plaques without aggravation of hypercholesterolemia. To evaluate other predisposition risk factors to atherosclerosis in this model, we studied blood pressure (BP) and cardiac and vascular functions, as well as exercise tolerance in young adult ApoE(-/-)TRα(0/0) mice before the development of atherosclerotic plaques. Telemetric BP recorded for 4 consecutive days showed that the spontaneous systolic BP was slightly decreased in ApoE(-/-)TRα(0/0) compared with ApoE(-/-) mice associated with a reduced locomotor activity. The percentage of animals that completed endurance (57% vs. 89%) and maximal running (0% vs. 89% at 46 cm/s speed in ApoE(-/-)TRα(0/0) and ApoE(-/-) mice, respectively) tests was lower in ApoE(-/-)TRα(0/0) mice. Moreover, during the maximal running test, both maximal running speed and running distance were significantly reduced in ApoE(-/-)TRα(0/0) mice, associated with a blunted BP response to exercise. Transthoracic echocardiography revealed a decreased interventricular septum thickness and an increased end-systolic left ventricular volume in ApoE(-/-)TRα(0/0) mice. Accordingly, left ventricular fractional shortening, ejection fraction, and stroke volume were all significantly decreased in ApoE(-/-)TRα(0/0) mice with a concomitant blunted cardiac output. No interstrain difference was observed in vascular reactivity, except that ApoE(-/-)TRα(0/0) mice exhibited an enhanced acetylcholine-induced relaxation in mesenteric and distal femoral arteries. In conclusion, the deletion of TRα in ApoE(-/-) mice alters cardiac structure and contractility; both could contribute to blunted BP response to physical exercise and impaired exercise performance.