Interleukin-2 enhances the release of endothelin-1 from the rat mesenteric artery

We measured the ET-1 concentration in plasma and in the perfusate of the mesenteric arteries of rats treated with a therapeutic dose of IL-2 for 7 days (100000 U/Kg, iv.). The plasma ET-1 concentration in rats given IL-2 was 14.2 +/- 3.2 pg/ml which was significantly greater than that in the controls (2.5 +/- 0.4 pg/ml, P less than 0.05). The mesenteric arteries also released a significantly greater amount of ET-1 (29.5 +/- 1.6 pg/h) than that in controls (16.8 +/- 2.3 pg/h, P less than 0.01). The arterial blood pressure was significantly lower after IL-2 treatment than the pre-dosing level (P less than 0.05). It is concluded that IL-2 induces ET-1 release from the vascular wall, possibly as a result of reversible endothelial dysfunction caused by IL-2.     

Late-gestation betamethasone enhances coronary artery responsiveness to angiotensin II in fetal sheep

Antenatal glucocorticoids are used to promote the maturation of fetuses at risk for preterm delivery. While perinatal glucocorticoid exposure has clear immediate benefits to cardiorespiratory function, there is emerging evidence of adverse long-term effects. To determine if antenatal betamethasone alters vascular reactivity, we examined isometric contraction of endothelium-intact coronary and mesenteric arteries isolated from twin fetal sheep at 121-124 days gestation (term being 145 days). One twin received betamethasone (10 microg/h iv) while the second twin received vehicle (0.9% NaCl) for 48 h immediately before the final physiological measurements and tissue harvesting. Fetuses that received betamethasone had higher mean arterial blood pressures than the saline-treated twin controls (53 +/- 1 vs. 48 +/- 1 mmHg, P < 0.05). Coronary vessels from betamethasone-treated fetuses exhibited enhanced peak responses to ANG II (72 +/- 17 vs. 23 +/- 6% of the maximal response to 120 mM KCl, P < 0.05). There was no significant difference in response of the coronary arteries to other vasoactive compounds [KCl, U-46619, sodium nitroprusside, 8-bromo-cGMP (8-BrcGMP), isoproterenol, and forskolin]. Contractile responses to ANG II were similar in betamethasone and control mesenteric arteries (48 +/- 17 vs. 36 +/- 12% of the maximal response to 10-6 M U-46619). Western blot analysis revealed AT1 receptor protein expression was increased by betamethasone in coronary but not in mesenteric arteries. These findings demonstrate that antenatal betamethasone exposure enhances coronary but not mesenteric artery vasoconstriction to ANG II by selectively upregulating coronary artery AT1 receptor protein expression.     

Elevated dietary salt suppresses renin secretion but not thirst evoked by arterial hypotension in rats

Increased dietary salt intake was used as a nonpharmacological tool to blunt hypotension-induced increases in plasma renin activity (PRA) in order to evaluate the contribution of the renin-angiotensin system (RAS) to hypotension-induced thirst. Rats were maintained on 8% NaCl (high) or 1% NaCl (standard) diet for at least 2 wk, and then arterial hypotension was produced by administration of the arteriolar vasodilator diazoxide. Despite marked reductions in PRA, rats maintained on the high-salt diet drank similar amounts of water, displayed similar latencies to drink, and had similar degrees of hypotension compared with rats maintained on the standard diet. Furthermore, blockade of ANG II production by an intravenous infusion of the angiotensin-converting enzyme inhibitor captopril attenuated the hypotension-induced water intake similarly in rats fed standard and high-salt diet. Additional experiments showed that increases in dietary salt did not alter thirst stimulated by the acetylcholine agonist carbachol administered into the lateral ventricle; however, increases in dietary salt did enhance thirst evoked by central ANG II. Collectively, the present findings suggest that hypotension-evoked thirst in rats fed a high-salt diet is dependent on the peripheral RAS despite marked reductions in PRA.     

Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension

Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K, 1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar-Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K,1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat

Obesity is an emerging risk factor for renal dysfunction, but the mechanisms are poorly understood. Obese patients show heightened renal vasodilation to blockade of the renin-angiotensin system, suggesting deficits in vascular responses to angiotensin II (ANG II). This study tested the hypothesis that obesity augments renal vasoconstriction to ANG II. Lean (LZR), prediabetic obese (OZR), and nonobese fructose-fed Zucker rats (FF-LZR) were studied to determine the effects of obesity and insulin resistance on reactivity of blood pressure and renal blood flow to vasoconstrictors. OZR showed enlargement of the kidneys, elevated urine output, increased sodium intake, and decreased plasma renin activity (PRA) vs. LZR, and renal vasoconstriction to ANG II was augmented in OZR. Renal reactivity to norepinephrine and mesenteric vascular reactivity to ANG II were similar between LZR and OZR. Insulin-resistant FF-LZR had normal reactivity to ANG II, indicating the insulin resistance was an unlikely explanation for the changes observed in OZR. Four weeks on a low-sodium diet (0.08%) to raise PRA reduced reactivity to ANG II in OZR back to normal levels without effect on LZR. From these data, we conclude that in the prediabetic stages of obesity, a decrease in PRA is observed in Zucker rats that may lead to increased renal vascular reactivity to ANG II. This increased reactivity to ANG II may explain the elevated renal vasodilator effects observed in obese humans and provide insight into early changes in renal function that predispose to nephropathy in later stages of the disease.     

Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity

Excessive exposure of the fetus to maternally derived corticosteroids has been linked to the development of adult-onset diseases. To determine if early gestation corticosteroid exposure alters subsequent coronary artery reactivity, we administered dexamethasone (0.28 mg.kg(-1).day(-1)) to pregnant ewes at 27-28 days gestation (term being 145 days). Vascular responsiveness was assessed in endothelium-intact coronary and mesenteric arteries isolated from steroid-exposed and age-matched control fetal sheep at 123-126 days gestation and lambs at 4 mo of age. Lambs exposed to maternal dexamethasone had higher mean arterial blood pressures than the age-matched controls (93 +/- 3 vs. 83 +/- 5 mmHg, P < 0.05). Mesenteric arteries from the steroid-exposed fetuses displayed diminished responses to ANG II, relative to controls. In 4-mo-old lambs, prenatal dexamethasone exposure significantly increased coronary artery vasoconstriction to ANG II, ACh, and U-46619, but not KCl. In contrast, postnatal mesenteric artery reactivity was unaltered by steroid exposure. Compared with fetal mesenteric reactivity, postnatal mesenteric reactivity to ANG II, phenylephrine, and U-46619 was diminished, whereas the response to 120 mmol/l KCl was heightened. Coronary artery ANG II receptor protein expression was not significantly altered by steroid exposure in either age group. These findings demonstrate that early-gestation glucocorticoid exposure programs postnatal elevations in blood pressure and selectively enhances coronary artery responsiveness to second messenger-dependent vasoconstrictors. Glucocorticoid-induced alterations in coronary vascular smooth muscle structure or function may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease.     

Vascular responses to sodium arachidonate in experimental hypertension

This study characterizes vascular responsiveness to sodium arachidonate (C 20:4) in four models of hypertension [deoxycorticosterone acetate (DOCA) hypertensive rats, two kidney-one clip (2K-1C) renal hypertensive rats, spontaneously hypertensive rats (SHR), and psychosocial hypertensive mice]. Isolated arterial strips (aorta, mesenteric artery, tail artery) were equilibrated under optimal resting tension in physiological salt solution for measurement of isometric force generation. Dose-response curves to arachidonate (10(-10) to 10(-4) g/ml) in arteries from DOCA and 2K-1C hypertensive rats were shifted to the left compared to those in arteries from control rats. In arteries from SHR and psychosocial hypertensive mice, the dose-response relationships were unchanged compared to normotensive values. Arteries from DOCA hypertensive and 2K-1C hypertensive rats developed greater maximal contractile responses to arachidonate than controls; maximal responses in arteries from SHR and psychosocial hypertensive mice were unchanged compared to normotensive values. Contractions to arachidonate were inhibited by indomethacin (0.5 and 5 micrograms/ml) and by aspirin (5 and 50 micrograms/ml). The fatty acid, oleate (C 18:1), had no effect on the contractile state of the arteries, whereas prostaglandin F2 alpha caused contraction. These results indicate altered responsiveness to exogenous arachidonate in arteries from DOCA and 2K-1C hypertensive rats, but not in arteries from SHR and psychosocial hypertensive mice.     

Xanthine oxidase and mitochondria contribute to vascular superoxide anion generation in DOCA-salt hypertensive rats

Vascular superoxide anion (O(2)(*-)) levels are increased in DOCA-salt hypertensive rats. We hypothesized that the endothelin (ET)-1-induced generation of ROS in the aorta and resistance arteries of DOCA-salt rats originates partly from xanthine oxidase (XO) and mitochondria. Accordingly, we blocked XO and the mitochondrial oxidative phosphorylation chain to investigate their contribution to ROS production in mesenteric resistance arteries and the aorta from DOCA-salt rats. Systolic blood pressure rose in DOCA-salt rats and was reduced after 3 wk by apocynin [NAD(P)H oxidase inhibitor and/or radical scavenger], allopurinol (XO inhibitor), bosentan (ET(A/B) receptor antagonist), BMS-182874 (BMS; ET(A) receptor antagonist), and hydralazine. Plasma uric acid levels in DOCA-salt rats were similar to control unilaterally nephrectomized (UniNx) rats, reduced with allopurinol and bosentan, and increased with BMS. Levels of thiobarbituric acid-reacting substances were increased in DOCA-salt rats versus UniNx rats, and BMS, bosentan, and hydralazine prevented their increase. Dihydroethidium staining showed reduced O(2)(*-) production in mesenteric arteries and the aorta from BMS- and bosentan-treated DOCA-salt rats compared with untreated DOCA-salt rats. Increased O(2)(*-) derived from XO was reduced or prevented by all treatments in mesenteric arteries, whereas bosentan and BMS had no effect on aortas from DOCA-salt rats. O(2)(*-) generation decreased with in situ treatment by tenoyltrifluoroacetone and CCCP, inhibitors of mitochondrial electron transport complexes II and IV, respectively, whereas rotenone (mitochondrial complex I inhibitor) had no effect. Our findings demonstrate the involvement of ET(A) receptor-modulated O(2)(*-) derived from XO and from mitochondrial oxidative enzymes in arteries from DOCA-salt rats.     

AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control (n=6); trained (n=6); control+losartan (10 mg.kg(-1).day(-1), n=6); trained+losartan (n=6); control+high-salt diet (1%, n=6); and trained+high-salt diet (1%, n=6). High salt was used to inhibit the systemic RAS and losartan to block the AT1 receptor. The exercise protocol consisted of: 4x12 bouts, 5x/wk during 8 wk, with 65-75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained+high-salt diet groups (8.5% and 10.6%, P<0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and alphaMHC (alpha-myosin heavy chain)-to-betaMHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac AT2 receptor levels, whereas the AT1 receptor gene (56%, P<0.05) and protein (31%, P<0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27+/-2.4 vs. 22.01+/-0.8 pg/mg, P>0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of AT1 receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response.     

Novel expression and regulation of the renin-angiotensin system in metanephric organ culture

To evaluate the presence and regulation of the renin-angiotensin system (RAS) in metanephric organ culture, embryonic day 14 (E14) rat metanephroi were cultured for 6 days. mRNAs for renin and both ANG II receptors (AT(1) and AT(2)) are expressed at E14, and all three genes continue to be expressed in culture. Renin mRNA is localized to developing tubules and ureteral branches in the cultured explants. At E14, renin immunostaining is found in isolated cells scattered within the mesenchyme. As differentiation progresses, renin localizes to the ureteric epithelium, developing tubules and glomeruli. E14 metanephroi contain ANG II, and peptide production persists in culture. Renin activity is present at E14 (6.13 +/- 0.61 pg ANG I. kidney(-1). h(-1)) and in cultured explants (28.84 +/- 1. 13 pg ANG I. kidney(-1). h(-1)). Renin activity in explants is increased by ANG II treatment (70.1 +/- 6.36 vs. 40.97 +/- 1.94 pg ANG I. kidney(-1). h(-1) in control). This increase is prevented by AT(1) blockade, whereas AT(2) antagonism has no effect. These studies document an operational local RAS and a previously undescribed positive-feedback mechanism for renin generation in avascular, cultured developing metanephroi. This novel expression pattern and regulatory mechanism highlight the unique ability of developing renal cells to express an active RAS.     

Evidence that the renin decrease during hypoxia is adenosine mediated in conscious dogs.

This study investigated whether adenosine mediates the decrease in plasma renin activity (PRA) during acute hypoxia. Eight chronically tracheotomized, conscious beagle dogs were kept under standardized environmental conditions and received a low-sodium diet (0.5 mmol.kg body wt(-1).day(-1)). During the experiments, the dogs were breathing spontaneously via a ventilator circuit: first hour, normoxia (21% inspiratory concentration of O(2)); second and third hours, hypoxia (10% inspiratory concentration of O(2)). Each of the eight dogs was studied twice in randomized order in control and theophylline experiments. In theophylline experiments, theophylline, an A(1)-receptor antagonist, was infused intravenously during hypoxia (loading dose: 3 mg/kg within 30 min, maintenance: 0.5 mg. kg(-1). h(-1)). In theophylline experiments, PRA (5.9 +/- 0.8 ng ANG I. ml(-1). h(-1)) and ANG II plasma concentration (15.9 +/- 2.3 pg/ml) did not decrease during hypoxia, whereas plasma aldosterone concentration decreased from 277 +/- 63 to 132 +/- 23 pg/ml (P < 0.05). In control experiments, PRA decreased from 6.8 +/- 0.8 during normoxia to 3.0 +/- 0.5 ng ANG I. ml(-1). h(-1) during hypoxia, ANG II decreased from 13.3 +/- 1.9 to 7.3 +/- 1.9 pg/ml, and plasma aldosterone concentration decreased from 316 +/- 50 to 70 +/- 13 pg/ml (P < 0.05). Thus infusion of the adenosine receptor antagonist theophylline inhibited the suppression of the renin-angiotensin system during acute hypoxia. The decrease in aldosterone occurred independently and is apparently directly related to hypoxia. In conclusion, it is likely that adenosine mediates the decrease in PRA during acute hypoxia in conscious dogs.     

Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia

Reduced alveolar Po(2) in rats produces a rapid systemic inflammation characterized by reactive O(2) species generation, mast cell (MC) degranulation, leukocyte-endothelial interactions, and increased vascular permeability. The inflammation is not initiated by the low systemic Po(2) but rather by the release of monocyte chemoattractant protein-1 (MCP-1) from alveolar macrophages (AMO) activated by alveolar hypoxia. Circulating AMO-borne MCP-1 induces MC degranulation, which activates the local renin-angiotensin system (RAS) and mediates the microvascular inflammation. This study was directed to determine the mechanism of RAS activation by MCP-1-induced MC degranulation. Experiments in isolated rat peritoneal MCs showed the following: 1) Western blots and immunocytochemistry demonstrated the presence of renin and angiotensin-converting enzyme (ACE) in MCs and their release upon degranulation; 2) MCP-1-induced degranulation of MCs incubated in plasma produced an increase in angiotensin II (ANG II) concentration; and 3) this increase was inhibited completely by the following agents: the MCP-1 receptor antagonist RS-102895, the specific rat renin inhibitor WFML, or the ACE inhibitor captopril administered separately. Captopril also inhibited ANG II generation by MCs incubated in culture medium plus ANG I. The results show that peritoneal MCs contain active renin, which activates the RAS upon degranulation, and that peritoneal MCs are a source of ACE and suggest that conversion of ANG I to ANG II is mediated predominantly by ACE. This study provides novel evidence of the presence of active renin in rat peritoneal MCs and helps explain the mechanism of activation of the RAS during alveolar hypoxia.     

Time-dependent changes in autonomic control of splanchnic vascular resistance and heart rate in ANG II-salt hypertension

Previous studies suggest that ANG II-induced hypertension in rats fed a high-salt (HS) diet (ANG II-salt hypertension) has a neurogenic component dependent on an enhanced sympathetic tone to the splanchnic veins and independent from changes in sympathetic nerve activity to the kidney or hind limb. The purpose of this study was to extend these findings and test whether altered autonomic control of splanchnic resistance arteries and the heart also contributes to the neurogenic component. Mean arterial pressure (MAP), heart rate (HR), superior mesenteric artery blood flow, and mesenteric vascular resistance (MVR) were measured during 4 control days, 14 days of ANG II delivered subcutaneously (150 ng·kg(-1)·min(-1)), and 4 days of recovery in conscious rats fed a HS (2% NaCl) or low-salt (LS; 0.1% NaCl) diet. Autonomic effects on MAP, HR, and MVR were assessed by acute ganglionic blockade with hexamethonium (20 mg/kg iv) on day 3 of control, days 1, 3, 5, 7, 10, and 13 of ANG II, and day 4 of recovery. MVR increased during ANG II infusion in HS and LS rats but remained elevated only in HS rats. Additionally, the MVR response to hexamethonium was enhanced on days 10 and 13 of ANG II selectively in HS rats. Compared with LS rats, HR in HS rats was higher during the 2nd wk of ANG II, and its response to hexamethonium was greater on days 7, 10, and 13 of ANG II. These results suggest that ANG II-salt hypertension is associated with delayed changes in autonomic control of splanchnic resistance arteries and the heart.     

Production of endothelin-1 from the mesenteric arteries of streptozotocin-induced diabetic rats

Release of endothelin-1 (ET-1) from the mesenteric arteries of Wistar rats with streptozotocin-induced diabetes (STZ-DM) rats and nondiabetic rats was measured by a specific enzyme immunoassay following purification using an immunoaffinity column. The mesenteric arteries from STZ-DM rats released a significantly higher amount of ET-1 as compared to control rats (35.8 +/- 2.8 vs 14.9 +/- 2.0 pg/1hr, p less than 0.05). The plasma level of ET-1 in STZ-DM rats was also elevated to a significant extent as compared to controls (5.1 +/- 0.4 vs 3.0 +/- 0.4 pg/ml, p less than 0.05). The systolic blood pressure of STZ-DM rats was significantly higher than of the controls (p less than 0.05). The increased level of plasma ET-1 as well as its release from the mesenteric artery of STZ-DM rats may suggest its release following damage to the endothelium caused by diabetes and/or by associated changes in blood pressure.     

Enhanced intrarenal receptor-mediated prorenin activation in chronic progressive anti-thymocyte serum nephritis rats on high salt intake

Despite suppression of the circulating renin-angiotensin system (RAS), high salt intake (HSI) aggravates kidney injury in chronic kidney disease. To elucidate the effect of HSI on intrarenal RAS, we investigated the levels of intrarenal prorenin, renin, (pro)renin receptor (PRR), receptor-mediated prorenin activation, and ANG II in chronic anti-thymocyte serum (ATS) nephritic rats on HSI. Kidney fibrosis grew more severe in the nephritic rats on HSI than normal salt intake. Despite suppression of plasma renin and ANG II, marked increases in tubular prorenin and renin proteins without concomitant rises in renin mRNA, non-proteolytically activated prorenin, and ANG II were noted in the nephritic rats on HSI. Redistribution of PRR from the cytoplasm to the apical membrane, along with elevated non-proteolytically activated prorenin and ANG II, was observed in the collecting ducts and connecting tubules in the nephritic rats on HSI. Olmesartan decreased cortical prorenin, non-proteolytically activated prorenin and ANG II, and apical membranous PRR in the collecting ducts and connecting tubules, and attenuated the renal lesions. Cell surface trafficking of PRR was enhanced by ANG II and was suppressed by olmesartan in Madin-Darby canine kidney cells. These data suggest the involvement of the ANG II-dependent increase in apical membrane PRR in the augmentation of intrarenal binding of prorenin and renin, followed by nonproteolytic activation of prorenin, enhancement of renin catalytic activity, ANG II generation, and progression of kidney fibrosis in the nephritic rat kidneys on HSI. The origin of the increased tubular prorenin and renin remains to be clarified. Further studies measuring the urinary prorenin and renin are needed.     

Cerebral intraventricular 6-hydroxydopamine prevents vascular changes in the mineralocorticoid hypertensive rat

The effect of cerebral intraventricular administration of 6-hydroxydopamine (6-OHDA) on blood pressure and vascular smooth muscle responsiveness in deoxycorticosterone acetate (DOCA)-treated rats was assessed. Rats treated with 6-OHDA and DOCA had significantly lower systolic blood pressures (142 +/- 8 mm Hg) than rats treated with DOCA alone (185 +/- 5 mm Hg). After 5 weeks of DOCA treatment, femoral arteries and aortae were excised from these rats, cut helically into strips, and placed in a muscle bath to record isometric force. Dose-response curves to serotonin were shifted to the left in femoral arteries from DOCA-treated rats compared to both control and 6-OHDA-DOCA-treated rats (ED50: DOCA = 6.8 X 10(-8) M, control = 27.9 X 10(-8) M, 6-OHDA-DOCA = 13.4 X 10(-8) M). Arachidonic acid, the prostaglandin precursor, produced greater maximal contractions in femoral artery strips of DOCA-treated rats (358 +/- 56 mg) than in those from controls (115 +/- 31 mg). The maximal response to arachidonic acid in arteries from 6-OHDA-DOCA rats (203 +/- 78 mg) was not different from control values. Ouabain produced a greater maximal response in aortic strips from DOCA rats (658 +/- 165 mg) compared to those from control (196 +/- 72 mg) or 6-OHDA-DOCA (309 +/- 87 mg) rats. We conclude that increased vascular responsiveness to serotonin, arachidonic acid, and ouabain in DOCA hypertensive rats is secondary to a central action of the mineralocorticoid.     

Impaired substance P release from renal sensory nerves in SHR involves a pertussis toxin-sensitive mechanism

Stretching the renal pelvic wall activates renal mechanosensory nerves by a PGE2-mediated release of substance P via activation of the cAMP-PKA pathway. Renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing the PGE2-mediated activation of adenylyl cyclase via a pertussis toxin (PTX)-sensitive mechanism. In SHR, activation of renal mechanosensory nerves is impaired. This is due to suppressed release of substance P in response to increased pelvic pressure. The present study was performed to investigate whether the PGE2-mediated release of substance P was suppressed in SHR vs. WKY and, if so, whether the impaired PGE2-mediated release of substance P was due to ANG II activating a PTX-sensitive mechanism. In an isolated renal pelvic wall preparation, PGE2, 0.14 microM, increased substance P release from 9 +/- 3 to 22 +/- 3 pg/min (P < 0.01) in Wistar-Kyoto rats (WKY), but had no effect in spontaneously hypertensive rats (SHR). A tenfold higher concentration of PGE2, 1.4 microM, was required to increase substance P release in SHR, from 7 +/- 1 to 22 +/- 3 pg/min (P < 0.01). In SHR, treating renal pelvises with losartan enhanced the release of substance P produced by subthreshold concentration of PGE2, 0.3 microM, from 16 +/- 2 to 26 +/- 3 pg/min (P < 0.01). Likewise, treating renal pelvises with PTX enhanced the PGE2-mediated release of substance P from 10 +/- 1 to 33 +/- 3 pg/min (P < 0.01) in SHR. In WKY, neither losartan nor PTX had an effect on the release of substance P produced by subthreshold concentrations of PGE2, 0.03 microM. In conclusion, the impaired responsiveness of renal sensory nerves in SHR involves endogenous ANG II suppressing the PGE2-mediated release of substance P via a PTX-sensitive mechanism.     

Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin

Increasing renal pelvic pressure results in PGE(2)-mediated release of substance P. Substance P increases afferent renal nerve activity (ARNA), which leads to a reflex increase in urinary sodium excretion (U(Na)V). Endogenous ANG II modulates the responsiveness of renal mechanosensory nerves. The ARNA and U(Na)V responses are suppressed by low- and enhanced by high-sodium diet. We examined whether the ARNA responses are altered in rats with congestive heart failure (CHF), a condition characterized by increased ANG II and sodium retention. The ARNA responses to increasing renal pelvic pressure 相似文献   

Effect of oral contraceptives on the renin angiotensin system and renal function

We examined the effect of oral contraceptive (OC) usage on the renin angiotensin system (RAS) in two related experiments. In the first experiment, subjects were 34 healthy, normotensive, premenopausal women, 15 OC users and 19 OC nonusers, mean age 25 +/- 1 yr, ingesting a controlled sodium diet. We assessed arterial pressure, glomerular filtration rate, effective renal plasma flow, renal vascular resistance (RVR), and filtration fraction (FF) using inulin and p-aminohippurate clearance techniques, both at baseline and in response to the ANG II receptor blocker losartan. In the second experiment, in similar subjects, 10 OC users and 10 nonusers, we examined circulating RAS components [angiotensinogen, ANG II, aldosterone, plasma renin activity (PRA), and active renin] in response to incremental lower body negative pressure (LBNP), to determine whether renin secretion is suppressed by OC usage. OC users exhibited elevations in systolic blood pressure, RVR, and FF compared with nonusers, which were partially corrected by losartan. In the LBNP phase of the study, baseline measures of PRA, angiotensinogen, ANG II, and aldosterone were all increased in the OC group compared with the control group. Active renin levels did not differ between groups. Incremental LBNP resulted in increased circulating levels of RAS components in both groups. We conclude that the RAS is activated in women using OCs. There was no evidence that decreases in renin secretion result in normalization of the RAS as a whole.     

Antihypertensive therapy increases tetrahydrobiopterin levels and NO/cGMP signaling in small arteries of angiotensin II-infused hypertensive rats

We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H(2)O(2) and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH(4))-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH(4) therapy were studied. Both triple therapy and oral BH(4) therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH(4) levels and BH(4)-to-BH(2) ratio similar to ANG rats with BH(4) supplementation. Furthermore, triple therapy (but not oral BH(4) therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH(4) in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH(4) levels and NOS3 phosphorylation at Ser1177.