bluuebunny/crossref_metadata_2025 huggingface dataset:
Early interstitial changes in hypertension-induced renal injury.
Authors: Mai M , Geiger H , Hilgers K F , Veelken R , Mann J F , Dämmrich J , Luft F C
Published: June 2012

To elucidate the mechanisms of hypertensive renal injury, we investigated the time course and extent of changes in matrix composition, as well as cell proliferation and infiltration in two-kidney, one clip rats. The nonclipped kidneys from hypertensive and sham-operated control rats (n = 5 to 10 in each group) were studied at 7, 14, 21, and 28 days after clipping. Systolic blood pressure was elevated by day 7 (154 +/- 3 versus 111 +/- 4 mm Hg in sham group, P < .001, n = 10 each). Hypertension resulted in an early expansion of the interstitial volume by 37%, whereas hypertensive vascular changes and glomerular injury did not become evident until day 21. Immunofluorescence studies revealed an early interstitial accumulation of collagens I, III, IV, V, VI, and fibronectin by day 7. In contrast, the glomeruli showed a mild to moderate increase in collagens I, III, IV, V, laminin, and fibronectin but not collagen VI later in the established phase of hypertension. Staining for proliferating cell nuclear antigen as a marker of cell replication was increased in tubular epithelial but not interstitial or glomerular cells. A progressive infiltration of macrophages (16 +/- 2 versus 9 +/- 1 ED1+ cells/mm2, P < .05, n = 6) and T lymphocytes (93 +/- 15 versus 74 +/- 7 CD4+ cells/mm2, n = 8) in the cortical interstitium had already occurred by day 7. On the other hand, only macrophages increased in number within the glomeruli. Thus, renovascular hypertension leads to an early tubular cell proliferation, mononuclear cell recruitment, and deposition of matrix proteins primarily within the interstitium. We conclude that the injury producing nephrosclerosis in this model extends far beyond the glomeruli. Both the tubules and the interstitium are actively involved and may be the more important initial sites of injury.
Wave reflections and cardiac hypertrophy in chronic uremia. Influence of body size.
Authors: Marchais S J , Guerin A P , Pannier B M , Levy B I , Safar M E , London G M
Published: June 2012

Arterial wave reflections (AWRs), an important determinant of cardiac afterload, are increased in hemodialysis patients. However, an association between AWRs and left ventricular hypertrophy has not been established in these subjects. We therefore sought an association between these two parameters in a cross-sectional study of two outpatient hemodialysis populations. AWRs were quantified (augmentation index, percent) as the ratio of the height of the late systolic peak to the total height of the carotid pulse wave recorded with a micromanometer-tipped probe. AWRs were determined in 44 hemodialysis patients, 22 with pronounced AWRs (group A: augmentation index > 12%), and 22 with small or moderate AWRs (group B: augmentation index < 12%). The groups were matched for age, sex, blood pressure, and hemodialysis duration. Left ventricular size was determined by echocardiography. Despite lower body size (P < .005) and similar blood pressure, cardiac output, peripheral resistance, and aortic pulse wave velocity, group A patients had greater left ventricular mass (P < .01). For the population as a whole, left ventricular mass and AWRs were positively correlated (P < .0001) independent of age, blood pressure, hemodialysis duration, or body size. Lesser body height was the principal factor associated with increased AWRs in group A (P < .001). We conclude that in hemodialysis patients AWRs are associated with the development of left ventricular hypertrophy and that small body height is a risk factor for long-term cardiovascular complications.
Combination treatment of enalapril with nitrendipine in rats with renovascular hypertension.
Authors: Wenzel U O , Helmchen U , Schoeppe W , Schwietzer G
Published: June 2012

We have recently shown that treatment with the calcium channel blocker nitrendipine may aggravate albuminuria and glomerular injury in rats with two-kidney, one clip renovascular hypertension if arterial blood pressure is not reduced. To test whether nitrendipine also exerts its adverse renal effects when normotension is achieved, we examined the effect of combined therapy with nitrendipine and the converting enzyme inhibitor enalapril on blood pressure, albuminuria, glomerular filtration rate, and morphology of the nonclipped kidney. Rats treated with enalapril alone or in combination with the diuretic hydrochlorothiazide or rats treated with nitrendipine alone served as controls. Therapy was started 6 weeks after clipping of one renal artery. Nitrendipine alone did not reduce blood pressure but significantly increased albuminuria, diuresis, glomerular filtration rate, and glomerular volume and injury compared with untreated hypertensive controls. Increase of glomerular filtration rate, diuresis, and albuminuria was reversible after withdrawal of nitrendipine. Treatment with enalapril alone decreased blood pressure significantly but not to normotensive levels and was without significant effect on albuminuria and glomerular morphology. The combination of nitrendipine and enalapril reduced blood pressure to normotensive levels and not only prevented the increase of glomerular volume, glomerular filtration rate, diuresis, and albuminuria caused by nitrendipine alone but furthermore improved glomerular injury and albuminuria to levels not significantly different from normotensive controls. Enalapril in combination with the diuretic had similar beneficial effects on blood pressure, albuminuria, and glomerular injury. These data demonstrate that the adverse effects of nitrendipine monotherapy on glomerular structure and function can be prevented by the combination of nitrendipine and enalapril when blood pressure is normalized.
Responses to converting enzyme and renin inhibition. Role of angiotensin II in humans.
Authors: Fisher N D , Allan D , Kifor I , Gaboury C L , Williams G H , Moore T J , Hollenberg N K
Published: June 2012

We compared the renal vascular responses to angiotensin converting enzyme inhibition and renin inhibition to assess the influence of angiotensin II (Ang II). We examined the renal and endocrine responses to the renin inhibitor enalkiren, to captopril, and to placebo in nine healthy and nine hypertensive men on a 10-mmol sodium diet. Ang II was infused to assess effects of the agents on renal and adrenal responsiveness to Ang II. Plasma Ang II concentration was suppressed similarly with enalkiren and captopril--an identical level of blockade was achieved. Although renal plasma flow was stable during placebo, a substantial rise was seen with both enalkiren (+133 +/- 26 mL/min per 1.73 m2) and captopril (+99.4 +/- 22.6). There was remarkable intrasubject concordance between the renal plasma flow responses to renin inhibition and converting enzyme inhibition (r = .90, P < .004). The vasodilator response to both agents correlated inversely with the fall in renal plasma flow induced by Ang II alone (r = -.66, P < .05). Both agents significantly enhanced the renal vascular response to Ang II (P = .01), and, furthermore, the renal vasodilator response to captopril predicted the potentiation of the renal plasma flow response to Ang II after either agent (enalkiren: r = .91, P < .001; captopril: r = .56, P < .05). Concordance of the maximal renal plasma flow response to the two agents appeared in the hypertensive men as well. Our results indicate that the acute renal response to captopril largely reflects a reduction in Ang II formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Antihypertensive effect of interleukin-2 in salt-sensitive Dahl rats.
Authors: Ishimitsu T , Uehara Y , Numabe A , Tsukada H , Ogawa Y , Yagi S
Published: June 2012

We investigated the effects of interleukin-2, which stimulates the proliferation and maturation of thymus-derived lymphocytes, on hypertension and organ injuries in genetically hypertensive rats. Interleukin-2 (5 x 10(4) U/kg body wt) was subcutaneously injected into Dahl salt-sensitive rats fed a 4% NaCl diet and spontaneously hypertensive rats once a week for 10 weeks. The effects on blood pressure, cardiovascular hypertrophy, and renal function were evaluated. Interleukin-2 treatment lowered blood pressure in Dahl salt-sensitive rats (162 versus 187 mm Hg, P < .005). This antihypertensive effect was associated with an increase in glomerular filtration rate (589 versus 428 mL/d per 100 g body weight, P < .005) and reduction in cardiac weight (268 versus 305 mg/100 g body weight, P < .05). Interleukin-2 also alleviated the marked glomerular sclerosis in Dahl salt-sensitive rats (glomerular injury score, 151 versus 220; P < .001). In contrast, interleukin-2 did not affect the development of hypertension or organ injuries in spontaneously hypertensive rats. Histologically, glomerular and arterial lesions of the kidney were much less marked in spontaneously hypertensive rats than in Dahl salt-sensitive rats. These data indicate that interleukin-2 ameliorates the development of hypertension and cardiac and renal injuries in Dahl salt-sensitive rats.
Renal artery stenosis and ischemia. Effect on renal blood flow and extraction fraction.
Authors: Taylor A , Eshima D
Published: June 2012

The clearance of [131I]orthoiodohippurate and 99mTc-mercaptoacetyltriglycine provide a measure of effective renal plasma flow, yet these clearances are proportional to renal plasma flow only if the extraction fraction remains constant. To determine the effect of unilateral renal artery stenosis, captopril, renal ischemia, and partial renal vein occlusion on renal blood flow and the extraction fraction of [131I]orthoiodohippurate, 99mTc-mercaptoacetyltriglycine, and [125I]iothalamate, we conducted a series of constant infusion studies in Sprague-Dawley rats. Renal artery flow reduction of approximately 70% decreased the extraction fraction of all three agents (P < or = .05). Captopril had no effect on extraction fraction in controls, but it produced a further decrease in extraction fraction of 99mTc-mercaptoacetyltriglycine and [131I]orthoiodohippurate in rats with renal artery stenosis (P < or = .05). Ischemia resulted in a 16% decrease in flow (P < .01) but a much larger (47% to 65%) decrease in extraction fraction of all three agents (P < .002). Partial renal vein occlusion also decreased the extraction fraction of all three agents (P < or = .05). The changes in extraction fraction imply that the clearances of [131I]orthoiodohippurate and 99mTc-mercaptoacetyltriglycine in disease states may not be proportional to renal plasma flow. Furthermore, in rats with renal artery stenosis it appears that renal blood flow must fall below a critical threshold of approximately 58% before extraction fraction decreases; as renal blood flow is further reduced below this threshold, there is a corresponding reduction in extraction fraction (P < .01).
OPC-21268, a vasopressin V1 antagonist, produces hypotension in spontaneously hypertensive rats.
Authors: Yamada Y , Yamamura Y , Chihara T , Onogawa T , Nakamura S , Yamashita T , Mori T , Tominaga M , Yabuuchi Y
Published: June 2012

We studied the hypotensive effects of OPC-21268, an orally effective nonpeptide vasopressin V1 receptor antagonist, in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). OPC-21268 was given intravenously to conscious, freely moving SHR and SHRSP. We used young and aged animals to examine the contribution of vasopressin to the development and maintenance of hypertension in both types of rats. In SHR, hypertension was fully established at 38 weeks of age, and intravenous injection of OPC-21268 produced slight hypotensive effects at either 38 or 70 weeks of age. In SHRSP, hypertension developed at 25 weeks of age, and blood pressure was sustained at a high level (approximately 250 mm Hg systolic blood pressure) thereafter. Intravenous administration of OPC-21268 did not cause hypotensive effects in young rats at 15 weeks, but at 25 weeks a significant decrease in blood pressure was observed. Furthermore, in the malignant state of SHRSP (35 to 41 weeks), OPC-21268 significantly decreased mean blood pressure by 32.4 +/- 7.9 mm Hg (mean +/- SEM) at 3 mg/kg IV, and the decrease was dose dependent (0.3 to 3.0 mg/kg). Plasma vasopressin concentrations were increased in a more malignant phase of SHRSP at 45 weeks of age, whereas at other ages of SHRSP or in SHR, plasma vasopressin levels were not increased. These results suggest that vasopressin plays an important role through V1 receptors in the maintenance of hypertension, at least in the malignant phase of SHRSP, and OPC-21268 may be therapeutically useful in the treatment of some types of hypertension.
Endothelin blockade lowers total peripheral resistance in hemorrhagic shock recovery.
Authors: Zimmerman R S , Maymind M , Barbee R W
Published: June 2012

To determine whether endothelin (ET) has a role in maintaining circulatory support during hypotensive hemorrhage, we (1) examined cardiac and systemic hemodynamics after a 6-mL hemorrhage in the presence and absence of the ETA receptor blocker BQ-123, (2) examined cardiac and systemic hemodynamics during BQ-123 infusion in nonhemorrhaged rats, (3) measured changes in circulating immunoreactive endothelin (IR-ET) after a 6-mL hemorrhage, and (4) infused pathophysiological doses of ET-1 into rats anesthetized with thiobutabarbital. Twenty minutes after hemorrhage, cardiac output and mean arterial pressure had stabilized in part because of an increase in systemic vascular resistance from 0.86 +/- 0.04 (baseline) to 1.04 +/- 0.05 (20 minutes) mm Hg/mL per minute. The rise in systemic vascular resistance was temporally associated with a significant (24%) increase in circulating IR-ET from 29 +/- 2 to 36 +/- 3 pg/mL 20 minutes after hemorrhage. During BQ-123 infusion mean arterial pressure at 5, 10, and 20 minutes after hemorrhage was 9 +/- 2, 23 +/- 4, and 23 +/- 3 mm Hg lower than values obtained after hemorrhage alone (P < .05). Mean arterial pressure was unaffected by BQ-123 infusion at baseline and 30 minutes after hemorrhage. Systemic vascular resistance was not affected at baseline by BQ-123 infusion. However, systemic vascular resistance was significantly lower 5, 10, 20, and 30 minutes after hemorrhage during BQ-123 infusion compared with hemorrhage alone at each time point. Infusion of BQ-123 into nonhemorrhaged rats had no effect on mean arterial pressure, systemic vascular resistance, or cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)
Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats.
Authors: Bhanot S , McNeill J H , Bryer-Ash M
Published: June 2012

To determine whether insulin resistance and hyperinsulinemia are causally related to fructose-induced hypertension, we used vanadyl sulfate, a drug that improves insulin sensitivity in rats. Chronic oral vanadyl treatment was initiated in 6-week-old male Sprague-Dawley rats. One week after vanadyl was started, rats were fed either normal rat chow or a fructose-enriched diet. Plasma glucose and insulin levels and systolic blood pressure were measured weekly for 4 weeks. Fructose feeding induced hyperinsulinemia (fructose-fed, 366.6 +/- 8.4 versus control, 276 +/- 10.8 pmol/L, P < .001) and increased blood pressure (fructose-fed, 160 +/- 3.0 versus control, 124 +/- 3.0 mm Hg, P < .001). Vanadyl (0.4 to 0.6 mmol/kg per day) prevented the rise in plasma insulin (treated, 211.2 +/- 6.0 pmol/L, P < .001) and blood pressure (treated, 127 +/- 3.0 mm Hg, P < .001) in the fructose-fed rats without a change in plasma glucose. No change in blood pressure was seen in the control group. After 4 weeks, euglycemic clamps were performed on 20-hour fasted, conscious, mobile rats. Low-dose porcine insulin infusion (14 pmol/kg per minute) with concomitant somatostatin infusion resulted in similar steady-state plasma glucose and insulin levels in the various groups. Hepatic glucose production was suppressed and similar among various groups under clamp conditions. Insulin sensitivity index (micromoles of glucose per kilogram per hour per picomole per liter of insulin) was reduced in the fructose-fed rats compared with controls (fructose-fed, 0.9 +/- 0.4 versus control, 5.4 +/- 1.2, P < .002).(ABSTRACT TRUNCATED AT 250 WORDS)
Defective modulation of angiotensin II-induced renal vasoconstriction in hypertensive rats.
Authors: Jackson E K , Herzer W A
Published: June 2012

In a previous study we observed that the ability of intravenous infusions of prostaglandin I2 to attenuate vasoconstriction caused by intravenous infusions of angiotensin II was reduced in the renal but not mesenteric vasculature of spontaneously hypertensive rats (SHR). One objective of the current study was to determine whether a renal defect in the angiotensin II/prostaglandin I2 interaction in SHR could be confirmed even when confounding hemodynamic changes induced by intravenous infusions of prostaglandin I2 were avoided. The second objective was to determine whether abnormal modulation of angiotensin II-induced renal vasoconstriction was present even in SHR that were maintained normotensive from an early age. Four-week-old SHR and normotensive Wistar-Kyoto rats were randomized to receive either normal drinking water or drinking water containing captopril (100 mg/kg per day). At 14 to 18 weeks of age, rats were pretreated with indomethacin to block the production of endogenous prostaglandin I2, and changes in mesenteric and renal vascular resistances induced by suprarenal/supramesenteric aortic infusions of angiotensin II (10, 30, and 100 ng/kg per minute) were elicited in the presence and absence of aortic infusions of prostaglandin I2 (0.1 and 0.3 micrograms/kg per minute). Data were analyzed globally using four- and three-factor ANOVAs. The ability of prostaglandin I2 to attenuate the renal vasoconstrictor response to angiotensin II was strain specific (P = .0138), and this strain-specific interaction was not influenced by chronic treatment with captopril (P = .3526).(ABSTRACT TRUNCATED AT 250 WORDS)
Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction.
Authors: Madhavan S , Ooi W L , Cohen H , Alderman M H
Published: June 2012

The prognostic value of pretreatment pulse pressure as a predictor of myocardial infarction and the relation of pulse pressure and in-treatment diastolic blood pressure reduction to myocardial infarction were investigated in a union-sponsored systematic hypertension control program. In a prospective study, 2207 hypertensive patients with a pretreatment systolic blood pressure greater than or equal to 160 mm Hg and/or diastolic pressure greater than or equal to 95 mm Hg grouped according to tertile of pulse pressure (PP1, < or = 46; PP2, 47 to 62; PP3, > or = 63 mm Hg) were further stratified by the degree of diastolic fall: large (L), > or = 18; moderate (M), 7 to 17; small (S), < or = 6 mm Hg. During an average follow-up of 5 years, 132 cardiovascular events (50 myocardial infarctions, 23 strokes) were observed. Myocardial infarction rates per 1000 person-years were positively related to pulse pressure (PP1, 3.5; PP2, 2.9; PP3, 7.5; PP3 versus PP1, P = .02). Wide pulse pressure was identified as a predictor of myocardial infarction (PP3 versus [PP1 + PP2]: relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.2-4.1), controlling for other known risk factors by Cox regression. A curvilinear relation (resembling a J shape) between diastolic fall and myocardial infarction was observed in patients with the widest pulse pressure, PP3 (L, 9.5; M, 3.9; S, 11.2; L versus M: RR = 2.5, 95% CI = 1.0-6.2; S versus M: RR = 2.9, 95% CI = 1.1-8.0).(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides.
Authors: Campbell D J , Kladis A , Duncan A M
Published: June 2012

We examined the dose-related effects of angiotensin-converting enzyme inhibitors on circulating and tissue levels of angiotensin and bradykinin peptides by administering perindopril or lisinopril to rats in drinking water for 7 days. A reduction in the ratio of plasma angiotensin II (Ang II) to Ang I was seen for 0.006 mg/kg per day perindopril, with an increase in plasma renin and Ang I at 0.017 mg/kg per day. Plasma Ang II levels did not decrease until 1.4 mg/kg per day perindopril, at which dose plasma Ang I levels reached a plateau of an approximate 25-fold increase. The effects of perindopril on Ang II and Ang I levels in heart, lung, aorta, and brown adipose tissue were parallel to those observed for plasma. By contrast, renal Ang I levels did not increase, and renal Ang II levels decreased by 40% at 0.017 mg/kg per day, the same threshold seen for the increase in plasma renin. Perindopril increased circulating bradykinin-(1-9) levels approximately eightfold, with a threshold dose of 0.052 mg/kg per day, and increased bradykinin-(1-9) levels in kidney, heart, and lung in parallel with the changes observed for plasma. By contrast, aortic and brown adipose tissue bradykinin-(1-9) and bradykinin-(1-7) levels increased severalfold for perindopril doses as low as 0.006 mg/kg per day. Lisinopril also increased aortic bradykinin-(1-9) and bradykinin-(1-7) levels at doses below the threshold for the decrease in the ratio of Ang II to Ang I. These data indicate that renal Ang II levels and vascular bradykinin-(1-9) levels respond to low doses of converting enzyme inhibitor and may be important mediators of the effects of these compounds. The parallel increases in bradykinin-(1-9) and bradykinin-(1-7) levels in aorta and brown adipose tissue, at inhibitor doses below the threshold for inhibition of Ang I conversion, may result from a mechanism different from inhibition of "classic" angiotensin-converting enzyme.
Parathyroid hormone/adenylate cyclase coupling in vascular smooth muscle cells.
Authors: Hanson A S , Linas S L
Published: June 2012

Parathyroid hormone (PTH) has been implicated in hypertension, but PTH infusion results in vasodilation. PTH activates adenylate cyclase in vascular smooth muscle, but little is known about the factors that regulate PTH receptor/adenylate cyclase coupling in vascular cells. To characterize hormone-receptor signaling, we measured cyclic AMP levels in rat arterial smooth muscle cells in culture exposed to PTH (bovine 1-34). PTH yielded time- and concentration-dependent increases in cyclic AMP levels. Compared with isoproterenol, PTH was more potent, with a threshold at 2 x 10(-9) versus 5 x 10(-8) mol/L and half maximal responses at 10(-8) versus 2.4 x 10(-7) mol/L. PTH-induced increases in cyclic AMP were independent of extracellular calcium, cyclooxygenase metabolites, phospholipase C, and protein kinase C because PTH-induced increases in cyclic AMP were not prevented by variations in extracellular calcium, indomethacin, angiotensin II, vasopressin, and protein kinase C activators or inhibitors. PTH/adenylate cyclase coupling was G protein-dependent because increases in cyclic AMP were prevented by preincubation with cholera toxin but not with pertussis toxin. Prolonged exposure to PTH resulted in time- and concentration-dependent homologous desensitization of cyclic AMP responses. Desensitization occurred proximal to G protein/adenylate cyclase because after prolonged PTH, responses to forskolin and cholera toxin remained intact. Desensitization was independent of protein kinase A and receptor sequestration because cyclic AMP responses remained after prolonged exposure to forskolin and pretreatment with phenylarsine oxide, colchicine, and cytochalasin D. We conclude that in vascular smooth muscle cells, PTH is coupled to adenylate cyclase through a cholera toxin-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal sodium handling in patients with untreated hypertension and white coat hypertension.
Authors: Burnier M , Biollaz J , Magnin J L , Bidlingmeyer M , Brunner H R
Published: June 2012

Renal tubular sodium handling was investigated prospectively in 48 normotensive subjects, 53 untreated hypertensive patients, and 13 patients with white coat hypertension using endogenous trace lithium as a marker of proximal sodium reabsorption. A 12-hour daytime ambulatory blood pressure recording was performed in all patients to confirm the diagnosis of hypertension. Patients were included in the white coat hypertension group if their office blood pressure was above 160/90 mm Hg but the mean value of their 12-hour ambulatory recording was lower than 140/90 mm Hg. All participants were studied on their normal diet and ate salt freely. Fractional excretions of sodium (FENa), lithium (FELi), and potassium (FEK) were measured simultaneously before blood pressure recording. FENa was significantly higher in hypertensive patients (0.84 +/- 0.05%, P < .05) than in normotensive control subjects (0.60 +/- 0.06%), and FELi was comparable in the two groups (15.4 +/- 0.65% in hypertensive patients and 17.0 +/- 0.9% in control subjects). However, the relation between FENa and FELi was significantly different in normotensive subjects and hypertensive patients (P < .001), so that for a given increase in FENa a smaller increase in FELi was observed in hypertensive patients. In addition, the ratios of urinary lithium to sodium and urinary potassium to sodium were significantly reduced in hypertensive patients, suggesting an increased proximal reabsorption of sodium. Similar alterations in renal tubular sodium handling were observed in patients with white coat hypertension. These results suggest that an increased sodium reabsorption in the proximal tubule may contribute to the maintenance of hypertension and that white coat hypertension might represent a prehypertensive state.
Regulation of intracellular pH in the spontaneously hypertensive rat. Role of bicarbonate-dependent transporters.
Authors: Redon J , Batlle D
Published: June 2012

Previous studies that have evaluated the Na(+)-H+ antiporter in cells from hypertensive subjects were generally performed under conditions in which HCO3-CO2, the physiological buffer system, was absent from the assay media. The objective of this study was to evaluate the activity of the Na(+)-H+ antiporter and that of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchangers in cells assayed in the presence of HCO3-CO2 in the media. Lymphocytes from 6- to 8-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats were obtained from the thymus gland and assayed immediately after isolation. The activity of the Na(+)-H+ antiporter after stimulation by cell acidification (pHi approximately 6.4) was similar in SHR and WKY rats (18.67 +/- 1.03 and 16.12 +/- 0.92 mmol H+/L per minute, respectively). Recovery from cell alkalinization was effected by an Na(+)-independent Cl(-)-HCO3- exchanger, with maximal activity at an alkaline pHi (approximately 7.7). The stimulated activity of this Na(+)-independent Cl(-)-HCO3- exchanger was also not different between SHR and WKY cells (2.65 +/- 0.25 and 2.55 +/- 0.32 mmol H+/L per minute, respectively). Acute chloride removal produced a rise in pHi that was Na(+)-dependent and sensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) but resistant to ethylisopropylamiloride (EIPA), reflecting the activity of an Na(+)-dependent Cl(-)-HCO3- exchanger. Unlike the Na(+)-H+ exchanger and the Na(+)-independent Cl(-)-HCO3- exchanger, which had their highest activities at extremes of pHi (low pHi, Na(+)-H+ exchanger, and high pHi, Na(+)-independent Cl(-)-HCO3- exchanger), the Na(+)-dependent Cl(-)-HCO3- exchanger had its maximal activity near steady-state pHi (approximately 7.1). No significant differences were found in the stimulated activity of this exchanger between cells from SHR and WKY rats (2.23 +/- 0.26 and 2.50 +/- 0.43 mmol H+/L per minute, respectively). The kinetic properties of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchanger, examined as a function of external Cl-, were also virtually identical in cells from SHR and WKY rats. We conclude that in lymphocytes from SHR and WKY rats, the activity of the two Cl(-)-HCO3- exchangers, like that of the Na(+)-H+ exchanger, is dependent on the prevailing pHi. The Na(+)-dependent Cl(-)-HCO3- exchanger has its highest activity near steady-state pHi, suggesting an important role in the cell defense against intracellular acidosis under physiological conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
Is ouabain an authentic endogenous mammalian substance derived from the adrenal?
Authors: Doris P A , Jenkins L A , Stocco D M
Published: June 2012

Ouabain has recently been reported to be an endogenous mammalian substance released by the adrenal cortex and present in normal plasma. We have attempted to confirm and extend this observation. Using a ouabain radioimmunoassay developed in this laboratory, we fractionated by high-performance liquid chromatography (HPLC) normal human plasma from healthy volunteers to determine the presence of ouabain immunoreactivity and compare this immunoreactivity with authentic ouabain. In most subjects no ouabain immunoreactivity that coeluted with authentic ouabain was observed. Some subjects had ouabain-immunoreactive material present at low levels, but it was largely attributable to cross-reactivity with diverse substances found not to be ouabain. Similar results were obtained after analysis of plasma collected from 10 patients entering a medical intensive care unit. Studies of serum-free medium conditioned by bovine adrenocortical cells showed some ouabain immunoreactivity. To determine whether this material might be a steroid product of cholesterol side-chain cleavage, we performed chemical blockade of steroidogenesis, which effectively suppressed progesterone production by these cells but had no consistent effect on ouabain immunoreactivity in this medium. Stimulation of steroidogenesis with 22-R-OH-cholesterol in bovine adrenocortical cells did not produce any increase in the ouabain immunoreactivity present in conditioned medium. Subsequent HPLC studies of ouabain immunoreactivity in bovine adrenocortical cell-conditioned medium indicated that authentic ouabain did not account for most of the ouabain immunoreactivity in serum-free medium. Studies with bovine adrenocortical cells incubated in a minimal salt and glucose medium indicated a small peak of immunoreactivity that may correspond to authentic ouabain.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of glucose intolerance in cardiac diastolic function in essential hypertension.
Authors: Nagano N , Nagano M , Yo Y , Iiyama K , Higaki J , Mikami H , Ogihara T
Published: June 2012

Insulin resistance and glucose intolerance have been suggested to be involved in the pathogenesis of various cardiovascular diseases. We examined the role of glucose intolerance in cardiac performance and cardiac hypertrophy in 33 patients with essential hypertension (28 to 71 years of age, mean +/- SD: 53 +/- 13 years) who had never been treated. Patients with obesity (body mass index > 30 kg/m2) or overt diabetes were excluded. Plasma glucose and insulin were measured after oral administration of 75 g glucose. The incremental areas of glucose and insulin were used as indices of glucose intolerance and insulin resistance, respectively. Patients with impaired glucose tolerance according to World Health Organization criteria (n = 12) showed a significantly higher ratio of peak velocity during atrial contraction to early left ventricular filling phase (A/E ratio) than those with normal glucose tolerance (n = 21) despite similar age, blood pressure, and left ventricular mass index. By regression analysis, left ventricular mass index positively correlated with systolic blood pressure (r = .392, P < .05) but not with any parameters of glucose and insulin metabolism. A/E ratio determined by a Doppler system significantly correlated with age ( r = .776) and fasting and peak levels and incremental area of plasma glucose (r = .529, r = .468, and r = .634) but not with those parameters of insulin. In contrast, ejection fraction was not related to blood pressure, glucose tolerance, or insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions.
Authors: Förstermann U , Closs E I , Pollock J S , Nakane M , Schwarz P , Gath I , Kleinert H
Published: June 2012

Three isozymes of nitric oxide (NO) synthase (EC 1.14.13.39) have been identified and the cDNAs for these enzymes isolated. In humans, isozymes I (in neuronal and epithelial cells), II (in cytokine-induced cells), and III (in endothelial cells) are encoded for by three different genes located on chromosomes 12, 17, and 7, respectively. The deduced amino acid sequences of the human isozymes show less than 59% identity. Across species, amino acid sequences for each isoform are well conserved (> 90% for isoforms I and III, > 80% for isoform II). All isoforms use L-arginine and molecular oxygen as substrates and require the cofactors NADPH, 6(R)-5,6,7,8-tetrahydrobiopterin, flavin adenine dinucleotide, and flavin mononucleotide. They all bind calmodulin and contain heme. Isoform I is constitutively present in central and peripheral neuronal cells and certain epithelial cells. Its activity is regulated by Ca2+ and calmodulin. Its functions include long-term regulation of synaptic transmission in the central nervous system, central regulation of blood pressure, smooth muscle relaxation, and vasodilation via peripheral nitrergic nerves. It has also been implicated in neuronal death in cerebrovascular stroke. Expression of isoform II of NO synthase can be induced with lipopolysaccharide and cytokines in a multitude of different cells. Based on sequencing data there is no evidence for more than one inducible isozyme at this time. NO synthase II is not regulated by Ca2+; it produces large amounts of NO that has cytostatic effects on parasitic target cells by inhibiting iron-containing enzymes and causing DNA fragmentation. Induced NO synthase II is involved in the pathophysiology of autoimmune diseases and septic shock. Isoform III of NO synthase has been found mostly in endothelial cells. It is constitutively expressed, but expression can be enhanced, eg, by shear stress. Its activity is regulated by Ca2+ and calmodulin. NO from endothelial cells keeps blood vessels dilated, prevents the adhesion of platelets and white cells, and probably inhibits vascular smooth muscle proliferation.
Glucose and insulin levels during diuretic therapy in hypertensive men.
Authors: Siegel D , Saliba P , Haffner S
Published: June 2012

We investigated serum glucose and insulin levels resulting from thiazide or thiazide-like diuretic administration and determined whether they were associated with serum or intracellular potassium or magnesium values. We also explored the role of obesity both alone and with thiazides on serum insulin and glucose. Hypertensive men were withdrawn from diuretics and repleted with oral potassium and magnesium and then randomized to 2 months of treatment with (1) hydrochlorothiazide, (2) hydrochlorothiazide with oral potassium, (3) hydrochlorothiazide with oral potassium and magnesium (4) hydrochlorothiazide and triamterene, (5) chlorthalidone, or (6) placebo. Serum was available from 202 participants for insulin and glucose determinations. Mean fasting serum glucose and insulin did not change significantly after 2 months of randomized therapy with the exception of participants randomized to chlorthalidone, who had significant increases in both serum insulin and glucose (P < .05 and P < .01, respectively). As body mass index increased, there was a corresponding increase in serum insulin and to a lesser degree in serum glucose. Also, as body mass index increased, participants taking hydrochlorothiazide had a corresponding increase of serum insulin (P < .05). After treatment, intracellular potassium and magnesium were both associated with higher serum insulin (P < .001 for each), and serum potassium was associated with higher and serum magnesium with lower serum glucose (P < .01 for each). In most hypertensive men, treatment with 50 mg chlorthalidone increases glucose and insulin levels, whereas administration of 50 mg hydrochlorothiazide, with or without potassium and/or magnesium conserving strategies, does not.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood pressure-lowering effect of an orally active vasopressin V1 receptor antagonist in mineralocorticoid hypertension in the rat.
Authors: Burrell L M , Phillips P A , Stephenson J M , Risvanis J , Rolls K A , Johnston C I
Published: June 2012

We studied the contribution of vasopressin to the maintenance of high blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat using the nonpeptide orally effective vasopressin V1 receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the vasopressin V1 receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140 +/- 4 mm Hg (n = 12) in DOCA-salt rats compared with 111 +/- 2 mm Hg in salt control rats (n = 18). Acute oral OPC-21268 (30 mg/kg) significantly (P < .01) reduced mean intra-arterial pressure in DOCA-salt hypertension, with an average maximal decrease of 24 +/- 3 mm Hg occurring at 2.5 +/- 0.7 hours after dosing. Systolic blood pressure (tail-cuff) in DOCA-salt rats was 178 +/- 2 mm Hg. Chronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly (P < .01) reduced systolic blood pressure in DOCA-salt hypertension, with an average maximal decrease of 27 +/- 5 mm Hg. The antihypertensive effect was reversed 5 days after treatment with OPC-21268 was stopped. In water control rats basal systolic pressure (120 +/- 1 mm Hg, n = 20) was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 days), and this was confirmed by direct measurement of mean intra-arterial pressure. After chronic oral OPC-21268 (30 mg/kg twice daily for 7 days) hepatic V1 receptor binding was significantly reduced for up to 10 hours (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term administration of L-arginine improves nitric oxide release from kidney in deoxycorticosterone acetate-salt hypertensive rats.
Authors: Hayakawa H , Hirata Y , Suzuki E , Kimura K , Kikuchi K , Nagano T , Hirobe M , Omata M
Published: June 2012

To examine the effects of L-arginine (L-Arg) on endothelial function, we administered 0.5 g/L L-Arg in drinking water to deoxycorticosterone acetate (DOCA)-salt rats for 8 weeks and then measured nitric oxide (NO) release from isolated kidneys using a newly developed real-time chemiluminescence method. Renal pathology was also analyzed. Acetylcholine caused much smaller declines in renal perfusion pressure (10(-7) mol/L acetylcholine: -24 +/- 2% [SEM] versus -50 +/- 2%, P < .001) and NO release in DOCA-salt rats (+3 +/- 1 versus +33 +/- 3 fmol/min per gram kidney weight, P < .001) compared with control rats. L-Arg did not influence the time course of systolic blood pressure elevation in DOCA-salt rats (211 +/- 5 versus 208 +/- 6 mmHg, DOCA versus L-Arg/DOCA, P = NS). However, oral administration of L-Arg improved acetylcholine-induced declines in renal perfusion pressure (10(-7) mol/L acetylcholine: L-Arg/DOCA, -39 +/- 3%, P < .01 versus DOCA). This change was associated with an increase in NO release by acetylcholine (10(-7) mol/L acetylcholine: L-Arg/DOCA, +10 +/- 1 fmol/min per gram kidney weight, P < .05 versus DOCA). However, morphological changes in renal vessels and glomeruli were similar between DOCA and L-Arg/DOCA rats. These results suggest that L-Arg administration partially reverses renal endothelial function with respect to vasorelaxation and NO release independent of blood pressure changes, indicating that hypertensive vessels seem to be depleted of L-Arg and/or have defects in the availability of L-Arg for NO synthesis.
Active and passive arteriolar regulation in spontaneously hypertensive rats.
Authors: Bohlen H G , Lash J M
Published: June 2012

This study determined to what extent active and passive wall tensions increase in in vivo intestinal arterioles of 13- to 15-week-old and 25- to 27-week-old spontaneously hypertensive rats (SHR) to maintain normal or smaller arteriolar diameters during microvascular hypertension. Acetylcholine and nitroprusside were used to determine whether vascular muscle relaxation to endothelium-derived relaxing factor or cyclic GMP is impaired. Large arterioles of hypertensive rats have passive tension-circumference relations that are steeper and shifted to the left compared with those of age-matched controls; passive resistance to distension limits vasodilation in hypertensive rats except at their naturally elevated arteriolar pressure. Passive tension contributes approximately 30% of the total resting tension in arterioles of hypertensive and normotensive rats because a greater passive tension occurs at the 20% to 25% constricted resting diameter in hypertensive rats. Absolute and relative changes in the diameter of SHR arterioles during acetylcholine and nitroprusside application were equal to or greater than those in Wistar-Kyoto rats. However, reduction in active tension was suppressed in older SHR and remained approximately 50% higher than that found in older Wistar-Kyoto rats during drug application. Vasoconstriction and increased passive resistance to distension of the arteriolar wall diminish the active tension required to maintain normal or smaller resting diameters against microvascular hypertension. However, the elevated microvascular pressure in hypertensive rats is required to allow near-normal dilation to compensate for their increased passive resistance to stretch and decreased ability to relax active tension through cyclic GMP mechanisms.
Unlike human hypertension, blood pressure in a hereditary hypertensive rat strain shows no linkage to the angiotensinogen locus.
Authors: Hübner N , Kreutz R , Takahashi S , Ganten D , Lindpaintner K
Published: June 2012

Recently, evidence has been presented for genetic linkage between the angiotensinogen gene and primary hypertension in humans. In the present study we examined whether a similar linkage between blood pressure and the angiotensinogen gene locus can be demonstrated in a widely used animal model of primary hypertension, the stroke-prone spontaneously hypertensive rat (Heidelberg colony, SHRSPHD). In 115 F2 hybrids bred from SHRSPHD and a normotensive reference strain, the Wistar-KyotoHD (WKYHD) rat, systolic and diastolic blood pressures and heart rate were determined by indwelling arterial catheters in the presence and absence of dietary sodium loading. In addition, left and right ventricular heart weight was measured. Using a newly developed polymorphic marker assay for the angiotensinogen gene based on polymerase chain reaction amplification of an exon 2 fragment and subsequent restriction endonuclease digestion, we performed a cosegregation study in this cohort. No evidence for cosegregation between the angiotensinogen gene locus and blood pressure or any other phenotypic parameter assessed was found. Although the SHRSP serves as a valuable model of hypertension, our data emphasize that disease-relevant genetic loci in humans and rats cannot be assumed to coincide.
Vasoconstrictor action of angiotensin I-convertase and the synthetic substrate (Pro11,D-Ala12)-angiotensin I.
Authors: Mangiapane M L , Rauch A L , MacAndrew J T , Ellery S S , Hoover K W , Knight D R , Johnson H A , Magee W P , Cushing D J , Buchholz R A
Published: June 2012

A chymase (also referred to as angiotensin I-convertase) specific for the conversion of angiotensin (Ang) I to Ang II has been identified in human heart. This serine protease is also present in dog and marmoset vasculature. We examined the vasoconstrictor effects of Ang II putatively generated from an angiotensin-converting enzyme (ACE)-resistant convertase synthetic substrate (SUB) in vivo and in vitro. In marmosets, SUB (7 to 700 micrograms/kg i.v.) or Ang I (0.1 to 30 micrograms/kg) caused similar dose-dependent increases in mean arterial pressure (10 to 100 mm Hg) and decreases in heart rate. Pressor effects of SUB were slightly attenuated at low (but not high) doses by captopril (CAP, 1 mg/kg i.v.) and blocked by losartan (5 mg/kg i.v.); in contrast Ang I pressor effects were substantially blocked by both. In isolated canine superior mesenteric artery, Ang I-induced contraction was eliminated by losartan and reduced but not eliminated by 10 mumol/L CAP. When combined with the serine protease inhibitor chymostatin, CAP eliminated Ang I-induced contraction, but chymostatin alone had no effect. SUB-induced contraction was not blocked by CAP but was equally blocked by chymostatin (25 mumol/L) alone or by the combination of CAP (10 mumol/L) and chymostatin (25 mumol/L); losartan (10 mumol/L) eliminated SUB-induced responses. Previous studies have suggested that Ang I-convertase is important for production of Ang II in the heart. Our results are consistent with a potential role for Ang I-convertase in the production of Ang II in the vasculature, resulting in Ang II-mediated vasoconstriction.
Vascular renin in the guinea pig. Suppression by the renin inhibitor remikiren.
Authors: Hilgers K F , Fischli W , Veelken R , Mann J F
Published: June 2012

Angiotensin I and II are generated by the vascular wall. Whether this generation depends on renin or on other enzymes is debated. We tested the hypothesis that remikiren, a highly specific inhibitor of human and guinea pig renin, may inhibit the vascular renin-angiotensin system. Isolated hindquarters from guinea pigs were perfused with an artificial medium, and angiotensin I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Guinea pig hindquarters released angiotensin I (23.8 +/- 5.6 fmol/30 min; n = 13) and angiotensin II (95.2 +/- 19 fmol/30 min; n = 13) spontaneously. Inhibition of the angiotensin I-converting enzyme by captopril (10 nmol/mL) suppressed angiotensin II by 85% and increased angiotensin I by 352% (n = 5, P < .05). Infusion of remikiren (1.6 nmol/mL) in addition to captopril decreased angiotensin I release by 68% (P < .05 versus captopril alone, n = 5 each). We conclude that renin generates angiotensin I in an isolated guinea pig resistance vessel bed. Our study demonstrates that renin rather than nonrenin enzymes is responsible for the major part of vascular angiotensin formation.
A photoactivable source of relaxing factor in genetic hypertension.
Authors: Charpie J R , Peters A , Webb R C
Published: June 2012

Deendothelialized rings of rabbit aorta relax after exposure to UV light because of release of a relaxing factor that is similar if not identical to nitric oxide. We tested the hypothesis that production of the photo-induced relaxing factor is impaired in a rat model of genetic hypertension. Thoracic aortas were removed from adult Wistar-Kyoto rats and stroke-prone spontaneously hypertensive rats. The vessels were cut into rings, denuded of endothelium, and placed in a muscle bath for isometric force measurement. Rings were contracted with phenylephrine, and relaxation was measured after exposure to UV light. Aortic rings from stroke-prone spontaneously hypertensive rats relaxed to a greater extent after exposure to UV light than did rings from Wistar-Kyoto rats. An inhibitor of nitric oxide synthase (N omega-nitro-L-arginine) greatly potentiated the relaxation responses to light in both strains, and these enhanced relaxations were attenuated by tetraethylammonium chloride, potassium chloride, ouabain, or inhibitors of guanylate cyclase. These results suggest that UV irradiation induces relaxation in aortic smooth muscle that is greater in hypertensive than normotensive rats and is greatly enhanced after addition of inhibitors of nitric oxide production. Thus, the unidentified photo-induced relaxing factor is not solely nitric oxide but may also represent either a hyperpolarizing factor, because depolarization blocks the responses entirely, or possibly smooth muscle guanylate cyclase that might itself be photoactivable.