bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute ACE Inhibition Causes Plasma Extravasation in Mice That is Mediated by Bradykinin and Substance P
Authors: Emanueli Costanza , Grady Eileen F. , Madeddu Paolo , Figini Michela , Bunnett Nigel W. , Parisi Deborah , Regoli Domenico , Geppetti Pierangelo
Published: June 2012

Abstract
—The use of angiotensin-converting enzyme (ACE) has been associated with the occurrence of adverse effects, including cough and angioneurotic edema. Accumulation of kinins has been suggested to play a major role in these adverse effects of ACE inhibitor, although conclusive evidence for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of neurogenic inflammatory mechanisms. Intravenous captopril and enalapril increased the extravasation of Evans blue dye in all tissues examined (trachea, stomach, duodenum, and pancreas). This effect was evident 15 minutes after drug administration. The particulate dye Monastral blue identified the sites of captopril-induced leakage in the microvasculature. Pretreatment with the bradykinin B
2
receptor antagonist Hoe 140 or with the tachykinin NK
1
receptor antagonist SR 140333 inhibited captopril-evoked increase in plasma extravasation. In mice in which the gene encoding the bradykinin B
2
receptor was disrupted by gene targeting, neither bradykinin nor captopril increased plasma extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive response induced by captopril. The present findings suggest that ACE inhibition increases kinin levels in tissues and/or plasma. These increased kinin levels increase microvascular leakage in mouse airways and digestive tract via the release of tachykinins from terminals of primary sensory neurons. Exaggerated kinin production and the subsequent stimulation of peptide release from sensory nerves may be involved in adverse effects of ACE inhibitors.
Losartan but Not Verapamil Inhibits Angiotensin II–Induced Tissue Endothelin-1 Increase
Authors: d’Uscio Livius V. , Shaw Sidney , Barton Matthias , Lüscher Thomas F.
Published: June 2012

Abstract
—Endothelin partially mediates angiotensin (Ang) II–induced vascular changes in vivo. This study investigated the effects of the angiotensin type 1 receptor antagonist losartan and the calcium channel blocker verapamil on vascular reactivity and tissue endothelin-1 levels in aortas of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng · kg
−1
· min
−1
). Ang II increased systolic blood pressure (39±4 mm Hg,
P
<0.05). Concomitant treatment with losartan abolished the Ang II–induced pressure increase (
P
<0.05), whereas verapamil reduced it only partially (
P
<0.05). In the aortas of rats with Ang II–induced hypertension, tissue endothelin-1 content was increased threefold and contractions to endothelin-1 were impaired (
P
<0.05). Interestingly, these alterations were normalized by losartan (
P
<0.05) but not by verapamil. Hence, there was a strong, negative correlation between contractions to endothelin-1 and tissue endothelin-1 content (
r
=−0.733,
P
<0.0001). In contrast, both antihypertensive drugs normalized impaired endothelium-dependent relaxations to acetylcholine and reduced the sensitivity of vascular smooth muscle to sodium nitroprusside compared with Ang II–treated rats (
P
<0.05). Ang II–induced hypertension enhanced endothelium-dependent contractions to acetylcholine, and these were normalized by either drug. In conclusion, these findings suggest that long-term treatment with Ang II modulates endothelin-1 protein expression in the rat aorta. Although both antihypertensive agents lowered blood pressure and normalized endothelial function, only losartan prevented the increase in tissue endothelin-1 content, suggesting that angiotensin type 1 receptor antagonists but not calcium antagonists modulate tissue endothelin-1 in vivo.
Eclamptic Plasma Stimulates Norepinephrine Release in Cultured Sympathetic Nerve
Authors: Khatun Selina , Kanayama Naohiro , Sato Eiji , Belayet Hossain M. , Kobayashi Takao , Terao Toshihiko
Published: June 2012

Abstract
—The purpose of the present study was to evaluate the effect of plasma from eclamptic and preeclamptic patients on cultured sympathetic nerve. Sympathetic neurons from 12- to 14-day-old chick embryos were cultured; the neurons were then stimulated with 50% plasma from eclamptic, preeclamptic, hypertensive, normotensive pregnant, hypertensive, and normotensive nonpregnant women (n=7). Similarly, neurons were individually incubated with mixtures of 50% corresponding plasma with 0.25% bupivacaine or bupivacaine only (n=7). Furthermore, the effects of 1%, 10%, and 50% plasma from eclamptic, preeclamptic, and normotensive pregnant patients (n=7) were also evaluated. Norepinephrine concentrations were measured by high-performance liquid chromatography. Electron microscopic studies of nerve cells were also performed. Stimulation with plasma from eclamptic and preeclamptic women significantly increased norepinephrine concentration (
P
<0.0001) compared with control. The release of norepinephrine was found to be concentration-dependent. Conversely, norepinephrine secretion was significantly hampered by bupivacaine treatment (
P
<0.0001). Electron microscopic studies in eclamptic and preeclamptic plasma–stimulated nerve cells showed that perikarya were in close contact with each other and with nerve cell processes. After treatment with bupivacaine, nerve cells were irregular in shape and the cell membranes were demyelinated. These results suggest that eclamptic and preeclamptic plasma has an excitotoxic effect on sympathetic nerve via axoplasmic membrane depolarization, thus increasing norepinephrine secretion that is blocked by bupivacaine. A preeclamptic condition may be improved by depression of sympathetic nerve stimulation.
Prenatal Malnutrition-Induced Changes in Blood Pressure
Authors: Tonkiss John , Trzcińska Monika , Galler Janina R. , Ruiz-Opazo Nelson , Herrera Victoria L. M.
Published: June 2012

Abstract
—A link between prenatal malnutrition and hypertension in human populations has recently been proposed. Rat models of prenatal malnutrition have provided major support for this theory on the basis of tail-cuff measurements. However, this technique requires restraint and elevated temperature, both potential sources of stress. To determine the effect of prenatal protein malnutrition on blood pressure under nonstress conditions, 24-hour radiotelemetric measurements were taken in the home cage. Male rats born to dams fed a 6% casein diet for 5 weeks before mating and throughout pregnancy were studied in early adulthood (from 96 days of age). During the waking phase of their cycle but not the sleep phase, prenatal malnutrition gave rise to small but significant elevations of diastolic blood pressure and heart rate compared with well-nourished controls. Direct effects of stress on blood pressure responses were determined in a second experiment using an olfactory stressor. Prenatally malnourished rats showed a greater increase in both systolic and diastolic pressures compared with well-nourished controls during the first exposure to ammonia. A different pattern of change of cardiovascular responses was also observed during subsequent presentations of the stressor. These findings of a small baseline increase in diastolic pressure consequent to prenatal malnutrition, but an augmented elevation of both systolic and diastolic pressures after first exposure to stress, suggest the need to reevaluate interpretation of the large elevations in blood pressure previously observed in malnourished animals using the stressful tail-cuff procedure.
Familial Hypertension, Insulin, Sympathetic Activity, and Blood Pressure Elevation
Authors: Masuo Kazuko , Mikami Hiroshi , Ogihara Toshio , Tuck Michael L.
Published: June 2012

Abstract
—This study evaluated the effects of a positive family history of hypertension (FH+) on the contributions of sympathetic nervous system (SNS) activity and insulin to blood pressure elevation (BPE). The study design was longitudinal and evaluated BP, body mass index (BMI), and fasting plasma insulin and norepinephrine (NE) levels for 10 years in 557 young, nonobese Japanese men who were normotensive at entry. FH+ was defined as hypertension in first-degree relatives as verified by historical records or direct determination. BPE was defined as a ≥10% rise in systolic and diastolic BP over entry levels during the 10-year period. In the total group FH+ was noted in 16%, and BPE occurred in 18% of normotensive subjects. When evaluated by FH, the prevalence of BPE was 33% in FH+ compared with 16% in FH− (
P
<0.05). BP levels were greater both at entry and at year 10 in the FH+ group. The absolute increment in plasma NE over 10 years was greater in the BPE group than in those without BPE (
P
<0.01). Of note, the rise in plasma NE levels in BPE individuals was identical in FH+ and FH− subjects. Plasma insulin increments were also greater in normotensive subjects with BPE than in normotensive subjects without BPE. However, compared with NE, development of hyperinsulinemia was more pronounced in the FH+ subjects. The results indicate that SNS hyperactivity may be a less genetically determined predictor of hypertension than is hyperinsulinemia. Because SNS changes in this initially normotensive population appeared more closely related to the development of hypertension than to hyperinsulinemia, environmental rather than genetic factors may be the main determinant of early BPE in nonobese normotensive subjects.
Effect of Genetic Deficiency of Angiotensinogen on the Renin-Angiotensin System
Authors: Tamura Kouichi , Umemura Satoshi , Sumida Yoichi , Nyui Nobuo , Kobayashi Shun-ichi , Ishigami Tomoaki , Kihara Minoru , Sugaya Takeshi , Fukamizu Akiyoshi , Miyazaki Hitoshi , Murakami Kazuo , Ishii Masao
Published: June 2012

Abstract
—This study examined expression of renin-angiotensin system (RAS) component mRNAs in angiotensinogen gene knockout (
Atg
−/−) mice. Wild-type (
Atg
+/+) and
Atg
−/− mice were fed a normal-salt (0.3% NaCl) or high-salt (4% NaCl) diet for 2 weeks. Angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin II type 1a receptor (AT
1A
), and angiotensin II type 2 receptor (AT
2
) mRNA levels were measured by Northern blot analysis. In
Atg
+/+ mice, activities of circulating RAS and renal angiotensinogen mRNA level were decreased by salt loading, whereas levels of renal and cardiac ACE; renal, brain, and cardiac AT
1A
; and brain and cardiac AT
2
mRNA were increased by salt loading. Although activities of circulating RAS were not detected in
Atg
−/− mice, salt loading increased blood pressure in
Atg
−/− mice. In
Atg
−/− mice, renal renin mRNA level was decreased by salt loading; in contrast, salt loading increased renal AT
1A
and cardiac AT
2
mRNA levels in
Atg
−/− mice, and these activated levels in
Atg
−/− mice were higher than those in
Atg
+/+ mice fed the high-salt diet. Thus, expression of each component of the RAS is regulated in a tissue-specific manner that is distinct from other components of systemic and local RAS and that appears to be mediated by a mechanism other than changes in the circulating or tissue levels of angiotensin peptides.
Angiotensin Receptor Blockade Blunts Hyperinsulinemia-Induced Hypertension in Rats
Authors: Fang Te-Chao , Huang Wann-Chu
Published: June 2012

Abstract
—The study was conducted to examine the effects of the angiotensin subtype 1 and 2 receptor antagonists (losartan and
PD123319
, respectively) on blood pressure (BP) and renal excretory function in chronic hyperinsulinemia–induced hypertension in rats. Hyperinsulinemia was achieved by insulin infusion (21.5 pmol/kg per minute) via osmotic minipump for 6 weeks. Losartan or
PD123319
was coinfused either at the beginning or after 4 weeks of insulin infusion. The results showed that insulin infusion significantly increased the plasma insulin concentration from 259.0±22.2 to 646.5±33.0 and 713.9±26.5 pmol/L (
P
<0.05) by the end of the fourth and sixth weeks, respectively, after insulin infusion. There were no significant changes in plasma glucose and triglyceride concentrations. Systolic BP increased from 139±3 to 156±1 and 157±2 mm Hg (
P
<0.05) at the corresponding time points. Combined losartan (3.5 μg/kg per minute) and insulin infusion prevented the rise in BP and improved insulin resistance. When hypertension had been established after 4 weeks of insulin infusion, superimposed infusion of losartan on insulin reversed the elevated BP to control levels within 1 week. In contrast, administration of
PD123319
(0.5 and 10 μg/kg per minute) failed to alter insulin-induced hypertension. Combined
PD123319
with losartan did not alter the losartan-induced hypotensive effect in insulin-infused rats. There were no significant differences in water intake, urine flow, body weight gain, and sodium gain before and after antagonist administration among groups. These results indicate that angiotensin type 1 receptors play a determinant role in the pathogenesis of insulin-induced hypertension in rats.
Biphasic Effect of Bradykinin on Rabbit Afferent Arterioles
Authors: Yu Hong , Carretero Oscar A. , Juncos Luis A. , Garvin Jeffrey L.
Published: June 2012

Abstract
—Bradykinin plays an important role in the regulation of renal hemodynamics. However, there have been few studies of the effect of bradykinin on isolated afferent arterioles, vascular segments that are important for the regulation of renal blood flow and glomerular filtration rate. Our purpose was to study (1) the effects of bradykinin on isolated perfused rabbit afferent arterioles and (2) the mechanisms of actions. Afferent arterioles dissected from rabbits were perfused in vitro at 60 mm Hg. In afferent arterioles preconstricted with phenylephrine, 10
−12
to 10
−10
mol/L bradykinin increased luminal diameter from 9.0±1.0 to 14.3±1.2 μm (
P
<0.003). In contrast, 10
−9
and 10
−8
mol/L bradykinin decreased luminal diameter to 10.8±1.4 and 9.7±1.2 μm, respectively (
P
<0.001). Bradykinin added to the bath had no effect on preconstricted afferent arterioles. The addition of [des-Arg
9
]-bradykinin (10
−9
and 10
−8
mol/L), a B
1
receptor agonist, to the lumen decreased diameter from 9.7±1.2 to 6.7±1.2 μm at 10
−8
mol/L (
P
<0.002). Icatibant (Hoe 140), a B
2
receptor antagonist, blocked both the vasodilation and vasoconstriction induced by bradykinin as well as the vasoconstriction induced by [des-Arg
9
]-bradykinin. L-NAME had no effect on bradykinin-induced dilation or constriction. Indomethacin blocked both the dilation induced by 10
−12
to 10
−10
mol/L bradykinin and the constriction induced by 10
−9
to 10
−8
mol/L bradykinin. In fact, in the presence of indomethacin, 10
−9
and 10
−8
mol/L bradykinin increased luminal diameter from 6.2±0.7 to 10.7±0.6 μm at 10
−8
mol/L (
P
<0.001), which was attenuated by L-NAME. Finally, in the presence of SQ29548, a prostaglandin H
2
/thromboxane A
2
receptor antagonist, bradykinin caused dilation at all concentrations tested. In conclusion, bradykinin has a biphasic effect on afferent arterioles. Both dilation and constriction may be mediated by bradykinin B
2
receptors. The mechanisms of vasodilation and vasoconstriction are due to cyclooxygenase products, not nitric oxide.
Assessment of Vasoactive Agents and Vascular Aging by the Second Derivative of Photoplethysmogram Waveform
Authors: Takazawa Kenji , Tanaka Nobuhiro , Fujita Masami , Matsuoka Osamu , Saiki Tokuyu , Aikawa Masaru , Tamura Sinobu , Ibukiyama Chiharu
Published: June 2012

Abstract
—To evaluate the clinical application of the second derivative of the fingertip photoplethysmogram waveform, we performed drug administration studies (study 1) and epidemiological studies (study 2). In study 1, ascending aortic pressure was recorded simultaneously with the fingertip photoplethysmogram and its second derivative in 39 patients with a mean±SD age of 54±11 years. The augmentation index was defined as the ratio of the height of the late systolic peak to that of the early systolic peak in the pulse. The second derivative consists of an a, b, c, and d wave in systole and an e wave in diastole. Ascending aortic pressure increased after injection of 2.5 μg angiotensin from 126/74 to 160/91 mm Hg and decreased after 0.3 mg sublingual nitroglycerin to 111/73 mm Hg. The d/a, the ratio of the height of the d wave to that of the a wave, decreased after angiotensin from −0.40±0.13 to −0.62±0.19 and increased after nitroglycerin to −0.25±0.12 (
P
<0.001 and
P
<0.001, respectively). The negative d/a increased with increases in plethysmographic and ascending aortic augmentation indices (
r
=0.79,
P
<0.001, and
r
=0.80,
P
<0.001, respectively). The negative d/a reflects the late systolic pressure augmentation in the ascending aorta and may be useful for noninvasive evaluation of the effects of vasoactive agents. In study 2, the second derivative of the plethysmogram waveform was measured in a total of 600 subjects (50 men and 50 women in each decade from the 3rd to the 8th) in our health assessment center. The b/a ratio increased with age, and c/a, d/a, and e/a ratios decreased with age. Thus, the second derivative aging index was defined as b-c-d-e/a. The second derivative wave aging index (
y
) increased with age (
x
) (
r
=0.80,
P
<0.001,
y
=0.023
x
−1.515). The second derivative aging index was higher in 126 subjects with any history of diabetes mellitus, hypertension, hypercholesterolemia, and ischemic heart disease than in age-matched subjects without such a history (−0.06±0.36 versus −0.22±0.41,
P
<0.01). Women had a higher aging index than men (
P
<0.01). The b-c-d-e/a ratio may be useful for evaluation of vascular aging and for screening of arteriosclerotic disease.
Large Artery Remodeling During Aging
Authors: Gaballa Mohamed A. , Jacob Christopher T. , Raya Thomas E. , Liu Jia , Simon Bruce , Goldman Steven
Published: June 2012

Abstract
—To examine arterial mechanical changes during aging, pressure-radius and axial force–radius curves were measured in vivo in carotid arteries from 6- and 23-month-old Brown Norway X Fischer 344 rats. Incremental passive circumferential stiffness (measured at 50, 100, and 200 mm Hg) was higher (
P
<0.01) in the 23- compared with the 6-month-old rats (14.02±1.23 versus 6.58±1.51; 2.68±0.56 versus 0.99±0.34; 1.10±0.24 versus 0.69±0.15 dyne/mm
2
×10
3
, respectively). Incremental passive axial stiffness was increased (
P
<0.01) in the 23- compared with the 6-month-old rats (7.95±0.70 versus 4.24±0.81; 1.91±0.10 versus 0.61±0.16; 0.58±0.09 versus 0.36±0.06 dyne/mm
2
×10
3
, respectively). Active incremental circumferential arterial stiffness at 100 and 200 mm Hg was increased (
P
<0.01) in the older rats. In 6-month-old rats, activation of vascular smooth muscle enhanced (
P
<0.01) the incremental circumferential and axial stiffness measured at 200 mm Hg. In 23-month-old rats, only active incremental stiffness was increased (
P
<0.01) at 200 mm Hg. Aging increased (
P
<0.05) media thickness, collagen content, and the collagen/elastin ratio by 12%, 21%, and 38%, respectively. Elastin density and the number of smooth muscle cell nuclei were decreased by 20% and 31%, respectively, with aging. Thus, structural alterations that occur with aging are associated with changes in both active and passive stiffness. Vascular smooth muscle tone modulates arterial wall anisotropy differently during aging.
Nitric Oxide Synthesis Inhibition Retards Surgical Reversal of One-Kidney Goldblatt Hypertension in Rats
Authors: Huang Wann-Chu , Tsai Ren-Yu
Published: June 2012

Abstract
—Surgical correction of renal artery stenosis in Goldblatt hypertension rapidly normalizes blood pressure and increases renal function. This study was conducted in 1-kidney, 1 clip (1K1C) Goldblatt hypertensive rats to examine whether the unclipping-induced reversal of blood pressure and renal function is mediated by nitric oxide (NO). The 1K1C rats were prepared and given tap water with or without supplementation of
N
G
-nitro-
l
-arginine methyl ester (L-NAME). Systolic blood pressure (SBP) before and after renal artery clipping was measured with the tail-cuff method. Four weeks later, surgical unclipping was performed while blood pressure and renal function responses were determined. The results show that clipping the renal artery for 4 weeks increased SBP from 140±5 to 183±6 mm Hg (
P
<0.05). Concurrent L-NAME treatment accelerated and aggravated the clipping-induced increases in SBP from 138±6 to 219±8 mm Hg (
P
<0.05). Surgical unclipping reduced blood pressure to normotensive levels within 2 hours in all hypertensive rats with and without chronic or acute L-NAME treatment. However, the magnitude of reductions in blood pressure in the initial 1 hour after unclipping was significantly less in L-NAME–treated rats than in nontreated rats (9±2% versus 16±1%,
P
<0.05). Despite reducing blood pressure, unclipping significantly increased glomerular filtration rate, urine flow, and sodium and potassium excretions, but the extent of the increases in these renal functions was significantly attenuated in L-NAME–treated rats. These data suggest that NO production partly contributes to the hypotensive and renal responses to unclipping but does not mediate the reversal of renovascular hypertension of this model.
Lack of Association Between Renin-Angiotensin System, Gene Polymorphisms, and Wall Thickness of the Radial and Carotid Arteries
Authors: Girerd Xavier , Hanon Olivier , Mourad Jean Jacques , Boutouyrie Pierre , Laurent Stéphane , Jeunemaitre Xavier
Published: June 2012

Abstract
—To investigate the relationship between polymorphisms of the angiotensin-converting enzyme (ACE) and the angiotensin II type 1 receptor (AT
1
R) genes and structural phenotypes of arteries, we studied a cohort of 340 subjects (aged 49±12 years) without evidence of cardiovascular disease and who had never been treated previously with any cardiovascular treatments. Structural phenotypes (wall thickness and internal diameter) were evaluated for the common carotid and the radial arteries using high-resolution echo-tracking devices (NIUS-02 and Wall Track System). The influence of ACE insertion/deletion (I/D) and AT
1
R A/C
1166
polymorphism genotypes on structural parameters was tested by ANOVA and logistic regression analysis. For the radial artery, mean wall thickness among subjects according to the ACE I/D or AT
1
R A/C
1166
genotypes was not different. This lack of association persisted in a logistic regression analysis or when the comparison was restricted to a subgroup of subjects potentially at high genetic risk (DD and CC or AC) compared with subjects at low genetic risk (AA and II or ID). Also, no association was observed between the carotid artery intima-media thickness and the 2 polymorphisms. In conclusion, the ACE I/D and the AT
1
R A/C
1166
gene polymorphisms are not markers of vascular hypertrophy in subjects with no evidence of cardiovascular disease. These results suggest that these gene polymorphisms have an undetectable role in the geometry of the radial and carotid arteries compared with usual determinants such as blood pressure and age.
Chronic Sodium Balance and Blood Pressure Response to Captopril in Conscious Mice
Authors: Mattson David L. , Krauski Kristyn R.
Published: June 2012

Abstract
—The influence of chronic administration of the converting enzyme inhibitor captopril on blood pressure and sodium balance was evaluated in conscious Swiss Webster mice. Arterial pressure was measured with chronic indwelling catheters, and sodium balance was determined by infusing sodium intravenously in isotonic saline and collecting urine 24 h/d. Experiments to validate sodium balance measurements in mice demonstrated recovery of 100±3% of sodium intake under steady-state conditions (n=20 mice on 70 individual days, sodium intake range 160 to 1000 μmol/d). It was further demonstrated that mean arterial pressure, heart rate, and body weight were unaltered from 115±7 mm Hg, 646±12 bpm, and 34±0.6 g, respectively, as sodium intake was increased stepwise from 150 to 900 μmol NaCl per day. An additional validation group (n=7) demonstrated that daily and cumulative sodium balance can be accurately determined during and after the intravenous administration of an agent known to alter renal sodium handling (furosemide 50 mg · kg
−1
· d
−1
). Experiments were then performed to examine the influence of intravenous captopril infusion (40 mg · kg
−1
· d
−1
, n=7) in mice in which the daily sodium intake was fixed at ≈200 μmol/d. This dose of captopril was determined to significantly decrease the pressor response to a 10-ng bolus of angiotensin I (Ang I) from 24±5 in the control state to 6±2 mm Hg (n=5). After 5 days of infusion of the converting enzyme inhibitor, mean arterial pressure significantly fell from 114±3 to 58±2 mm Hg, body weight significantly decreased from 36±1 to 33±1 g, and cumulative sodium balance significantly decreased to −270±55 μmol. These parameters returned toward control during 5 postcontrol days. Results of this study demonstrate that accurate sodium balance measurements can be obtained from individual conscious mice over a 5-fold range of sodium intake. The experiments also indicate that converting enzyme inhibition has a potent influence to lower blood pressure in normal mice; the hypotensive response appears to be due in part to increased urinary sodium excretion.
Both Brain Angiotensin II and “Ouabain” Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake
Authors: Huang Bing S. , Leenen Frans H. H.
Published: June 2012

Abstract
—Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats from 5 to 9 weeks of age received a regular or high salt diet and concomitantly an intracerebroventricular infusion of the angiotensin type 1 blocker losartan (1 mg · kg
−1
· d
−1
) or antibody Fab fragments, which bind ouabain and related steroids with high affinity, or γ-globulins as control (200 μg/d for both). At 9 weeks of age, blood pressure (BP), heart rate (HR), central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air stress and to intracerebroventricular α
2
-agonist guanabenz (50 μg) and ouabain (0.5 μg). Baroreflex function was assessed by acute volume expansion with intravenous 5% dextrose and ramp changes of BP by ±50 mm Hg induced by intravenous phenylephrine and sodium nitroprusside. In Dahl S but not R rats, high salt significantly increased BP and HR; enhanced BP, HR, and renal sympathetic nerve activity responses to air stress and guanabenz; and attenuated cardiopulmonary and arterial baroreflex control of renal sympathetic nerve activity and HR. Both losartan and Fab fragments prevented these responses to high salt to a similar extent in Dahl S rats but had no effect in Dahl R rats on high salt. Sympathoexcitatory responses to ouabain were attenuated in Dahl S on high versus regular salt and were abolished in Dahl R or S treated with losartan or Fab fragments. Consistent with previous studies in SHR, the present data indicate that in Dahl S on high salt, both brain “ouabain” and angiotensin II contribute to decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex, and therefore hypertension.
Biophysical Signals Underlying Myogenic Responses in Rat Interlobular Artery
Authors: Takenaka Tsuneo , Suzuki Hiromichi , Okada Hirokazu , Hayashi Koichi , Ozawa Yuri , Saruta Takao
Published: June 2012

Abstract
—To assess cellular mechanisms mediating myogenic responses of interlobular artery (ILA), experiments were performed with the use of isolated perfused hydronephrotic kidneys. ILAs were divided into 3 groups according to their basal diameters: proximal (>60 μm), intermediate (40 to 60 μm), and distal (<40 μm) ILAs. Myogenic responses were obtained by stepwise increase in perfusion pressure. Greater myogenic responsiveness was observed in ILAs with smaller diameters. Diltiazem (10 μmol/L) inhibited myogenic responses of all segments of ILAs. Furthermore, gadolinium (10 μmol/L), a mechanosensitive cation channel blocker, abolished myogenic responses of distal but not proximal ILA. In contrast, 2-nitro-4-carboxyphenyl-
N
,
N
-diphenyl-carbamate (200 μmol/L), an inhibitor of phospholipase C, prevented myogenic responses of proximal but not distal ILA. Finally, basal proximal ILA diameters were increased by treatment with 50 nmol/L of staurosporine (
P
<0.05), and subsequent addition of thapsigargin (1 μmol/L) blocked myogenic contraction of proximal ILAs. Myogenic responses of intermediate ILAs exhibited characteristics between those of distal and proximal ILAs. Our data indicate that underlying mechanisms for myogenic responses differ in distinct segments of ILAs. The present results suggest that mechanosensitive cation channels are involved in myogenic constriction of distal ILAs. Finally, our findings provide evidence that the stimulation of phospholipase C mediates myogenic contraction of proximal ILAs.
Decreased Flow-Induced Dilation and Increased Production of cGMP in Spontaneously Hypertensive Rats
Authors: Qiu Hong Ying , Henrion Daniel , Benessiano Joëlle , Heymes Christophe , Tournier Bruno , Levy Bernard I.
Published: June 2012

Abstract
—We investigated flow (shear stress)– and agonist-induced cGMP release in mesenteric vascular beds of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The mesenteric vascular bed was perfused in situ with Tyrode’s solution. Vascular relaxation and cGMP release in the perfusate were determined on stimulation by flow or by acetylcholine (0.1 μmol/L) or sodium nitroprusside (0.1 mmol/L). Flow-induced release of cGMP was significantly greater in SHR than in WKY (
P
<0.01), despite a lower flow-induced dilation in SHR. In both strains,
N
G
-nitro-
l
-arginine methyl ester (L-NAME) completely inhibited cGMP release in response to flow (
P
<0.001), although flow-induced dilation was not affected by L-NAME in SHR. Moreover, the activity of the constitutive nitric oxide synthase (NOS) was significantly greater in SHR (82±3.5 fmol/min) than in WKY (66±3.5 fmol/min;
P
<0.05) and was associated with increased expression of endothelial NOS mRNA in SHR. Sodium nitroprusside induced larger increases in cGMP release in SHR (3593±304 fmol/min) than in WKY (2467±302 fmol/min;
P
<0.05). The release of cGMP in response to acetylcholine was significantly lower in SHR (292±80 fmol/min) than in WKY (798±218 fmol/min;
P
<0.05) in parallel with smaller acetylcholine-induced relaxation in SHR. Despite increased cGMP production in response to flow and NOS activity, flow-induced dilation was decreased in SHR, suggesting an upregulation of the NO/cGMP pathway to compensate for the increased vascular tone in SHR.
Increased Expression of Matrix Metalloproteinase-2 in the Thickened Intima of Aged Rats
Authors: Li Zhihe , Froehlich Jeffrey , Galis Zorina S. , Lakatta Edward G.
Published: June 2012

Abstract
—To characterize remodeling of elastic arteries with aging and to investigate its potential mechanisms, matrix metalloproteinase-2 (MMP-2), intracellular adhesive molecule-1 (ICAM-1), transforming growth factor-β (TGF-β), and fibronectin protein levels were measured in the aortas of young adult (6 months) and aged (30 months) Fischer 344XBN rats. At 30 versus 6 months, the thickness of the intima was 5-fold greater and contained marked increases in TGF-β and ICAM-1, and fibronectin expression was enhanced throughout the aortic wall. Total MMP-2 protein (Western blot) of 30-month-old rats was increased 8-fold over that of 6-month-old rats (0.166±0.032 versus 0.020±0.006;
P
<0.01), and staining and activity were regionally localized to the intima, often near breaks in the internal elastic membrane and lamellae. Early passage, explanted smooth muscle cells (SMC) from aged aorta secreted more MMP-2 than those from young aorta; while basal MMP-2 production did not differ with age, after stimulation with cytokines (interleukin-1, tumor necrosis factor-α, or TGF-β, 10 ng/mL each for 24 hours), MMP-2 production in SMC from 30-month-old rats increased to levels greater than those in 6-month-old rats. Thus, enhanced expression of TGF-β, MMP-2, and ICAM-1 in the thickened vascular intima of aged rats may in part be produced by exaggerated SMC responses to cytokines and may have potential roles in intimal remodeling with aging.
Inotropic Effects of Endothelin-1
Authors: Beyer Martin E. , Slesak Günther , Hövelborn Tobias , Kazmaier Silke , Nerz Stefan , Hoffmeister Hans Martin
Published: June 2012

Abstract
—In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ET
B
receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ET
A
receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 μg/kg of the ET
A
receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: −62%; molsidomine+ET-1: −47%; BQ 610+ET-1: −27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: −2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ET
A
receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ET
B
receptors.
Purinoceptor-Mediated Calcium Signaling in Preglomerular Smooth Muscle Cells
Authors: Inscho Edward W. , LeBlanc Elizabeth A. , Pham Bao Thang , White Steven M. , Imig John D.
Published: June 2012

Abstract
—The current studies were performed to determine the contribution of calcium mobilization and voltage-dependent calcium influx to the increase in [Ca
2+
]
i
elicited by ATP and UTP. Suspensions of freshly isolated smooth muscle cells were prepared from preglomerular microvessels by enzymatic digestion and loaded with the Ca
2+
-sensitive dye fura 2. The effect of ATP and UTP on [Ca
2+
]
i
was studied on single cells with standard microscope-based fluorescence photometry techniques. Resting [Ca
2+
]
i
averaged 80±3 nmol/L (n=219 single cells from 58 dispersions). ATP (100 μmol/L) increased [Ca
2+
]
i
to a peak value of 845±55 nmol/L (n=70 single cells from 38 dispersions) before stabilizing at 124±81 nmol/L. Similarly, 100 μmol/L UTP (n=39 single cells from 26 dispersions) stimulated a peak increase in [Ca
2+
]
i
of 1426±584 nmol/L before reaching a stable plateau of 123±10 nmol/L. The [Ca
2+
]
i
response to ATP and UTP was also assessed in the absence of extracellular calcium. In these studies, exposure to 100 μmol/L ATP induced a transient peak increase in [Ca
2+
]
i
, with the plateau phase being totally abolished. In contrast, exposure to 100 μmol/L UTP under calcium-free conditions resulted in no detectable change in the UTP-mediated increase in [Ca
2+
]
i
. The role of L-type calcium channels in the response was assessed with the calcium channel antagonist diltiazem. Incubation with diltiazem (10 μmol/L) markedly reduced the response to ATP, whereas the response to UTP was only slightly reduced. These data demonstrate that both ATP and UTP directly stimulate a biphasic increase in [Ca
2+
]
i
in renal microvascular smooth muscle cells. Furthermore, the data suggest that the elevation of [Ca
2+
]
i
elicited by ATP is largely dependent on calcium influx through L-type calcium channels, whereas the response to UTP appears to derive primarily from mobilization of calcium from intracellular stores.
Enalapril Prevents Tubulointerstitial Lesions by Hyperoxaluria
Authors: Toblli Jorge Eduardo , Stella Inés , de Cavanagh Elena , Angerosa Margarita , Inserra Felipe , Ferder León
Published: June 2012

Abstract
—Hyperoxaluria is a recognized cause of tubulointerstitial lesions, and this could contribute to development of hypertension and chronic renal failure. Enalapril has been effective against the progression of tubulointerstitial lesions in various animal models. The aim of the present study was to evaluate the usefulness of enalapril on the tubulointerstitial damage produced by oxalates. Two-month-old male Sprague-Dawley rats were separated into 4 groups, control with tap water (G1), hyperoxaluric (G2), hyperoxaluric+enalapril (G3), enalapril (G4), for 4 weeks. G2 and G3 rats were given 1% ethyleneglycol (ETG, precursor for oxalates), and G3 and G4 rats were given enalapril 20 mg/L in drinking water. At the end of the study, we evaluated renal tubulointerstitial lesions by a semiquantitative score. Urine albumin excretion, serum and urine nitric oxide production, tubulointerstitial immunostaining by α-smooth muscle actin, transforming growth factor-β
1
, and collagen type III were measured. Rats belonging to the hyperoxaluric group treated with enalapril (G3) showed fewer tubulointerstitial lesions (1.3±0.2 versus 3±0.2;
P
<0.01), lower urine albumin excretion (8±2 mg/d versus 25±2 mg/d;
P
<0.01), less percentage of α-smooth muscle actin in renal interstitium (2±0.4% versus 13.5±2.4%;
P
<0.01), less percentage of transforming growth factor-β
1
in tubulointerstitial area (3.3±1% versus 13.3±2.1%;
P
<0.01), less percentage of collagen type III interstitial deposition (0.7±0.5% versus 7±2.6%;
P
<0.01), and increased NO production in serum as well as urine (both
P
<0.01), when compared with the hyperoxaluric group not treated with enalapril (G2). Considering these data, we believe that enalapril, by several mechanisms of action, could provide an important benefit in the prevention of inflammatory response, transforming growth factor-β
1
tubulointerstitial production, collagen type III interstitial deposition, and finally, the progressive tubulointerstitial fibrosis caused by oxalates.
Telemetry for Cardiovascular Monitoring in a Pharmacological Study
Authors: Anderson Niall H. , Devlin Alison M. , Graham Delyth , Morton James J. , Hamilton Carlene A. , Reid John L. , Schork Nicholas J. , Dominiczak Anna F.
Published: June 2012

Abstract
—Radio-telemetry systems offer the ability to measure blood pressure and heart rate in experimental models of hypertension without the stress artifacts induced by some other methods. We therefore aimed to develop improved, nonparametric regression methods for radio-telemetry data and to use these to assess the effects of pharmacological interventions on cardiac and vascular hypertrophy in the stroke-prone spontaneously hypertensive rat. One control group and 5 groups treated either with losartan (alone or in combination with
N
G
-nitro-
l
-arginine methyl ester [
l
-NAME]), perindopril (also alone or in combination with
l
-NAME), or hydralazine plus hydrochlorothiazide were monitored for 4 weeks. Cardiac hypertrophy was assessed by the left ventricle plus septum weight to body weight ratio and vascular hypertrophy by flow-cytometry analysis of vascular smooth muscle cell polyploidy. Hemodynamic series were split into trend and cyclic components by the seasonal and trend decomposition procedure based on Loess and compared between groups by Loess regression modeling. Systolic and diastolic blood pressures were reduced systematically by losartan and perindopril (
P
<10
−10
) but to a lesser extent by hydralazine plus hydrochlorothiazide (
P
<10
−8
), and diurnal variation was reduced in the latter group (
P
<10
−6
).
l
-NAME significantly reduced the hypotensive effect only of losartan. Vascular and cardiac hypertrophy were significantly attenuated with losartan or perindopril, but were unchanged with other treatments. The new analysis proposed here identifies differential effects on trends and cyclic variation and associations with regression of end-organ damage for losartan and perindopril compared with hydralazine plus hydrochlorothiazide. The method offers a powerful tool for detailed investigation of radio-telemetry data.
Angiotensin II Type 1 Receptor–Mediated Peroxide Production in Human Macrophages
Authors: Yanagitani Yoshihiro , Rakugi Hiromi , Okamura Atsunori , Moriguchi Koichi , Takiuchi Shin , Ohishi Mitsuru , Suzuki Keiichiro , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Abstract
—Our previous experiments demonstrated upregulation of the renin-angiotensin system in macrophages, including angiotensin II type 1 (AT1) and type 2 (AT2) receptors, during transformation from monocytes. We investigated the role of angiotensin II in oxidative stress of monocytes/macrophages, which plays a role in the advance of atherosclerosis. THP1, a human monocytic leukemia cell line, was differentiated to macrophages by adding of phorbol 12-myristate 13-acetate for 24 hours. The intracellular production of peroxide was measured by a cytofluorometric assay with 2′,7′-dichlorofluorescein-diacetate with a flow cytometer scan. Peroxide was detected in monocytes and upregulated during the transformation to macrophages by 3.18±0.52 times in relative fluorescein of peak value (
P
<0.01). Angiotensin II (1 μmol/L) induced oxidative stress in macrophages, with the peak at 15 minutes by 451±223%, and returned to the control level within 1 hour. EC
50
was 5.4×10
−9
mol/L. AT1 antagonist (CV11974, 1 μmol/L) significantly decreased angiotensin II–induced oxidative stress in macrophages, but AT2 antagonist (
PD123319
, 1 μmol/L) did not. Of interest, AT1 antagonist also decreased basal levels of peroxide production in macrophages in a dose-dependent manner. These results suggest that upregulation of the expression of AT1 receptor in macrophages contributes in part to upregulation of peroxide production. AT1 receptor antagonists may be useful to suppress oxidative stress of macrophages in atherosclerotic lesions.
Angiotensin II Type 1 Receptor Antisense Gene Therapy Prevents Altered Renal Vascular Calcium Homeostasis in Hypertension
Authors: Gelband Craig H. , Reaves Phyllis Y. , Evans Jenafer , Wang Hongwei , Katovich Michael J. , Raizada Mohan K.
Published: June 2012

Abstract
—Intracellular Ca
2+
([Ca
2+
]
i
) homeostasis regulates vascular smooth muscle tone, and alteration in [Ca
2+
]
i
handling is associated with the development and establishment of hypertension. We have previously established in the spontaneously hypertensive rat (SHR) that virally mediated delivery of angiotensin II type 1 receptor antisense (AT
1
R-AS) prevents the development of high blood pressure and some pathophysiology associated with hypertension for 120 days. In light of this, our objectives in this study were to determine whether AT
1
R-AS gene therapy (1) could have a longer duration in the prevention of hypertension and (2) would attenuate the alterations in renal vascular Ca
2+
homeostasis and therefore vasoconstriction, characteristics of hypertension. Intracardiac delivery of AT
1
R-AS in neonates prevented the development of hypertension in SHR for at least 210 days. At this time, untreated SHR renal resistance arterioles showed a significantly enhanced contractile response to KCl and angiotensin II (Ang II) when compared with normotensive Wistar-Kyoto rats. In addition, L-type Ca
2+
current density and Ang II–dependent increases in [Ca
2+
]
i
were significantly increased in cells dissociated from renal resistance arterioles of the untreated SHR. AT
1
R-AS treatment prevented all of the above vascular alterations associated with the hypertensive state in SHR. Finally, Western blot analysis of L-type Ca
2+
channel (α
1C
) protein levels in renal resistance arterioles of untreated SHR showed no significant difference when compared with control. These results are novel and demonstrate that viral-mediated delivery of AT
1
R-AS not only attenuates the development of hypertension on a long-term basis but prevents changes in renal vascular Ca
2+
homeostasis associated with the disease.
Effects of Vasodilatory β-Adrenoceptor Antagonists on Endothelium-Derived Nitric Oxide Release in Rat Kidney
Authors: Kakoki Masao , Hirata Yasunobu , Hayakawa Hiroshi , Nishimatsu Hiroaki , Suzuki Yasuko , Nagata Daisuke , Suzuki Etsu , Kikuchi Kazuya , Nagano Tetsuo , Omata Masao
Published: June 2012

Abstract
—The mechanisms for the vascular actions of vasodilatory β-blockers remain undetermined. For some kinds of β-blockers, the involvement of nitric oxide (NO) has been suggested. We studied the effects of vasodilatory β-blockers on renal perfusion pressure (RPP) and NO release in the rat kidney. Infusion of bopindolol, celiprolol, and nebivolol caused a dose-dependent reduction in RPP and an increase in NO release (RPP: bopindolol 10
−6
mol/L, −23±2%; celiprolol 10
−4
mol/L, −27±2%; nebivolol 10
−5
mol/L, −35±3%; NO: bopindolol 10
−6
mol/L, +33±2; celiprolol 10
−4
mol/L, +41±2; nebivolol 10
−5
mol/L, +45±5 fmol · min
−1
· g kidney
−1
, mean±SEM). Metergoline (10
−6
mol/L), a 5-hydroxytryptamine (5-HT)
1/2
antagonist, or NAN-190 (10
−6
mol/L), a 5-HT
1A
antagonist, almost completely abolished the vasorelaxation and NO release caused by bopindolol, celiprolol, and nebivolol. However, neither propranolol nor bisoprolol decreased RPP. Celiprolol and nebivolol caused vasodilation in the rat thoracic aorta, and it was markedly reduced by endothelial denudation, N
ω
-nitro-
l
-arginine methyl ester (10
−4
mol/L), or NAN-190 (10
−6
mol/L). In deoxycorticosterone acetate-salt hypertensive rats, 4-week administration of celiprolol (50 mg · kg
−1
· d
−1
IV) restored the responses regarding RPP and NO release to acetylcholine. These results suggest that several β-blockers exert their vasodilatory action through the 5-HT
1A
receptor/NO pathway and that treatment with these β-blockers may protect against endothelial injury in hypertension.