bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronary artery constriction caused by the cold pressor test in human hypertension.
Authors: Antony I , Aptecar E , Lerebours G , Nitenberg A
Published: June 2012

Hypertensive patients with angiographically normal coronary arteries may have myocardial ischemia when metabolic demand increases. Abnormal epicardial coronary artery vasomotion in response to sympathetic stimulation may contribute to ischemia in such patients. We studied the vasomotor response of smooth coronary arteries to a cold pressor test in 10 hypertensive patients without other risk factors and in 9 control subjects. Vessel dimensions were measured by quantitative angiography, and blood flow was calculated using an intracoronary Doppler catheter in the left anterior descending coronary artery. In response to cold pressor stimulation, arteries of control subjects dilated 13.0 +/- 5.9% (P < .001), and they constricted 8.2 +/- 8.5% in hypertensive patients (P < .001). Rate-pressure product increased from 9466 +/- 1677 to 12,547 +/- 2367 beats per minute (bpm).mm Hg in control subjects (P < .001) and from 13,720 +/- 1823 to 17,353 +/- 2037 bpm.mm Hg in hypertensive patients (P < .001). Coronary blood flow velocity and blood flow increased 51 +/- 26% (P < .05) and 87 +/- 27% (P < .001), respectively, in control subjects and 68 +/- 52% (P < .05) and 36 +/- 33% (P < .01) in hypertensive patients. At peak cold pressor test, despite a significant higher rate-pressure product in hypertensive patients, blood flow was similar in both groups, suggesting an uncoupling between myocardial metabolic demand and supply. Thus, hypertension impairs the vasodilator response of angiographically normal coronary arteries to a cold pressor test. This abnormal response may be due to enhanced catecholamine reactivity and/or impairment of endothelial flow-mediated vasodilator response.
Insulin blunts sympathetic vasoconstriction through the alpha 2-adrenergic pathway in humans.
Authors: Lembo G , Iaccarino G , Rendina V , Volpe M , Trimarco B
Published: June 2012

We investigated the mechanisms underlying the insulin-induced attenuation of sympathetic forearm vasoconstriction in healthy humans. In 5 subjects, we applied 20 mm Hg lower body negative pressure for 30 minutes in control conditions and during a 60-minute infusion of insulin (0.05 mU/kg per minute) in the brachial artery and measured forearm norepinephrine kinetics and hemodynamics. In 11 subjects, we applied graded lower body negative pressure at 5, 10, 15, and 20 mm Hg for 5 minutes each in control conditions and during the simultaneous intrabrachial administration of insulin (0.05 mU/kg per minute) (5 subjects) or insulin plus ouabain (3.5 micrograms/min per liter) (6 subjects) to investigate whether insulin acts through a potentiation of the vascular smooth muscle Na+,K(+)-ATPase. To assess a possible effect of insulin on a specific adrenergic receptor pathway, in a further study group we evaluated (1) the forearm vascular response to intrabrachial infusion of the alpha 1-adrenergic receptor agonist phenylephrine (0.5, 1, and 2 micrograms/kg per minute; n = 7) and of the alpha 2-adrenergic receptor agonist BHT-933 (0.5, 1, 2, and 4 micrograms/kg per minute; n = 9), and (2) the effects of intra-arterial infusion of prazosin (0.5 microgram/100 mL per minute) alone or combined with insulin on the forearm vascular response to graded lower body negative pressure (7 subjects). Insulin blunted the peak increase in forearm vascular resistance (from 13 +/- 2 to 6 +/- 2 U, P < .05) but not the rise in forearm norepinephrine spillover induced by 20 mm Hg lower body negative pressure (from 8.3 +/- 1.8 to 11.1 +/- 3.5 pmol/min per liter, P = NS). Ouabain administration did not prevent the insulin-induced attenuation of the forearm vasoconstrictive response to graded lower body negative pressure. Insulin infusion in the brachial artery did not modify the forearm vasoconstriction induced by intra-arterial infusion of phenylephrine but significantly reduced the increase in forearm vascular resistance induced by BHT-933 (F = 6.111, P < .001). Finally, intra-arterial infusion of prazosin significantly attenuated the forearm vasoconstriction induced by graded lower body negative pressure. The residual vasoconstrictive response was abolished by insulin infusion. Taken together, these findings suggest that insulin interacts with the sympathetic nervous system at the vascular level predominantly through the alpha 2-adrenergic vasoconstrictive pathway.
Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans?
Authors: Hansen J , Jacobsen T N , Victor R G
Published: June 2012

Recent studies in experimental animals have advanced the concept that neuronal nitric oxide is an important component of the signal transduction pathways that tonically restrain sympathetic vasoconstrictor outflow from the brain stem. To determine whether or not this concept can be extended to the control of sympathetic outflow in humans, we recorded muscle sympathetic nerve activity (microelectrodes, peroneal nerve) in healthy human subjects during intravenous infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (3.6 to 6.7 mg/kg). The major new finding is that during intravenous L-NMMA mean arterial pressure increased (10 +/- 2 mm Hg, P < .05), whereas heart rate and sympathetic nerve activity decreased (P < .05) by 10 +/- 2 beats per minute and 61 +/- 5%, respectively. These reflex decreases were indistinguishable from those produced when blood pressure was increased comparably with phenylephrine, an internal vasoconstrictor control. When the L-NMMA-induced increase in blood pressure was attenuated experimentally to minimize baroreflex activation, sympathetic nerve activity and heart rate were unchanged. Furthermore, during infusion of L-arginine (323 to 513 mg/kg IV) to increase nitric oxide synthesis, mean arterial pressure decreased (12 +/- 2 mm Hg, P < .05), but heart rate and sympathetic nerve activity increased (P < .05) by 11 +/- 2 beats per minute and 98 +/- 27%, respectively. Thus, our experiments in humans provide no support for the emerging concept that nitric oxide is involved in the tonic restraint of central sympathetic outflow.
Converting enzyme inhibition and renal tissue angiotensin II in the rat.
Authors: Allan D R , McKnight J A , Kifor I , Coletti C M , Hollenberg N K
Published: June 2012

Multiple observations suggest local control of renal function via an intrarenal renin-angiotensin system, including evidence for local angiotensin (Ang) II production. Our first goal was to examine renal tissue Ang I:Ang II relations to ascertain whether Ang II formation differs in the circulation and in renal tissue. We have recently shown an authentic Ang II/Ang I ratio of 1.5:1 in renal lymph, the opposite of the Ang II:Ang I relation in plasma. Our second goal was to examine the influence of maximal angiotensin converting enzyme inhibition on these relations in plasma and in renal tissue. We used two converting enzyme inhibitors with differing lipid solubility, on the premise that tissue penetration and action might differ on that basis. We measured Ang I and Ang II in plasma and renal tissue of rats given an intravenous dose of either vehicle, enalapril, or ramipril, over a wide dose range, from 0.1 to 10.0 mg/kg i.v. Renal and plasma angiotensin concentrations were measured by high-performance liquid chromatography and radioimmunoassay. Whereas the Ang I concentration in normal rat plasma (273 +/- 84 fmol/mL) was over threefold the plasma Ang II concentration (83 +/- 12 fmol/mL), the ratio was reversed in the kidney (Ang II, 178 +/- 12 versus Ang I, 91 +/- 3 fmol/g; P < .001). Although ramipril and enalapril induced an indistinguishable dose-related acute fall in blood pressure and plasma Ang II concentration, lower enalapril doses were less effective in reducing renal tissue Ang I:Ang II conversion and Ang II concentration (P < .025).(ABSTRACT TRUNCATED AT 250 WORDS)
Autonomic responses of women with parental hypertension. Effects of physical activity and fitness.
Authors: Buckworth J , Dishman R K , Cureton K J
Published: June 2012

We studied the moderating effects of cardiorespiratory fitness and physical activity on heart rate and blood pressure responses to psychophysiological stressors and the carotid-cardiac baroreflex in young normotensive women with a parental history of hypertension (n = 31). Testing occurred during the follicular menstrual phase. Subjects were divided into high versus moderate (46.6 +/- 6.5 versus 35.9 +/- 1.9 mL.kg-1.min-1) VO2peak and high versus moderate (1217.7 +/- 98.4 versus 1015.5 +/- 49.4 J.kg-1.wk-1) physical activity groups. The groups did not differ in heart rate or blood pressure responses to mental arithmetic or the cold-face test. However, the highly fit women had longer maximal R-R intervals compared with the moderately fit women when the carotid-cardiac baroreflex was stimulated by negative pressures applied to the neck during resting conditions (P < .01). The carotid-cardiac baroreflex was attenuated during mental arithmetic compared with rest in both the moderately fit and moderately active women but not in the highly fit and highly active groups. We find no evidence that aerobic fitness reduces sympathetic responses to laboratory stressors in young women with parental hypertension. Our findings are consistent with greater parasympathetic tone during sympathetic challenge for the highly fit and highly active subjects. Clarification of autonomic balance during carotid baroreflex stimulation at rest and during sympathetic challenge after exercise training would provide important information regarding mechanisms that regulate cardiovascular responses to autonomic challenge in women at risk for hypertension.
Angiotensinogen gene in human hypertension. Lack of an association of the 235T allele among African Americans.
Authors: Rotimi C , Morrison L , Cooper R , Oyejide C , Effiong E , Ladipo M , Osotemihen B , Ward R
Published: June 2012

The frequency of the 235T and 174M alleles of the angiotensinogen gene, previously reported to be associated with hypertension in Caucasians and Japanese, was compared between 57 hypertensive African Americans and 130 normotensive African Americans sampled as part of a community survey of hypertension in the Chicago area. The frequency of the 235T allele was unrelated to hypertension status (cases, 83%, control subjects, 82%), as was true for the 174M allele. Compared with Caucasians, the frequency of the 235T allele was twice as high in this African American population, while the frequency of the 174M allele was similar. Even higher frequencies of the 235T allele (93%) were noted in a sample of 122 Nigerians. It appears that the 235T allele is very common in populations of West African origin, although we found no evidence that it confers risk of hypertension.
Vanadyl sulfate lowers plasma insulin and blood pressure in spontaneously hypertensive rats.
Authors: Bhanot S , McNeill J H
Published: June 2012

Spontaneously hypertensive rats (SHR) are hyperinsulinemic compared with their Wistar-Kyoto (WKY) controls. Since previous studies have demonstrated that vanadyl sulfate lowers insulin levels in nondiabetic rats, we used vanadyl to explore the relation between hyperinsulinemia and hypertension. In a prevention study, 5-week-old SHR and WKY rats were started on long-term vanadyl sulfate treatment. Vanadyl in doses of 0.4 to 0.6 mmol/kg per day lowered plasma insulin (252 +/- 22.8 versus 336 +/- 12.6 pmol/L, treated versus untreated, P < .01) and systolic blood pressure (158 +/- 2 versus 189 +/- 1 mm Hg, P < .001) in SHR without causing any change in plasma glucose. No changes were seen in the treated WKY rats. At 11 weeks of age, a group of untreated rats from the prevention study was started on vanadyl treatment as before. Again, vanadyl caused significant and sustained decreases in plasma insulin (264 +/- 12.6 versus 342 +/- 6.6 pmol/L, treated versus untreated, P < .001) and blood pressure (161 +/- 1 versus 188 +/- 1 mm Hg, P < .001) in SHR but had no effect in the normotensive WKY controls. Furthermore, restoration of plasma insulin in the vanadyl-treated SHR to pretreatment levels (subcutaneous insulin, 14,000 pmol/kg per day) reversed the effects of vanadyl on blood pressure (vanadyl with insulin, 190 +/- 3.0 mm Hg versus vanadyl without insulin, 152 +/- 3.0 mm Hg, P < .001). Since vanadyl treatment resulted in decreased weight gain, treated SHR were compared with a corresponding pair-fed group.(ABSTRACT TRUNCATED AT 250 WORDS)
Genetic and environmental influences on blood pressure in elderly twins.
Authors: Hong Y , de Faire U , Heller D A , McClearn G E , Pedersen N
Published: June 2012

We used 289 pairs of Swedish twins reared apart or together to evaluate the importance of genetic and environmental influences on blood pressure. Unlike other twin and family studies, the adoption/twin design allows a distinction between estimates of the importance of shared rearing environments and genetic effects. Genetic factors were observed to play an important role for individual differences in blood pressure. Model-fitting analyses suggested upper limits of heritability for systolic and diastolic blood pressures in the entire sample of 0.44 and 0.34, respectively. More interestingly, substantial influences of shared family effects accounting for up to 27% of the variation were also revealed. Effects of correlated environment, which might reflect, for example, the intrauterine environment, existed to some extent later in life. The influence of genetic factors tended to decrease across age groups for systolic blood pressure (0.62 in individuals less than 65 years old; 0.12 in those 65 years and older) but not for diastolic blood pressure (0.22 for the middle-aged group; 0.26 for the older group). However, this declining trend for systolic blood pressure did not reach significance (chi 2 = 8.07, df = 4, P = .09).
Na(+)-H+ exchanger expression in vascular smooth muscle of spontaneously hypertensive and Wistar-Kyoto rats.
Authors: Lucchesi P A , DeRoux N , Berk B C
Published: June 2012

The Na(+)-H+ exchanger has important modulatory effects on vascular smooth muscle cell proliferation and contractility. Increased Na(+)-H+ exchange activity is a general property of many tissues, including mesenteric artery and cultured vascular smooth muscle cells, in the spontaneously hypertensive rat (SHR). In the present work, we investigated whether alterations in the steady-state levels of specific Na(+)-H+ exchanger mRNA isoforms (NHE-1 through NHE-4) are associated with the observed increases in exchanger activity. Poly(A+) mRNA prepared from 12-week-old hypertensive SHR and normotensive Wistar-Kyoto (WKY) aorta, kidney, and intestine was hybridized to cDNAs specific for each NHE isoform. By Northern blot analysis, NHE-1 was detected in all tissues as well as cultured vascular smooth muscle cells and was not regulated differently in SHR compared with WKY tissues. There was no expression of NHE-2, NHE-3, or NHE-4 in SHR and WKY aortas or in cultured vascular smooth muscle cells from SHR and WKY aortas. Stimulation of NHE-1 mRNA expression by growth factors was similar in cultured SHR and WKY vascular smooth muscle cells. We conclude that the previously observed increase in exchanger activity in blood vessels and cultured vascular smooth muscle cells of the SHR is not caused by induction of the NHE-2, NHE-3, and NHE-4 isoforms or by alterations in steady-state NHE-1 mRNA expression. These findings suggest that posttranslational regulation of the Na(+)-H+ exchanger is responsible for increased activity in the SHR.
Long-term infusion of kallikrein attenuates renal injury in Dahl salt-sensitive rats.
Authors: Uehara Y , Hirawa N , Kawabata Y , Suzuki T , Ohshima N , Oka K , Ikeda T , Goto A , Toyo-oka T , Kizuki K
Published: June 2012

We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive rats. A subdepressor dose of purified rat urinary kallikrein (700 ng/d IV) was infused by osmotic minipump for 4 weeks in male Dahl salt-sensitive rats fed a high salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure; however, urinary protein excretion was significantly decreased, and glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl salt-sensitive rats. Kallikrein infusion increased urinary excretion of bradykinin and stimulated excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by rat urinary kallikrein infusion. The alterations induced by kallikrein infusion were potentiated by the concomitant administration of the angiotensin-converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl salt-sensitive rats.
Rise of blood pressure with age. New evidence of population differences.
Authors: Rodriguez B L , Labarthe D R , Huang B , Lopez-Gomez J
Published: June 2012

Epstein and Eckoff in 1967 devised a scheme to summarize population differences in the rise of mean values of systolic blood pressure by age in accordance with their slopes and levels. For the first time, the validity of this scheme can be examined with data from a single study, INTERSALT. This study included 52 populations in 32 countries. On the basis of these data, collected in an exceptionally well-standardized mode under a common protocol, the diversity of populations in the slopes of age differences in median values of systolic blood pressure has been strongly reconfirmed. Populations with no increase in median systolic blood pressure were again observed and remained exceptional. The analyses of these data also indicate a positive relation between the slope of rising systolic blood pressure with age and urinary sodium, urinary sodium-potassium ratio, and reported alcohol consumption as well as a negative association between urinary potassium excretion and blood pressure slope. The present analyses therefore add to the previous knowledge and results published by the INTERSALT investigators in the following three respects: (1) they relate INTERSALT results to the postulated biological gradient of variation among populations as presented by Epstein and Eckoff, including explanatory variables; (2) they demonstrate strong correlation between ranks of median blood pressure at 40 to 49 years and values at 20 to 29 years; and (3) they therefore support the original Epstein and Eckoff concept of population variation, link this with blood pressure risk factors, and call attention to the large degree of population differences already evident among populations at 20 to 29 years of age.
β-Adrenergic Receptors and Angiotensinogen Gene Expression in Mouse Hepatoma Cells In Vitro
Authors: Ming Ming , Wu Jie , Lachance Silvana , Delalandre Aline , Carrière Serge , Chan John S. D.
Published: June 2012

Abstract
We have previously reported that addition of 8-bromo-cyclic AMP enhances the stimulatory effect of dexamethasone on the expression of the angiotensinogen gene in mouse hepatoma cells in vitro. Isoproterenol is known to stimulate the synthesis of hepatic intracellular cyclic AMP via β-adrenergic receptors. To study the possible effect of β-adrenergic receptors on the expression of the angiotensinogen gene in mouse hepatoma cells, we transiently transfected them with a fusion gene with the 5′-flanking region of the angiotensinogen gene linked to a bacterial chloramphenicol acetyltransferase coding sequence as a reporter, pOCAT (ANG N-1498/+18). The addition of isoproterenol (10
−9
to 10
−5
mol/L) alone had no stimulatory effect on the expression of pOCAT (ANG N-1498/+18). In the presence of dexamethasone (10
−6
mol/L), however, isoproterenol enhanced the stimulatory effect of the dexamethasone on the expression of pOCAT (ANG N-1498/+18). The enhancing effect of isoproterenol was inhibited by the presence of propranolol (β
1
- and β
2
-adrenergic receptor antagonist) and ICI 118,551 (β
2
-adrenergic receptor antagonist) but not by the presence of atenolol (β
1
-adrenergic receptor antagonist). Furthermore, the addition of Rp-cAMP (an inhibitor of protein kinase A I and II) blocked the enhancing effect of isoproterenol. These studies demonstrated that isoproterenol enhances the stimulatory effect of dexamethasone on the expression of the angiotensinogen gene in mouse hepatoma cells via β
2
-adrenergic receptor and cyclic AMP–dependent protein kinase pathways. Our data may be important in understanding the molecular mechanism(s) of the stimulatory effect of catecholamines/glucocorticoid-induced expression of the angiotensinogen gene in the liver.
Wistar Fatty Rat Is Obese and Spontaneously Hypertensive
Authors: Yamakawa Tadashi , Tanaka Shun-ichi , Tamura Kouichi , Isoda Fumiko , Ukawa Kunio , Yamakura Yoshiko , Takanashi Yoshinori , Kiuchi Yoshihiro , Umemura Satoshi , Ishii Masao , Sekihara Hisahiko
Published: June 2012

Abstract
The purpose of this study was to determine whether genetically obese Wistar fatty rats have higher blood pressure than their lean littermates and if so to elucidate the mechanism of this obesity-related hypertension. We measured blood glucose and plasma insulin levels, blood pressure, and catecholamine and sodium excretions in age-matched female Wistar fatty and lean rats. After 12 weeks of age, the body weight of Wistar fatty rats was significantly greater than that of their lean counterparts. Fasting blood glucose and plasma insulin concentrations were higher in the fatty than the lean rats throughout the observation period (8 to 24 weeks of age). Systolic blood pressure of fatty rats measured by the tail-cuff method was similar to that of lean rats at 8 weeks of age (135±2 [mean±SEM] versus 134±3 mm Hg) but significantly higher at 16 (158±2 versus 136±3 mm Hg,
P
<.01) and 24 (166±5 versus 142±2 mm Hg,
P
<.01) weeks of age. Urinary norepinephrine excretion was significantly increased in the fatty rats at both 16 (1755±173 versus 977±128 ng/24 h,
P
<.05) and 24 (1907±283 versus 737±173 ng/24 h,
P
<.01) weeks of age. The ratio of urinary norepinephrine excretion to body weight was also significantly increased in the fatty rats. These results show that with increasing body weight Wistar fatty rats develop hypertension, which may be attributable to an increased sympathetic nerve activity. Since these characteristics are similar to those observed in human obesity–related hypertension, we consider that this rat may be a good model for further analysis of the mechanism of obesity-related hypertension.
Myocardial Remodeling in Hypertensive Ren-2 Transgenic Rats
Authors: Villarreal F. J. , MacKenna D. A. , Omens J. H. , Dillmann W. H.
Published: June 2012

Abstract
Rats harboring the mouse Ren-2 transgene develop hypertension despite low levels of plasma renin. We determined the extent of left ventricular remodeling present in Ren-2 rats at 16 weeks of age by measuring blood pressure, ratio of heart weight to body weight, left ventricular wall thickness, passive (diastolic) left ventricular compliance, and left ventricular collagen content using hydroxyproline and collagen area fraction. Changes in perivascular fibronectin and collagen type I and III were examined with immunohistochemistry. Blood pressure values at time of death were 244±15 mm Hg for Ren-2 rats (mean±SD, n=5). Ratios of heart weight to body weight (grams per kilogram) for Ren-2 animals were 4.1±0.2 versus 3.1±0.1 for controls (n=6,
P
<.001). Wall thickness values for control animals were 2.6±0.1 versus 4.1±0.4 mm for Ren-2 animals (
P
<.001). Left ventricular Ren-2 hydroxyproline measurements were significantly decreased (3.4±0.2 versus 4.7±0.9 mg/g dry wt for controls). Significant decreases of approximately 30% were also observed in collagen area fraction in Ren-2 rats. Immunohistochemical and picrosirius red staining indicated increased amounts of perivascular fibrosis in all Ren-2 animals (when compared with controls) with enhanced levels of perivascular fibronectin and type I and type III collagen proteins. Left ventricular compliance measurements indicated a decrease in left ventricular volume for all left ventricular pressures (
P
=.07). In conclusion, Ren-2 animals at 16 weeks of age demonstrated a substantial degree of cardiac hypertrophy that was accompanied by perivascular but not diffuse fibrosis and a stiffened left ventricle.
Production of Aldosterone in Isolated Rat Blood Vessels
Authors: Takeda Yoshiyu , Miyamori Isamu , Yoneda Takashi , Iki Kazuhiro , Hatakeyama Haruhiko , Blair Ian A. , Hsieh Feng-Yin , Takeda Ryoyu
Published: June 2012

Abstract
Angiotensin I (Ang I), Ang II, angiotensinogen, and renin are formed locally in the vasculature. We undertook this study to determine whether the rat mesenteric artery produces aldosterone and to investigate the effects of adrenalectomy, an angiotensin-converting enzyme inhibitor, Ang II, or potassium on aldosterone production in vascular tissue. Isolated rat mesenteric arteries were perfused with Krebs-Ringer solution for 4 hours. The perfusate was collected and chromatographed in a reversed-phase high-performance liquid chromatographic (HPLC) system. The fraction corresponding to synthetic aldosterone was collected and analyzed by mass spectrometry. The aldosterone concentration in the perfusate from the adrenalectomized rats and rats treated with an angiotensin-converting enzyme inhibitor was measured using radioimmunoassay after HPLC separation. The mass spectra of synthetic aldosterone and aldosterone isolated from the perfusate of rat mesenteric arteries were identical. Aldosterone production in the mesenteric arteries of adrenalectomized rats was increased and of rats treated with an angiotensin-converting enzyme inhibitor was reduced compared with that of controls. Ang II (1.9×10
−10
mol/L) and potassium (6.0 mmol/L) increased aldosterone production in mesenteric arteries. This study shows that the rat mesenteric artery produces aldosterone and that the intravascular renin-angiotensin-aldosterone system may contribute to vascular tone.
Different Mechanisms of Endothelial Dysfunction With Aging and Hypertension in Rat Aorta
Authors: Küng Christoph F. , Lüscher Thomas F.
Published: June 2012

Abstract
We analyzed the effects and mechanisms of aging in aortic endothelium and vascular smooth muscle of 12-week-old (adult) and 72-week-old (senescent) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aortas were suspended in organ chambers filled with physiological salt solution (95% O
2
/5% CO
2
; 37°C), and isometric tension was measured. In WKY, endothelium-dependent relaxations to acetylcholine were diminished with aging (
P
<.05); in SHR, they were reduced compared with WKY (
P
<.05) but unchanged with aging. The thromboxane/endoperoxide receptor antagonist SQ 30741 increased relaxations only in adult SHR. Relaxations to sodium nitroprusside were slightly enhanced with age in WKY and SHR (
P
<.05). Endothelium-dependent contractions to acetylcholine were unmasked by
N
G
-nitro-
l
-arginine methyl ester (
P
<.05) and prevented by SQ 30741 or endothelium removal. In WKY, contractions increased with age. In adult SHR, marked endothelium-dependent contractions occurred (
P
<.05 versus WKY), which diminished with age (
P
=NS versus senescent WKY). The thromboxane analogue U46619 elicited similar contractions in adult and senescent WKY and adult SHR, whereas responses in senescent SHR were weaker (
P
<.05). In WKY and SHR, contractions to norepinephrine were similar and unaltered by aging. In WKY, contractions to endothelin-1 remained unaffected by aging. Adult SHR exhibited contractions to endothelin-1 comparable to those in WKY, whereas senescent SHR contracted less (
P
<.05). Bosentan, a combined endothelin-A/endothelin-B receptor antagonist, inhibited endothelin-1 markedly, especially in SHR (
P
<.05). Thus, aging causes different alterations in endothelium and smooth muscle in WKY and SHR aorta. In adult SHR, endothelium-dependent relaxations are reduced because of formation of prostaglandin H
2
, whereas in senescent SHR and senescent WKY, impaired formation or increased inactivation of nitric oxide must be involved. Contractions to endothelin but not to norepinephrine are reduced with aging only in SHR.
Glomerular Dynamics and Morphology of Aged Spontaneously Hypertensive Rats
Authors: Komatsu Kazutoshi , Frohlich Edward D. , Ono Hidehiko , Ono Yuko , Numabe Atushi , Willis Gladden W.
Published: June 2012

Abstract
Relationships between glomerular dynamics and renal injury, micropuncture and histological studies were assessed in 73 week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats divided into untreated and angiotension-converting enzyme inhibitor–treated (quinapril; 3 mg/kg/day; for 3 weeks) groups. Urinary protein excretion (UPE) and histologic arteriolar (AIS) and glomerular (GIS) injury scores were determined. Mean arterial pressure (MAP) of untreated SHR was increased compared with WKY (200±6 vs 119±4 mm Hg;
P
<0.01), effective renal plasma flow (ERPF) was reduced (1.47±0.21 vs 3.06±0.26 ml/min/per g;
P
>0.01), and filtration fraction (FF) and total renal vascular resistance (RVR) of SHR were increased (
P
<0.01). Single-nephron plasma flow (SNPF) of untreated SHR was decreased (174±17 vs 80±9 ml/min;
P
<0.01), and single-nephron filtration fraction and afferent arteriolar resistance (R
A
) were increased (19.4±1.8 vs 30.0±2.5% and 1.90±0.25 vs 9.05±1.35 U, respectively; both
P
<0.01). Despite reduced SNPF, glomerular capillary pressure (P
G
) increased (49.7±0.7 vs 53.8±1.3 mm Hg;
P
<0.05), the result of efferent arteriolar constriction (1.15±0.18 vs 2.84±0.36 U;
P
<0.01). Untreated SHR had higher UPE (13.9±1.5 vs 42.8±3.2; mg/100 g per day;
P
<0.01) and GIS and AIS scores than WKY (4.3±1.1 vs 64.3±8.4 and 16.6±3.1 vs 96.3±14.4; both
P
<0.01). Quinapril reduced SHR MAP (to 173±7 mm Hg), FF and RVR (all
P
<0.01) and increased ERPF (to 2.40±0.26 ml/min per g;
P
<0.05), and P
G
decreased (to 49.1±1.1 mm Hg;
P
<0.01); in association with R
A
and R
E
(to 5.18±0.8 U;
P
<0.01 and 1.74±0.31 U;
P
<0.05). Although quinapril reduced UPE (to 23.6±1.8 mg/100 g per day;
P
<0.01) with GIS and AIS (
P
<0.05) in SHR, these indices remained higher than in WKY. These data demonstrate that SHR naturally develop glomerular hypertension and ischemia with arteriolar constriction and glomerular sclerosis, and that intrarenal hemodynamic, pathologic, and proteinuric changes begin to reverse after 3 weeks of treatment.
Cellular Distribution of Angiotensin-Converting Enzyme After Myocardial Infarction
Authors: Falkenhahn Mechthild , Franke Folker , Bohle Rainer Maria , Zhu Yi-Chun , Stauss Harald Martin , Bachmann Sebastian , Danilov Sergei , Unger Thomas
Published: June 2012

Abstract
We studied the cellular distribution of angiotensin-converting enzyme (ACE) in the heart related to the cell types involved in left ventricular repair and remodeling before and after myocardial infarction by immunohistochemical techniques using monoclonal and polyclonal antibodies. In noninfarcted myocardium of both human and rat, ACE expression was confined to endothelial cells and subendocardial cell layers of the aortic valve. ACE was prominent in endothelia of small arteries and arterioles, whereas only half the coronary capillaries were immunoreactive and venous vessels were almost completely devoid of the enzyme. In a rat model of myocardial infarction, ACE distribution was determined 1, 3, and 7 days and 2, 3, and 6 weeks after coronary occlusion. Three and 7 days after infarction, endothelial cells of sprouting capillaries and macrophages in the marginal zone of necrosis revealed ACE expression. In both human and rat with the onset of fibrosis, intense staining of the enzyme was found in the marginal zone of the repair tissue. In situ hybridization for collagen type I in the rat revealed that zones with high collagen content had almost no ACE immunoreactivity. Vascular smooth muscle cells and cardiomyocytes revealed no ACE expression throughout the study. We conclude that endothelial cells are the principal source for the expression of ACE after myocardial infarction. The observed induction of ACE with the onset of fibrosis suggests a role of this enzyme that is related to tissue repair and remodeling.
Cardiac Glucose and Fatty Acid Oxidation in the Streptozotocin-Induced Diabetic Spontaneously Hypertensive Rat
Authors: Christe Michael E. , Rodgers Robert L.
Published: June 2012

Abstract
Hypertension intensifies the cardiac dysfunction of diabetes. We investigated the possible role of altered exogenous fuel oxidation in this phenomenon. Diabetes was induced by streptozotocin in spontaneously hypertensive rats and normotensive Sprague-Dawley rats. Two weeks later, mechanical performance and the oxidation of glucose and palmitate were quantified in working hearts ex vivo at intermediate and high workloads. The results showed that the nondiabetic spontaneously hypertensive rat hearts, compared with those of the normotensive controls, oxidized glucose at a higher rate but oxidized palmitate at a much lower rate, as reported previously. The effects of diabetes in the hypertensive rats, compared with its effects in the normotensive strain, were characterized by (1) a more pronounced decrease in heart performance, (2) either a similar or a less marked reduction in the rate of glucose oxidation, depending on the workload, and (3) a relatively greater increase in palmitate oxidation, particularly at the higher workload. These findings suggest that the exaggerated stimulation of fatty acid oxidation by diabetes in the hypertrophic left ventricle may be a more important contributor to the premature mechanical dysfunction than the inhibition of glucose oxidation. Possible mechanisms include antagonism of energetically favorable shifts in fuel oxidation or inhibition of accelerated membrane lipid biosynthesis in left ventricular hypertrophy.
Glucocorticoids Induce Angiotensin-Converting Enzyme Expression in Vascular Smooth Muscle
Authors: Fishel Robert S. , Eisenberg Steven , Shai Shaw-Yung , Redden Robert A. , Bernstein Kenneth E. , Berk Bradford C.
Published: June 2012

Abstract
Angiotensin-converting enzyme (ACE) activity plays a central role in vessel growth and remodeling as shown by the fact that ACE inhibitors reduce neointimal proliferation after rat carotid injury. To investigate the mechanisms that regulate smooth muscle cell ACE expression, we studied the effects of steroids on ACE activity and mRNA in cultured rat aortic smooth muscle cells. ACE activity was present at low levels independent of growth state. In response to the glucocorticoid dexamethasone (100 nmol/L for 72 hours), ACE activity (hydrolysis of [
3
H]benzoyl-Phe-Ala-Pro) increased 10.1±3.1-fold. The increase in activity occurred within 12 hours and peaked after 72 hours of treatment. The increase in ACE activity was specific for glucocorticoids and paralleled their potency (dexamethasone>hydrocortisone=prednisolone). Dexamethasone increased the steady-state level of ACE mRNA in a concentration-dependent manner (21.4±0.4-fold at 100 nmol/L for 72 hours). Dexamethasone stimulation of ACE expression appeared to be due to both increased transcription and stabilization of ACE enzyme mRNA. This was suggested by the finding that dexamethasone stimulated nuclear run-on expression of ACE mRNA by only threefold, in contrast to the 21-fold increase in steady-state mRNA. These findings establish that ACE is a dynamically regulated enzyme in rat aortic smooth muscle cells. In addition, the present findings suggest an important role for stress steroids in the vascular response to injury in vivo.
Enhanced Responses of the Basilar Artery to Activation of Endothelin-B Receptors in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Kitazono Takanari , Heistad Donald D. , Faraci Frank M.
Published: June 2012

Abstract
We tested the hypothesis that responses of the basilar artery to selective activation of endothelin-B receptors are altered during chronic hypertension. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to a selective endothelin-B receptor agonist, IRL 1620, in stroke-prone spontaneously hypertensive rats (SHRSP). Under control conditions, baseline basilar artery diameter was smaller in SHRSP (196±8 μm [mean±SEM]) than in normotensive Wistar-Kyoto rats (WKY) (245±9 μm,
P
<.05). Topical application of IRL 1620 (10
−8
mol/L) dilated the basilar artery by 27±5% in WKY and 56±4% in SHRSP (
P
<.05). Dilatation of the basilar artery in response to sodium nitroprusside was similar in WKY and SHRSP. In contrast, acetylcholine-induced vasodilatation in SHRSP was markedly impaired.
N
G
-Nitro-
l
-arginine methyl ester and
N
G
-nitro-
l
-arginine, inhibitors of nitric oxide synthase, inhibited IRL 1620–induced vasodilatation in WKY. Neither
N
G
-nitro-
l
-arginine methyl ester nor indomethacin attenuated vasodilatation produced by IRL 1620 in SHRSP. The major finding is that dilator responses of the basilar artery to selective activation of endothelin-B receptors are paradoxically enhanced in SHRSP compared with WKY. Dilator responses of the basilar artery to endothelin-B receptor activation are mediated by endothelium-derived relaxing factor in WKY. In contrast, responses to activation of endothelin receptors in SHRSP do not depend on the production of nitric oxide or prostanoids.
Effect of Chronic Treatment of Adult Spontaneously Hypertensive Rats With an Endothelin Receptor Antagonist
Authors: Li Jin-S. , Schiffrin Ernesto L.
Published: June 2012

Abstract
We previously showed that endothelin-1 expression was increased in vascular endothelium of deoxycorticosterone acetate–salt hypertensive rats, whereas in spontaneously hypertensive rats (SHR) it is similar to or less than that in normotensive rats. Treatment with the combined endothelin type A/endothelin type B receptor antagonist bosentan moderately reduced blood pressure rise and nearly completely blunted the development of vascular hypertrophy, particularly in small arteries, in the deoxycorticosterone acetate–salt hypertensive model, suggesting a paracrine role for vascular endothelin-1 in the induction of blood vessel hypertrophy in some forms of experimental hypertension. In the present study we examined the effect of chronic oral treatment for 4 weeks of 12-week-old SHR and Wistar-Kyoto rats (WKY) with 100 mg/kg per day bosentan. Blood pressure rose to hypertensive levels similarly in bosentan-treated and untreated SHR; systolic pressure of WKY was also unaffected. The wet weights of the heart, of aortic segments, and of the mesenteric arterial bed were similar in treated and untreated SHR. When coronary, renal arcuate, mesenteric, and femoral small arteries were evaluated on a wire myograph, the media width and media-to-lumen ratio were greater and the lumen diameter was smaller in vessels from SHR relative to those from WKY, except in small arteries from the renal cortex, in which the lumen was not significantly different in both strains. The media cross-sectional area of small arteries from the four vascular beds was similar in both strains. Identical morphometric parameters were found in the four vascular beds in bosentan-treated and untreated rats of each strain. We conclude that endothelins do not play a role in the maintenance of elevated blood pressure or in vascular hypertrophy or remodeling in adult SHR. This study also showed similar morphometric changes consistent with remodeling in small arteries of the coronary, mesenteric, and femoral vascular beds of SHR, whereas the changes in renal cortical small arteries were consistent with vascular hypertrophy.
Impaired Maze Learning and Cerebral Glucose Utilization in Aged Hypertensive Rats
Authors: Mori Sakan , Kato Motohiro , Fujishima Masatoshi
Published: June 2012

Abstract
To elucidate the effects of prolonged hypertension on brain function during aging, we examined learning of an eight-arm radial maze task and local cerebral glucose utilization in young-adult (3 to 4 months old) and aged (16 to 17 months old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Young-adult SHR learned the task more slowly than young-adult WKY, but cerebral glucose utilization, measured by the [
14
C]2-deoxyglucose method in 24 brain structures, was not significantly different in the two groups. The aged SHR and WKY exhibited impaired learning ability. Cerebral glucose utilization was reduced (13% to 23%) in six regions in aged WKY and in 12 regions in aged SHR compared with values in the respective young-adult groups. Furthermore, the aged SHR showed a greater disturbance of learning acquisition and more profound reduction of cerebral glucose utilization in five regions than the aged WKY. In SHR, hypometabolism, indicated by a decrease in glucose utilization in 15 brain structures including the cerebral cortex, hippocampus, and visual system, was significantly correlated with impaired learning acquisition, indicated by an increase in total error choices. These findings show that (1) hypertension per se does not impair maze learning or cerebral glucose utilization in young-adult rats, and (2) brain function is impaired during aging and prolonged hypertension is an additional factor facilitating brain dysfunction associated with neuronal hypoactivities, resulting in behavioral deterioration including learning disability. Thus, early control of hypertension seems important for preventing or reducing brain dysfunction in senescence.
Job Status and High-Effort Coping Influence Work Blood Pressure in Women and Blacks
Authors: Light Kathleen C. , Brownley Kimberly A. , Turner J. Rick , Hinderliter Alan L. , Girdler Susan S. , Sherwood Andrew , Anderson Norman B.
Published: June 2012

Abstract
Work-related stress has been associated with an increased risk of hypertension and more severe cardiovascular problems in white men but has been less studied in women and black men. To determine whether the trait of high-effort coping (John Henryism) was related to higher blood pressure during work and laboratory challenges, we studied a biracial sample of 72 men and 71 women working full time outside the home who underwent ambulatory blood pressure monitoring for one 8-hour workday. This was followed by laboratory monitoring of blood pressure during resting baseline and five brief stressors. Women who were high-effort copers and had high status jobs had higher diastolic pressures at work and in the lab than other women; their pressure levels did not differ from those of men, but other women had lower pressures than men. In blacks, the same combination of high-effort coping plus high job status was similarly associated with high work and laboratory diastolic pressure, as well as higher work systolic pressure. The trait of high-effort coping was observed in the large majority (71%) of the women and blacks who had achieved high status jobs but was seen in a minority (36%) of white men with high status jobs and was unrelated to increased blood pressure in the latter group.
Sympathetic Activation in Obese Normotensive Subjects
Authors: Grassi Guido , Seravalle Gino , Cattaneo Bianca M. , Bolla Giovanni B. , Lanfranchi Antonio , Colombo Manuela , Giannattasio Cristina , Brunani Amelia , Cavagnini Francesco , Mancia Giuseppe
Published: June 2012

Abstract
Human obesity is characterized by profound alterations in the hemodynamic and metabolic states. Whether these alterations involve sympathetic drive is controversial. In 10 young obese subjects (body mass index, 40.5±1.2 kg/m
2
, mean±SEM) with normal blood pressure and 8 age-matched lean normotensive control subjects, we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (electrocardiogram), postganglionic muscle sympathetic nerve activity (microneurography at the peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography). The measurements were performed in baseline conditions and, with the exception of plasma norepinephrine, during baroreceptor stimulation and deactivation caused by increases and reductions of blood pressure via intravenous infusions of phenylephrine and nitroprusside. Baseline blood pressure and heart rate were similar in obese and control subjects. Plasma norepinephrine was also similar in the two groups. Muscle sympathetic nerve activity, however, was 38.6±5.1 bursts per minute in obese subjects and less than half that level in control subjects (18.7±1.3 bursts per minute), the difference being highly statistically significant (
P
<.02). Muscle sympathetic nerve activity and heart rate were reduced during phenylephrine infusion and increased during nitroprusside infusion, but the changes were about half as great in obese subjects as in control subjects. Thus, even in the absence of any blood pressure alteration, human obesity is characterized by a marked sympathetic activation, possibly because of an impairment of reflex sympathetic restraint. This may be involved in the high rate of hypertension and cardiovascular complications seen in obesity.
Short-term and Sustained Renal Effects of Angiotensin II Receptor Blockade in Healthy Subjects
Authors: Burnier Michel , Hagman Michael , Nussberger Jurg , Biollaz Jérôme , Armagnac Catherine , Brouard Rémi , Waeber Bernard , Brunner Hans R.
Published: June 2012

Abstract
We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t
1/2
of 15 to 17 hours). Irbesartan had no significant effect on urinary potassium and uric acid excretions on days 1 and 8. Together, these results demonstrate that in healthy subjects the Ang II receptor antagonist irbesartan decreases filtration fraction and promotes urinary sodium excretion without affecting urinary uric acid excretion and that these renal hemodynamic and tubular effects are maintained during a repeated 8-day administration.