bluuebunny/crossref_metadata_2025 huggingface dataset:
Amplification of Kinin-Induced Hypotension by Nitric Oxide Synthesis in Spontaneously Hypertensive Rats
Authors: Bjørnstad-Østensen Anniken , Holte Hege Ruge , Berg Torill
Published: June 2012

We studied the role of nitric oxide and adrenergic activation in the blood pressure (BP) response to exogenous bradykinin in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rats (WKY). Rats were pretreated with the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME), the α-adrenergic receptor antagonist phentolamine together with L-NAME, or phentolamine alone. Sham-injected rats were used as controls. All rats subsequently received bradykinin (3, 6, and 30 μg/kg IV). Bradykinin induced a concentration-dependent fall in BP in both WKY and SHR (
P
<.0005). The change in BP was greater in SHR than WKY (
P
<.0001). BP before bradykinin administration was elevated in the L-NAME group in both strains. In WKY, L-NAME or L-NAME plus phentolamine did not alter the ΔBP concentration-response curve to bradykinin (
P
=NS), whereas in SHR, the ΔBP concentration-response curve was attenuated (
P
<.0048). The attenuation was observed for the two lower bradykinin doses (
P
<.0005) but not the highest. In SHR, phentolamine alone reduced BP before bradykinin to the same level as in WKY controls, and its ΔBP concentration-response curve was not different from that of the normotensive controls or L-NAME and L-NAME plus phentolamine SHR groups. No difference was observed in the duration of the hypotensive response in SHR compared with WKY. The present results confirm that in normotensive rats, the hypotensive effect of bradykinin was mediated by an unknown mechanism other than through the release of nitric oxide. However, in SHR, this mechanism was amplified by additional activation of nitric oxide synthesis. This bradykinin-activated nitric oxide production may be a pressure-induced mechanism to counteract the hypertensive condition.
Oral Calcium Supplementation Reduces Intraplatelet Free Calcium Concentration and Insulin Resistance in Essential Hypertensive Patients
Authors: Sánchez Miquel , de la Sierra Alejandro , Coca Antonio , Poch Esteban , Giner Vicent , Urbano-Márquez Alvaro
Published: June 2012

We evaluated the effect of oral calcium supplementation on blood pressure, calcium metabolism, and insulin resistance in essential hypertension. After receiving a standard diet with 500 mg of calcium per day during a 4-week period, 20 nondiabetic, essential hypertensive patients were randomized in a double-blind fashion to receive oral calcium supplementation (1500 mg of calcium per day) or placebo for 8 weeks. At the end of the 4-week period of low-calcium diet and after the 8-week period of intervention, we measured blood pressure (by both office and 24-hour ambulatory blood pressure monitoring), calcium-regulating hormones [urinary hydroxyproline and serum osteocalcin, parathormone, and 1,25(OH)
2
-vitamin D
3
], intra-platelet free calcium concentration, fasting plasma glucose and insulin levels, and the insulin-sensitivity index (euglycemic-hyperinsulinemic clamp). Compared with patients maintained at low calcium intake, essential hypertensive patients under oral calcium supplementation significantly reduced serum osteocalcin (from 22.2±1.9 to 17.9±2.0 μg/L;
P
=.0015), parathormone (from 4.20±0.38 to 3.30±0.36 pmol/L;
P
=.0003), and 1,25(OH)
2
-vitamin D
3
(from 98.0±11.0 to 61.6±5.7 pmol/L;
P
=.0062). Likewise, we found a significant reduction in intraplatelet free calcium concentration (from 35.9±1.2 to 26.5±0.8 nmol/L;
P
=.0005) and fasting plasma insulin levels (from 71.8±5.9 to 64.6±6.2 pmol/L;
P
=.05) and a significant increase in the insulin-sensitivity index (from 2.89±0.77 to 4.00±0.95 mg·kg
−1
·
−1
;
P
=.0007). None of these parameters were significantly modified in patients maintained at low calcium intake. Office and 24-hour mean values of systolic and diastolic blood pressure did not change after 8 weeks of oral calcium supplementation or placebo.
Urinary Endothelin-1 Excretion Is Enhanced by Low-Dose Infusion of Brain Natriuretic Peptide in Normal Humans
Authors: De Feo Maria Laura , La Villa Giorgio , Lazzeri Chiara , Tosti-Guerra Cristina , Becorpi Angela , Pupilli Cinzia , Mannelli Massimo
Published: June 2012

To evaluate the functional relationship between cardiac natriuretic peptides and endothelin-1 within the human kidney, we studied the effects exerted by infusion of brain natriuretic peptide on urinary endothelin-1 excretion. We studied twice in a single-blind manner five normal volunteers who received a constant infusion of 5% dextrose (250 mL/h) or human brain natriuretic peptide-32 at a dose of 4 pmol/kg per minute. Blood samples were drawn at intervals for measurement of hematocrit and concentrations of creatinine, electrolytes, brain natriuretic peptide, and endothelin-1. Urine was collected at intervals for measurement of flow rate and concentrations of creatinine, sodium, cGMP, and endothelin-1. Blood pressure and heart rate were measured every 15 minutes. Placebo administration did not change blood pressure, heart rate, or any of the other parameters measured in plasma and urine. As expected, brain natriuretic peptide infusion caused significant increases in its own plasma levels (basal versus peak levels [mean±SD], 1.45±0.20 versus 50.5±6.0 pmol/L,
P
<.01), in urinary cGMP (0.75±0.16 versus 1.92±0.81 fmol/min,
P
<.05), and in urinary sodium excretion (140.0±38.7 versus 624.2±181.6 μmol/min,
P
<.01). In addition, it caused an increase in urinary endothelin-1 excretion (4.32±2.11 versus 19.67±9.52 fmol/min,
P
<.05), without modifying plasma endothelin-1, blood pressure, heart rate, creatinine clearance, and urinary flow rate. Our data indicate that brain natriuretic peptide, at plasma levels comparable to those observed in patients with heart failure, causes a significant increase in urinary but not plasma endothelin-1, thus demonstrating a functional link between cardiac natriuretic peptides and renal release of endothelin-1.
Hypoxia Stimulates Atrial Natriuretic Peptide Gene Expression in Cultured Atrial Cardiocytes
Authors: Chen Yiu-Fai , Durand Joan , Claycomb William C.
Published: June 2012

The current study tested the hypothesis that hypoxia stimulates atrial natriuretic peptide (ANP) gene expression and secretion in cultured atrial myocytes (AT-1 cells). AT-1 cells were obtained from a transplantable mouse atrial cardiomyocyte tumor lineage. Confluent AT-1 cells were exposed to hypoxia (1% oxygen) or normoxia (21% oxygen) as controls for 6 hours to 7 days. Medium ANP levels were measured by radioimmunoassay, and intracellular ANP gene transcripts were quantified by Northern and slot blot analyses. Exposure to hypoxia resulted in a significant increase in cellular ANP mRNA levels within 36 hours, which peaked (3.6-fold increase) at 2 days after hypoxic exposure, and produced a time-dependent increase in the release of ANP from AT-1 cells for 2 to 7 days. Transfection studies with recombinant DNA constructs that contained fragments of the −3003/+62 sequence of the ANP promoter and the luciferase reporter gene revealed that the regulatory sequences that mediate the hypoxia-induced increase in transcription are located within a region that extends from −638 to −518 bp to the transcriptional start site of the ANP gene. Gel mobility shift assays demonstrated that hypoxia-inducible nuclear proteins that bound to the 120-bp putative hypoxia-responsive elements of the ANP gene were produced during hypoxic exposure. We have thus defined a 120-bp region within the ANP gene promoter that contains hypoxia-responsive elements that might be responsible for the enhancement of ANP gene expression in atrial myocytes during hypoxic exposure.
High Prevalence of Concentric Remodeling in Elderly Individuals With Isolated Systolic Hypertension From a Population Survey
Authors: Heesen Wilfred F. , Beltman Frank W. , May Johan F. , Smit Andries J. , de Graeff Pieter A. , Havinga Tjeerd K. , Schuurman Frits H. , van der Veur Enno , Hamer Johannes P.M. , Jong Betty Meyboom-de , Lie Kong I.
Published: June 2012

Echocardiographic determination of left ventricular mass index (LVMI) is shown to be valuable in the assessment of cardiovascular risk. Determination of left ventricular geometry, including concentric remodeling, provides additional prognostic information. In isolated systolic hypertension (ISH), the few echocardiographic studies available show an increased LVMI, but criteria and patient populations differ. No comparison with diastolic hypertension (DH) has been made, nor has left ventricular geometry (with concentric remodeling) been evaluated. We compared both LVMI and left ventricular geometry of newly diagnosed ISH subjects with normotensive and DH subjects, all previously untreated and from the same population. The echocardiographic LVMI of 97 previously untreated ISH subjects (4× systolic pressure ≥160 mm Hg, diastolic pressure <95 mm Hg) was clearly elevated compared with values in age- and sex-matched normotensive subjects (98 and 71 g/m
2
, respectively;
P
<.001). The geometric pattern was abnormal in most ISH subjects, with a high prevalence (43%) of concentric remodeling. Both LVMI and left ventricular geometry of ISH subjects did not differ significantly from values in DH subjects (LVMI, 92 g/m
2
; concentric remodeling, 56%). Sex differences in LV geometry in ISH were present only with the Framingham criteria, not with the Koren criteria. This study shows a high prevalence of concentric remodeling in elderly individuals with previously untreated ISH. The increase of LVMI and abnormality in left ventricular geometry are comparable with those in DH subjects, further defining the place of ISH as a cardiovascular risk factor in the elderly. Whether there are sex differences in cardiac adaptation in ISH and whether the geometric classification can be used to adjust treatment remain to be investigated.
Increased Na
+
-H
+
Exchange in Red Blood Cells of Patients With Primary Aldosteronism
Authors: Koren Wladimir , Postnov Ilya Y. , Postnov Yuvenaly V.
Published: June 2012

We measured Na
+
-H
+
exchange as the amiloride-inhibited fraction of H
+
efflux from red blood cells into a sodium-containing medium (pH
o
7.95 to 8.05) at pH
i
values of 6.05 to 6.15, 6.35 to 6.45, 6.95 to 7.05, and 7.35 to 7.45 in 12 drug-free patients with primary aldosteronism before and after excision of histologically proven aldosterone-producing adrenal adenoma, 12 drug-free essential hypertensive patients, and 12 healthy control subjects. Red blood cell Na
+
-H
+
exchange was increased in patients with primary aldosteronism similarly to the mean exchanger velocity in essential hypertensive patients compared with values in healthy subjects (334±25 and 310±29 versus 139±21 μmol H
+
/L cells per minute, respectively;
P
<.001 and .01). The kinetic parameters of Na
+
-H
+
exchange returned to normal on day 2 after removal of the aldosterone-producing mass.
K
m
for [Na
+
]
o
was not affected by aldosterone, whereas
K
m
for [H
+
]
i
was decreased in patients with primary aldosteronism. The kinetic characteristics did not differ in essential hypertensive patients and control subjects. Protein kinase C inhibition in vitro by calphostin C (60 nmol/L) increased
K
m
for [H
+
]
i
and caused up to a 65% suppression of Na
+
-H
+
exchange (pH
i
6.05 to 6.15), while diminishing
K
m
for [Na+]
o
in red blood cells of patients with primary aldosteronism. The calmodulin antagonist W-13 (60 mmol/L) decreased exchanger velocity and increased
K
m
for both H
+
and Na
+
. We conclude that aldosterone stimulates red blood cell Na
+
-H
+
exchange by a nongenomic mechanism that augments the exchanger affinity to Na
+
and H
+
. In primary aldosteronism, protein kinase C and calmodulin seem to have synergistic stimulatory effects on red blood cell Na
+
-H
+
exchange, and both increase the affinity of the exchanger to H
+
, while their effect on Na
+
binding is opposite.
Increased Brain Transcription Factor Expression by Angiotensin in Genetic Hypertension
Authors: Blume Annegret , Lebrun Christine J. , Herdegen Thomas , Bravo Rodrigo , Linz Wolfgang , Möllenhoff Eva , Unger Thomas
Published: June 2012

A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR), in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II–induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II–induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II–induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.
Additive Effects of Losartan and Enalapril on Blood Pressure and Plasma Active Renin
Authors: Azizi Michel , Guyene Thanh-Tam , Chatellier Gilles , Wargon Mathias , Ménard Joël
Published: June 2012

The combination of single oral doses of an angiotensin I–converting enzyme inhibitor (captopril) and a type 1 angiotensin II receptor antagonist (losartan) has additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. We planned the present study to determine whether the magnitude of the hemodynamic and hormonal consequences of renin-angiotensin system blockade by such a combination is larger than that obtained by doubling the dose of the angiotensin-converting enzyme inhibitor given alone. In a single-dose, double-blind, randomized, three-way crossover study, 10 mg enalapril, 20 mg enalapril, and the combination of 50 mg losartan and 10 mg enalapril were administered orally to 12 sodium-depleted normotensive subjects. The area under the time curve from 0 to 24 hours (AUC
0-24
) of the mean blood pressure fall after losartan-enalapril combination intake (−220±91 mm Hg·h) was significantly greater than that of either 10 or 20 mg enalapril (−124±91 and −149±85 mm Hg·h, respectively;
P
<.05 vs both doses). The combination significantly increased by 2.3±1.2-fold the AUC
0-24
of plasma active renin compared with either 10 or 20 mg enalapril given alone (
P
<.05) but had no additive effect on plasma aldosterone fall. The losartan-enalapril combination is more effective in decreasing blood pressure and increasing plasma active renin than doubling of the enalapril dose.
Bradykinin B
2
Receptor Modulates Renal Prostaglandin E
2
and Nitric Oxide
Authors: Siragy Helmy M. , Jaffa Ayad A. , Margolius Harry S.
Published: June 2012

Bradykinin and lys-bradykinin generated intrarenally appear to be important renal paracrine hormones. However, the renal effects of endogenously generated bradykinin are still not clearly defined. In this study, we measured acute changes in renal excretory and hemodynamic functions and renal cortical interstitial fluid levels of bradykinin, prostaglandin E
2
, and cGMP in response to an acute intrarenal arterial infusion of the bradykinin B
2
receptor antagonist Hoe 140 (icatibant), cyclooxygenase inhibitor indomethacin, or nitric oxide synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA) given individually or combined in uninephrectomized, conscious dogs (n=10) in low sodium balance. Icatibant caused a significant decrease in urine flow, urinary sodium excretion, and renal plasma flow rate (each
P
<.001). Glomerular filtration rate did not change during icatibant administration. Icatibant produced an unexpected large increase in renal interstitial fluid bradykinin (
P
<.0001) while decreasing renal interstitial fluid prostaglandin E
2
and cGMP (each
P
<.001). Both indomethacin and L-NMMA when given individually caused significant antidiuresis and antinatriuresis and decreased renal blood flow (each
P
<.001). Glomerular filtration rate decreased during L-NMMA administration (
P
<.001) and did not change during indomethacin administration. Combined administration of icatibant and indomethacin or L-NMMA caused significant decreases in renal excretory and hemodynamic functions, which were not different from changes observed with icatibant alone. The failure of icatibant to change renal function after inhibition of cyclooxygenase and nitric oxide synthase activity suggests that the effects of kinin B
2
receptor are mediated by intrarenal prostaglandin E
2
and nitric oxide generation. The increase in renal interstitial fluid bradykinin during icatibant requires further study of possible alterations in kinin synthesis, degradation, or clearance as a result of B
2
receptor blockade.
Blood Pressure and Vascular Effects of Endothelin Blockade in Chronic Nitric Oxide–Deficient Hypertension
Authors: Moreau Pierre , Takase Hiroyuki , Küng Christoph F. , Shaw Sidney , Lüscher Thomas F.
Published: June 2012

Because nitric oxide inhibits the synthesis and vasoconstrictor effect of endothelin-1, the effect of endothelin-1 may be enhanced under conditions of chronic inhibition of nitric oxide synthesis. We studied the effect of chronic therapy with bosentan, a combined endothelin-A/endothelin-B receptor antagonist, on blood pressure and vascular function and structure of small arteries as well as on the reactivity of the aorta in
N
ω
-nitro-
l
-arginine methyl ester (L-NAME)–induced hypertension. Six-week-old Wistar-Kyoto rats were randomly treated for 6 weeks with placebo (control), L-NAME (70 mg/kg per day), or L-NAME plus bosentan (100 mg/kg per day). The treatments were stopped 2 to 3 days before the in vitro experiments so that only the long-term effects of the drugs could be observed. L-NAME increased systolic blood pressure; bosentan did not prevent this effect although the initial blood pressure rise was delayed (
P
=NS versus L-NAME group). Bosentan administration did not modify the structural alteration of the resistance vessels induced by L-NAME, nor did it improve endothelium-dependent relaxation of resistance vessels or the aorta. However, bosentan therapy markedly increased endothelium-dependent contraction to acetylcholine, which was slightly enhanced by L-NAME. In contrast, bosentan inhibited aortic endothelium-dependent contractions when applied acutely in vitro. This observation, together with the increased maximal vasoconstriction to the thromboxane A
2
receptor agonist U46619 after 2 weeks of bosentan administration, suggests that bosentan also interacts with the receptors mediating endothelium-dependent contractions. In conclusion, our experiments suggest a minor role of endothelin in chronic L-NAME–induced hypertension as well as in the concomitant alterations of vascular structure.
Structural and Functional Analysis of Small Arteries From Young Spontaneously Hypertensive Rats
Authors: Dickhout Jeffrey G. , Lee Robert M.K.W.
Published: June 2012

We studied structural and functional changes of small muscular arteries from the mesenteric vascular bed of young spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) using a new morphometric protocol involving the use of confocal microscopy and a pressurized artery system. At 3 and 4 weeks of age, systolic pressure of SHR and WKY was similar; however, significant structural changes in the mesenteric vasculature were already present in SHR. Arteries fixed under pressure in vitro from SHR had a larger medial volume and increased number of smooth muscle cell layers but similar lumen size compared with arteries from WKY in maximally relaxed conditions. Functional studies showed that SHR arteries contracted more in response to stimulation by KCl and norepinephrine, resulting in a significantly smaller lumen size in these vessels than in those from WKY. SHR arteries precontracted with KCl were also able to maintain a smaller lumen diameter than WKY arteries when challenged with increasing pressure levels. No difference in the sensitivity of response of these arteries to norepinephrine stimulation was found. At 3 and 4 weeks of age, mesenteric arteries from some SHR and WKY were not responsive to periarterial nerve stimulation, and the number of responders was higher in the WKY than SHR. However, a greater degree of contraction was found in SHR arteries responding to field stimulation at 4 weeks than in WKY arteries. We conclude that there is a temporal difference in the rate of functional maturation of the innervation in SHR arteries compared with WKY arteries. Structural changes of the small muscular arteries, caused by an increase in the medial volume, and increased number of smooth muscle cell layers are primary changes that contribute to the development of hypertension in the SHR because these changes are present at the age when blood pressure is similar in SHR and WKY.
Induction of Renin in Medial Smooth Muscle Cells by Balloon Injury
Authors: Iwai Naoharu , Izumi Masafumi , Inagami Tadashi , Kinoshita Masahiko
Published: June 2012

Abstract
We studied the expression of each component of the renin-angiotensin system (renin, angiotensin I–converting enzyme, angiotensinogen, and angiotensin II type I receptor) in balloon-injured rat carotid artery. We assessed the expression levels of the respective mRNAs by competitive polymerase chain reaction. Renin mRNA concentration was markedly increased 24 hours after balloon injury and remained higher than that in the control at 7 days after balloon injury. Angiotensin-converting enzyme mRNA concentration was decreased 24 hours after balloon injury and was increased at 14 days after balloon injury. No significant change in angiotensinogen mRNA concentration was observed throughout the study period. Angiotensin type I receptor mRNA concentration was increased beginning 3 days after balloon injury and remained higher than that in the control at 14 days after balloon injury. Immunohistochemical analysis showed that renin was transiently expressed in medial smooth muscle cells after balloon injury. Administration of quinapril markedly reduced neointimal formation and was accompanied by an attenuation of the increase in the concentrations of angiotensin type I receptor and angiotensin-converting enzyme mRNAs. The upregulation of renin mRNA in balloon-injured rat carotid artery preceded and may play a role in neointimal formation.
Role of Nitric Oxide in the Development of Vascular α
1
-Adrenoreceptor Desensitization and Pressure Diuresis in Conscious Rats
Authors: Minami Naoyoshi , Imai Yutaka , Nishiyama Hisamitu , Abe Keishi
Published: June 2012

Abstract
We evaluated whether a minor impairment of the
l
-arginine–nitric oxide pathway would affect the desensitization of vascular α-adrenoreceptor and pressure diuresis induced by prolonged intravenous infusion of phenylephrine (an α-adrenoreceptor agonist) in conscious Wistar-Kyoto rats. We examined dose-pressor–response curves to phenylephrine after an intravenous infusion of phenylephrine (2.5 μg·kg
−1
·min
−1
) or saline for 9 hours with and without concomitant infusion of
N
ω
-
l
-arginine methyl ester (L-NAME) given to partially inhibit the
l
-arginine–nitric oxide pathway. In addition, to evaluate the effect of plasma volume loss on the pressor response to phenylephrine, we evaluated the dose-pressor–response curves to phenylephrine after intravenous injection of furosemide (5 mg/kg) or infusion of phenylephrine (5 μg·kg
−1
·min
−1
) for 9 hours. The renin-angiotensin, vasopressin and autonomic nervous systems were blocked before the examination of dose-pressor responses. Prolonged infusion of phenylephrine (2.5 μg·kg
−1
·min
−1
) shifted the dose pressor–response curve to this agent rightward, with significantly increased log ED
50
(the dose needed to reach 50% of the maximal response) to a similar extent in both L-NAME–treated (0.51±0.05 versus 0.93±0.07 μg/kg) and –untreated (0.79±0.06 versus 1.08±0.03 μg/kg) rats. The log ED
50
value after phenylephrine infusion (5 μg·kg
−1
·min
−1
) was significantly higher than that after furosemide injection (1.28±0.06 versus 1.02±0.01 μg/kg, respectively,
P
<.01), although the two treatments induced a similar loss of plasma volume. The slope in the linear relationship between the average change in mean arterial pressure during the 9-hour infusion period and the rate of urine excretion was significantly depressed in L-NAME–treated versus control rats (L-NAME: 0.057 mL·kg
−1
·h
−1
·mm Hg
−1
, control: 0.146 mL·kg
−1
·h
−1
·mm Hg
−1
,
P
<.05). In conclusion, a minor impairment of the
l
-arginine–nitric oxide pathway does not appear to interfere with the desensitization of vascular α-adrenoreceptor but does inhibit the pressure-diuresis response in conscious normotensive rats.
Cancer Risk in Users of Calcium Channel Blockers
Authors: Olsen Jørgen H. , Sørensen Henrik Toft , Friis Søren , McLaughlin Joseph K. , Steffensen Flemming Hald , Nielsen Gunnar Lauge , Andersen Morten , Fraumeni Joseph F. , Olsen Jørn
Published: June 2012

Abstract
Ca
2+
channel blockers may cause cancer by inhibiting apoptosis or reducing intracellular Ca
2+
in certain tissues. Recent findings suggest that drug users are at increased risk for cancer in general and for colon cancer in particular. We conducted a study in one Danish county of 17 911 patients who received at least one prescription of Ca
2+
channel blockers between 1 January 1991 and 31 December 1993. The patients were identified from records in the National Health Insurance Program, which refunds part of the price of such drugs. Cancer occurrence and rate were determined by use of the files of the Danish Cancer Registry and compared with county-specific incidence rates for various categories of cancer. During the follow-up period of up to 3 years, 412 cancers were observed among users of Ca
2+
channel blockers, compared with 414 expected, to yield an age- and sex-standardized incidence ratio (SIR) of 1.00 (95% confidence interval, 0.90 to 1.10). There was no indication of an excess risk in the subgroup of likely long-term users or users of specific drugs. The SIR of colon cancer, a site of a priori interest, was 0.8 (95% confidence interval, 0.5 to 1.1) on the basis of 34 cases. Although the results are reassuring, the lack of association could reflect the relatively short follow-up after registration in the prescription database. Continued monitoring of cancer risk is planned.
Baroreflex Sensitivity Assessed by Complex Demodulation of Cardiovascular Variability
Authors: Kim Shin Y. , Euler David E.
Published: June 2012

Abstract
We used complex demodulation of cardiac interval and systolic arterial blood pressure oscillations in the low-frequency band (0.04 to 0.14 Hz) to investigate baroreceptor control of heart rate. Baroreflex sensitivity was defined as the instantaneous amplitude of complex-demodulated oscillations in the RR interval divided by the instantaneous amplitude of complex-demodulated oscillations in systolic blood pressure. We evaluated the method using both simulated and actual data obtained from 33 healthy nonsmokers during supine and standing postures. To test the validity and reliability of the method, we compared the mean values of baroreflex sensitivity calculated using complex demodulation with the values obtained using power spectral analysis and sequential analysis of spontaneous variations in blood pressure and RR interval. All three methods applied to the simulated data yielded the same values of baroreceptor sensitivity. Mean values of baroreflex sensitivity assessed by complex demodulation of the actual data were similar to those calculated by both power spectral analysis and sequential analysis (13.9±5.2 versus 13.7±6.7 or 14.3±6.5 ms/mm Hg for supine and 7.3±2.8 versus 7.0±3.0 or 7.2±2.8 ms/mm Hg for standing, respectively). In addition, a significant correlation existed between the values obtained by complex demodulation and power spectral analysis (
r
=.97,
P
=.0001) and sequential analysis (
r
=.98,
P
=.0001). Furthermore, complex demodulation–derived baroreflex sensitivity fluctuated across time during both the supine and standing postures, and this could not be discerned by power spectral analysis. The results indicate that complex demodulation provides a dynamic assessment of baroreflex sensitivity and may be a useful tool in exploring reflex autonomic control of the cardiovascular system.
Adrenomedullin Stimulates Renin Release and Renin mRNA in Mouse Juxtaglomerular Granular Cells
Authors: Jensen Boye L. , Krämer Bernhard K. , Kurtz Armin
Published: June 2012

Abstract
The recently discovered peptide adrenomedullin (AM) alters blood pressure through effects on the resistance vessels. Moreover, AM modifies the secretion of corticotropin and aldosterone and could thereby indirectly influence blood pressure through the renin-angiotensin-aldosterone system. Although plasma AM and renin concentrations have been found to directly correlate, a causal linkage between AM and renin has not been shown. The present study tested the influence of AM on renin secretion and renin gene expression by renal juxtaglomerular granular cells. Prominent expression and release of AM by vascular structures has been reported; therefore, we investigated the local expression of AM in juxtaglomerular structures. Renin release from isolated perfused rat kidneys was dose-dependently increased by AM (1 to 30 nmol/L), whereas renal perfusate flow rate increased up to 17% at a constant perfusion pressure of 100 mm Hg. In primary cultures of mouse granular cells, AM augmented renin release, renin mRNA accumulation, and cAMP production in a dose- and time-dependent manner (threshold values in the range 10 pmol/L to 1 nmol/L). By reverse transcription–polymerase chain reaction, significant expression of the AM gene was detected in microdissected rat glomeruli with afferent arterioles and in primary cultures of mesangial and granular cells. We conclude that AM is expressed in juxtaglomerular structures and that it has a direct stimulatory effect on renin secretion and renin mRNA abundance by receptors on juxtaglomerular cells, possibly through increases in cAMP. AM could act as an autocrine/paracrine stimulatory factor in the control of renin secretion and renin gene expression.
Effect of Mechanical Loading on Vascular α
1D
- and α
1B
-Adrenergic Receptor Expression
Authors: Clements Mary L. , Banes Albert J. , Faber James E.
Published: June 2012

Abstract
Heterogeneous distribution and function of α
1
-adrenergic receptor subtypes on arterial and venous vessels, together with evidence for altered α-adrenergic receptor expression in hypertension, led us to examine whether mechanical load influences expression of α
1B
-and α
1D
-adrenergic receptors in rat aortic smooth muscle cells (SMCs). We used RNase protection and radioligand binding assays to measure mRNA and α
1
-adrenergic receptor density. In the first model, SMCs were subjected to phasic loading using flexible culture plates. As a positive control for the load stimulus, postconfluent, quiescent passage 5 cells demonstrated the expected load-dependent morphological realignment. However, no changes were detected in expression of either α
1D
- or α
1B
-adrenergic receptor mRNAs or receptor density after 24 to 48 hours of loading. β-Actin and SMC-specific α-actin mRNA, as well as cell number and per-cell total RNA and protein, were also unaffected. In a second model, intact thoracic aortas, in either the presence or absence of endothelial cells, were cultured for 48 hours under tonic load. Like cultured cells, 48 hours of load did not affect SMC expression of α
1
-adrenergic receptor mRNAs. We used suprarenal aortic coarctation to examine effects of increased pressure in vivo. As with the previous in vitro and in situ models, hypertension (30 days) had no effect on expression of α
1B
- and α
1D
-adrenergic receptor mRNAs in the suprarenal aorta compared with sham coarctation. To separate pressure per se from humoral influences, we also measured mRNAs in the subrenal, normotensive aorta. α
1B
mRNA levels decreased to 68±14% of sham-coarcted controls in subrenal aorta exposed to normal blood pressure but also to systemic humoral changes induced by coarctation. As a positive control for a load effect, SMC-specific α-actin mRNA increased for loaded aorta in organ culture and in hypertensive aorta in vivo, whereas expression of β-actin mRNA was unaffected. These results from cell culture, organ culture, and in vivo models suggest that pressure (load) alone has no effect on α
1B
- and α
1D
-adrenergic receptor expression. In coarctation hypertension, smooth muscle protected from the hypertension showed a decline in α
1B
mRNA that may be due to a humoral factor or factors.
Prognostic Significance of the White Coat Effect
Authors: Verdecchia Paolo , Schillaci Giuseppe , Borgioni Claudia , Ciucci Antonella , Porcellati Carlo
Published: June 2012

Abstract
The difference between clinic and ambulatory blood pressure (BP) has been used to quantify the pressure reactivity to the doctor’s visit (white coat effect). We investigated the prognostic significance of the clinic-ambulatory BP difference in the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study. A total of 1522 subjects contributed 6371 person-years of observation. All subjects had an initial off-therapy diagnostic workup including 24-hour noninvasive ambulatory BP monitoring. The predicted values of ambulatory BP progressively diverged from the identity line (white coat effect of 0 mm Hg) with increasing clinic BP, but the predicted values of clinic BP tended toward the identity line with increasing ambulatory BP. Hence, the clinic-ambulatory BP difference showed a direct association with clinic BP and an inverse association with ambulatory BP. Consequently, a high clinic-ambulatory BP difference predicted both a high clinic and a low ambulatory BP, whereas a low clinic-ambulatory BP difference predicted both a low clinic and a high ambulatory BP. The clinic-ambulatory BP difference showed also a direct association with age. During up to 9 years of follow-up (mean, 4.2 years), there were 157 major cardiovascular morbid events (125 nonfatal and 32 fatal). The rate of total cardiovascular morbid events did not differ (log-rank test) among the four quartiles of the distribution of the clinic-ambulatory BP difference (2.13, 2.92, 2.10, and 2.83 events per 100 patient-years for systolic BP and 2.94, 2.14, 2.58, and 2.16 events per 100 patient-years for diastolic BP). Also, the rate of fatal cardiovascular events did not differ among the four quartiles of the distribution of the clinic-ambulatory BP difference. The clinic-ambulatory BP difference, taken as a measure of the white coat effect, does not predict cardiovascular morbidity and mortality in subjects with essential hypertension.
A 90-kD Na
+
-H
+
Exchanger Kinase Has Increased Activity in Spontaneously Hypertensive Rat Vascular Smooth Muscle Cells
Authors: Phan Van N. , Kusuhara Masatoshi , Lucchesi Pamela A. , Berk Bradford C.
Published: June 2012

Abstract
Increased activity of the Na
+
-H
+
exchanger (NHE-1 isoform) has been observed in cells and tissues from hypertensive humans and animals, including the spontaneously hypertensive rat (SHR). No mutation in NHE-1 DNA sequence or alteration in NHE-1 mRNA and protein expression has been demonstrated in hypertension, indicating that alterations in proteins that regulate NHE-1 activity are responsible for increased activity. The recent finding that NHE-1 phosphorylation in SHR vascular smooth muscle cells (VSMCs) was greater than in Wistar-Kyoto rat (WKY) VSMCs suggested that NHE-1 kinases may represent an abnormal regulatory pathway present in hypertension. To define NHE-1 kinases altered in the hypertensive phenotype, we measured NHE-1 kinase activity by an in-gel-kinase assay using a recombinant glutathione
S
-transferase NHE-1 fusion protein as a substrate. At least 7 NHE-1 kinases (42 to 90 kD) were present in VSMCs. We studied a 90-kD kinase because it was the major NHE-1 kinase and exhibited differences between SHR and WKY. Comparison of 90-kD kinase activity revealed that SHR VSMCs had increased activity in growth-arrested cells and in cells stimulated by angiotensin II (100 nmol/L for 5 minutes). Activation of the 90-kD kinase by angiotensin II was Ca
2+
dependent, PKC independent, and partially dependent on the mitogen-activated protein kinase pathway. These findings indicate that increased activity of a 90-kD NHE-1 kinase is a characteristic of SHR VSMCs in culture and suggest that alterations in the 90-kD NHE-1 kinase and/or proteins that regulate its activity may be a pathogenic component in hypertension in the SHR.
Estrogen Maintains Nitric Oxide Synthesis in Arterioles of Female Hypertensive Rats
Authors: Huang An , Sun Dong , Kaley Gabor , Koller Akos
Published: June 2012

Abstract
We hypothesized that in female spontaneously hypertensive rats (SHR), estrogen moderates the dysfunction of arterioles by preserving nitric oxide synthesis. To this end, we conducted experiments on isolated gracilis muscle arterioles (approximately 55 μm in diameter) of 12-week-old SHR divided into four groups: females (fSHR), ovariectomized females (fSHR-OV), ovariectomized females with estrogen replacement (fSHR-OV+ES, 50 μg/kg SC 17β-estradiol benzoate every 48 hours), and males (mSHR). Arteriolar diameter in the presence of perfusion pressures of 60, 80, 100, and 120 mm Hg were obtained, and diameter changes were measured (at 80 mm Hg) in response to various concentrations of substance P (10
−9
to 5×10
−8
mol/L), sodium nitroprusside (10
−8
to 10
−6
mol/L), and A23187 (5×10
−8
to 10
−6
mol/L). The pressure-induced diameter of mSHR and fSHR-OV arterioles was significantly less (by approximately 10%) than that of fSHR and fSHR-OV+ES arterioles.
N
ω
-nitro-
l
-arginine (10
−4
mol/L), a nitric oxide synthase inhibitor, elicited a significant decrease in basal arteriolar diameter of fSHR (by approximately 19%) and fSHR-OV+ES (by approximately 17%), thereby eliminating the differences in tone among the various groups. Dilations of fSHR and fSHR-OV+ES arterioles to substance P were significantly greater (by 140% at a concentration of 5×10
−8
mol/L) than those of mSHR and fSHR-OV arterioles, whereas dilations to sodium nitroprusside were not different among the groups. A23187 (a nitric oxide releaser) elicited dilations in arterioles of fSHR (5.9±1.5%, 13.0±1.8%, and 19.2±2.1%) and fSHR-OV+ES (4.3±1.0%, 10.3±2.4%, and 15.0±4.0%) but constrictions in those of mSHR (−7.5±1.6%, −25.3±39%, and −36.9±4.1%) and fSHR-OV (−2.6±1.7%, −7.4±3.3%, and −11.5±6.1%). We conclude that estrogen in fSHR is responsible for the preservation of nitric oxide synthesis in skeletal muscle arterioles, resulting in a greater modulation of pressure-induced myogenic tone than in mSHR and maintenance of nitric oxide–mediated dilations.
Role of endogenous prostaglandins in volume expansion and during furosemide infusion in conscious dogs.
Authors: Sreenivasan V , Walker B , Krasney J , Mookerjee B , Venuto R
Published: June 2012

The renal effects of two structurally dissimilar inhibitors of prostaglandin synthesis (Meclofenamate and RO-20-5720) were studied in conscious, chronically instrumented dogs during mild volume expansion and during a constant infusion of furosemide. When either inhibitor was administered following volume expansion, urinary excretion of PGE2 and urine flow rate were reduced by more than 50%. In contrast, renal plasma flow fell by less than 10% while glomerular filtration rate, sodium excretion, and plasma renin activity (PRA) were unchanged. In separate studies, infusion of furosemide increased renal plasma flow, urine flow rate, sodium excretion, PRA, and urinary excretion of PGE2, while glomerular filtration rate decreased. Administration of inhibitors of prostaglandin synthesis during constant infusion of furosemide reduced the urinary excretion of PGE2 to control levels, as renal plasma flow and glomerular filtration rate fell below control level. Despite these hemodynamic alterations, the furosemide-induced diuresis and increase in PRA were only partly attenuated by prostaglandin inhibition. It is concluded that in conscious dogs, intrarenal prostaglandins modulate urine flow rate during mild volume expansion and play a major role in mediating the renal hemodynamic effects of furosemide.
Impaired renal blood flow and cortical pressure autoregulation in contralateral kidneys of Goldblatt hypertensive rats.
Authors: Ploth D W , Roy R N , Huang W C , Navar L G
Published: June 2012

Experiments were conducted on two-kidney, one clip renal vascular hypertensive rats to assess the ability of the kidney contralateral to renal vascular stenosis to autoregulate renal blood flow (RBF), glomerular filtration rate (GFR), and hydrostatic pressures in cortical structures during conditions of acutely reduced renal arterial blood pressure (BP). When observed at their respective, spontaneous BPs, RBF and GFR were not different in the contralateral kidneys of the hypertensive rats (n = 11) compared to normal animals (n = 7). However, the contralateral kidneys exhibited a significantly higher renal vascular resistance (RVR), 28.9 +/- 2.8 mm Hg . min/ml than the control animals, 23.1 +/- 1.5 mm Hg . min/ml. At spontaneous BP (169 +/- 5 mm Hg), urine flow, absolute and fractional sodium excretion, and absolute and fractional potassium excretion were all significantly greater in the contralateral kidneys of hypertensive rats than in kidneys of normal rats. Hydrostatic pressures in cortical structures were similar in the two groups. When BP was reduced acutely, the kidney contralateral to the renal artery stenosis achieved only small decreases in RVR that failed to allow RBF, GFR, or cortical pressures to be maintained. In contrast, normal rats efficiently autoregulated RBF and GFR. In addition, hydrostatic pressures in proximal tubules, distal tubules, and first order peritubular capillaries were maintained during reductions in BP to as low as 100 mm Hg. Urine flow and electrolyte excretion decreased to a greater extent in the hypertensive kidneys, such that at comparable BP these indices of excretory function were not different in the two groups. These observations indicate that the capacity of the contralateral kidney to maintain hemodynamic and glomerular function at reduced BP is compromised severely and suggest the possibility that the impaired autoregulatory capability may contribute to the maintenance of hypertension observed in this model.
Does vasopressin contribute to salt-induced hypertension in the Dahl strain?
Authors: Matsuguchi H , Schmid P G , Van Orden D , Mark A L
Published: June 2012

A humoral factor has been implicated in Dahl salt-sensitive genetically hypertensive rats. The goal of this study was to evaluate the pressor role of vasopressin (AVP) in Dahl rats. Salt-sensitive (S) and resistant (R) rats were fed either high (8%) or low (.04%) NaCl diets for 6 to 8 weeks. Blood pressure was elevated in S rats fed high salt diets (p less than 0.05). Plasma AVP increased with high salt diet in both groups (p less than 0.05), but was higher in S than R rats (2.0 +/- 0.3 and 1.3 +/- 0.2 microU/ml respectively, mean +/- SE, p less than 0.05). With low salt diet, plasma AVP did not differ significantly in S and R rats (1.0 +/- 0.2 and 0.7 +/- 0.2 microU/ml respectively). Pressor responses to intravenous injection of AVP were greater in S than R rats (p less than 0.05), but this difference was also observed with pressor responses to norepinephrine (S greater than R, p less than 0.05); there was no difference in pressor responses to AVP in S rats fed high vs low salt diet. Injection of 50 micrograms of d(CH2)5 VDAVP, which selectively inhibits vasoconstrictor effects of AVP, failed to lower blood pressure in S and R rats fed high or low salt diets despite the fact that this dose decreased pressor responses to 8 microU of AVP more than 90%. Although plasma AVP and vasopressor responses to AVP and NE are slightly elevated in S rats fed high salt, results with d(CH2)5 VDAVP suggest that vasoconstrictor effects of AVP do not play an important role in the maintenance of hypertension in Dahl S rats.
Prolonged isometric exercise. Part 2: Effect on circulation and on renal excretion of sodium and potassium in young males genetically predisposed to hypertension.
Authors: Parfrey P S , Wright P , Ledingham J M
Published: June 2012

The effect of stress, in the form of prolonged isometric exercise, on the circulation and on the renal excretion of sodium and potassium was studied in 16 male medical students whose parental blood pressure (BP) was less than 140/85 mm Hg, and in 17 male students with one or two parents who had BPs greater than 150/95 mm Hg. After the subjects rested initially for 90 minutes, basal measurements were made of heart rate, BP, and the rates of sodium and potassium excretion. The subjects then underwent a 1-hour period of intermittent isometric exercise involving all four limbs in rotation, during which BP and heart rate were measured. A 5-hour period of rest followed, during which BP, heart rate, and the rate of electrolyte excretion were measured at half-hourly intervals for the first 2 hours and at hourly intervals for the last 3 hours. The precise protocol was repeated on another day in the absence of the period of isometric exercise. The electrolyte excretion responses of each subject were then expressed as the ratio of the changes from basal values observed on exercise and rest days. At no time was there any difference in systolic and diastolic BP, heart rate, and rate of sodium and potassium excretion following exercise when sons of normotensive parents were compared to the sons of hypertensive parent(s). These results indicate that the retention of sodium and potassium following isometric exercise seen in patients with hypertension does not occur in subjects genetically predisposed to hypertension and suggest that the effect is a consequence of, rather than a predisposing factor to, hypertension.
Properties of angiotensin-converting enzyme in intact cerebral microvessels.
Authors: Brecher P , Tercyak A , Chobanian A V
Published: June 2012

Angiotensin-converting enzyme (ACE) was studied in preparations of microvessels isolated from rabbit cerebral cortex. Activity was determined by measuring the degradation of hippuryl-histidyl-leucine (Hip-His-Leu) by the intact microvessels in a physiological salt solution at pH 7.4. ACE activity was dependent on both substrate and chloride ion concentration and was inhibited by captopril in a manner similar to that observed previously with tissue homogenates. Angiotensin I was rapidly degraded by the intact microvessels, even in the presence of 10(-6)M captopril. An advantage of the methodology employed was the ability to pretreat the microvessels and then assess the effect of pretreatment by transfer to a postincubation assay system. Pretreatment with a hyperosmolar urea solution did not change ACE activity or cause release of ACE from the microvessels, although lactic dehydrogenase and lysosomal enzymes were released. Pretreatment with captopril caused a lag in the subsequent degradation of Hip-His-Leu, presumably reflecting dissociation of inhibitor from the cell-associated enzyme. ACE activity was unaffected by hypoxic or anoxic incubation conditions. The ability to measure ACE activity of the microvessels in vitro provides a unique opportunity to study the properties of the enzyme in intact cerebrovascular endothelial cells.