bluuebunny/crossref_metadata_2025 huggingface dataset:
ACE D/I Polymorphism and Incidence of Post-PTCA Restenosis
Authors: Zee Robert Y. L. , Fernandez-Ortiz Antonio , Macaya Carlos , Pintor Emilio , Lindpaintner Klaus , Fernandez-Cruz Arturo
Published: June 2012

Early restenosis is the major complication of percutaneous transluminal coronary angioplasty (PTCA), occurring in ≈30% of all initially successful procedures. The
D/I
polymorphism of the
ACE
gene, which has variably been reported to represent a risk factor for manifestations of ischemic heart disease, has recently been implicated in the pathophysiology of restenosis after PTCA by some investigators but not by others. All studies conducted thus far involved relatively small sample sizes. We investigated the possible association of
ACE D/I
genotype and post-PTCA restenosis in a large, prospective sample of patients followed by quantitative coronary angiography. The
ACE
D/I
gene polymorphism was characterized in a cohort of 779 patients, of whom 342 (cases) had developed restenosis (as defined by >50% loss of lumen compared with immediate postprocedure results) at repeat quantitative coronary angiography at 6 months after PTCA. Allele frequencies for the
ACE D
and
I
alleles were 0.58 and 0.42 in cases and 0.58 and 0.42 in control subjects. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and restenosis or degree of lumen loss. The data from this largest study of its kind conducted so far provide no evidence for an association of the
ACE D/I
allelic polymorphism with incidence of restenosis after PTCA. On the basis of the power of this study, we conclude that in a general population, the
ACE D/I
polymorphism is not a useful marker to assess risk of post-PTCA restenosis.
Restoration of Nitric Oxide Availability After Calcium Antagonist Treatment in Essential Hypertension
Authors: Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Magagna Armando , Favilla Stefania , Pompella Alfonso , Salvetti Antonio
Published: June 2012

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxygen free radical–induced nitric oxide (NO) breakdown. Because calcium antagonists can improve endothelial function in patients with essential hypertension, in this study we tested the hypothesis that this beneficial effect could be related to restoration of NO availability by antioxidant properties. In 15 healthy subjects and 15 hypertensive patients, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (ACh; 0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator in basal conditions, during infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA, 100 μg/100 mL forearm tissue per minute), an NO-synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), and finally, simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (SNP; 1, 2, and 4 μg/100 mL forearm tissue per minute) was also evaluated. In control subjects, vasodilation to ACh was inhibited by L-NMMA and not changed by vitamin C. In hypertensive patients, vasodilation to ACh was blunted as compared with control subjects and resistant to L-NMMA. Vitamin C, which decreased plasma isoprostanes and increased plasma antioxidant capacity, increased the response to ACh and restored the inhibiting effect of L-NMMA. In hypertensive patients, the study was repeated after 3-month treatment with nifedipine gastrointestinal therapeutic system (30 to 60 mg/daily). Nifedipine treatment decreased circulating plasma lipoperoxides and isoprostanes and increased plasma antioxidant capacity. Moreover, nifedipine increased the vasodilation to ACh but not to SNP and restored the inhibiting effect of L-NMMA on ACh-induced vasodilation, whereas vitamin C no longer exerted its facilitating activity. These results indicate that nifedipine increases endothelium-dependent vasodilation by restoring NO availability, an effect probably determined by antioxidant activity.
Diabetes, Hypertension, and Cardiovascular Disease
Authors: Sowers James R. , Epstein Murray , Frohlich Edward D.
Published: June 2012

Abstract
—Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and “diabetic cardiomyopathy.” The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.
Cancer Incidence in Hypertensive Patients in North Karelia, Finland
Authors: Lindgren Annamarja , Pukkala Eero , Nissinen Aulikki , Kataja Vesa , Notkola Irma-Leena , Tuomilehto Jaakko
Published: June 2012

Abstract
—Cancer incidence of 20 529 hypertensive patients included in the community-based hypertension register of the North Karelia Project was determined. A total of 2511 incident cancer cases were obtained among the patients in record linkage with the nationwide Finnish Cancer Registry during the mean follow-up time of 16 years. The age-adjusted incidence rates per 100 000 person-years were 248.4 for men and 171.7 for women, which correspond to that of the general population in the area. The Cox regression model was used to analyze the effect of hypertension-related variables on cancer incidence. In men, the diastolic blood pressure was associated with an increased cancer risk but only in those who smoked >10 cigarettes per day. The functional diagnosis of hypertension (stage I, hypertension with no end-organ damage; stage II, hypertension with left cardiac hypertrophy; and stage III, hypertension with extracardiac organ damage) was associated with the increased risk significantly in men who used antihypertensive drugs at baseline. In women, the diastolic blood pressure was associated with an increased cancer risk in those who did not use antihypertensive drugs at baseline. The functional diagnosis of hypertension was associated with an increased risk only in those who smoked >10 cigarettes per day, but the number of women and cancer cases in this group was small. These results indicate a complex pattern of diastolic blood pressure, functional diagnosis, use of antihypertensive drugs, smoking, and gender in the cancer risk of hypertensive patients.
Effect of Antihypertensive Therapy on Renal Artery Structure in Type 2 Diabetic Rats With Hypertension
Authors: Reddi Alluru S. , Nimmagadda Venkata R. , Arora Rohit
Published: June 2012

Abstract
—We have previously demonstrated that antihypertensive treatment with doxazosin (DZN), an α-adrenergic blocker, and lisinopril (LIS), an ACE inhibitor, reverse glomerular sclerosis in corpulent spontaneously hypertensive rats with type 2 diabetes. In this study, we examined the effects of the above-mentioned antihypertensive drugs alone and in combination on the structure of interlobular and arcuate arteries in these rats. Both male and female rats aged 6 months were treated with antihypertensive drugs for 16 weeks. Various structural parameters were evaluated by light microscopy, with the use of digital image analysis, in kidney sections stained with periodic acid–Schiff. Systolic blood pressure was significantly lower in treated than in untreated rats. Untreated diabetic rats had a significantly higher media/lumen ratio (smaller luminal diameter) of both arteries compared with the ratio in treated rats (for interlobular artery, 0.72±0.06 [no treatment], 0.49±0.03 [DZN treatment], 0.54±0.06 [LIS treatment], and 0.52±0.04 [combination therapy],
P
<0.05 to <0.001 for no treatment versus treatment; for arcuate artery, 0.66±0.11 [no treatment], 0.40±0.02 [DZN treatment], 0.39±0.04 [LIS treatment], and 0.40±0.03 [combination therapy],
P
<0.05 for no treatment versus treatment). Antihypertensive treatment caused significant increases in total arterial cross-sectional area, internal and external diameters, luminal and medial cross-sectional area, and medial thickness in both interlobular and arcuate arteries. The improvement in arterial structure after antihypertensive treatment was due to remodeling and growth of the vessels. Both DZN and LIS were equally efficacious, and combination therapy had no additive or synergistic effect.
Insulin-Induced Biphasic Responses in Rat Mesenteric Vascular Bed
Authors: Misurski Derek A. , Wu Sheng-Qian , McNeill J. Robert , Wilson Thomas W. , Gopalakrishnan Venkat
Published: June 2012

Abstract
—The vasodilatory capacity of insulin has been widely reported, yet some investigators have not noted this effect. Because insulin has been shown to enhance endothelin release, we speculated that endothelin could be attenuating insulin-evoked vasodilation. We examined the effect of ex vivo insulin perfusion on vascular resistance by using the Sprague-Dawley rat mesenteric vascular bed. In methoxamine-preconstricted preparations, insulin (3.0 pmol/L to 10 nmol/L) evoked a concentration-dependent decrease in perfusion pressure (PP) with a maximal response of 42.0±9.2%, whereas continuous exposure to 10 nmol/L insulin induced a 51.8±3.5% relaxation. Further exposure to 10 nmol/L insulin resulted in the generation of endothelin and a subsequent loss of the vasodilatory response. Indomethacin had no effect on vascular responses. The vasodilatory response was significantly inhibited by nitric oxide synthase inhibition (20.5±4.2%;
P
<0.01) and calcium-activated potassium channel blockade (28.5±3.7%;
P
<0.05). Endothelial denudation attenuated the vasodilatory component (20.3±7.1%;
P
<0.01) and altered the biphasic pattern of the response. The decline in insulin-evoked vasodilation was significantly prevented by an endothelin-A antagonist (BQ123), an endothelin-B antagonist (BQ788), and nonselective endothelin blockade with both BQ123 and BQ788. These results demonstrate that the endothelium is intimately involved in regulating the vascular response to insulin. Insulin promotes the release of nitric oxide and endothelium-derived hyperpolarizing factor. During sustained exposure to higher concentrations, this vasodilatory effect is countered by the pathological generation of endothelin. Endothelin receptor blockade facilitates the maintenance of vasodilation despite high insulin concentrations.
Calcium Channel Blocker Nifedipine Slows Down Progression of Coronary Calcification in Hypertensive Patients Compared With Diuretics
Authors: Motro Michael , Shemesh Joseph
Published: June 2012

Abstract
—Calcium controls numerous events within the vessel wall. Permeability of the endothelium is calcium dependent, as are platelet activation and adhesion, vascular smooth muscle proliferation and migration, and synthesis of fibrous connective tissue. Double-helix computerized tomography is a noninvasive technique that can detect, measure, and compare coronary calcification in the coronary arteries. Using this method, our objective was to determine whether administration of nifedipine once daily in lieu of diuretics in high-risk hypertensive patients will arrest or slow down the progression of coronary artery calcification. The study was designed as a side arm of INSIGHT (International Nifedipine Study: Intervention as Goal for Hypertension Therapy), aimed to show the efficacy of nifedipine once daily versus co-amilozide (hydrochlorothiazide 25 mg, amiloride 2.5 mg) in high-risk hypertensive patients. A total of 201 patients with a total calcium score of ≥10 at the onset of study who underwent an annual double-helix computerized tomography for 3 years were analyzed for efficacy. Inhibition of coronary calcium progression was significant in the nifedipine versus the co-amilozide group during the first year (3.18% versus 27%, respectively,
P
=0.02), not significant during the second year (28.5% versus 47%, respectively,
P
=0.14), and significant during the third year (40% versus 78%, respectively,
P
=0.02). The results point to a slower progression of coronary calcification in hypertensive patients on nifedipine once daily versus co-amilozide.
Expression and Distribution of NOS1 and NOS3 in the Myocardium of Angiotensin II–Infused Rats
Authors: Tambascia Rosa C. , Fonseca Priscila M. , Corat Patrícia D. C. , Moreno Heitor , Saad Mario J. A. , Franchini Kleber G.
Published: June 2012

Abstract
—Studies have indicated a complex functional interaction between angiotensin (Ang) II and NO in the heart. The purpose of the present study was to examine the protein expression and tissue distribution of NO synthases 1 (NOS1) and 3 (NOS3) in the myocardium of rats that underwent continuous infusion of Ang II at 2 different rates (10 and 40 ng · kg
−1
· min
−1
) for 6 days. Mean arterial pressure increased by ≈15 mm Hg in rats infused with Ang II at 40 ng · kg
−1
· min
−1
, but it remained close to the values observed in saline-infused rats (≈110 mm Hg) when Ang II was infused at 10 ng · kg
−1
· min
−1
. The protein expression of a 160-kDa NOS1 and a 135-kDa NOS3 were found to increase (≈200%) in the myocardium of rats infused with both subpressor and pressor doses of Ang II. Immunohistochemistry studies showed that NOS1 and NOS3 are differentially expressed in myocardial cells. NOS1 was detected in cardiac myocytes and in smooth muscle cells of small and large coronary arteries, whereas NOS3 was detected in the endothelium and in perivascular and interstitial tissues, but NOS3 was not detected in cardiac or smooth muscle cells. Ang II infusion enhanced the tissue immunoreactivity of both isoforms in their specific locations but did not change the distribution throughout the myocardium. Myocardium staining with anti–angiotensin type 1 (AT
1
) receptor antibody indicated that AT
1
receptor is expressed in cardiac myocytes, coronary smooth muscle cells, and interstitial and perivascular tissues. Ang II infusion did not change the protein expression and distribution of AT
1
receptor in the myocardium. These results indicate that long-term increases in the circulating levels of Ang II modulate the protein expression of NOS1 and NOS3 and, consequently, the function of the local myocardial NO system.
Effect of Extracellular Matrix Elements on Angiotensin II–Induced Calcium Release in Vascular Smooth Muscle Cells From Normotensive and Hypertensive Rats
Authors: Bouillier Hélène , Samain Emmanuel , Rücker-Martin Catherine , Renaud Jean-François , Safar Michel , Dagher Georges
Published: June 2012

Abstract
—The interaction of the vascular smooth muscle cells (VSMCs) with the components of the matrix determines several functions of the cell, such as growth and differentiation. In contrast, an alteration in angiotensin (Ang) II–induced Ca
2+
mechanisms in VSMCs was reported in genetic hypertension. In this study, we wished to assess the effect of different components of the extracellular matrix on the increase of [Ca
2+
]
i
induced by Ang II in VSMCs from spontaneously hypertensive rats (SHR) compared with those from normotensive Wistar-Kyoto rats (WKY). Results demonstrate for the first time that elements of the extracellular matrix modulate the Ang II–induced Ca
2+
transport mechanisms. This modulation is different in cells from WKY compared with those from SHR. Thus, growing cells from SHR on collagen I, collagen IV, fibronectin, vitronectin, or Matrigel induced a significant decrease in Ang II–induced Ca
2+
release from internal stores, whereas in cells from WKY, no effect could be observed except for those grown on collagen I, which increased Ca
2+
release. Fibronectin and vitronectin, however, induced a decrease in Ang II–induced Ca
2+
influx in WKY, whereas no effect could be observed in SHR. Conversely, collagen I and collagen IV induced an increase in this influx in SHR but not in WKY, whereas Matrigel increased the influx in both strains. These results suggest a modulation of the Ang II–associated signaling events by the matrix elements via the focal adhesion points. The understanding of these synergies should provide insight into issues such as development of hypertrophy of large vessels in hypertension.
Impaired Insulin-Like Growth Factor I Vasorelaxant Effects in Hypertension
Authors: Vecchione Carmine , Colella Salvatore , Fratta Luigi , Gentile Maria Teresa , Selvetella Giulio , Frati Giacomo , Trimarco Bruno , Lembo Giuseppe
Published: June 2012

Abstract
—Insulin-like growth factor I (IGF-I) can be considered a factor potentially involved in arterial hypertension not only for its growth-promoting features but also for its effects on vascular tone. Nevertheless, the actions of the hormone on vascular reactivity are still unexplored in hypertension. Therefore, the vasodilation induced by increasing doses of IGF-I and the modulation of norepinephrine vasoconstriction induced by low levels of the hormone were tested on aortic rings of spontaneously hypertensive and normotensive rats. The results indicate that the vasodilation evoked by IGF-I is impaired in hypertensive rats (Δ% of maximal vasorelaxation, 30±1 versus 41±1;
P
<0.01), and after the removal of endothelium or the inhibition of endothelial NO synthase, the vasodilation evoked by the hormone was blunted in both rat strains and became similar between hypertensive and normotensive rats (Δ% of maximal vasorelaxation, 21±1 versus 20±1;
P
=NS). Moreover, IGF-I does not show any effect on norepinephrine vasoconstriction in hypertensive rats, and this alteration may depend on the lack of sensitizing effect exerted by IGF-I on α
2
-adrenergic–evoked NO vasorelaxation. The defect in IGF-I vascular action is also present in young spontaneously hypertensive rats (age 5 weeks). In conclusion, our data demonstrate that IGF-I vasorelaxant properties are impaired in spontaneously hypertensive rats, suggesting that such defect may play a causative or permissive role in the development of hypertensive conditions.
A Defect in Glycogen Synthesis Characterizes Insulin Resistance in Hypertensive Patients With Type 2 Diabetes
Authors: Solini Anna , Di Virgilio Francesco , Chiozzi Paola , Fioretto Paola , Passaro Angela , Fellin Renato
Published: June 2012

Abstract
—A subgroup of patients with type 2 diabetes shows a clustering of abnormalities such as peripheral insulin resistance, hypertension, and microalbuminuria. To evaluate whether these traits reflect intrinsic disorders of cell function rather than in vivo environmental effects, we studied a group of 7 nondiabetic hypertensive subjects with an altered albumin excretion rate (AER) (HyMA+) and 3 groups of patients with type 2 diabetes: 7 with normal blood pressure and normal AER (DH−MA−), 7 with high blood pressure and normal AER (DH+MA−), and 7 with both high blood pressure and altered AER (DH+MA+). Glucose disposal was measured during an hyperinsulinemic clamp (40 mU · m
2
−1
· min
−1
) with primed deuterated [6.6
2
H
2
] glucose infusion. In the same subjects, a skin biopsy was performed and the following parameters were investigated: glucose transport (as determined by [
3
H]2-deoxyglucose uptake); glycogen synthase activity (as determined by [
14
C] glucose incorporation from UDP-[U-
14
C] glucose into glycogen); glycogen phosphorylase activity (as measured by the incorporation of [U-
14
C]glucose 1-phosphate into glycogen); and total glycogen content. In vivo glucose disposal was significantly reduced in DH+MA− and DH+MA+, with respect to DH−MA−, HyMA+, and controls. Insulin-stimulated glucose transport was similar in the 3 groups of patients with diabetes. A significant reduction of intracellular glycogen content was observed in DH+MA− and DH+MA+ compared with DH−MA− in both basal and insulin-stimulated conditions, probably because of a major impairment of glycogen synthase activity. Glycogen phosphorylase activity did not show differences between the groups. These results suggest that (1) the combination of type 2 diabetes with hypertension and altered AER is associated with impaired insulin sensitivity, and (2) intrinsic, possibly genetic, factors may account for increased peripheral insulin resistance in hypertensive microalbuminuric patients with type 2 diabetes, pointing to the reduction of glycogen synthase activity as a shared common defect.
A Comparison Between Systolic and Diastolic Pulse Contour Analysis in the Evaluation of Arterial Stiffness
Authors: Rietzschel Ernst-R. , Boeykens Eva , De Buyzere Marc L. , Duprez Daniel A. , Clement Denis L.
Published: June 2012

Abstract
—Several methodologically independent measures of arterial stiffness derived from either the systolic or diastolic segments of the arterial pulse have been proposed. The exact nature of the large and small artery elasticity indices (C1 and C2, respectively) derived from diastolic pulse contour analysis remains largely unexplored, although C2 has controversially been termed to be “oscillatory” and “reflective.” We investigated the relation between C2 and, respectively, a prototype of arterial reflectivity (ie, the augmentation index, AIx) and a covariate of arterial reflectivity (body height). A validated transfer function is used to transform a tonometrically obtained radial pressure wave into an ascending aortic pressure wave, from which AIx is derived using systolic pulse contour analysis. Diastolic pulse contour analysis using a modified Windkessel model is used to derive C1 and C2. One hundred subjects, who were free from atherothrombotic disease and 19 to 77 years of age, with a wide pressure range (97 to 186/52 to 104 mm Hg) were studied. Mean values of C1, C2, AIx, and body height were, respectively, 13.8±4.3 mL/mm Hg×10, 5.9±3.1 mL/mm Hg×100, 128.5±24.9%, and 169±9 cm. Coefficients of variation were 32.8% for C1, 33.3% for C2, and 6.7% for AIx. C2 was significantly and inversely correlated to AIx (
r
=−0.707,
P
<0.001). Both AIx and C2 were correlated to body height (
r
=−0.487,
P
<0.001, and
r
=0.514,
P
<0.001). In conclusion, the results of this study provide the first clinical evidence that validates a probable biophysical equivalent of the C2 element of a third-order, 4-element modified Windkessel model. We suggest that C2 is, at least in part, a measure of arterial wave reflectance. However, although short-term reproducibility of AIx is excellent, C2 showed markedly increased variability with the devices used.
Potentiation of Kinin Analogues by Ramiprilat Is Exclusively Related to Their Degradation
Authors: Dendorfer Andreas , Reiβmann Siegmund , Wolfrum Sebastian , Raasch Walter , Dominiak Peter
Published: June 2012

The potentiation of kinin actions represents a cardioprotective property of ACE inhibitors. Although a clear contribution to this effect is related to the inhibition of bradykinin (BK) breakdown, the high efficacy of potentiation and the ability of ACE inhibitors to provoke a B
2
-receptor-mediated response even after receptor desensitization has also triggered hypotheses concerning additional mechanisms of kinin potentiation. The application of kinin analogues with enhanced metabolic stability for the demonstration of degradation-independent mechanisms of potentiation, however, has yielded inconsistent results. Therefore, the relation between the susceptibility of B
2
-agonists to ACE and the potentiation of their actions by ACE inhibitors was investigated with the use of minimally modified kinin derivatives that varied in their degree of ACE resistance. The B
2
-agonists BK,
d
-Arg-[Hyp
3
]-BK, [Hyp,
3
Tyr(Me)
8
]-BK, [ΔPhe
5
]-BK, [D-NMF
7
]-BK, and [Phe
8
ψ(CH
2
-NH)Arg
9
]-BK were tested for degradation by purified rabbit ACE and for their potency in contracting the endothelium-denuded rabbit jugular vein in the absence and presence of ramiprilat. Purified ACE degraded
d
-Arg-[Hyp
3
]-BK and [Hyp,
3
Tyr(Me)
8
]-BK at 81% and 71% of BK degradation activity, respectively, whereas other peptides were highly ([ΔPhe
5
]-BK) or completely ([D-NMF
7
]-BK, [Phe
8
ψ(CH
2
-NH)Arg
9
]-BK) resistant. The EC
50
of BK-induced venoconstriction (1.15±0.2 nmol/L) was reduced by a factor of 5.7 in the presence of ramiprilat. Likewise,
d
-Arg-[Hyp
3
]-BK and [Hyp,
3
Tyr(Me)
8
]-BK were both significantly potentiated by a factor of 4.4, whereas the activities of the other agonists were not affected. Ramiprilat exerted no influence on the maximum contraction induced by any of the agonists. It is concluded that the potentiation of kinin analogues during ACE inhibition correlates quantitatively with the susceptibility of each substance to degradation by ACE. As such, no evidence of degradation-independent potentiating actions of ACE inhibitors could be obtained.
Effects of Angiotensin-(1-7) on Forearm Circulation in Normotensive Subjects and Patients With Essential Hypertension
Authors: Sasaki Shota , Higashi Yukihito , Nakagawa Keigo , Matsuura Hideo , Kajiyama Goro , Oshima Tetsuya
Published: June 2012

Previous animal studies have shown that angiotensin (Ang)-(1-7) is a biologically active component of the renin-angiotensin system, acting as a vasoactive agent, and may play a role in the blood pressure regulation. There is little information, however, on the effect of Ang-(1-7) on human circulation or the mechanism of its action. To investigate the effect of Ang-(1-7) on forearm circulation and to determine whether this effect is altered in patients with essential hypertension, we measured change in forearm blood flow using venous occlusion plethysmography in response to intra-arterial infusion of Ang-(1-7) (10
−10
, 10
−9
, and 10
−8
mol/min; for 5 minutes) in normotensive control subjects (n=8) and patients with essential hypertension (n=8). Infusion of Ang-(1-7) significantly increased the forearm blood flow response in a dose-dependent manner in both normotensive control subjects (28.7±9.7%, at 10
−8
mol/min;
P
<0.05) and hypertensive patients (31.8±15.2%, at 10
−8
mol/min;
P
<0.05). The vasodilatory effect of Ang-(1-7) was similar in the two groups. Intra-arterial infusion of
N
G
-monomethyl-
l
-arginine, a nitric oxide synthesis inhibitor, did not alter the forearm blood flow response to Ang-(1-7) in either group. These findings suggest that Ang-(1-7) causes vasodilation in forearm circulation of normotensive subjects and patients with essential hypertension through a pathway that is independent of nitric oxide synthesis.
Genetic Dissection of Region Around the Sa Gene on Rat Chromosome 1
Authors: Frantz Simon , Clemitson Jenny-Rebecca , Bihoreau Marie-Therese , Gauguier Dominique , Samani Nilesh J.
Published: June 2012

A region with a major effect on blood pressure (BP) is located on rat chromosome 1 in the vicinity of the Sa gene, a candidate gene for BP regulation. Previously, we observed a single linkage peak for BP in this region in second filial generation rats derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY), and we have reported the isolation of the region containing the BP effect in reciprocal congenic strains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals. Here, we report the further genetic dissection of this region. Two congenic substrains each were derived from WKY.SHR-Sa (WISA1 and WISA2) and SHR.WKY-Sa (SISA1 and SISA2) by backcrossing to WKY and SHR, respectively. Although there was some overlap of the introgressed regions retained in the various substrains, the segments in WISA1 and SISA1 did not overlap. Furthermore, although the Sa allele in WISA1, WISA2, and SISA2 remained donor in origin, recombination in SISA1 reverted it back to the recipient (SHR) allele. Surprisingly, all 4 substrains demonstrated a highly significant BP difference compared with that of their respective parental strain, which was of a magnitude similar to those seen in the original congenic strains. The findings strongly indicate that there are at least 2 quantitative trait loci (QTLs) affecting BP in this region of rat chromosome 1. Furthermore, the BP effect seen in SISA1 indicates that at least a proportion of the BP effect of this region of rat chromosome 1 cannot be due to the Sa gene. SISA1 contains an introgressed segment of <3 cM, and this will facilitate the physical mapping of the BP QTL(s) located within it and the identification of the susceptibility-conferring genes. Our observations serve to illustrate the complexity of QTL dissection and the care needed to interpret findings from congenic studies.
Divergent Biological Actions of Coronary Endothelial Nitric Oxide During Progression of Cardiac Hypertrophy
Authors: Grieve David J. , MacCarthy Philip A. , Gall Nicholas P. , Cave Alison C. , Shah Ajay M.
Published: June 2012

Coronary endothelial NO synthase expression and NO bioactivity were investigated at sequential stages during the progression of left ventricular hypertrophy. Male guinea pigs underwent abdominal aortic banding or sham operation. Left ventricular contractile function was quantified in isolated ejecting hearts. Coronary endothelial and vasodilator function were assessed in isolated isovolumic hearts in response to boluses of bradykinin (0.001 to 10 μmol/L), substance P (0.01 to 100 μmol/L), diethylamine NONOate (DEA-NO) (0.1 to 1000 μmol/L),
N
G
-monomethyl-
l
-arginine monoacetate (L-NMMA) (10 mmol/L), and adenosine (10 mmol/L). At a stage of compensated left ventricular hypertrophy (3 weeks), left ventricular endothelial NO synthase protein expression was unaltered (Western blot and immunocytochemistry). Vasoconstriction in response to L-NMMA was increased in banded animals compared with sham-operated animals (13.8±2.1% versus 6.2±1.3%, n=10;
P
<0.05), but agonist- and DEA-NO-induced vasodilation was similar in the 2 groups. At a stage of decompensated left ventricular hypertrophy (8 to 10 weeks), left ventricular endothelial NO synthase protein expression was significantly lower in banded animals (on Western analysis: banded animals, 7.8±0.4 densitometric units; sham-operated animals, 12.2±1.7 densitometric units; n=5;
P
<0.05). At this time point, vasoconstriction in response to L-NMMA was similar in the 2 groups, but vasodilatation in response to bradykinin (30.9±2.4% versus 39.7±2.2%, n=10;
P
<0.05), DEA-NO (26.2±1.8% versus 34.6±1.8%, n=10;
P
<0.05), and adenosine (24.3±2.0% versus 35.7±2.0%, n=10;
P
<0.01) was attenuated in banded animals. These findings indicate that there is an increase in the basal activity of NO (without a significant change in endothelial NO synthase expression) in early compensated left ventricular hypertrophy, followed by a decrease in both endothelial NO synthase expression and NO bioactivity during the transition to myocardial failure.
Adrenergic and Endothelin B Receptor-Dependent Hypertension in Dopamine Receptor Type-2 Knockout Mice
Authors: Li Xiao Xi , Bek Martin , Asico Laureano D. , Yang Zhiwei , Grandy David K. , Goldstein David S. , Rubinstein Marcelo , Eisner Gilbert M. , Jose Pedro A.
Published: June 2012

Polymorphism of the dopamine receptor type-2 (D
2
) gene is associated with essential hypertension. To assess whether D
2
receptors participate in regulation of blood pressure (BP), we studied mice in which the D
2
receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D
2
homozygous and heterozygous mutant mice than in D
2
+/+ littermates. BP after α-adrenergic blockade decreased to a greater extent in D
2
−/− mice than in D
2
+/+ mice. Epinephrine excretion was greater in D
2
−/− mice than in D
2
+/+ mice, and acute adrenalectomy decreased BP to a similar level in D
2
−/− and D
2
+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D
2
−/− mice but not D
2
+/+ mice. ET(B) receptor expression was greater in D
2
−/− mice than in D
2
+/+ mice. In contrast, blockade of ET(A) and V
1
vasopressin receptors had no effect on BP in either D
2
−/− or D
2
+/+ mice. The hypotensive effect of an AT
1
antagonist was also similar in D
2
−/− and D
2
+/+ mice. Basal Na
+
,K
+
-ATPase activities in renal cortex and medulla were higher in D
2
+/+ mice than in D
2
−/− mice. Urine flow and sodium excretion were higher in D
2
−/− mice than in D
2
+/+ mice before and after acute saline loading. Thus, complete loss of the D
2
receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D
2
mutant mice may be caused by increased sympathetic and ET(B) receptor activities.
Hypertension After Neonatal Uninephrectomy in Rats Precedes Glomerular Damage
Authors: Woods Lori L. , Weeks Douglas A. , Rasch Ruth
Published: June 2012

The present study was designed to determine whether adult hypertension caused by a reduced number of nephrons from birth is due to preceding glomerular damage. Newborn male Sprague-Dawley rat pups were uninephrectomized during the first 24 hours after birth (UNX rats). At 20 weeks of age, chronically instrumented UNX animals were hypertensive on a normal-sodium (0.20%) diet compared with sham-operated controls (142±2 versus 124±2 mm Hg in controls). Body weights and the total kidney-to–body weight ratio were not significantly different in adult UNX animals compared with controls. Glomerular filtration rate (GFR) was reduced by 49% in UNX rats (1.85±0.24 versus 3.65±0.22 mL/min). Urine protein excretions were higher in UNX rats (20±2 versus 7±1 mg/d in controls). On a high-sodium (3.15%) diet, arterial pressure increased more in UNX than in controls (28±9 versus 3±1 mm Hg). In contrast, in animals studied at 8 weeks of age, GFR was only reduced by 26% in UNX animals (2.02±0.06 versus 2.73±0.07 mL/min). Their hypertension (125±2 versus 117±2 mm Hg) was also salt sensitive (increase on high-sodium diet of 35±11 versus 8±2 mm Hg in controls) but was not associated with proteinuria or histological signs of glomerular disease. Number of glomeruli per kidney in UNX animals was not different from controls, but individual glomerular volume increased by 41%. Thus, surgical removal of 50% of the nephrons, when done during development, causes reduced renal function and salt-sensitive hypertension in adulthood. Hypertension is present earlier in life than signs of glomerular disease, which suggests that hypertension is a major contributor to rather than primarily resulting from onset of renal disease.
Role of Angiotensin II and Free Radicals in Blood Pressure Regulation in a Rat Model of Renal Hypertension
Authors: Dobrian Anca D. , Schriver Suzanne D. , Prewitt Russell L.
Published: June 2012

One-kidney, 1-clip rats (1K1C) or uninephrectomized controls were treated with either the superoxide dismutase mimetic tempol (0.5 mmol · kg
−1
· d
−1
), angiotension type 1 receptor inhibitor losartan (50 mmol · L
−1
· kg
−1
· d
−1
), or both (n=6 per group) for 2 weeks. At the end of the study, systolic blood pressure (BP) decreased on average by 21% in tempol-treated and 29% in losartan-treated versus untreated 1K1C (217±4.4 mm Hg) and was normalized in the losartan plus tempol group. Mean BP also decreased from 159±3.7 mm Hg in 1K1C to 93±2.8 mm Hg in the losartan plus tempol group. Also, aortic wall area was reduced by 18% in losartan- or tempol-treated 1K1C and by 30% in losartan plus tempol rats compared with untreated 1K1C. Plasma renin activity was increased from 4.8±0.3 in untreated 1K1C to 15.9±0.9 ng · mL
−1
· h
−1
in losartan-treated but not tempol-treated 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin chemiluminescence was significantly decreased (by ≈40%) in all losartan, tempol, and losartan plus tempol groups compared with untreated 1K1C. Nitrotyrosine ELISA in the kidney displayed a significant reduction, from 59±13 ng/mg of protein in 1K1C to 12.5±5 ng/mg of protein in the losartan plus tempol 1K1C. Western blotting for nNOS in kidney cortex and medulla showed a protein increase in both fractions of 1K1C versus controls and was normalized by losartan plus tempol treatment. Collectively, data show a synergistic effect of losartan and tempol on BP reduction in 1K1C rats. The mechanism may involve reduced superoxide production and nitrotyrosine formation in kidney and decreased kidney neuronal-type NO synthase expression in treated animals. This status in the oxidative balance seems to affect BP in the renal hypertensive rats.
Effect of Neutral Endopeptidase Inhibition on the Actions of Adrenomedullin and Endothelin-1 in Resistance Arteries From Patients With Chronic Heart Failure
Authors: Petrie Mark C. , Hillier Chris , Johnston Fiona , McMurray John J.V.
Published: June 2012

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding −log concentrations of agonist required to effect a 50% response (pD
2
) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.
Relationship Between Left Ventricular Diastolic Relaxation and Systolic Function in Hypertension
Authors: Bella Jonathan N. , Palmieri Vittorio , Liu Jennifer E. , Kitzman Dalane W. , Oberman Albert , Hunt Steven C. , Hopkins Paul N. , Rao D.C. , Arnett Donna K. , Devereux Richard B.
Published: June 2012

The relation of impaired left ventricular relaxation, as measured by prolonged isovolumic relaxation time, to ventricular systolic function in hypertension remains uncertain in population-based samples. In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, echocardiograms were analyzed in 1457 hypertensive participants without diabetes, ≥2+ valvular regurgitation, or coronary disease. Impaired relaxation (isovolumic relaxation time >100 ms) was present in 219 (15%) of the participants; they were older and had higher arterial pressure than did those with normal relaxation. Ventricular chamber size, wall thicknesses, mass, and relative wall thickness were greater, and stress-corrected midwall shortening and end-systolic stress/end-systolic volume index were lower with impaired relaxation than with normal relaxation time. Fractional shortening and ejection fraction did not differ between the groups. In logistic regression, the likelihood of prolonged isovolumic relaxation time decreased with higher stress-corrected midwall shortening (odds ratio, 0.97%; 95% confidence interval, 0.96 to 0.99), independently of age, heart rate, and ventricular mass. Neither ejection fraction nor the end-systolic stress/end-systolic volume index was independently related to isovolumic relaxation time. In hypertension, impaired left ventricular relaxation parallels ventricular midwall dysfunction but not systolic chamber function. Whether combined diastolic and systolic dysfunction identifies hypertensive patients at especially high risk of cardiovascular events requires further study.
Effects of Valsartan on Mechanical Properties of the Carotid Artery in Spontaneously Hypertensive Rats Under High-Salt Diet
Authors: Labat Carlos , Lacolley Patrick , Lajemi Malika , de Gasparo Marc , Safar Michel E. , Benetos Athanase
Published: June 2012

The aim of this investigation was to evaluate the influence of a high-salt diet (HSD) on the effects of valsartan, an angiotensin II type 1 (AT
1
) receptor antagonist, on carotid arterial stiffness and structure in spontaneous hypertensive rats (SHR). Carotid arterial stiffness was studied in SHR receiving a HSD or a normal-salt diet (NSD) from the 10th to 20th week of age. Within each of the 2 groups, the animals received treatment with either placebo or valsartan (30 mg · kg
−1
· d
−1
) administered on the 4th to 20th week of age. Arterial pressure, wall stress, incremental elastic modulus (Einc), medial cross-sectional area, and EIIIA fibronectin isoform were significantly increased in placebo-HSD rats compared with placebo-NSD rats with no change in the ratio of collagen to elastin. Valsartan reduced mean arterial pressure in both NSD and HSD rats but reduced pulse pressure only in NSD rats. In NSD rats, valsartan reduced Einc and medial cross-sectional area. In HSD, valsartan increased Einc and did not modify medial cross-sectional area and fibronectin. In valsartan-treated rats, the ratio of collagen to elastin was greater in HSD than in NSD rats. In conclusion, the effects of AT
1
blockade are greatly influenced by salt intake in SHR. Despite a reduction in mean arterial pressure in HSD rats, AT
1
blockade was not able to prevent the effects of a HSD on pulse pressure, carotid artery stiffness, and hypertrophy.
Angiotensin-(1-7): Cardioprotective Effect in Myocardial Ischemia/Reperfusion
Authors: Ferreira Anderson J. , Santos Robson A.S. , Almeida Alvair P.
Published: June 2012

Abstract
—

— In this study we evaluate the effects of angiotensin-(1-7) on reperfusion arrhythmias in isolated rat hearts. Rat hearts were perfused according to Langendorff technique and maintained in heated (37±1°C) and continuously gassed (95% O
2
/5% CO
2
) Krebs-Ringer solution at constant pressure (65 mm Hg). The electrical activity was recorded with an ECG (bipolar). Local ischemia was induced by coronary ligation for 15 minutes. After ischemia, hearts were reperfused for 30 minutes. Cardiac arrhythmias were defined as the presence of ventricular tachycardia and/or ventricular fibrillation after the ligation of the coronary artery was released. Angiotensin II (0.20 nmol/L, n=10) produced a significant enhancement of reperfusion arrhythmias. On the other hand, Ang-(1-7) presented in the perfusion solution (0.22 nmol/L, n=11) reduced incidence and duration of arrhythmias. The antiarrhythmogenic effects of Ang-(1-7) was blocked by the selective Ang-(1-7) antagonist A-779 (2 nmol/L, n=9) and by indomethacin pretreatment (5 mg/kg IP, n=8) but not by the bradykinin B
2
antagonist HOE 140 (100 nmol/L, n=10) or by L-NAME pretreatment (30 mg/kg IP, n=8). These results suggest that the antiarrhythmogenic effect of low concentrations of Ang-(1-7) is mediated by a specific receptor and that release of endogenous prostaglandins .by Ang-(1-7) contributes to the alleviation of reversible and/or irreversible ischemia-reperfusion injury.
Evaluation of the Blood Pressure Load in the Diagnosis of Hypertension in Pregnancy
Authors: Hermida Ramón C. , Ayala Diana E.
Published: June 2012

Abstract
—

— The use of a set of new end points obtained from ambulatory blood pressure monitoring, in addition to the blood pressure values themselves, has been advocated to improve sensitivity and specificity in the diagnosis of hypertension and the evaluation of a patient’s response to treatment. Among these parameters is the use of blood pressure load, the percentage of values above a given constant reference limit or computed by reference to daytime and nighttime limits. We examined the effectiveness of this parameter as a potential screening test for the detection of hypertension in pregnancy. We analyzed 2014 blood pressure series systematically sampled by ambulatory monitoring for 48 consecutive hours every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery of 205 normotensive pregnant women and 123 women who developed gestational hypertension or preeclampsia. The blood pressure load was obtained as the percentage of values >140/110/90 mm Hg (systolic/mean arterial/diastolic blood pressure) during active hours or 120/95/80 mm Hg during resting hours, as well as by comparison with limits obtained by progressively reducing the previous limits by 5 mm Hg, up to a final threshold of 125/95/75 mm Hg (day) and 105/80/65 mm Hg (night). Sensitivity for the blood pressure load computed by reference to the highest limits used here is <55% in all trimesters of pregnancy. The best results were obtained when 130/100/80 mm Hg (day) and 110/85/70 mm Hg (night) were used as references in the third trimester, and when the lowest tested limits of 125/95/75 and 105/80/65 mm Hg were used as references in the first and second trimesters (sensitivity always >73%). The optimum reference limits for calculating the blood pressure load, markedly <

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mm Hg, must be defined as a function of gestational age, in keeping with the predictable trends in blood pressure along pregnancy previously documented.
Release and vasoactive actions of catecholamines during inhibition of prostaglandin synthesis in normal man.
Authors: Vierhapper H , Grubeck-Loebenstein B , Korn A , Waldhäusl W
Published: June 2012

To assess the effect of prostaglandin inhibition upon the vasoactive actions of endogenous and exogenous catecholamines in healthy man, indomethacin (150 mg/day for 3 days) was administered to six healthy men in the sodium-repleted state. Pretreatment with indomethacin did not interfere with the response of blood pressure and pulse rate to orthostasis (10 minutes), a cold pressor test (2 minutes), and the intravenous (i.v.) administration of norepinephrine (NE) (50, 100, and 200 ng kg-1 min-1). Basal plasma concentrations of epinephrine (E) and NE as well as the concentrations of E during orthostasis and cold pressor test remained uninfluenced by pretreatment with indomethacin. While the release of NE during orthostasis appeared to be suppressed in the indomethacin-treated state, it was unchanged during the cold pressor test. These results indicate that inhibition of endogenous prostaglandin synthesis may suppress the release of NE, but does not have a major impact on the vasoactive actions of endogenous and exogenous catecholamines in normal men.