bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Effects of Nitric Oxide and Adenosine in the Nucleus Tractus Solitarii of Rats
Authors: Lo Wan-Chen , Jan Chung-Ren , Wu Sheng-Nan , Tseng Ching-Jiunn
Published: June 2012

Abstract
—It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. We recently reported that NO was involved in central cardiovascular regulation, modulated the baroreflex, and was involved in a reciprocal release with excitatory amino acids in the nucleus tractus solitarii (NTS) of rats. We also reported previously that adenosine increased the release of glutamate in the NTS. The purpose of the present study was to investigate the possible interaction of NO and adenosine in the NTS. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of
l
-arginine (3.3 nmol/60 nL) into the NTS produced decreases in blood pressure and heart rate. Microinjection of adenosine (2.3 nmol/60 nL) also produced depressive and bradycardic effects. These cardiovascular effects were attenuated by prior administration of the specific adenosine receptor antagonist DPSPX (0.92 nmol). Similarly, prior administration of NO synthase inhibitor
N
G
-monomethyl-
l
-arginine or
N
G
-nitro-
l
-arginine methyl ester significantly attenuated the depressive and bradycardic effects of adenosine. These results demonstrate a reciprocal attenuation of adenosine receptor antagonist and NO synthase inhibitor on
l
-arginine and adenosine responses, respectively, in the NTS and implicate an interaction between NO and adenosine in central cardiovascular regulation.
Dopamine D
1
Receptor and Protein Kinase C Isoforms in Spontaneously Hypertensive Rats
Authors: Yao Lynne P. , Li Xiao Xi , Yu Pei-Ying , Xu Jing , Asico Laureano D. , Jose Pedro A.
Published: June 2012

Abstract
—Dopamine, via D
1
-like receptors, stimulates the activity of both protein kinase A (PKA) and protein kinase C (PKC), which results in inhibition of renal sodium transport. Since D
1
-like receptors differentially regulate sodium transport in normotensive and hypertensive rats, they may also differentially regulate PKC expression in these rat strains. Thus, 2 different D
1
-like agonists (fenoldopam or SKF 38393) were infused into the renal artery of anesthetized normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) (n=5 to 6/drug/strain). Ten or 60 minutes after starting the D
1
-like agonist infusion, both the infused kidney and the noninfused kidney that served as control were prepared for analysis. The D
1
-like agonists produced a greater diuresis and natriuresis and inhibited Na
+
,K
+
-ATPase activity in proximal tubule (PT) and medullary thick ascending limb (mTAL) to a greater extent in WKY (Δ20±1%) than in SHR (Δ7±1%,
P
<0.001). D
1
-like agonists had no effect on PKC-α or PKC-λ expression in either membrane or cytosol but increased PKC-θ expression in PT in both WKY and SHR at 10 minutes but not at 60 minutes. However, membranous PKC-δ expression in PT and mTAL decreased in WKY but increased in SHR with either 10 or 60 minutes of D
1
-like agonist infusion. D
1
-like agonists also decreased membranous PKC-ζ expression in PT and mTAL in WKY but increased it in PT but not in mTAL in SHR. We conclude that there is differential regulation of PKC isoform expression by D
1
-like agonists that inhibits membranous PKC-δ and PKC-ζ in WKY but stimulates them in SHR; this effect in SHR is similar to the stimulatory effect of norepinephrine and angiotensin II and may be a mechanism for their differential effects on sodium transport.
Thiazide-Induced Vasodilation in Humans Is Mediated by Potassium Channel Activation
Authors: Pickkers Peter , Hughes Alun D. , Russel Frans G. M. , Thien Theo , Smits Paul
Published: June 2012

Abstract
—Hydrochlorothiazide and indapamide are thought to exert their hypotensive efficacy through a combined vasodilator and diuretic effect, but in vivo evidence for a direct vascular effect is lacking. The presence and mechanism of a direct vascular action of hydrochlorothiazide in vivo in humans were examined and compared with those of the thiazide-like drug indapamide. Forearm vasodilator responses to infusion of placebo and increasing doses of hydrochlorothiazide (8, 25, and 75 μg · min
−1
· dL
−1
) into the brachial artery were recorded by venous occlusion plethysmography. Dose-response curves were repeated after local tetraethylammonium (TEA) administration to determine the role of potassium channel activation and, in patients with the Gitelman syndrome, to determine the role of the thiazide-sensitive Na-Cl cotransporter in the vasodilator effect of hydrochlorothiazide. Vascular effects of hydrochlorothiazide were compared with those of indapamide in both normotensive (mean arterial pressure, 85±7 mm Hg) and hypertensive (mean arterial pressure, 124±16 mm Hg) subjects. At the highest infusion rate, local plasma concentrations of hydrochlorothiazide averaged 11.0±1.6 μg/mL, and those of indapamide averaged 7.2±1.5 μg/mL. In contrast to indapamide, hydrochlorothiazide showed a direct vascular effect (maximal vasodilation, 55±14%;
P
=0.013), which was inhibited by TEA (maximal vasodilation after TEA, 13±10%;
P
=0.02). The response was not dependent on blood pressure and was similar in patients with Gitelman syndrome, indicating that absence of the Na-Cl cotransporter does not alter the vasodilatory effect of hydrochlorothiazide. The vasodilator effect of hydrochlorothiazide in the human forearm is small and only occurs at high concentrations. The mechanism of action is not mediated by inhibition of vascular Na-Cl cotransport but involves vascular potassium channel activation. In contrast, indapamide does not exert any direct vasoactivity in the forearm vascular bed.
Intracellular Angiotensin II Regulates the Inward Calcium Current in Cardiac Myocytes
Authors: De Mello Walmor C.
Published: June 2012

Abstract
—The influence of intracellular administration of angiotensin II (Ang II) on the inward calcium current (I
Ca
) was investigated in single myocytes isolated from adult rat ventricle. Comparative studies were also made in ventricular cells of Golden hamsters. The I
Ca
was measured in single cells using the whole-cell voltage clamp configuration. The results indicated that Ang II (10
−8
mmol/L) dialyzed into the rat myocytes reduced the peak I
Ca
by 35±5.5% (n=20;
P
<0.05). Losartan (10
−7
mmol/L) added to the bath did not suppress the effects of Ang II, indicating that the peptide is acting intracellularly. Moreover, the intracellular dialysis of losartan (10
−6
mmol/L) or [Sar
1
Val
5
Ala
8
] Ang II (10
−6
mmol/L) did not change the effect of Ang II. Stimulation of I
Ca
by exogenous cAMP or inhibition of protein kinase C did not alter the effect of Ang II on I
Ca
. Zaprinast (100 μmol/L), an inhibitor of cGMP phosphodiesterase, when added to the bath solution increased appreciably the effect of Ang II on I
Ca
(
P
<0.05). In ventricular myocytes of Golden hamsters, in which Ang II has a positive inotropic action, the intracellular administration of Ang II (10
−8
mmol/L) increased I
Ca
by 36±2.4% (n=20;
P
>0.05). The effect of the peptide was not altered by the intracellular administration of losartan (10
−6
mmol/L), by [Sar
1
Val
5
Ala
8
] Ang II (10
−6
mmol/L), or by the inhibitor of protein kinase A. The inhibition of protein kinase C, however, prevented the effect of Ang II I
Ca
in the hamster myocytes. The results particularly suggest that the activation of the cardiac renin-angiotensin system regulates I
Ca
and myocardial contractility, an effect that varies with the species.
Characteristics of 9194 Patients With Left Ventricular Hypertrophy
Authors: Dahlöf Björn , Devereux Richard B. , Julius Stevo , Kjeldsen Sverre E. , Beevers Gareth , de Faire Ulf , Fyhrquist Frej , Hedner Thomas , Ibsen Hans , Kristianson Krister , Lederballe-Pedersen Ole , Lindholm Lars H. , Nieminen Markku S. , Omvik Per , Oparil Suzanne , Wedel Hans
Published: June 2012

Abstract
—Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the β-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m
2
), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and ≈7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.
Role of the α
2B
-Adrenergic Receptor in the Development of Salt-Induced Hypertension
Authors: Makaritsis Konstantinos P. , Handy Diane E. , Johns Conrado , Kobilka Brian , Gavras Irene , Gavras Haralambos
Published: June 2012

Abstract
—Salt sensitivity is a common trait in patients with essential hypertension and seems to have both an inherited and an acquired component (eg, is influenced by aging and renal insufficiency). Experimental evidence suggests that salt loading induces hypertension via a neurogenic mechanism mediated by the α
2
-adrenergic receptors (α
2
-AR). To explore the α
2
-AR subtype involved in this mechanism, we studied 2 groups of mice genetically engineered to be deficient in one of the 3 α
2
-AR subtype genes (either α
2B
-AR +/− or α
2C
-AR −/− knockout mice) compared with their wild-type counterparts. The mice (n=10 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for up to 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intra-arterial BP recording. The α
2B
-AR–deficient mice had an attenuated BP response in this protocol (baseline 101.8±2.7 versus end point 109.9±2.8 mm Hg), whereas the BP of their wild-type counterparts went from a baseline 101.9±2.3 to an end point 141.4±7.1 mm Hg. The other 2 groups had BP increases of 44.6±5.17 and 46.7±7.01 mm Hg, with no difference between the mice deficient in the α
2C
-AR gene subtype versus their wild-type counterparts. Body weight, renal remnant weight, and residual renal function were no different among groups. These data suggest that a full complement of α
2B
-AR genes is necessary to raise BP in response to dietary salt loading, whereas complete absence of the α
2C
-AR subtype does not preclude salt-induced BP elevation. It is unclear whether the mechanism(s) involved in this process are of central origin (inability to increase sympathetic outflow), vascular origin (inability to vasoconstrict), or renal origin (inability to retain excess salt and fluid).
Structural Autoregulation of Terminal Vascular Beds
Authors: Pries Axel R. , Secomb Timothy W. , Gaehtgens Peter
Published: June 2012

Abstract
—It is widely accepted that the early phase of primary hypertension is characterized by elevated cardiac output, whereas in later stages the increased blood pressure is due to increased peripheral resistance. To study long-term effects of increased blood flow on peripheral resistance, structural adaptation of microvascular networks in response to changes in blood flow was simulated using a previously developed theoretical model. The diameter of each vessel segment was assumed to change in response to local levels of shear stress, transmural pressure, a metabolic stimulus dependent on blood flow rate, and a conducted stimulus. Network morphologies and topologies were derived from intravital microscopy of the rat mesentery. Adaptive responses to the 4 stimuli were quantitatively balanced to yield stable and realistic distributions of vascular diameters and blood flow rates when the total flow rate was set to observed levels. To simulate effects of increased cardiac output, network flow resistance after structural adaptation was determined for a range of flow rates. Resistance increased with increasing flow, and increases in pressure were up to 3-fold greater than proportional to the increases in flow. According to the model, flow-dependent changes of network resistance result mainly from the vascular response to transmural pressure, which also causes arteriovenous asymmetry of diameters and pressure drops. Therefore, in vascular beds that exhibit arteriovenous asymmetry, increased flow may trigger increased flow resistance by a mechanism involving the tendency of vascular segments to reduce their luminal diameters in response to increased transmural pressure.
Adenosine Inhibits Collagen and Total Protein Synthesis in Vascular Smooth Muscle Cells
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Jackson Edwin K.
Published: June 2012

Abstract
—The objective of this study was to characterize the effects of exogenous, drug-induced and cAMP-adenosine pathway–derived adenosine on collagen synthesis by and hypertrophy of vascular smooth muscle cells (SMCs). Confluent vascular SMCs were stimulated with 2.5% fetal calf serum in the presence and absence of adenosine receptor agonists [adenosine, 2-chloroadenosine,
N
6
-cyclopentyladenosine, 5′-
N
-ethylcarboxamidoadenosine, 5′-
N
-methylcarboxamidoadenosine, and 2-
p
-(2-carboxyethyl)phenethylamino-5′-
N
-ethylcarboxamino adenosine], drugs that increase levels of endogenous adenosine [erythro-9-(2-hydroxy-3-nonyl) adenine, dipyridamole, and iodotubericidin], and cAMP (increases adenosine by conversion to AMP and hence to adenosine via the cAMP-adenosine pathway). Adenosine receptor agonists inhibited fetal calf serum-induced collagen and total protein synthesis (as assessed by [
3
H]proline and [
3
H]leucine incorporation, respectively) with a relative potency profile consistent with the effects being mediated by adenosine A
2B
receptors. Erythro-9-(2-hydroxy-3-nonyl) adenine, dipyridamole, iodotubericidin, and cAMP also inhibited collagen and total protein synthesis. The effects of 2-chloroadenosine, erythro-9-(2-hydroxy-3-nonyl) adenine, iodotubericidin, and cAMP on collagen and total protein synthesis were attenuated by KF17837 and 1,3-dipropyl-8-
p
-sulfophenylxanthine (selective and nonselective A
2
receptor antagonists, respectively) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A
1
receptor antagonist). These studies indicate that exogenous, drug-induced and cAMP-adenosine pathway–derived adenosine inhibit vascular SMC collagen synthesis and hypertrophy via A
2B
receptors. Thus, exogenous A
2B
receptor agonists and drugs that modulate endogenous adenosine levels may protect against vasoocclusive disorders by attenuating extracellular matrix synthesis by and cellular hypertrophy of vascular SMCs. Moreover, the cAMP-adenosine pathway may protect against vascular hypertrophy.
Role of Aldosterone in Renal Vascular Injury in Stroke-Prone Hypertensive Rats
Authors: Rocha Ricardo , Chander Praveen N. , Zuckerman Andrea , Stier Charles T.
Published: June 2012

Abstract
—Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (n=8); captopril alone (50 mg · kg
−1
· d
−1
, orally) (n=10); aldosterone infusion alone (40 μg · kg
−1
· d
−1
, SC) (n=7); or captopril and aldosterone at 20 (n=6) or 40 (n=7) μg · kg
−1
· d
−1
. Systolic blood pressure was markedly elevated in all groups. Vehicle- and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21±3% and 29±3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 μg · kg
−1
· d
−1
in captopril-treated SHRSP resulted in the development of severe renal lesions (16±3% and 21±2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure.
Genomics and Hypertension
Authors: Pratt Richard E. , Dzau Victor J.
Published: June 2012

Abstract
—We are at the beginning of a biological revolution, spurred on by the Human Genome Project and associated studies. Within the next few years, expressed sequence tags (ESTs) representing all sequences expressed in humans will be determined and their genomic positions will be defined (STSs). The discovery of all the variants in the human genome that contribute to the genetic diversity of the human population will result in the construction of dense polymorphic maps. The rapid growth of the EST, STS, and single-nucleotide polymorphism (SNP) databases, coupled with impressive technological advances, will surely have a dramatic effect on biomedical research. In this review, we will examine the recent advances in genetics and genomics and place these within the context of medical research and patient care, with an emphasis on studies in the cardiovascular system.
Interleukin-1β Regulation of the Human Brain Natriuretic Peptide Promoter Involves Ras-, Rac-, and p38 Kinase–Dependent Pathways in Cardiac Myocytes
Authors: He Quan , LaPointe Margot C.
Published: June 2012

Abstract
—Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1β (IL-1β) are induced in the infarcted myocardium, localized production of IL-1β may regulate the BNP gene. We tested whether (1) IL-1β regulates the human BNP promoter, (2)
cis
elements in the proximal promoter respond to IL-1β, and (3) mitogen-activated protein kinase (MAPK) signaling pathways [p42/44, c-jun (JNK) and p38 kinase] are involved. We transferred the hBNP promoter coupled to a luciferase reporter gene or constructs with mutations in the proximal promoter GATA and M-CAT elements into neonatal rat ventricular myocytes and treated the cells with IL-1β for 24 hours. IL-1β–stimulated hBNP luciferase activity was eliminated by pretreatment with the transcription inhibitor actinomycin D. Both the p38 kinase inhibitor SB205380 (SB) and cotransfection of a dominant-negative mutant of p38 kinase reduced IL-1β stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1β–stimulated hBNP luciferase activity by 64% and 90%, respectively. Constitutively active forms of Rac and MKK6, the immediate upstream activator of p38, were stimulatory; however, only the effect of MKK6 was inhibited by SB. Neither the p42/44 nor the JNK pathway was involved in the action of IL-1β. Both IL-1β and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1β is a transcriptional activator of the hBNP promoter; (2) IL-1β acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1β acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1β activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.
Estrogen Regulation of Angiotensin-Converting Enzyme mRNA
Authors: Gallagher Patricia E. , Li Ping , Lenhart John R. , Chappell Mark C. , Brosnihan K. Bridget
Published: June 2012

Abstract
—Estrogen replacement therapy is cardioprotective in postmenopausal women; however, the precise molecular mechanisms for this modulation are not fully elucidated. We previously showed that chronic estrogen replacement therapy reduced angiotensin-converting enzyme (ACE) activity in tissue extracts and serum with an associated reduction in plasma angiotensin II. A reverse transcriptase–polymerase chain reaction assay was developed to determine whether estrogen treatment regulates tissue ACE mRNA concentration. Total RNA was isolated from kidney cortex, kidney medulla, lung, and aorta of ovariectomized Sprague-Dawley rats after 21 days of chronic 17β-estradiol replacement therapy (5 mg pellet per rat SC) or placebo. A marked decrease in densitometric intensity ratios of amplified ACE cDNA to elongation factor-1α control cDNA was observed in all tissues from placebo-treated rats compared with the estradiol-treated rats (renal cortex: 0.29±0.04 versus 0.14±0.02; renal medulla: 0.37±0.04 versus 0.24±0.03; lung: 4.49±0.37 versus 2.49±0.59; and aorta: 0.41±0.04 versus 0.29±0.02; all
P
<0.05). A comparable reduction in ACE activity was detected in tissue extracts from kidney cortex, kidney medulla, and lung of hormone-treated animals. Incubation of purified rat lung ACE with 1 or 10 μmol/L 17β-estradiol had no effect on enzyme activity. These results suggest that estrogen treatment regulates tissue ACE activity by reducing ACE mRNA concentrations. Thus, the beneficial cardiovascular effects of estrogen may be mediated in part by downregulation of ACE with a consequent reduction in the circulating levels of the vasoconstrictor angiotensin II, a decrease in the metabolism of the vasodilator bradykinin, and an increase in the production of the vasorelaxant angiotensin-(1–7).
Roles of AT
1
and AT
2
Receptors in the Hypertensive
Ren
-2 Gene Transgenic Rat Kidney
Authors: Zhuo Jialong , Ohishi Mitsuru , Mendelsohn Frederick A. O.
Published: June 2012

Abstract
—Adult
Ren
-2 gene transgenic rats, TGR(mRen-2)27, exhibit elevated circulating and kidney angiotensin II (Ang II) levels in the presence of severe hypertension. The aim of this study was to examine whether AT
1
and AT
2
receptors in the kidney and renal hemodynamic and tubular responses to blockade of these receptors were altered in the
Ren
-2 gene transgenic rats during the maintenance phase of hypertension. Renal AT
1
and AT
2
receptors were mapped by in vitro autoradiography (n=8), and the effects of blockade of these receptors on mean arterial pressure (MAP), heart rate (HR), and renal cortical (CBF) and medullary blood flows (MBF) were studied in anaesthetized, adult age-matched male homozygous TGR rats (n=12) and Sprague-Dawley (SD) rats (n=7). TGR rats showed higher basal MAP (
P
<0.001), heart and kidney weight (
P
<0.001), plasma renin activity (
P
<0.05) and plasma Ang II level (
P
<0.05), and CBF (
P
<0.05) and MBF (
P
<0.05) than SD rats. AT
1
receptor binding was significantly increased in the glomeruli, proximal tubules, and the inner stripe of the outer medulla of TGR rats (
P
<0.01), while the AT
2
receptor binding was low at all renal sites of TGR and SD rats. Immunohistochemistry revealed that this increased AT
1
receptor labeling occurred mainly in vascular smooth muscle layer of intrarenal blood vessels including afferent and efferent arterioles, juxtaglomerular apparatus, glomerular mesangial cells, proximal tubular cells, and renomedullary interstitial cells (RMICs) in the transgenic rats. Blockade of AT
1
receptors with losartan in TGR rats markedly reduced MAP to the normotensive level (
P
<0.001) without altering HR. Both CBF (
P
<0.005) and MBF (
P
<0.05) were significantly increased by losartan in the transgenic rats. By contrast, losartan only caused a smaller decrease in MAP and an increase in renal CBF in SD rats (
P
<0.05). PD 123319 was without any renal effect in both SD and TGR rats. These findings suggest that markedly increased AT
1
receptors in renal vasculature, glomerular mesangial cells, and RMICs in the presence of fulminant hypertension and elevated circulating and tissue Ang II levels may play an important role in the maintenance of hypertension in the
Ren
-2 gene transgenic rats.
Role of AT
2
Receptors in Angiotensin II–Stimulated Contraction of Small Mesenteric Arteries in Young SHR
Authors: Touyz Rhian M. , Endemann Dierk , He Gang , Li Jin-S. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—This study assesses the receptor subtype (AT
1
and AT
2
) through which angiotensin II (Ang II) mediates contraction in small arteries of young and adult spontaneously hypertensive rats (SHR). Segments of third-order mesenteric arteries (≈200 μm in lumen diameter) were mounted in a pressurized system. Systolic blood pressure and media:lumen ratio of small arteries were significantly greater (
P
<0.001) in young SHR and adult SHR than in age-matched Wistar-Kyoto rats (WKY). Ang II–induced contractile effects were significantly increased (
P
<0.05) in young SHR compared with age-matched WKY. AT
1
blockade with losartan, and combined AT
1
and AT
2
blockade with losartan and PD123319, abolished Ang II–stimulated contraction in young and adult rats. AT
2
blockade (PD123319) significantly reduced (
P
<0.01) Ang II–elicited contraction in young SHR but had no effect in WKY or adult SHR, indicating that AT
2
receptors may contribute to Ang II–induced contraction in young SHR. To determine the Ang receptor status in rat mesenteric vessels, AT
1
and AT
2
receptor mRNA expression was determined by reverse transcription–polymerase chain reaction. AT
1
and AT
2
receptor protein expression were detected by Western blot analysis. AT
1
receptor mRNA was equally expressed in age-matched rats, but expression was significantly lower in young rats compared with adult rats. AT
2
receptor mRNA was weakly expressed in WKY and adult SHR. In vessels from young SHR, AT
2
receptor mRNA expression was significantly increased compared with the other groups. AT
1
receptor protein was equally expressed in adult rats of both strains but was undetectable in young rats. AT
2
receptor protein was only detectable in young rats, with the magnitude of expression greater in SHR than WKY. In conclusion, Ang II–stimulated contractile responses are augmented in vessels from young SHR. These effects are reduced by selective AT
2
blockade and abolished by AT
1
blockade, indicating that both Ang receptor subtypes are involved in contraction in young SHR. In WKY and adult SHR, losartan, but not PD123319, inhibited Ang II–induced contraction, indicating the exclusive involvement of AT
1
receptors. Thus, in SHR, in the phase of developing hypertension, enhanced Ang II–stimulated vascular contraction may be associated with changes in Ang II receptor status, as evidenced pharmacologically and by increased vascular AT
2
receptor mRNA and protein expression.
Monocyte Infiltration and Adhesion Molecules in a Rat Model of High Human Renin Hypertension
Authors: Mervaala Eero M. A. , Müller Dominik N. , Park Joon-Keun , Schmidt Folke , Löhn Matthias , Breu Volker , Dragun Duska , Ganten Detlev , Haller Herman , Luft Friedrich C.
Published: June 2012

Abstract
—Hypertension and kidney damage in the double transgenic rat (dTGR) harboring both human renin and human angiotensinogen genes are dependent on the human components of the renin angiotensin system. We tested the hypothesis that monocyte infiltration and increased adhesion molecule expression are involved in the pathogenesis of kidney damage in dTGR. We also evaluated the effects of long-term angiotensin-converting enzyme (ACE) inhibition, AT
1
blockade, and human renin inhibition on monocyte recruitment and inflammatory response in dTGR. Systolic blood pressure and 24-hour albuminuria were markedly increased in 7-week-old dTGR as compared with age-matched normotensive Sprague Dawley rats. We found a significant monocyte/macrophage infiltration in the renal perivascular space and increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the interstitium, intima, and adventitia of the small renal vessels. α
L
β
2
integrin and α
4
β
1
integrin, the corresponding ligands for ICAM-1 and VCAM-1, were also found on infiltrating monocytes/macrophages. The expression of plasminogen activator inhibitor-1 and fibronectin in the kidneys of dTGR were increased and distributed similarly to ICAM-1. In 4-week-old dTGR, long-term treatment with ACE inhibition (cilazapril), AT
1
receptor blockade (valsartan), and human renin inhibition (RO 65-7219) (each drug 10 mg/kg by gavage once a day for 3 weeks) completely prevented the development of albuminuria. However, only cilazapril and valsartan were able to decrease blood pressure to normotensive levels. Interestingly, the drugs were all equally effective in preventing monocyte/macrophage infiltration and the overexpression of adhesion molecules, plasminogen activator inhibitor-1, and fibronectin in the kidney. Our findings indicate that angiotensin II causes monocyte recruitment and vascular inflammatory response in the kidney by blood pressure–dependent and blood pressure–independent mechanisms. ACE inhibition, AT
1
receptor blockade, and human renin inhibition all prevent monocyte/macrophage infiltration and increased adhesion molecule expression in the kidneys of dTGR.
Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors
Authors: Wagner Jens A. , Varga Károly , Járai Zoltán , Kunos George
Published: June 2012

Abstract
—Cannabinoids, including the endogenous ligand anandamide (arachidonyl ethanolamide), elicit pronounced hypotension in rats via activation of peripherally located CB1 cannabinoid receptors, which have been also implicated in endotoxin (lipopolysaccharide [LPS])-induced hypotension. The present study was designed to test the role of vascular CB1 receptors in cannabinoid- and endotoxin-induced mesenteric vasodilation. In the isolated, buffer-perfused rat mesenteric arterial bed precontracted with phenylephrine, anandamide induced long-lasting (up to 60 minutes) dose-dependent vasodilation (ED
50
: 79±3 nmol; maximal relaxation: 77±2%), inhibited by 0.5 to 5.0 μmol/L of the selective CB1 receptor antagonist SR141716A. Low doses of the calcium ionophore ionomycin also caused mesenteric vasodilation inhibited by SR141716A. The metabolically stable analogue R-methanandamide elicited mesenteric vasodilation (ED
50
: 286±29 nmol), whereas the potent synthetic CB1 receptor agonists WIN 55212-2 and HU-210 caused no change in vascular tone or only a minor dilator effect not affected by SR141716A, respectively. The endogenous ligand 2-arachidonyl glycerol caused no change in vascular tone, whereas Δ
9
-tetrahydrocannabinol and arachidonic acid caused mesenteric vasoconstriction. After endothelial denudation, the dilator response to anandamide was slightly reduced and was no longer inhibited by SR141716A. In preparations from LPS-pretreated rats, SR141716A alone caused a significant and prolonged increase in perfusion pressure, whereas it had no such effect in control preparations perfused in vitro with or without LPS or after endothelial denudation in preparations from rats pretreated with LPS. We conclude that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR141716A-sensitive “anandamide receptor” distinct from CB1 cannabinoid receptors and that activation of such receptors by an endocannabinoid, possibly anandamide, contributes to LPS-induced mesenteric vasodilation in vivo.
Interactions Between the Melanocortin System and Leptin in Control of Sympathetic Nerve Traffic
Authors: Haynes William G. , Morgan Donald A. , Djalali Ali , Sivitz William I. , Mark Allyn L.
Published: June 2012

Abstract
—Leptin plays an important role in regulation of body weight through regulation of food intake and sympathetically mediated thermogenesis. The hypothalamic melanocortin system, via activation of the melanocortin-4 receptor (MC4-R), decreases appetite and weight, but its effects on sympathetic nerve activity (SNA) are unknown. In addition, it is not known whether sympathoactivation to leptin is mediated by the melanocortin system. We tested the interactions between these systems in regulation of brown adipose tissue (BAT) and renal and lumbar SNA in anesthetized Sprague-Dawley rats. Intracerebroventricular administration of the MC4-R agonist MT-II (200 to 600 pmol) produced a dose-dependent sympathoexcitation affecting BAT and renal and lumbar beds. This response was completely blocked by the MC4-R antagonist SHU9119 (30 pmol ICV). Administration of leptin (1000 μg/kg IV) slowly increased BAT SNA (baseline, 41±6 spikes/s; 6 hours, 196±28 spikes/s;
P
=0.001) and renal SNA (baseline, 116±16 spikes/s; 6 hours, 169±26 spikes/s;
P
=0.014). Intracerebroventricular administration of SHU9119 did not inhibit leptin-induced BAT sympathoexcitation (baseline, 35±7 spikes/s; 6 hours, 158±34 spikes/s;
P
=0.71 versus leptin alone). However, renal sympathoexcitation to leptin was completely blocked by SHU9119 (baseline, 142±17 spikes/s; 6 hours, 146±25 spikes/s;
P
=0.007 versus leptin alone). This study demonstrates that the hypothalamic melanocortin system can act to increase sympathetic nerve traffic to thermogenic BAT and other tissues. Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system.
Ultrasonic Myocardial Texture Versus Doppler Analysis in Hypertensive Heart
Authors: Di Bello Vitantonio , Pedrinelli Roberto , Giorgi Davide , Bertini Alessio , Bianchi Massimiliano , Paterni Marco , Romano Maria Francesca , Dell’Omo Giulia , Giusti Costantino
Published: June 2012

Abstract
—Doppler-derived parameters of transmitral flow are useful indices of diastolic dysfunction in the hypertensive heart. Different degrees of myocardial involvement in hypertensive heart can be detected by videodensitometric myocardial textural analysis. The aim of this study was to compare Doppler-derived and ultrasonic videodensitometric parameters in the differentiation of healthy hearts from hypertensive hearts. We compared a group of age-matched (59±9 years) male essential hypertensive patients (n=53) with normotensive healthy subjects as controls (n=32). All subjects provided ambulatory blood pressure measurements for the evaluation of 24-hour mean systolic and diastolic blood pressure. A transmitral flow Doppler analysis was performed on all subjects. A quantitative analysis of the echocardiographic digitized imaging was performed with the help of a calibrated digitization system to calculate the septum and the posterior wall textural parameters. The myocardial mean gray level (MGL) was calculated to derive the cyclic variation index (CVI): (MGL
end-diastolic
−MGL
end-systolic
)/MGL
end-diastolic
×100. When compared with controls, the hypertensive patients showed a significantly lower CVI for both septum (−11.1±26.8% versus 34.7±16.3%;
P
<0.001) and posterior wall (−11.2±27.6% versus 38.2±15.4%;
P
<0.001). Individual analyses for the ratio of peak transmitral flow velocity in early diastole to the peak transmitral flow velocity in late diastole showed that only 24% of the patients (13/53) were discriminated from normal subjects by this parameter. Individual analyses for CVI, however, at both septum and posterior wall levels, showed that 74% of the patients (39/53) were discriminated from normal subjects by this second parameter. In comparison with Doppler-derived indices of diastolic filling, the videodensitometric parameters showed a significantly higher ability to discriminate between hypertensive subjects and normal controls.
The Effect of Chronic Coffee Drinking on Blood Pressure
Authors: Jee Sun Ha , He Jiang , Whelton Paul K. , Suh Il , Klag Michael J.
Published: June 2012

Abstract
—We sought to assess the effect of coffee consumption on blood pressure in humans. Our data sources included a MEDLINE search of the literature published before December 1997, bibliography review, and expert consultation. We selected controlled trials in which coffee consumption was the only difference between the intervention and control groups, mean blood pressure change was reported for each group or period, and treatment lasted for >24 hours. Of 36 studies initially identified, 11 (522 participants) met these inclusion criteria. Information on sample size, study design, participant characteristics (gender, race, age, baseline blood pressure, and antihypertensive medications), and treatment results were abstracted by 3 reviewers using a standardized protocol. Treatment effect of coffee consumption on blood pressure was estimated with the use of a random-effects model. In the 11 trials, median duration was 56 days (range, 14 to 79 days), and median dose of coffee was 5 cups/d. Systolic and diastolic blood pressure increased by 2.4 (range, 1.0 to 3.7) mm Hg and 1.2 (range, 0.4 to 2.1) mm Hg, respectively, with coffee treatment compared with control. Multiple linear regression analysis identified an independent, positive relationship between cups of coffee consumed and subsequent change in systolic blood pressure, independent of age of study participants and study design characteristics. The effect of coffee drinking on systolic and diastolic blood pressure was greater in trials with younger participants. Our findings provide support for a relationship between coffee consumption and higher blood pressure. Trials of coffee cessation of longer duration and in persons with hypertension should be performed.
α
1
-Adrenergic Receptor Subtypes in Human Peripheral Blood Lymphocytes
Authors: Ricci Alberto , Bronzetti Elena , Conterno Andrea , Greco Stefania , Mulatero Paolo , Schena Marina , Schiavone Domenica , Tayebati Seyed K. , Veglio Franco , Amenta Francesco
Published: June 2012

Abstract
—We investigated the expression of α
1
-adrenergic receptor subtypes in intact human peripheral blood lymphocytes using reverse transcription–polymerase chain reaction (RT-PCR) and radioligand binding assay techniques combined with antibodies against the three subtypes of α
1
-adrenergic receptors (α
1A
, α
1B
, and α
1D
). RT-PCR amplified in peripheral blood lymphocytes a 348-bp α
1A
-adrenergic receptor fragment, a 689-bp α
1B
-adrenergic receptor fragment, and a 540-bp α
1D
-adrenergic receptor fragment. Radioligand binding assay with [
3
H]prazosin as radioligand revealed a high-affinity binding with a dissociation constant value of 0.65±0.05 nmol/L and a maximum density of binding sites of 175.3±20.5 fmol/10
6
cells. The pharmacological profile of [
3
H]prazosin binding to human peripheral blood lymphocytes was consistent with the labeling of α
1
-adrenergic receptors. Antibodies against α
1A
-, α
1B
-, and α
1D
-receptor subtypes decreased [
3
H]prazosin binding to a different extent. This indicates that human peripheral blood lymphocytes express the three α
1
-adrenergic receptor subtypes. Of the three different α
1
-adrenergic receptor subtypes, the α
1B
is the most represented and the α
1D
, the least. Future studies should clarify the functional relevance of α
1
-adrenergic receptors expressed by peripheral blood lymphocytes. The identification of these sites may represent a step for evaluating whether they represent a marker of α
1
-adrenergic receptors in cardiovascular disorders or for assessing responses to drug treatment on these receptors.
Magnetic Resonance Angiography Versus Duplex Sonography for Diagnosing Renovascular Disease
Authors: Leung Daniel A. , Hoffmann Ulrich , Pfammatter Thomas , Hany Thomas F. , Rainoni Lisa , Hilfiker Paul , Schneider Ernst , Zimmermann-Paul Gesine G. , Debatin Jörg F.
Published: June 2012

Abstract
—Noninvasive testing for renovascular disease is required to identify patients who may benefit from revascularization procedures without exposing an unnecessary amount of patients to the risks of catheter angiography. All available methods of diagnosing renal artery stenosis have significant limitations. We compared a new technique, contrast-enhanced magnetic resonance angiography, with an established technique, duplex ultrasonography, for the detection of renal artery stenosis using catheter angiography as the standard of reference. Eighty-nine patients with clinically suspected renovascular disease underwent duplex renal scanning and contrast-enhanced magnetic resonance angiography. Sixty of these also underwent catheter angiography. All studies were interpreted for the presence of renal artery stenosis blinded to the results of the other imaging modalities. For detection of hemodynamically significant (≥60% diameter reduction) main renal artery stenosis, sensitivity and specificity were 90% and 86%, respectively, for magnetic resonance angiography and 81% and 87% for duplex sonography. Most false readings involved differential grading of stenoses detected with all 3 techniques. When patients with fibromuscular dysplasia were excluded from the analysis, the sensitivity of magnetic resonance angiography increased to 97%, with a negative predictive value of 98%. Magnetic resonance angiography detected 96% and duplex 5% of accessory renal arteries seen at catheter angiography. Contrast-enhanced magnetic resonance angiography is a useful technique for diagnosing atherosclerotic renovascular disease. It overcomes the major limitations of duplex renal scanning. However, duplex has the advantage of providing hemodynamic information and appears better suited for the assessment of patients with suspected fibromuscular dysplasia.
Angiotensin-Converting Enzyme Is Upregulated in the Proximal Tubules of Rats With Intense Proteinuria
Authors: Largo Raquel , Gómez-Garre Dulcenombre , Soto Karina , Marrón Belén , Blanco Julia , Gazapo Rosa María , Plaza Juan José , Egido Jesús
Published: June 2012

Abstract
—Persistent proteinuria is considered a deleterious prognostic factor in most progressive renal diseases. However, the mechanisms by which proteinuria induces renal damage remain undetermined. Since proximal tubular cells possess all the machinery to generate angiotensin II (Ang II), we approached the hypothesis that proteinuria could elicit the renal activation of the renin-angiotensin system in a model of intense proteinuria and interstitial nephritis induced by protein overload. After uninephrectomy (UNX), Wistar-Kyoto rats received daily injections of 1 g BSA or saline for 8 days. The mean peak of proteinuria was observed at the fourth day (538±89 versus 3±1 mg/24 h in UNX controls; n=12;
P
<0.05) and was increased during the whole study period (at the eighth day: 438±49 mg/24 h; n=12;
P
=NS). Morphological examination of the kidneys at the end of the study showed marked tubular lesions (atrophy, vacuolization, dilation, and casts), interstitial infiltration of mononuclear cells, and mesangial expansion. In relation to UNX control rats, renal cortex of BSA-overloaded rats showed an increment in the gene expression of angiotensinogen (2.4-fold) and angiotensin-converting enzyme (ACE) (2.1-fold), as well as a diminution in renin gene expression. No changes were observed in angiotensin type 1 (AT
1
) receptor mRNA expression in both groups of rats. By in situ reverse transcription–polymerase chain reaction and immunohistochemistry, ACE expression (gene and protein) was mainly localized in proximal and distal tubules and in the glomeruli. By immunohistochemistry, angiotensinogen was localized only in proximal tubules, and AT
1
receptor was localized mainly in proximal and distal tubules. In the tubular brush border, an increase in ACE activity was also seen (5.5±0.5 versus 3.1±0.7 U/mg protein ×10
−4
in UNX control; n=7;
P
<0.05). Our results show that in the kidney of rats with intense proteinuria, ACE and angiotensinogen were upregulated, while gene expression of renin was inhibited and AT
1
was unmodified. On the whole, these data suggest an increase in Ang II intrarenal generation. Since Ang II can elicit renal cell growth and matrix production through the activation of AT
1
receptor, this peptide may be responsible for the tubulointerstitial lesions occurring in this model. These results suggest a novel mechanism by which proteinuria may participate in the progression of renal diseases.