bluuebunny/crossref_metadata_2025 huggingface dataset:
Mediators of Arachidonic Acid–Induced Relaxation of Bovine Coronary Artery
Authors: Pratt Phillip F. , Rosolowsky Mark , Campbell William B.
Published: June 2012

Bovine coronary arteries relax in response to bradykinin, methacholine, sodium nitroprusside, isoproterenol, and arachidonic acid in a concentration-dependent manner. The relaxations to methacholine, bradykinin, and arachidonic acid are lost when endothelium is removed. Indomethacin, a cyclooxygenase inhibitor, attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC
50
(control versus indomethacin) to each (1×10
−7
versus 3×10
−7
mol/L, 3×10
−10
versus 2×10
−9
mol/L, and 3×10
−7
versus 2×10
−6
mol/L, respectively). Nitro-
l
-arginine, a nitric oxide synthase inhibitor, also attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC
50
(control versus nitro-
l
-arginine) to each (1×10
−7
versus 3×10
−7
mol/L, 3×10
−10
versus >10
−9
mol/L, and 3×10
−7
versus >10
−6
mol/L, respectively). The combination of indomethacin and nitro-
l
-arginine blunted the relaxations to these agents and also shifted the EC
50
values (control versus indomethacin plus nitro-
l
-arginine) to each (1×10
−
7
versus 5×10
−
7
mol/L, 3×10
−
10
versus >10
−
9
mol/L, and 3×10
−
7
versus >10
−
6
mol/L, respectively). Methacholine, bradykinin, and arachidonic acid stimulated the release of prostaglandin I
2
, measured as 6-keto-PGF
1
α
. Indomethacin, but not nitro-
l
-arginine, inhibited arachidonic acid–induced release of 6-keto-PGF
1
α
. Vascular cGMP content was unchanged by arachidonic acid but was significantly elevated by bradykinin. Relaxations to prostaglandin I
2
and sodium nitroprusside, but not 8,9-epoxyeicosatrienoic acid or isoproterenol, were inhibited by nitro-
l
-arginine. We conclude that the endothelium-dependent relaxations to methacholine, bradykinin, and arachidonic acid are partly due to prostaglandin I
2
release. The remainder of the responses to these agents is due to the release of other relaxing factor or factors. Since bradykinin increased cGMP and nitro-
l
-arginine partially inhibited its relaxant effects, nitric oxide also appears to participate in the bradykinin-induced effect. Since the combination of indomethacin and nitro-
l
-arginine failed to completely block the relaxations to methacholine, bradykinin, and arachidonic acid, another endothelial factor must contribute to their vascular effects. Surprisingly, nitro-
l
-arginine attenuated the relaxations to arachidonic acid; however,
l
-arginine failed to reverse the effects of nitro-
l
-arginine on arachidonic acid–induced relaxations. In addition, arachidonic acid failed to increase cGMP. Nitro-
l
-arginine also reduced the responses to prostaglandin I
2
and sodium nitroprusside. These data indicate that these arginine analogues may have effects other than competitive inhibition of nitric oxide synthase.
Angiotensin I–Converting Enzyme Genotypes and Angiotensin II Receptors
Authors: Dieguez-Lucena Jose L. , Aranda-Lara Pedro , Ruiz-Galdón Maximiliano , García-Villanova Javier , Morell-Ocaña Miguel , Reyes-Engel Armando
Published: June 2012

In the present study, we studied angiotensin II type 1 (AT
1
) and type 2 (AT
2
) receptor messengers by quantitative reverse transcriptase–polymerase chain reaction. We examined peripheral blood mononuclear cells from 30 healthy subjects and 50 subjects with primary hypertension, in whom angiotensin I–converting enzyme genotype was determined, before and after 15 days of treatment with different antihypertensive drugs. The medication included a calcium channel antagonist, an angiotensin I–converting enzyme inhibitor, and a β
1
-blocker. We also studied the relationship between AT
1
receptor gene expression and biochemical parameters of the renin-angiotensin system. AT
1
receptor messenger levels were positively correlated with plasma renin activity in both normotensive and untreated hypertensive subjects. Increases of this messenger and plasma angiotensin II levels were correlated with the D allele in the same individuals. AT
1
receptor messenger levels decreased significantly with angiotensin I–converting enzyme inhibitor treatment in subjects with the DD genotype, and a significant decrease was observed in subjects with the II and ID genotypes treated with a calcium antagonist. No changes were observed in mRNA with the β
1
-blocker. We conclude that the AT
2
receptor is not expressed in peripheral leukocytes and that AT
1
receptor messenger levels vary in relation to angiotensin I–converting enzyme genotype and pharmacological treatment. These results suggest that angiotensin I–converting enzyme genotype may be an important factor when deciding on antihypertensive therapy in individuals with primary hypertension.
Dietary Sodium Intake Modulates Pituitary Proopiomelanocortin mRNA Abundance
Authors: Mayan Haim , Ling Kok-Tong , Lee Eva Y. , Wiedemann Eckehart , Kalinyak Judith E. , Humphreys Michael H.
Published: June 2012

The pituitary prohormone proopiomelanocortin gives rise to melanocortins of α, β, and γ primary structure in addition to corticotropin. Melanocortins have a variety of actions in mammals, and each is natriuretic. In particular, γ-melanocyte–stimulating hormone has been shown to mediate reflex natriuresis after acute unilateral nephrectomy. We examined whether this peptide could play a role in longer term adjustments in sodium balance by measuring plasma γ-melanocyte–stimulating hormone and corticotropin concentrations, as well as pituitary proopiomelanocortin mRNA abundance, in Sprague-Dawley rats ingesting either a low (0.07% NaCl) or high (7.5% NaCl) sodium diet. One week after the high sodium diet, plasma γ-melanocyte–stimulating hormone concentration was double the value seen in rats on the low sodium diet (158±5 [SE] versus 76±9 fmol/mL,
P
<.001), a change that was accompanied by a fivefold increase in plasma atrial natriuretic peptide concentration but no change in plasma corticotropin. Whole pituitary proopiomelanocortin mRNA abundance, measured with a probe to exon 3 of the rat proopiomelanocortin gene, was significantly increased after 1 week of the high sodium diet compared with the low sodium diet and increased further at 2 and 3 weeks. This increase occurred primarily in the neurointermediate lobe as demonstrated by in situ hybridization; the content of γ-melanocyte–stimulating hormone immunoreactivity was also increased in this lobe, but not the anterior lobe, after 1 week of the high sodium diet. These results demonstrate that high dietary sodium intake increases neurointermediate lobe proopiomelanocortin mRNA abundance compared with a very low sodium diet and also suggest that proopiomelanocortin is preferentially processed into γ-melanocyte–stimulating hormone rather than corticotropin. These observations consequently raise the possibility of a role for this peptide hormone system in the adjustments to a high salt diet.
Cyclosporin A Impairs the Nocturnal Blood Pressure Fall in Renal Transplant Recipients
Authors: van den Dorpel Marinus A. , van den Meiracker Anton H. , Lameris Thomas W. , Boomsma Frans , Levi Marcel , Man in 't Veld Arie J. , Weimar Willem , Schalekamp Maarten A.D.H.
Published: June 2012

In renal transplant recipients, hypertension and a diminished nocturnal blood pressure fall are frequently found. To investigate whether this diminished nocturnal blood pressure fall is related to the use of cyclosporin A or to other factors, such as the use of glucocorticoids, we measured 24-hour ambulatory blood pressure in 18 renal transplant recipients both before and 16 weeks after conversion from cyclosporin A to azathioprine. Renal blood flow and glomerular filtration rate were estimated from
131
I-hippurate and
125
I-iothalamate clearances, respectively, and plasma concentrations of renin, atrial natriuretic peptide, norepinephrine, prostaglandin E
2
, and thromboxane B
2
were determined. During cyclosporin A treatment, mean 24-hour blood pressure was 117±3 mm Hg, and the nocturnal fall in blood pressure was 4±9 mm Hg. A nondipping diurnal blood pressure pattern was present in 13 patients. After conversion to azathioprine, mean 24-hour blood pressure decreased to 109±3 mm Hg (
P
<.001), the nocturnal fall increased to 9±6 mm Hg, and the number of patients with a nondipping diurnal blood pressure pattern decreased to 9. The nocturnal fall in heart rate (17±10 beats per minute) during cyclosporin A did not change after conversion. Body weight and plasma concentrations of norepinephrine and renin did not change. Plasma concentrations of prostaglandin E
2
and thromboxane B
2
decreased after conversion, as did plasma atrial natriuretic peptide. Renal blood flow and glomerular filtration rate increased after conversion. In conclusion, cyclosporin A appears to be involved in the disturbance of the circadian blood pressure rhythm in renal transplant recipients. Although the precise mechanism is unclear, the elevated plasma atrial natriuretic peptide and slightly suppressed plasma renin concentrations suggest that intravascular volume expansion may contribute to the observed hemodynamic alterations.
Activation of the Sodium-Potassium Pump Contributes to Insulin-Induced Vasodilation in Humans
Authors: Tack Cees J.J. , Lutterman Jos A. , Vervoort Gerald , Thien Theo , Smits Paul
Published: June 2012

Systemic hyperinsulinemia induces vasodilation in human skeletal muscle. This vasodilation contributes to insulin-stimulated glucose uptake and has been found to be reduced in various insulin-resistant states. The mechanism of the effect of insulin on vascular tone is not completely understood. We hypothesized that activation of the sodium-potassium pump (Na
+
,K
+
-ATPase) located in endothelial or smooth muscle cells would be involved in the insulin-mediated vasodilation. Therefore, in 24 healthy, nonsmoking, nonobese, normotensive volunteers, we infused ouabain, a specific inhibitor of Na
+
,K
+
-ATPase, into the brachial artery before and during euglycemic hyperinsulinemia. As expected, insulin (systemic concentrations, approximately 700 [low] and 1400 [high] pmol·L
−1
) induced vasodilation in the control arm (forearm blood flow [FBF, plethysmography] from 1.6±0.2 to 2.1±0.4 mL·dL
−1
·min
−1
[low insulin] and from 1.6±0.2 to 2.1±0.2 [high insulin],
P
<.05 for both), but the increase in FBF was abolished in the ouabain-infused forearm (from 1.3±0.1 to 1.4±0.2 mL·dL
−1
·min
−1
[low] and from 1.3±0.1 to 1.3±0.1 [high],
P
=NS). Ouabain-induced increases in forearm potassium release were partly reversed by insulin. To investigate whether the mechanism of action could be at the endothelial level, we infused
N
G
-monomethyl-
l
-arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthase (0.05, 0.1, and 0.2 mg·dL
−1
·min
−1
) intra-arterially in 12 subjects and induced a clear dose-dependent decrease of FBF from 1.7±0.2 to 1.2±0.1 mL·dL
−1
·min
−1
(
P
<.01). In contrast, after ouabain (and continued insulin) infusion, L-NMMA had no effect on FBF (from 1.6±0.4 to 1.5±0.3 mL·dL
−1
·min
−1
, n=6,
P
=.66). These results demonstrate that insulin induces vasodilation by stimulation of Na
+
,K
+
-ATPase. This activation of Na
+
,K
+
-ATPase could occur at the level of the endothelium rather than that of vascular smooth muscle and contributes to the endothelium-dependent vasodilator response to insulin.
Thromboxane A
2
Mediates the Stimulation of Inositol 1,4,5-Trisphosphate Production and Intracellular Calcium Mobilization by Bradykinin in Neonatal Rat Ventricular Cardiomyocytes
Authors: Nakamura Fumiaki , Minshall Richard D. , Le Breton Guy C. , Rabito Sara F.
Published: June 2012

Bradykinin is a mediator of the protection of myocardium by angiotensin I–converting enzyme/kininase II inhibitors. We reported that the activation of B
2
bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP
3
). Here we examine the regulation of IP
3
formation stimulated by bradykinin. Activation of myocytes with 1 μmol/L bradykinin increased IP
3
production from 117±8.3 to 1011±48.6 pmol/mg protein. Treatment of the cells with 10 μmol/L indomethacin or 1 μmol/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (
p
-amylcinnamoyl) anthranilic acid, a phospholipase A
2
inhibitor, blunted the IP
3
response to bradykinin. Because thromboxane A
2
stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A
2
receptor antagonist BM 13177 (1 μmol/L), which strongly attenuated the stimulated IP
3
production. Since thromboxane A
2
appears to partly mediate the IP
3
response to bradykinin, we examined the effect of the stable thromboxane A
2
mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629±14.5 versus 1011±48.6 pmol IP
3
/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A
2
blunted the IP
3
response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 μmol/L) attenuated the IP
3
accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 μmol/L staurosporine, a protein kinase C inhibitor. Treatment with 1 μg/mL cholera toxin or pertussis toxin for 4 hours amplified the IP
3
response to 10 nmol/L bradykinin from 570±20.0 to 1150±51.3 and to 1016.7±21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B
2
bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 μmol/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP
3
production mostly via phospholipase A
2
stimulation and thromboxane A
2
formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP
3
and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A
2
, is negatively regulated by protein kinase C activation.
Hypertension-Associated Hypalgesia
Authors: Ghione Sergio
Published: June 2012

A behavioral hypalgesia (increased response threshold to noxious stimuli) has been consistently, although not invariably, reported in spontaneous and experimental acute and chronic hypertension in the rat. Studies in human hypertension have also demonstrated a diminished perception of pain, assessed as pain thresholds or ratings. The sensitivity to painful stimuli correlated inversely with blood pressure levels, and this relationship extended into the normotensive range. Evidence in humans and rats points to a role of the baroreflex system in modulating nociception. In the rat, blood pressure–related antinociception may be due to attenuated transmission of noxious stimuli at the spinal level secondary to descending inhibitory influences that are projected from brain stem sites involved in cardiovascular regulation and that may depend on baroreceptor activation and/or on a central “drive.” Both endorphinergic and noradrenergic central neurons (the latter acting through postsynaptic α
2
-receptors) have been shown to be involved, and other mediators probably also play a role. Functionally, blood pressure–related antinociception may represent an aspect of a more-complex coordinated adaptive response of the body to “stressful” situations. It is still uncertain whether in human essential hypertension hypalgesia is secondary to elevated blood pressure or whether both depend on some common mechanism. Studies on the effect of hypotensive treatment are too few to allow conclusions. According to one hypothesis, the reduction in pain perception caused by baroreceptor activation secondary to blood pressure elevation may represent a rewarding mechanism that may be reinforced with repeated stress and may be involved in the development of hypertension in some individuals. Hypertension-associated hypalgesia may have clinically relevant consequences, especially in silent myocardial ischemia and unrecognized myocardial infarction, both of which are more prevalent in hypertensive individuals.
Insulin Resistance as an Independent Risk Factor for Carotid Wall Thickening
Authors: Suzuki Masaaki , Shinozaki Kazuya , Kanazawa Akio , Hara Yasushi , Hattori Yuichi , Tsushima Motoo , Harano Yutaka
Published: June 2012

It has been reported that insulin resistance is associated with essential hypertension and that an aggregation of risk factors—hypertension, dyslipidemia, and glucose intolerance—together with insulin resistance leads to the more frequent appearance of coronary artery disease. We examined the relation between early asymptomatic atherosclerosis and these risk factors in 72 nondiabetic subjects with essential hypertension (41 men, 31 women) aged 50 to 59 years. Intima-media thickness and plaque formation of the carotid artery were assessed by B-mode ultrasonography, and insulin sensitivity was measured by the steady-state plasma glucose method. Lipoprotein profile was analyzed by ultracentrifugation. The intima-media thickness of the common carotid artery significantly correlated with systolic pressure; mean blood pressure; steady-state plasma glucose, indicating insulin resistance; fasting insulin; area under the curve of plasma insulin and glucose; body mass index; apolipoprotein B; apolipoprotein B in low-density lipoprotein; lower ratio of cholesterol to apolipoprotein B of low-density lipoprotein; and decreased high-density lipoprotein cholesterol. By multiple regression analysis, steady-state plasma glucose was the strongest risk, followed by lower high-density lipoprotein and systolic pressure. These three factors accounted for 54.9% of all the risk for increased intima-media thickness of the common carotid artery. In conclusion, insulin resistance was the strongest risk factor for carotid intima-media thickness, followed by lower high-density lipoprotein cholesterol and hypertension. An effort to maintain normal insulin sensitivity is essential for the prevention of early atheromatous lesions in essential hypertension.
Cyclic AMP–Adenosine Pathway Inhibits Vascular Smooth Muscle Cell Growth
Authors: Dubey Raghvendra K. , Mi Zaichuan , Gillespie Delbert G. , Jackson Edwin K.
Published: June 2012

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 μmol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), α,β-methyleneadenosine 5′-diphosphate (AMP-CP, 100 μmol/L; an ecto-5′-nucleotidase inhibitor), and 1,3-dipropyl-8-
p
-sulfophenylxanthine (DPSPX, 100 μmol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5′-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10
−4
mol/L) and 8-bromo-cAMP (10
−4
mol/L) on fetal calf serum–induced DNA synthesis ([
3
H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A
2
adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5′-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
Intracellular Ca
2+
Modulation by Angiotensin II and Endothelin-1 in Cardiomyocytes and Fibroblasts From Hypertrophied Hearts of Spontaneously Hypertensive Rats
Authors: Touyz Rhian M. , Fareh Jeannette , Thibault Gaétan , Schiffrin Ernesto L.
Published: June 2012

The vasoactive peptides angiotensin II (Ang II) and endothelin-1 (ET-1) have been implicated in cardiac hypertrophy. This study investigates Ang II and ET-1 effects on intracellular free calcium concentration and the receptor subtype through which agonist-induced calcium responses are mediated in isolated cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats (SHR). We measured intracellular free calcium concentration by fura 2 methodology and determined receptor status by radioligand binding assays. Ang II (10
−12
to 10
−7
mol/L) had no effect on cardiomyocyte calcium levels in control Wistar-Kyoto rats but significantly increased (
P<
.01) intracellular free calcium concentration in a dose-dependent manner in cardiomyocytes from SHR. Ang II total and specific binding were increased (
P<
.05) in SHR cardiomyocytes. Calcium responses elicited by 10
−7
to 10
−5
mol/L Ang II were significantly reduced (
P<
.01) in SHR fibroblasts despite no significant change in Ang II receptor density. The angiotensin type 1 receptor blocker losartan (1 μmol/L) blocked Ang II–stimulated calcium transients, whereas the angiotensin type 2 receptor blocker PD 123319 had no effect. ET-1– and sarafotoxin S6c–induced calcium responses in cardiomyocytes and fibroblasts were not different between hypertensive and control groups. In conclusion, Ang II and ET-1 elicit distinct and differential responses in a cell-specific manner in cardiomyocytes and fibroblasts from hypertrophied hearts of SHR. Whereas Ang II–mediated effects, which are elicited via angiotensin type 1 receptors, are detectable in cardiomyocytes from SHR, responses to Ang II are blunted in fibroblasts from SHR, and ET-1–related actions are similar in cells from both rat groups. Stimulation of cardiomyocytes by Ang II in hypertrophied hearts associated with pressure overload in genetic hypertension suggests that Ang II could modulate the function of cardiomyocytes of SHR but not those of Wistar-Kyoto rats, whereas cardiac actions of ET-1 do not change with the development of hypertension.
Nerve-Mediated Antidiuresis and Antinatriuresis After Air-Jet Stress Is Modulated by Angiotensin II
Authors: Veelken Roland , Hilgers Karl F. , Stetter Alexander , Siebert Hans-Georg , Schmieder Roland E. , Mann Johannes F.E.
Published: June 2012

A putative interaction between angiotensin II (Ang II) and the sympathetic nervous system within the kidney has been reported. We tested the hypothesis in conscious rats that endogenous Ang II modulates the renal effects of a stress-induced increase in sympathetic nerve activity. We recorded mean arterial blood pressure, heart rate, renal sympathetic nerve activity, renal hemodynamics, urine volume, and urinary sodium content in conscious rats. We used the Ang II type 1 receptor blocker ZD 7155 to inhibit the effects of endogenous Ang II. Ten minutes of air-jet stress increased renal sympathetic nerve activity by 98±4% (n=6) without changing systemic hemodynamics. Air-jet stress reduced urine volume (from 31±3 to 8±4 μL/min per gram kidney weight,
P
<.05, n=12) and sodium excretion (from 4.3±0.9 to 1.2±0.3 μmol/min per gram kidney weight,
P
<.05, n=12). After renal denervation, air-jet stress had no effect on either parameter. Six micrograms of the Ang II type 1 receptor inhibitor ZD 7155 blunted the decrease in urine volume and sodium excretion in response to air-jet stress, although the increase in renal sympathetic nerve activity during air-jet stress and the pressor response to exogenous Ang II were not affected. Glomerular filtration rate and renal plasma flow were also not affected. Higher doses of 30 and 60 μg ZD 7155 inhibited the pressor response to exogenous Ang II and abolished the changes in urine volume and sodium excretion in response to air-jet stress. None of the ZD 7155 doses affected urinary sodium excretion permanently. Hence, the Ang II type 1 receptor antagonist ZD 7155 impaired or abolished the renal nerve–mediated antinatriuresis and anitidiuresis in response to air-jet stress. We conclude that endogenous Ang II modulates the renal effects of centrally mediated changes of sympathetic nerve activity in conscious rats.
Influence of Age on the Inotropic Response to Acute Ethanol Exposure in Spontaneously Hypertensive Rats
Authors: Brown Ricardo A. , Savage Adedapo O. , Lloyd Thomas C.
Published: June 2012

Acute ethanol exposure depresses cardiac electromechanical function, whereas chronic ethanol consumption leads to the development of a specific myopathic state. Chronic hypertension and aging have similar effects in the impairment of myocardial function. However, little is known about the effects of ethanol on cardiac mechanical function in hypertension. We studied the effect of age on baseline mechanical properties and the inotropic response to clinically relevant concentrations of ethanol (18 to 71 mmol/L) using papillary muscles from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 10 and 25 weeks of age. Mechanical parameters measured were peak tension developed, time to peak tension, time to 90% relaxation, and maximal velocities of tension development and tension decline. SHR exhibited elevated systolic pressure and body weight as well as cardiomegaly and hepatomegaly at 10 and 25 weeks of age. Baseline mechanical properties were similar in SHR and WKY muscles at 10 weeks, whereas at 25 weeks, SHR muscles developed less tension, and both maximal velocities of tension development and tension decline were markedly depressed. Ethanol exposure produced concentration-dependent negative inotropic effects in both groups at both ages. Ethanol (>18 mmol/L) decreased peak tension developed in both groups at 10 weeks, although higher concentrations were required at 25 weeks. The negative inotropic effect of ethanol resulted in the shortening of time to 90% relaxation in both groups at 10 weeks and was associated with a slowing of maximal velocities of both tension development and tension decline. The results suggest that aging depresses baseline mechanical properties when coupled with hypertension. In addition, the magnitude of the negative inotropic effect of ethanol was attenuated in both groups at 25 weeks of age.
Variation at the Angiotensin-Converting Enzyme Gene and Angiotensinogen Gene Loci in Relation to Blood Pressure
Authors: Kiema Tiila-Riikka , Kauma Heikki , Rantala Asko O. , Lilja Mauno , Reunanen Antti , Kesäniemi Y. Antero , Savolainen Markku J.
Published: June 2012

To investigate whether the polymorphisms in the angiotensin-converting enzyme and angiotensinogen genes are associated with hypertension, we carried out a case-control study of 508 hypertensive and 523 control subjects randomly selected from the Social Insurance Institution register. The cohorts were well characterized and matched for age and sex. The insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the methionine→threonine variant at position 235 of the angiotensinogen gene were determined by the polymerase chain reaction technique. The allele frequencies and genotype distributions of both polymorphisms were similar in hypertensive and control subjects. Systolic and diastolic pressures adjusted for age, body mass index, and alcohol consumption did not differ significantly between the different genotypes of the angiotensin-converting enzyme and angiotensinogen genes. The variation at the angiotensinogen and angiotensin-converting enzyme genes did not have any statistically significant synergistic effect on blood pressure levels. In conclusion, the polymorphisms in the renin-angiotensin cascade genes do not confer a significantly increased risk for the development of hypertension in this middle-aged, population-based cohort.
Influence of the Angiotensin II Type 1 Receptor Gene Polymorphism on the Effects of Perindopril and Nitrendipine on Arterial Stiffness in Hypertensive Individuals
Authors: Benetos Athanase , Cambien François , Gautier Sylvie , Ricard Sylvain , Safar Michel , Laurent Stephane , Lacolley Patrick , Poirier Odette , Topouchian Jirar , Asmar Roland
Published: June 2012

Angiotensin-converting enzyme inhibitors improve arterial stiffness independently of blood pressure reduction. Since we have recently shown that in hypertensive individuals the A
1166
C polymorphism of the angiotensin II type 1 receptor (AT
1
-R) is an independent determinant of aortic stiffness, we designed the present study to assess the influence of this polymorphism on the changes of aortic stiffness after chronic treatment with the angiotensin-converting enzyme inhibitor perindopril and the calcium channel blocker nitrendipine. Forty perindopril- and 42 nitrendipine-treated hypertensive individuals were studied. We evaluated aortic stiffness by measuring the carotid-femoral pulse wave velocity. Carriers of the AT
1
-R C allele showed higher baseline values of pulse wave velocity than AA homozygotes (
P
<.05). In the perindopril group, a threefold greater reduction in pulse wave velocity was observed in carriers of the C allele than in AA homozygotes (−2.85±0.62 versus −0.94±0.32 m/s, respectively;
P
<.001), whereas in the nitrendipine group, pulse wave velocity decreased only in AA homozygotes and not in AT
1
-R C carriers (−1.38±0.35 versus +0.04±0.60 m/s, respectively;
P
<.01). These results indicate that according to the AT
1
-R A
1166
C genotype, an angiotensin-converting enzyme inhibitor and a calcium channel blocker affect pulse wave velocity in opposite ways. Since some evidence shows that increased pulse wave velocity may enhance cardiovascular risk, it might be useful for physicians to consider the AT
1
-R genotype when prescribing an angiotensin-converting enzyme inhibitor or calcium channel blocker to a hypertensive individual.
Analysis of Quantitative Trait Loci for Blood Pressure on Rat Chromosomes 2 and 13
Authors: Samani Nilesh J. , Gauguier Dominique , Vincent Madeleine , Kaiser Michael A. , Bihoreau Marie-Therese , Lodwick David , Wallis Robert , Parent Valerie , Kimber Phillip , Rattray Fraser , Thompson John R. , Sassard Jean , Lathrop Mark
Published: June 2012

Previous studies have suggested the presence of quantitative trait loci (QTLs) influencing blood pressure on rat chromosomes 2 and 13. In this study, we mapped the QTLs in F
2
rats derived from a cross of the spontaneously hypertensive rat and the Wistar-Kyoto rat and analyzed the effect of the QTLs on blood pressures measured longitudinally between 12 and 25 weeks of age. We analyzed 16 polymorphic markers spanning 147.3 cM on chromosome 2 and 13 markers spanning 91.6 cM on chromosome 13. Both chromosomes contained QTLs with highly significant effects on blood pressure (peak logarithm of the odds [LOD] scores, 5.64 and 5.75, respectively). On chromosome 2, the peak was localized to a position at anonymous marker
D2Wox7
, 2.9 cM away from the gene for the sodium-potassium ATPase α
1
-subunit. On chromosome 13, the major peak coincided with the marker
D13Mit2
, 21.7 cM away from the renin gene, but there was a suggestion of multiple peaks. The effect of the QTL on chromosome 2 was seen throughout from 12 to 25 weeks of age, whereas interestingly, the effect for the QTL on chromosome 13 was maximal at 20 weeks of age but disappeared at 25 weeks of age, presumably because of the effect of either epistatic factors or environmental influences. The findings provide important information on QTLs influencing blood pressure on rat chromosomes 2 and 13 that will be useful in localizing and identifying the causative genes and emphasize the importance of age being taken into account when the effects of individual QTLs on a trait that shows significant age-related changes are being analyzed.
In Vivo Gene Transfer and Gene Modulation in Hypertension Research
Authors: Dzau Victor J. , Horiuchi Masatsugu
Published: June 2012

Transgenic technologies and homologous recombination approaches have been useful for studying the roles of specific genes in systemic hypertension. Recently, we and others have introduced the use of in vivo gene transfer to study the effects of local gene overexpression or inactivation in hypertension. Using in vivo gene transfer for the blood vessel, we have documented the direct hypertrophic action of local angiotensin and the growth-inhibitory effect of nitric oxide. In vivo gene transfer is also an effective method for discovering the unknown functions of a newly cloned gene. Using this approach, we identified the in vivo growth-inhibitory action of the angiotensin II type 2 receptor. In addition, we have developed a novel strategy using transcriptional factor “decoy” oligonucleotides to regulate the interaction of
cis
- and
trans
-acting factors involved in the modulation of gene expression in vivo. Thus, the decoy approach can “switch” on or off specific genes in selective tissues in vivo, thereby influencing local gene expression and tissue function. For example, using decoy oligonucleotides, we have “turned on” renin gene expression in the rat liver, in which it is usually not expressed, resulting in increased hepatic and plasma renin levels. Thus, in vivo gene transfer technology provides us with a new tool for in vivo characterization of genes involved in hypertension that has potential application in human therapy.
Inherited Forms of Mineralocorticoid Hypertension
Authors: White Perrin C.
Published: June 2012

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11β-hydroxylase or 17α-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the
CYP11B1
and
CYP17
genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11β-hydroxylase (
CYP11B1
) and aldosterone synthase (
CYP11B2
), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11β-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the
HSD11K
(
HSD11B2
) gene.
Short-term Variability of Blood Pressure During Sleep in Snorers With or Without Apnea
Authors: Leroy Michel , Van Surell Catherine , Pilliere Remi , Hagenmuller Marie-Pascale , Aegerter Philippe , Raffestin Bernadette , Foucher Arlette
Published: June 2012

In normal subjects, the level and variability of blood pressure decrease during non–rapid eye movement (non-REM) sleep. In contrast, sleep apnea is associated with large swings in nocturnal pressure. In this study, we evaluated a computer-derived index of all-night blood pressure variability in normotensive snorers with or without sleep apnea. We also examined this index in snorers receiving medical treatment for coexistent ischemic heart disease. Beat-to-beat blood pressure was recorded with a photoplethysmographic device (Finapres) throughout polysomnography. Subjects were categorized into four groups: those without cardiovascular disease without or with sleep apnea (≥15 apnea plus hypopnea per hour of sleep), and those with ischemic heart disease without or with sleep apnea. A frequency distribution histogram of all increases and decreases of blood pressure according to their amplitudes was drawn and the SD of the distribution used as an estimation of variability. Mean systolic and diastolic pressures during the total sleep time were not different among the four groups. In contrast, the SD of the distribution of systolic and diastolic pressure variations that were higher in the apneic than in the nonapneic groups (
P
<.05) correlated with apnea plus hypopnea (
P
<.0001) and transient electroencephalographic arousal number per hour of sleep (
P
<.0001). In both apneic and nonapneic subjects, blood pressure variability as assessed by SD decreased during stages 3 and 4 of non-REM sleep compared with stages 1 and 2 and REM sleep (
P
<.001). Blood pressure variability was similarly increased in apneic subjects with or without ischemic heart disease. We speculate that in apneic individuals with coexistent ischemic heart disease, pressure variability that is increased despite treatment with β-blockers or calcium antagonists may be a risk factor for acute coronary events.
Losartan Reduces Phenylephrine Constrictor Response in Aortic Rings From Spontaneously Hypertensive Rats
Authors: Maeso Rosaura , Navarro-Cid Josefa , Muñoz-García Raquel , Rodrigo Elena , Ruilope Luis Miguel , Lahera Vicente , Cachofeiro Victoria
Published: June 2012

Nitric oxide seems to be involved in the mechanisms underlying the antihypertensive and renal responses of losartan in spontaneously hypertensive rats (SHR). We investigated the contribution of nitric oxide to the effect of this angiotensin II (Ang II) type 1 (AT
1
) receptor antagonist on the constrictor response of phenylephrine in aortic rings from SHR. Furthermore, since it has been suggested that Ang II could bind to unblocked AT
2
receptors, during administration of an AT
1
receptor antagonist, we also studied the effect of the AT
2
receptor antagonist PD 123319 on the contractile response to phenylephrine in aortic rings from SHR. To this end, we studied dose-response curves of phenylephrine (10
−9
to 10
−5
mol/L) in the presence and absence of losartan (10
−9
, 10
−7
, and 10
−5
mol/L) in SHR aortic rings. Preincubation with losartan reduced the constrictor response to phenylephrine but not to KCl (10 to 120 mmol/L) in a dose-dependent manner. On the other hand, the presence of captopril (10
−5
mol/L) in the incubation medium did not alter the response to phenylephrine, even at the dose of 10
−3
mol/L. The reduced response to phenylephrine in the presence of losartan was abolished in both endothelium-denuded rings and rings treated with a nitric oxide synthesis inhibitor. A similar situation was observed in PD 123319–pretreated rings, in which the effect of losartan on the contractile response to phenylephrine was reversed. Losartan was not able to stimulate the production of aortic cGMP compared with the control group. Likewise, losartan did not modify the relaxing responses to either acetylcholine or sodium nitroprusside in phenylephrine-preconstricted aortic rings. Furthermore, losartan did not alter isometric tension in aortic rings in either basal or phenylephrine-preconstricted conditions. These data demonstrate that Ang II potentiates the vasoconstriction induced by phenylephrine through the stimulation of AT
1
receptors. Moreover, AT
2
receptors and nitric oxide appear to be involved in this effect.
Genetically Complex Cardiovascular Traits
Authors: Schork Nicholas J.
Published: June 2012

Modern molecular genetic analysis tools are making it possible for researchers to investigate, and in many cases actually disclose, mutations and other genetic factors that contribute to disease susceptibility. However, the ease with which these factors can be identified is dictated by not only the number of factors underlying or influencing the trait, but also by the manner in which these factors interact. Traits that are influenced by multiple genetic and nongenetic factors are termed “complex” genetic traits and are receiving a great deal of attention in the current medical literature. Hypertension and blood pressure regulation are considered paradigmatic complex traits. In this paper, the origin, nature, and dilemmas associated with the analysis of complex traits are considered. Basic biochemical and physiological determinants of blood pressure are described in an effort to show how genetic complexity could arise within an individual, and fundamental concepts in population genetics and evolutionary theory are discussed to expose the reasons certain forms of genetic complexity can emerge and be sustained in the population at large. Methods for approaching the genetic dissection of complex traits and diseases are also enumerated, with simple descriptions of the scientific motivation offered for each. Problems plaguing these approaches are also discussed. Finally, areas for future research are outlined with the hope of sparking further debate on the subject.
Role of Nitric Oxide in Modulating the Long-term Renal and Hypertensive Actions of Norepinephrine
Authors: Granger Joey , Schnackenberg Christine , Novak Jackie , Tucker Brett , Miller Todd , Morgan Stephen , Kassab Salah
Published: June 2012

We have previously reported that nitric oxide (NO) plays an important role in protecting the renal vasculature from acute norepinephrine-induced vasoconstriction. The purpose of this study was to determine the importance of this interaction between NO and norepinephrine in long-term control of renal hemodynamics and arterial pressure. To achieve this goal, we examined the effects of an intrarenal infusion of norepinephrine (NE) (0.1 μg·kg
−1
·min
−1
) for 7 days in conscious, chronically instrumented control dogs and in dogs pretreated with a synthesis inhibitor, L-NAME (3 μg·kg
−1
·min
−1
intrarenally). Both groups of dogs also received captopril (15 μg·kg
−1
·min
−1
) plus angiotensin II intravenously to clamp the renin-angiotensin system throughout the protocol. In control dogs (n=6), intrarenal infusion of NE decreased renal plasma flow by 9% (134±10 to 122±14 mL/min) and glomerular filtration rate by 16% (49±4 to 41±5 mL/min) while having no effect on mean arterial pressure (100±3 to 98±4 mm Hg). In marked contrast, in dogs pretreated with intrarenal L-NAME (n=9), NE decreased renal plasma flow by 37% (129±8 to 81±16 mL/min) and glomerular filtration rate by 32% (47±3 to 32±5 mL/min) while increasing mean arterial pressure from 104±5 to 113±6 mm Hg. The results of this study demonstrate that NO plays an important role in modulating the long-term actions of NE on renal function and arterial pressure.
Smooth Muscle Apoptosis During Vascular Regression in Spontaneously Hypertensive Rats
Authors: deBlois Denis , Tea Bun-Seng , Dam Than-Vinh , Tremblay Johanne , Hamet Pavel
Published: June 2012

We previously reported that apoptosis is increased in smooth muscle cells cultured from the aorta of spontaneously hypertensive rats versus normotensive controls. As an initial in vivo exploration, we now examined smooth muscle cell apoptosis regulation during the regression of vascular hypertrophy in the thoracic aorta media of spontaneously hypertensive rats receiving the antihypertensive drug enalapril (30 mg·kg
−1
·d
−1
), losartan (30 mg·kg
−1
·d
−1
), nifedipine (35 mg·kg
−1
·d
−1
), hydralazine (40 mg·kg
−1
·d
−1
), propranolol (50 mg·kg
−1
·d
−1
), or hydrochlo-rothiazide (75 mg·kg
−1
·d
−1
) for 1 to 4 weeks starting at 10 to 11 weeks of age. Three criteria were used to evaluate smooth muscle cell apoptosis: (1) oligonucleosomal fragmentation of the extracted aortic DNA, (2) reduction in aortic DNA content, and (3) depletion of smooth muscle cells in the arterial media. Arterial DNA synthesis was evaluated by [

3

H]thymidine incorporation in vivo. After 4 weeks of treatment, systolic blood pressure was reduced significantly by <42% with losartan, enalapril, and hydralazine, and by 23% with nifedipine, versus control values of 220±5 mm Hg. However, these agents affected vascular growth and apoptosis differently. Losartan, enalapril, and nifedipine stimulated smooth muscle cell apoptosis threefold to fivefold before there was a significant reduction in DNA synthesis (<25%), vascular mass (<19%), or vascular DNA content (<38%), and these treatments markedly reduced (by 38% to 50%) medial cell number as measured at 4 weeks by the three-dimensional disector method. Losartan and nifedipine stimulated smooth muscle cell apoptosis before reducing blood pressure. In contrast, hydralazine did not affect vascular mass, apoptosis, or DNA synthesis, although blood pressure was lowered. Propranolol or hydrochlorothiazide failed to affect hypertension or vascular growth. Thus, smooth muscle cell apoptosis represents a novel therapeutic target for the control of hypertensive vessel remodeling in response to therapeutic agents.
Association of Serum Antibodies to Heat-Shock Protein 65 With Borderline Hypertension
Authors: Frostegård Johan , Lemne Carola , Andersson Birger , van der Zee Ruurd , Kiessling Rolf , de Faire Ulf
Published: June 2012

Heat-shock proteins protect cells from damage but are also often the target of immune responses in inflammation and may therefore both induce and perpetuate the chronic inflammation characterizing atherosclerosis. Hypertension is a well-established risk factor for atherosclerosis, and recently, borderline hypertension also has been related to atherosclerosis. The present study investigated the possible role of heat-shock proteins in borderline hypertension and their relation to atherosclerosis by investigating antibody titers against the 65-kD heat-shock protein (HSP65). Sixty-six men with borderline hypertension and 67 age-matched normotensive men (diastolic pressure, 85 to 94 and <80 mm Hg, respectively) were recruited from a population screening program. Titers of antibodies to HSP65 were determined by enzyme-linked immunosorbent assay. The presence of carotid atherosclerosis was determined by B-mode ultrasonography. Twenty-seven individuals had atherosclerotic plaques; 48 were smokers (more than one to two cigarettes per day). Borderline hypertensive men had higher anti-HSP65 reactivity than normotensive control subjects (
P
=.034). Smokers with atherosclerosis had low levels of antibodies to HSP65 compared with nonsmokers with atherosclerosis (
P
=.002). Furthermore, when high-risk individuals (borderline hypertension plus plaque, n=15) were compared with matched low-risk individuals (normotensive with no plaque, n=15), the high-risk men had significantly enhanced antibody titers to HSP65 (
P
=.041). In conclusion, we demonstrate that serum antibody titers to HSP65 are enhanced in individuals with borderline hypertension, which may indicate an ongoing immune reaction in the artery wall.