bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Distensibility of the Common Carotid Artery in Patients Treated With Ergotamine
Authors: Barenbrock M. , Spieker C. , Witta J. , Evers S. , Hoeks A.P.G. , Rahn K.H. , Zidek W.
Published: June 2012

To investigate the effect of vascular smooth muscle contraction on mechanical vessel wall properties of proximal “elastic” arteries, we investigated the effect of the vasoconstrictor ergotamine on the distensibility of the common carotid artery in 10 migraine patients with ergotamine intake, in 10 control patients with migraine headache but no prior ergotamine intake, and in 10 healthy control subjects. The patients and control subjects were matched for age, blood pressure, and sex. In the ergotamine group, 2.2±1.4 mg ergotamine tartrate (0.25 to 6 mg) was taken within 12 hours before investigation. Differences in mean 24-hour blood pressure between the study groups were excluded by 24-hour blood pressure recording and differences in arterial wall thickness by high-resolution B-mode ultrasound. A multigate Doppler system was used for measurement of vessel wall movements by M-mode Doppler analysis. Blood pressure was determined by sphygmomanometry. The end-diastolic diameter of the common carotid artery was insignificantly reduced in the ergotamine group compared with the healthy control subjects and control patients (healthy control subjects, 6.6±0.4 mm; control patients, 6.7±0.5 mm; patients with ergotamine intake, 6.3±0.4 mm;
P
=NS). Arterial distensibility was significantly lower in the patients with ergotamine intake (17.4±4.0 10
−
3
/kPa) than in the healthy control subjects (22.3±5.1 10
−
3
/kPa) and control patients (22.8±3.6 10
−
3
/kPa) (one-way ANOVA,
P
=.014). The results show that ergotamine reduces the distensibility of the common carotid artery. The data suggest that vascular smooth muscle contraction can modulate the buffering function of the arterial system independently of blood pressure changes.
Dispersion of the QT Interval and Autonomic Modulation of Heart Rate in Hypertensive Men With and Without Left Ventricular Hypertrophy
Authors: Perkiömäki Juha S. , Ikäheimo Markku J. , Pikkujämsä Sirkku M. , Rantala Asko , Lilja Mauno , Kesäniemi Y. Antero , Huikuri Heikki V.
Published: June 2012

Left ventricular hypertrophy is an independent risk factor for sudden cardiac death in hypertension, but the mechanisms of electrical instability associated with hypertrophy are not well known. We studied dispersion of the QT interval, an index of inhomogeneity of repolarization, and heart rate variability, a measure of cardiac autonomic modulation, in a randomly selected population of 162 men with systemic hypertension and made comparisons between the patients with echocardiographic evidence of left ventricular hypertrophy (left ventricular mass index ≥131 g/m
2
, n=44) and those without hypertrophy (left ventricular mass index <131 g/m
2
, n=118). The heart rate-corrected QT dispersion (67±37 versus 53±21 milliseconds,
P
<.05) and QT apex dispersion (55±22 versus 44±16 milliseconds,
P
<.01) were significantly longer in the patients with left ventricular hypertrophy than in those without hypertrophy. Thirteen of the 44 patients (30%) with hypertrophy versus 7 of the 118 patients (6%) without hypertrophy had an abnormally long QT apex dispersion (>70 milliseconds) (
P
<.001). The time and frequency domain measures of heart rate variability did not differ significantly between the patient groups with and without left ventricular hypertrophy. The measures of heart rate variability were not related to QT dispersion or left ventricular mass index but had a negative correlation with blood pressure values (eg,
r
=−.30 between the low-frequency component of heart rate variability and systolic pressure,
P
<.001). Age, body mass index, antihypertensive medication, and the other demographic variables were similar between the groups, but the patients with left ventricular hypertrophy had higher systolic (
P
<.01) and diastolic (
P
<.01) pressures compared with the patients without hypertrophy. Left ventricular hypertrophy in hypertensive men is associated with inhomogeneity of the early phase of ventricular repolarization, favoring susceptibility to reentrant ventricular tachyarrhythmias. Abnormalities in cardiac autonomic function, which may trigger a spontaneous onset of arrhythmias, are related to elevated blood pressure but not specifically to left ventricular hypertrophy.
Effect of Hypertension on Aortic Root Size and Prevalence of Aortic Regurgitation
Authors: Kim Michael , Roman Mary J. , Cavallini M. Chiara , Schwartz Joseph E. , Pickering Thomas G. , Devereux Richard B.
Published: June 2012

Although early reports suggested that hypertension predisposed to aortic root enlargement and consequent aortic regurgitation, more recent pathological and M-mode echocardiographic studies have not found an association between hypertension and aortic enlargement when age is considered. These discrepancies may partially reflect methodological shortcomings in the accuracy and reproducibility of aortic and blood pressure measurements. Therefore, we measured two-dimensional echocardiographic diameters of the aortic root at four locations and compared findings with ambulatory and resting blood pressures and measures of body size in 110 normotensive and 110 hypertensive men and women matched for age and sex. Aortic diameters at the anulus (2.41±0.29 versus 2.34±0.24 cm,
P
=.06) and sinuses (3.47±0.44 versus 3.37±0.36 cm,
P
=.08) were marginally higher, whereas diameters at the supra-aortic ridge (2.94±0.38 versus 2.81±0.32 cm,
P
<.01) and ascending aorta (3.26±0.45 versus 3.11±0.32 cm,
P
<.01) were significantly increased in hypertensive subjects. Aortic diameters increased with increasing quartiles of diastolic and systolic pressures, particularly at the supra-aortic ridge and ascending aorta. In multivariate analyses, blood pressure remained an independent determinant of distal aortic diameters after body size and age were considered. Aortic regurgitation was seen in 5 normotensive and 7 hypertensive subjects and did not differ in severity. Thus, hypertension is associated with a slight increase in aortic root size, most notably of the supra-aortic ridge and proximal ascending aorta. Although dilatation at the commissural attachment might be expected to predispose to an increase in aortic regurgitation, we did not detect such a difference in this population of healthy, asymptomatic individuals.
Comparison of Effect of Endothelin Antagonism and Angiotensin-Converting Enzyme Inhibition on Blood Pressure and Vascular Structure in Spontaneously Hypertensive Rats Treated With
N
ω
-Nitro-
l
-Arginine Methyl Ester
Authors: Li Jin-S. , Deng Li Y. , Grove Kevin , Deschepper Christian F. , Schiffrin Ernesto L.
Published: June 2012

Inhibition of nitric oxide synthase by
l
-arginine analogues such as
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR) is associated with malignant hypertension and enhanced expression of the endothelin-1 gene in some blood vessels. In this study, SHR treated chronically with L-NAME (SHR–L-NAME) were given the angiotensin I–converting enzyme inhibitor cilazapril or the endothelin-A/endothelin-B receptor antagonist bosentan for 3 weeks. Systolic pressure was lowered slightly by cilazapril (213±2 versus 229±2 mm Hg in untreated SHR–L-NAME,
P
<.01) but was not significantly lowered by bosentan (223±2 mm Hg). Hypertrophy of aorta and small arteries (coronary, renal, mesenteric, and femoral) was decreased by cilazapril treatment and unaffected by bosentan. Expression of the endothelin-1 gene was evaluated in SHR–L-NAME by in situ hybridization histochemistry, which showed that endothelin-1 expression was enhanced in the endothelium of aorta but not in small mesenteric arteries in these rats. The absence of enhancement of endothelin-1 gene expression in small arteries may account for the absence of increased severity of hypertrophy of small vessels in SHR–L-NAME and may be a mechanism whereby L-NAME inhibits cardiovascular growth. These results suggest that in the absence of enhanced small-artery endothelin-1 expression, endothelin antagonism does not lower blood pressure. The blood pressure–lowering effect of angiotensin I–converting enzyme inhibition suggests a role for the renin-angiotensin system in the malignant form of hypertension that develops in SHR treated with L-NAME.
Trial of Stress Reduction for Hypertension in Older African Americans
Authors: Alexander Charles N. , Schneider Robert H. , Staggers Frank , Sheppard William , Clayborne B. Mawiyah , Rainforth Maxwell , Salerno John , Kondwani Kofi , Smith Sandra , Walton Kenneth G. , Egan Brent
Published: June 2012

Our objective was to test the short-term efficacy and feasibility of two stress-reduction approaches for the treatment of hypertension in older African Americans, focusing on subgroup analysis by sex and by high and low risk on six measures of hypertension risk: psychosocial stress, obesity, alcohol use, physical inactivity, dietary sodium-potassium ratio, and a composite measure. The study involved a follow-up subgroup analysis of a 3-month randomized, controlled, single-blind trial conducted in a primary care, inner-city health center. Subjects were 127 African American men and women, aged 55 to 85 years, with diastolic pressure of 90 to 104 mm Hg and systolic pressure less than or equal to 179 mm Hg. Of these, 16 did not complete follow-up blood pressure measurements. Mental and physical stress-reduction approaches—the Transcendental Meditation technique and progressive muscle relaxation, respectively—were compared with a lifestyle modification education control and with each other. Both systolic and diastolic pressures changed from baseline to follow-up for both sexes and for high and low risk level (defined by median split) on the six measures of hypertension risk. Compared with education control subjects, women practicing the Transcendental Meditation technique showed adjusted declines in systolic (10.4 mm Hg,
P<
.01) and diastolic (5.9 mm Hg,
P<
.01) pressures. Men in this treatment group also declined in both systolic (12.7 mm Hg,
P
<.01) and diastolic (8.1 mm Hg,
P
<.001) pressures compared with control subjects. Women practicing muscle relaxation did not show a significant decrease compared with control subjects, and men declined significantly in diastolic pressure only (6.2 mm Hg,
P
<.01). For the measure of psychosocial stress, both the high and low risk subgroups using the Transcendental Meditation technique declined in systolic (high risk,
P
=.0003; low,
P
=.06) and diastolic (high risk,
P
=.001; low,
P
=.008) pressures compared with control subjects, whereas for muscle relaxation, blood pressure dropped significantly only in the high risk subgroup and only for systolic pressure (
P
=.03) compared with control subjects. For each of the other five risk measures, Transcendental Meditation subjects in both the high and low risk groups declined significantly in systolic and diastolic pressures compared with control subjects. Effects of stress reduction on blood pressure were found to generalize to both sexes and diverse risk factor subgroups and were significantly greater in the Transcendental Meditation treatment group. These effects (along with high compliance) even in individuals with multiple risk factors for hypertension clearly warrant longer-term investigation in this and other populations.
Variability in Salt Sensitivity Classifications in Black Male Versus Female Adolescents
Authors: Wilson Dawn K. , Bayer Laura , Sica Domenic A.
Published: June 2012

Salt sensitivity (changes in blood pressure in response to alterations in salt intake) may be a risk factor for hypertension. In the present study, we examined the prevalence of salt sensitivity based on two different classifications in healthy black male and female adolescents (aged 13 to 16 years). A total of 135 black adolescents participated in a 50 mmol/24 h low sodium diet for 5 days and a 150 mmol/24 h NaCl supplement for 10 days. Dietary compliance was defined as sodium excretion less than or equal to 50 mmol/24 h for the low sodium diet and greater than or equal to 165 mmol/24 h for the high NaCl supplement. Salt sensitivity was defined by two classifications: (1) as a decrease in mean blood pressure greater than or equal to 5 mm Hg from baseline to the low sodium diet, and (2) as an increase in mean blood pressure greater than or equal to 5 mm Hg from the low sodium diet to the high NaCl supplement. With classification 1, 14% of boys were identified as salt sensitive compared with 22% of girls. With classification 2, however, 31% of boys were identified as salt sensitive compared with 18% of girls. Analyses based on changes in systolic pressure demonstrated similar findings across sex, although overall classifications based on systolic pressure yielded a greater percentage of salt-sensitive subjects. These sex differences in classification patterns were not due to differences in other important variables, such as changes in sodium excretion, potassium excretion, or Quetelet index. These results suggest that the prevalence of salt sensitivity differs by sex depending on the type of protocol used for the classification of salt sensitivity in a black pediatric population.
Salt Intake and Plasma Atrial Natriuretic Peptide and Nitric Oxide in Hypertension
Authors: Campese Vito M. , Tawadrous Medhat , Bigazzi Roberto , Bianchi Stefano , Mann Amardeep S. , Oparil Suzanne , Raij Leopoldo
Published: June 2012

In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO
2
+NO
3
in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (
P
<.01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO
2
+NO
3
levels were higher (
P
<.05) in salt-sensitive (189±7.9 μmol/L) and salt-resistant (195±13.5 μmol/L) black patients than in control subjects (108±9.7 μmol/L). During high salt intake, plasma NO
2
+NO
3
decreased significantly (
P
<.01) in both salt-sensitive (150±7.0 μmol/L) and salt-resistant (142±9.0 μmol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.
Use-Dependent Loss of Acetylcholine- and Bradykinin-Mediated Vasodilation After Nitric Oxide Synthase Inhibition
Authors: Davisson Robin L. , Bates James N. , Johnson A. Kim , Lewis Stephen J.
Published: June 2012

In the present study, we examined the possibility that the endothelium-dependent vasodilators acetylcholine and bradykinin release preformed pools of nitric oxide–containing factors. Successive injections of selected doses of acetylcholine (1.18±0.3 μg/kg IV) or bradykinin (5 μg/kg IV) caused reproducible hypotensive and vasodilator responses within sympathetically intact and sympathetically denervated hindlimbs of conscious rats. After administration of the nitric oxide synthesis inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, 25 μmol/kg IV), the first injection of acetylcholine or bradykinin produced pronounced depressor and vasodilator responses that, in the case of bradykinin, were greater than those observed before L-NAME administration. However, each successive injection of acetylcholine and bradykinin produced progressively smaller responses, such that the later injections elicited a markedly diminished hypotension and vasodilation. This “use-dependent” loss of endothelium-dependent vasodilation was not due to the diminished vasorelaxant potency of nitric oxide–containing factors because the vasodilator effects of the nitric oxide donor sodium nitroprusside (32 μg/kg IV) and the
S
-nitrosothiol compound
S
-nitrosocysteine (200 nmol/kg IV) were augmented in the presence of L-NAME. These results suggest that the use-dependent loss of the hemodynamic effects of acetylcholine and bradykinin in L-NAME–treated rats may be due to the release and subsequent depletion of a factor whose synthesis depends on the bioavailability of nitric oxide. Taken together, these results suggest that preformed pools of nitric oxide–containing factors exist within the endothelium of resistance vessels and that endothelium-dependent agonists exert their vasorelaxant effects at least in part by the mobilization of these preformed pools.
Effects of Losartan on Insulin Sensitivity in Hypertensive Subjects
Authors: Laakso Markku , Karjalainen Leena , Lempiäinen-Kuosa Päivi
Published: June 2012

Losartan, the first specific and orally available angiotensin II receptor antagonist, is a potent antihypertensive drug with a low incidence of side effects in humans. However, the effects of losartan on insulin sensitivity and glucose metabolism have not been investigated in detail. Therefore, we carried out a randomized, double-blind study to compare the effects of losartan (50 mg QD) and metoprolol (95 mg QD) on insulin sensitivity, insulin secretion, glucose tolerance, and lipids and lipoproteins in 20 hyperinsulinemic subjects with essential hypertension. The fall in blood pressure was greater with losartan than with metoprolol. Insulin sensitivity evaluated by the euglycemic clamp technique did not change in either group after 12 weeks of treatment. Similarly, glucose oxidation (losartan: 17.0±0.9 versus 16.9±1.0 μmol/kg per minute [before versus after,
P
=NS]; metoprolol: 17.9±1.3 versus 16.8±1.6 [
P
=NS]) and nonoxidation (losartan: 22.3±4.0 versus 23.5±3.4 μmol/kg per minute [
P
=NS]; metoprolol: 23.3±3.2 versus 25.6±4.7 [
P
=NS]) remained unchanged during the last 30 minutes of the 3-hour euglycemic clamp. Losartan and metoprolol did not have any significant adverse effects on insulin secretion, glucose tolerance, or lipids and lipoproteins. In conclusion, losartan is metabolically neutral, without any significant adverse effect on glucose and lipid metabolism.
Cardiac and Vascular Effects of Long-term Losartan Treatment in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Gohlke Peter , Linz Wolfgang , Schölkens Bernward A. , Wiemer Gabriele , Unger Thomas
Published: June 2012

In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B
2
) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT
1
) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dt
max
) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT
1
receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT
1
receptors are discussed to explain the cardiac and vascular actions of losartan.
Vesicular Monoamine Transport Inhibitors
Authors: Mahata Manjula , Mahata Sushil K. , Parmer Robert J. , O'Connor Daniel T.
Published: June 2012

Vesicular monoamine transport (VMAT) inhibitors, such as reserpine and tetrabenazine, impair vesicular catecholamine storage in chromaffin cells and sympathetic neurons, thereby lowering blood pressure. Here we describe a novel action of VMAT inhibitors—blockade of L-type voltage-gated calcium channels—that may also influence catecholamine release from both PC12 rat pheochromocytoma cells and bovine adrenal chromaffin cells. When given alone, VMAT inhibitors acutely release catecholamines from chromaffin cells in a dose-dependent fashion. However, VMAT inhibitors block catecholamine secretion stimulated by either nicotinic cholinergic agonists or cell membrane depolarization, each of which rely on the opening of L-type channels; the inhibition was more potent after long-term exposure to VMAT inhibitors (IC
50
<100 nmol/L). Reserpine blocked nicotinic-stimulated catecholamine release from neurite-bearing PC12 cells. Reserpine also antagonized catecholamine release triggered by combined membrane depolarization and the dihydropyridine L-type channel agonist Bay K8644, and reserpine blocked cellular uptake of extracellular
45
Ca
2+
in response to nicotine. Taken together, these results indicate that VMAT inhibitors are also antagonists at L-type voltage-gated calcium channels. Classic L-type channel antagonists (verapamil or nifedipine) also exhibited the reciprocal actions; acutely, they released norepinephrine from chromaffin cells, and chronically, they depleted cellular catecholamine stores, albeit with inferior molar potency to reserpine (IC
50
<1 nmol/L). We conclude that VMAT inhibitors and L-type calcium channel antagonists exert reciprocal inhibitory actions on each other's more classic pharmacological targets. Furthermore, these novel actions are seen at concentrations of these compounds frequently taken to be specific in vitro and likely to occur during antihypertensive treatment in vivo.
Low Blood Pressure in Down's Syndrome
Authors: Morrison Rhona A. , McGrath Alice , Davidson Gillian , Brown Jehoiada J. , Murray Gordon D. , Lever Anthony F.
Published: June 2012

Low blood pressure is reported in Down's syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score −33 mm Hg,
P
<.0001) and DS outpatients (−25 mm Hg,
P
<.0001). It was normal in non-DS outpatients (−4.0 mm Hg,
P
=.3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimer's disease (AD) because blood pressure is also low in Alzheimer's and a high proportion of DS patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimer's by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.
Epicardial Bradykinin B
2
Receptors Elicit a Sympathoexcitatory Reflex in Rats
Authors: Veelken Roland , Glabasnia Alexander , Stetter Alexander , Hilgers Karl F. , Mann Johannes F.E. , Schmieder Roland E.
Published: June 2012

Bradykinin may be generated in the heart during ischemia and is involved in nociception. We tested the hypothesis that bradykinin elicits a sympathoexcitatory reflex in rats by stimulating cardiac afferent nerve fibers. Rats were implanted with femoral catheters for measurement of blood pressure and heart rate, a bipolar electrode for measurement of renal sympathetic nerve activity, and a pericardial catheter for intrapericardial injection of substances. Rats were slightly anesthetized with hexobarbital so pain reactions were prevented. Graded doses of bradykinin (2.5, 12, 25 μg) were injected intravenously or intrapericardially into control rats, intrapericardially after vagotomy, intrapericardially after intrapericardial pretreatment with the bradykinin B
2
receptor antagonist Hoe 140, and intrapericardially after cardiac autonomic blockade (intrapericardial pretreatment with 10% procaine). For comparison, the serotonin 5-HT
3
agonist phenylbiguanide, a substance known to elicit sympathoinhibitory reflexes by cardiac vagal afferents, and adenosine, putatively inducing sympathoexcitatory responses via the heart, were applied intrapericardially. Bradykinin increased blood pressure when administered intrapericardially but decreased blood pressure when injected intravenously; both intrapericardial and intravenous bradykinin increased renal sympathetic nerve activity. Intrapericardial adenosine had no effect on circulatory control. Intrapericardial pretreatment with the B
2
receptor antagonist Hoe 140 completely inhibited the increases of blood pressure and renal sympathetic nerve activity in response to intrapericardial bradykinin but did not affect the responses to intrapericardial phenylbiguanide. Bilateral cervical vagotomy abolished the decreases of blood pressure, heart rate, and renal sympathetic nerve activity after intrapericardial phenylbiguanide but did not influence the responses to intrapericardial bradykinin. Cardiac autonomic blockade with intrapericardial procaine abolished all responses to bradykinin and phenylbiguanide. We conclude that cardiac bradykinin elicits a sympathoexcitatory reflex by epicardial B
2
receptors in rats. The afferent portion of the reflex is most likely contained within sympathetic cardiac afferent fibers. Bradykinin may contribute to increased sympathetic nerve activity in pathophysiological situations of coronary artery disease and cardiac ischemia.
Renal Na,K-ATPase in Genetic Hypertension
Authors: Ferrandi Mara , Tripodi Grazia , Salardi Sergio , Florio Monica , Modica Rossana , Barassi Paolo , Parenti Paolo , Shainskaya Alla , Karlish Steven , Bianchi Giuseppe , Ferrari Patrizia
Published: June 2012

Milan hypertensive rats (MHS) develop hypertension because of a primary renal alteration. Both apical and basolateral sodium transport are faster in membrane vesicles derived from renal tubules of MHS than in those of Milan normotensive control rats (MNS). These findings suggest that the increased renal sodium retention and concomitant development of hypertension in MHS may be linked to an altered transepithelial sodium transport. Since this transport is mainly under the control of the Na-K pump, we investigated whether an alteration of the enzymatic activity and/or protein expression of the renal Na,K-ATPase is detectable in prehypertensive MHS. We measured the Na,K-ATPase activity, Rb
+
occlusion, turnover number, α
1
- and β
1
-subunit protein abundance, and α
1
and β
1
mRNA levels in microsomes from renal outer medulla of young (prehypertensive) and adult (hypertensive) MHS and in age-matched MNS. In both young and adult MHS, the Na,K-ATPase activity was significantly higher because of an enhanced number of active pump sites, as determined by Rb
+
occlusion maximal binding. The higher number of pump sites was associated with a significant pretranslational increase of α
1
and β
1
mRNA levels that preceded the development of hypertension in MHS. Since a molecular alteration of the cytoskeletal protein adducin is genetically associated with hypertension in MHS and is able to affect the actin-cytoskeleton and Na-K pump activity in transfected renal cells, we propose that the in vivo upregulation of Na-K pump in MHS is primary and linked to a genetic alteration of adducin.
Hypertension in Obese Zucker Rats
Authors: Alonso-Galicia Magdalena , Brands Michael W. , Zappe Dion H. , Hall John E.
Published: June 2012

We designed our studies to determine whether blood pressure is elevated in obese Zucker rats compared with lean control rats and to test the importance of the renin-angiotensin and adrenergic nervous systems in long-term blood pressure control in this genetic model of obesity. We monitored mean arterial pressure 24 hours per day using computerized methods in 13- to 14-week-old lean and obese Zucker rats maintained on a fixed, normal sodium intake (3.3 mmol/d). Mean arterial pressure (average of 5 days) was higher in obese (100±1 mm Hg) than in lean (86±1) rats. Although control plasma renin activity was lower in obese than in lean rats (3.66±0.15 versus 5.48±0.11 ng angiotensin I/mL per hour), blood pressure sensitivity to exogenous angiotensin II was greater in obese than in lean rats. Blockade of endogenous angiotensin II receptors with losartan (10 mg/kg per day) for 7 days also caused a greater decrease in blood pressure in obese (36±2 mm Hg, n=6) than in lean (25±1, n=5) rats. However, combined α- and β-adrenergic blockade with terazosin (10 mg/kg per day) and propranolol (10 mg/kg per day), respectively, for 8 days caused only modest decreases in blood pressure in obese (9±3 mm Hg, n=8) and lean (4±2, n=6) rats, despite effective α- and β-adrenergic blockade. These results suggest that increased arterial pressure in obese Zucker rats depends in part on angiotensin II. However, additional mechanisms may also contribute to increased blood pressure in obese Zucker rats.
Angiotensin II Type 1 Receptor A/C
1166
Polymorphism
Authors: Castellano Maurizio , Muiesan Maria Lorenza , Beschi Marina , Rizzoni Damiano , Cinelli Angelo , Salvetti Massimo , Pasini Gianfranco , Porteri Enzo , Bettoni Giorgio , Zulli Roberto , Agabiti-Rosei Enrico
Published: June 2012

The angiotensin II type 1 (AT
1
) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II. It has been reported that a polymorphism of the AT
1
receptor gene (an A/C transversion at position 1166) may be associated with cardiovascular phenotypes, such as arterial blood pressure and aortic stiffness, that underlie a condition of increased cardiovascular risk. We examined a sample of 212 subjects randomly selected from a general population in northern Italy to investigate the role of AT
1
receptor gene polymorphism in the regulation of blood pressure and cardiovascular growth. We measured blood pressure (both clinic and 24-hour ambulatory recording), left ventricular mass (echocardiography), and carotid artery wall thickness (B-mode ultrasound); we assessed the AT
1
receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization. Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes; the difference was statistically significant for clinic measurements (mean difference for mean blood pressure, −6.6 mm Hg,
P
=.01; 95% confidence interval, −1.6 to −11.7 mm Hg) but not for ambulatory blood pressure measurements. CC homozygotes also presented a lower incidence of a positive family history of hypertension (
P
=.027). No statistically significant differences among AT
1
receptor A/C
1166
genotypes were observed for left ventricular mass or carotid artery wall thickness. We conclude that the present study does not support a major role of the AT
1
receptor gene A/C
1166
polymorphism as a marker of conditions associated with increased cardiovascular risk.
Selective Guanylyl Cyclase Inhibitor Reverses Nitric Oxide-Induced Vasorelaxation
Authors: Olson Linda J. , Knych Edward T. , Herzig Thomas C. , Drewett James G.
Published: June 2012

Effects of a novel soluble guanylyl cyclase inhibitor, 1
H
-[1,2,4]oxadiazolo[4,3-
a
]quinoxalin-1-one (ODQ), were characterized on guanylyl cyclase activity in cytosolic fraction of COS-7 cells overexpressing the α
1
and β
1
subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn
2+
or Mn
2+
-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 μmol/L) reduced deta nonoate-stimulated cGMP production in COS-7 cells overexpressing soluble guanylyl cyclase and in rat aortic vascular smooth muscle cells. ODQ did not inhibit particulate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxidize deta nonoate-donated NO in the presence of cells at physiological pH. Therefore, ODQ is a selective inhibitor of soluble guanylyl cyclase. Using ODQ in isolated aortic ring preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with NO. Phenylephrine (100 nmol/L)-precontracted, isolated rat aortas were relaxed in a concentration-dependent manner by deta nonoate (0.01 to 100 μmol/L) and nitroglycerin (0.01 to 300 μmol/L). ODQ (10 μmol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimak-alim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.
Cyclooxygenase Inhibition Restores Nitric Oxide Activity in Essential Hypertension
Authors: Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Magagna Armando , Salvetti Antonio
Published: June 2012

To evaluate whether cyclooxygenase constrictor substances can impair nitric oxide-mediated vasodilation in essential hypertension, in seven normotensive subjects (43.3±4.1 years; BP, 117±6/81±2 mm Hg) and seven essential hypertensive patients (47.1±5.2 years; BP, 151±8/98±4 mm Hg) we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15,0.45, 1.5, 4.5, 15 μg·100 mL
−1
·min
−1
) in basal conditions, during infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA; 100 μg·100 mL
−1
·min
−1
), a nitric oxide synthase inhibitor, or indomethacin (50 μg·100 mL
−1
·min
−1
), a cyclooxygenase inhibitor, or simultaneous indomethacin and L-NMMA. In normotensives, vasodilation to acetylcholine was blunted by L-NMMA (maximum flow increase: 671±64% and 386±42%, respectively;
P
<.01), and this effect was unchanged by indomethacin. In contrast, in hypertensive patients, vasodilation to acetylcholine (maximum flow increase: 458±33%) was unchanged by L-NMMA. Indomethacin significantly (
P
<.01) increased the response to acetylcholine (maximum flow increase: 635±53%) and restored the inhibitory effect of L-NMMA (maximum flow increase: 445±36%;
P
<.01 versus indomethacin alone). In an adjunctive seven normotensives (51.4±4.2 years; BP, 114±5/79±3 mm Hg) and seven essential hypertensives (53.2±7.6 years; BP, 153±9/100±3 mm Hg) we repeated the same protocol by replacing L-NMMA with
l
-arginine (200 μg·100 mL
−1
·min
−1
), the substrate for NO synthase. In normotensives, vasodilation to acetylcholine was increased by
l
-arginine (maximum flow increase: 539±48% and 806±61%, respectively) and this effect was unchanged by indomethacin. In hypertensive patients, vasodilation to acetyl-choline (maximum flow increase: 339±32%) was unchanged by
l
-arginine but was significantly (
P
<.01) increased by indomethacin (maximum flow increase: 592±38%). Moreover, indomethacin restored the facilitatory effect of
l
-arginine (maximum flow increase: 804±56%;
P
<.01 versus indomethacin alone). Therefore, cyclooxygenase inhibition restores nitric oxide-mediated vasodilation in essential hypertension, suggesting that cyclooxygenase-dependent substances can impair nitric oxide production.
Thromboxane Is Required for Full Expression of Angiotensin Hypertension in Rats
Authors: Keen Henry L. , Brands Michael W. , Smith Manis J. , Shek Eugene W. , Hall John E
Published: June 2012

Recent studies suggest that thromboxane (TX) mediates a significant component of angiotensin II (ANG II)- induced hypertension. However, there is little information to support the hypothesis that this relationship is important during chronic, physiological increases in ANG II, particularly while controlling for variation in endogeneous ANG II levels induced by TX inhibition. This study tested that hypothesis in 27 chronically instrumented rats. After baseline measurements, suppression of endogenous TX was induced and maintained throughout the study in 13 rats by IV infusion of the TX synthesis inhibitor (TSI) U63557A; the other 14 rats received vehicle. Baseline mean arterial pressure (MAP) was not different between groups and was unchanged by TSI or vehicle. Continuous inhibition of ANG II production was then initiated in both groups of rats by IV infusion of the angiotensin-converting enzyme inhibitor (ACEI) benazepril. ACEI reduced blood pressure similarly in vehicle and TSI rats, from 105±2 to 91±2 mm Hg and 103±1 to 89±1 mm Hg, respectively. ANG II was then infused at 5 ng·kg
−1
·min
−1
IV for 7 days in six rats from each group to restore ANG II activity to baseline levels. This dose increased MAP to 103±2 and 101±1 mm Hg in vehicle and TSI rats, respectively, values not different from pre-ACEI levels. Seven TSI rats and eight vehicle rats received a higher dose of ANG II (20 ng·kg
−1
·min
−1
IV). After 7 days, MAP was higher in vehicle than in TSI rats (143±5 versus 120±4 mm Hg). These results suggest that endogenous TX is an important determinant of MAP in ANG II hypertension but may have a diminished role in blood pressure regulation when ANG II is at normal and subnormal levels.
Cholesterol Enhances Platelet-Derived Growth Factor-BB-Induced [Ca
2+
]
i
and DNA Synthesis in Rat Aortic Smooth Muscle Cells
Authors: Sachinidis Agapios , Liu Min , Weber Artur-Aron , Seul Claudia , Harth Volker , Seewald Stefan , Ko Yon , Vetter Hans
Published: June 2012

In the present study, we describe possible mechanisms by which hypercholesterolemia may contribute to the development of cardiovascular diseases. Treatment of rat aortic smooth muscle cells for 20 hours with cholesterol-rich liposomes (500 μg/mL cholesterol, 100 μg/mL low-density lipoprotein) resulted in a 76±12% increase in total cholesterol content. The effects of cholesterol enrichment were examined by determination of changes in cell membrane fluidity. Fluidity of the cholesterol-enriched cell membranes was decreased at all temperatures between 15°C and 40°C. Changes in membrane fluidity in whole cell membranes represented changes in fluidity of microsomal membranes isolated by Percoll gradient ultracentrifugation. The basal [Ca
2+
]
i
and the maximal platelet-derived growth factor (PDGF)-BB-induced [Ca
2+
]
i
was elevated by 30% and 90% in cholesterol-enriched cells, respectively. In contrast, the resting pH
i
and the PDGF-BB-induced stimulation of the Na
+
/H
+
exchange were not affected in cholesterol-enriched cells. The effect of PDGF-BB on [
3
H]thymidine incorporation in cholesterol-enriched cells was elevated by 40% in comparison with untreated cells. Our findings show that cellular cholesterol may be involved in the development of vascular diseases via modulation of the PDGF-induced increase in [Ca
2+
]
i
and DNA synthesis in vascular smooth muscle cells.
Vascular Aldosterone in Genetically Hypertensive Rats
Authors: Takeda Yoshiyu , Miyamori Isamu , Inaba Satoru , Furukawa Kenji , Hatakeyama Haruhiko , Yoneda Takashi , Mabuchi Hiroshi , Takeda Ryoyu
Published: June 2012

We have reported that aldosterone is synthesized and cytochrome P450aldo mRNA exists in the vasculature. To clarify the pathophysiological role of vascular aldosterone in hypertension, we compared aldosterone production in the mesenteric arteries of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats (WKY). The expressions of mRNA of cytochrome P450aldo, mineralocorticoid receptor, and α
1
Na,K-ATPase in the mesenteric arteries were compared between the two groups. Aldosterone concentration in the perfusate of the vasculature was measured by radioimmunoassay after purification with high-performance liquid chromatography. Cytochrome P450aldo and mineralocorticoid receptor mRNA levels were quantified by Southern blot analysis of the products of reverse-transcribed polymerase chain reaction. Levels of α
1
Na,K-ATPase mRNA were measured by Northern blot analysis. Vascular aldosterone and cytochrome P450aldo mRNA levels of 2-week-old SHRSP were significantly increased compared with those of age-matched WKY. However, vascular aldosterone in 4- and 9-week-old SHRSP did not differ from that in age-matched WKY. Expression levels of mineralocorticoid receptor mRNA in the vasculature of 4- and 9-week-old SHRSP were significantly increased compared with those in age-matched WKY. Concentrations of vascular α
1
Na,K-ATPase mRNA of 2-, 4-, and 9-week-old SHRSP also were significantly higher than those in age-matched WKY. These results suggest that vascular aldosterone contributes to the pathophysiology of hypertension in SHRSP in the early stage.
Sodium Intake, Angiotensin II Receptor Blockade, and Baroreflex Function in Conscious Rats
Authors: Xu Ling , Brooks Virginia L.
Published: June 2012

The hypothesis that endogenous angiotensin II (Ang II) chronically supports baroreflex control of lumbar sympathetic nerve activity (LSNA) and heart rate (HR) via AT1 but not AT2 receptors was tested in conscious, normotensive rats. Rats were fed either a sodium deficient diet (LS) to increase circulating Ang II or a high-sodium diet (HS) for 2 to 3 weeks. One to two days after surgery to implant catheters and nerve electrodes, baroreflex curves were produced before and 40 minutes after intravenous administration of the AT1 antagonist losartan (10 mg/kg) or the AT2 antagonist
PD123319
(500 μg/kg+50 μg/kg
−1
/min
−1
). Mean arterial pressure (MAP) after losartan was maintained at basal levels with methoxamine. Forty minutes after losartan in LS rats, LSNA (46±5 to 22±1% max) and HR (414±7 to 387±8 bpm) were decreased (
P
<.05). Losartan decreased reflex control of LSNA more in LS than in HS rats (
P
<.05), as indicated by reductions in maximum LSNA (98±2 to 78±3% max) and minimum LSNA (42±5 to 21±5% max). Losartan also shifted reflex control of LSNA to a lower pressure in both groups, but the effect was larger in LS rats (−21±3 [LS] versus −9±2 [HS] mm Hg at basal LSNA;
P
<.05). Maximum gain was unaltered in either group. Similarly, losartan reduced maximum HR (534±6 to 495±9 bpm) and shifted the HR curve leftward (114±5 to 105±4 mm Hg) in LS but not in HS rats. In general, no changes were observed in MAP or baroreflex control of LSNA and HR after
PD123319
in LS rats. These results suggest that in conscious, normotensive LS rats, endogenous Ang II supports LSNA and HR over a wide MAP range via AT1 but not AT2 receptors.
Cardiopulmonary Baroreflex in NaCl-Induced Hypertension in Borderline Hypertensive Rats
Authors: Grisk Olaf , DiBona Gerald F.
Published: June 2012

Borderline hypertensive rats fed an 8% NaCl diet develop increased arterial pressure in association with increased cardiopulmonary baroreflex sensitivity compared with rats fed a 1% NaCl diet. We performed experiments to localize the site of sensitization within the cardiopulmonary baroreflex. To determine whether decreased cardiopulmonary baroreflex sensitivity, as seen in other models of NaCl-induced hypertension, develops later in the course of the disease, we studied an older backcross population derived from borderline hypertensive rats and Wistar-Kyoto rats. Anesthetized borderline hypertensive rats fed 1% and 8% NaCl diets were volume-loaded while right atrial pressure, afferent vagal nerve activity, and renal sympathetic nerve activity were recorded. In 28- to 30-week-old backcross rats fed an 8% NaCl diet, renal sympathetic nerve activity, natriuresis, and diuresis were measured before and during volume loading. Renal sympathetic nerve activity was analyzed with the sympathetic peak detection algorithm. Increases in afferent vagal nerve activity and renal sympathoinhibition were similar in borderline hypertensive rats on either diet during a right atrial pressure rise of 3 mm Hg. In backcross rats, correlations between arterial pressure and renal sympathoinhibition, natriuresis, or diuresis were not found. During volume loading, the peak height of synchronized renal sympathetic nerve discharges decreased while their frequency increased. Attenuated renal sympathoinhibition during acute increases in intravascular volume is not involved in the development or maintenance of NaCl-induced hypertension in borderline hypertensive rats. Renal sympathetic nerve activity decreases because of a reduction in the number of active renal sympathetic nerve fibers.
Gonadal Hormones Modulate Deoxycorticosterone-Salt Hypertension in Male and Female Rats
Authors: Crofton Joan T. , Share Leonard
Published: June 2012

We have shown previously that, in rats with deoxycorticosterone (DOC)-salt hypertension, arterial blood pressure rises more rapidly and reaches a higher level in male than in female rats and that the course of the hypertension was ameliorated by gonadectomy in male rats and exacerbated by gonadectomy in female rats. The present investigation was undertaken to examine the role of the gonadal steroid hormones in modulating the course of DOC-salt hypertension in the rat. Our previous findings with respect to the effects of gender and gonadectomy on DOC-salt hypertension were confirmed in this study. Chronic treatment with gonadal steroids was begun 1 week before the start of the DOC-salt protocol. 17β-Estradiol attenuated the course of the hypertension in intact male rats and in gonadectomized females. Testosterone exacerbated the development of the hypertension in gonadectomized male rats but was without effect in intact females. Progesterone alone had no effect on the hypertension in ovariectomized rats but when given to ovariectomized rats in combination with estradiol transiently prevented the ameliorating effect of the estradiol. These effects of the gonadal steroid hormones could not be attributed to effects of saline intake. Thus, these findings demonstrate that the gonadal steroid hormones play an important role in modulating the pathogenesis of DOC-salt hypertension in the rat. It is suggested that the effects of the gonadal hormones on the course of the hypertension may be due to modulation of the cardiovascular and renal actions of vasopressin, since vasopressin is required for this model of hypertension.