bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Ventricular Filling in Arterial Hypertension
Authors: Mureddu Gian Francesco , de Simone Giovanni , Greco Rosanna , Rosato Giuseppe Flavio , Contaldo Franco
Published: June 2012

We assessed the relations of left ventricular filling to load and geometry by Doppler echocardiography in 80 normotensive subjects (40 normal-weight [36±12 years, 24 women] and 40 obese [35±13 years, 24 women]) and 61 hypertensive subjects without silent coronary heart disease (29 normal-weight [43±13 years, 15 women] and 32 obese [42±13 years, 19 women]) and comparable left ventricular midwall performance. Left ventricular mass divided by height to the 2.7 power was higher in all groups than in normotensive normal-weight subjects (all
P
<.0001) and in hypertensive than normotensive obese subjects (
P
<.001). After controlling for age, sex, blood pressure, and heart rate, isovolumic relaxation time was prolonged in hypertensive subjects and normotensive obese subjects compared with normotensive normal-weight subjects (all
P
<.0001). Body mass index, left ventricular dimension and mass, and circumferential end-systolic stress did not influence these differences. In pooled groups, prolonged isovolumic relaxation time was predicted by high mean blood pressure (β=0.52,
P
<.001), low end-systolic stress (β=−0.33,
P
<.001), increased left ventricular mass (β=0.24,
P
<.004), and high body mass index (β=0.14,
P
<.05, multiple
R
=.72, SEE=16.5 milliseconds,
P
<.0001). Between-group differences in peak early transmitral flow velocity, the deceleration time of early filling velocity, and the ratio of early to late left ventricular filling disappeared after controlling for left ventricular mass. Thus, (1) isovolumic relaxation time is prolonged in both arterial hypertension and obesity; (2) the presence of obesity does not significantly increase isovolumic relaxation time in hypertension; and (3) abnormalities of left ventricular filling in arterial hypertension are offset after controlling for left ventricular mass.
Mechanisms of Coronary Flow Reserve Impairment in Human Hypertension
Authors: Kozàkovà Michaela , Palombo Carlo , Pratali Lorenza , Pittella Giuseppe , Galetta Fabio , L'Abbate Antonio
Published: June 2012

The purpose of this study was to investigate the different mechanisms responsible for an impairment of coronary vasodilator capacity in hypertensive subjects by an integrated echocardiographic approach, including transesophageal Doppler echocardiography, which allows noninvasive monitoring of coronary flow velocity in the left anterior descending artery during pharmacological vasodilation. The study population consisted of 17 healthy control subjects and 33 hypertensive subjects: 10 without hypertrophy, 16 with mild to moderate hypertrophy, and 7 with severe left ventricular hypertrophy. Mean systolic and diastolic flow velocities were monitored basally (together with indexes of myocardial oxygen demand, such as heart rate, myocardial inotropism, and left ventricular wall stress) and during infusion of low-dose (0.56 mg/kg per 4 minutes) and high-dose (0.84 mg/kg per 9 minutes) dipyridamole. Coronary reserve was assessed as the ratio of mean diastolic velocity after high-dose dipyridamole and basal diastolic velocity, and minimum coronary resistance as the ratio of diastolic blood pressure and diastolic velocity after high-dose dipyridamole. Compared with the control group, in all hypertensive groups, coronary reserve was similarly decreased (3.54±0.84 versus 2.59±0.42, 2.29±0.46, and 2.43±0.71;
P
<.01) and minimum resistance increased (0.56±0.15 versus 0.75±0.31, 0.75±0.19, and 0.78±0.21 mm Hg·s
−1
·cm
−1
;
P
=NS). These results confirm that coronary reserve in hypertensive individuals is reduced even before the occurrence of left ventricular hypertrophy. The reduction in coronary reserve depends on both an increase in resting coronary flow and an impairment in maximal vasodilator capacity. An increase in resting flow is dependent on higher heart rate and wall stress in hypertensive subjects without ventricular hypertrophy and on increased myocardial mass in hypertensive subjects with hypertrophy. Hypertensive subjects with ventricular hypertrophy also demonstrated a significantly blunted response to low-dose dipyridamole.
Sympathoexcitatory Response to Cyclosporin A and Baroreflex Resetting
Authors: Ryuzaki Munekazu , Stahl Linda K. , Lyson Teresa , Victor Ronald G. , Bishop Vernon S.
Published: June 2012

We postulate that the sympathoexcitatory response associated with the immunosuppressive agent cyclosporin A is due to an upward resetting of the arterial baroreflex. We performed studies in conscious intact and sinoaortic-denervated rabbits instrumented with catheters and renal nerve electrodes. In intact rabbits, cyclosporin A (20 mg/kg IV, 30 minutes) produced significant increases in renal sympathetic nerve activity (100% to 269±74%,
P
<.05) but did not increase mean arterial pressure. In intact rabbits, we determined arterial baroreflex curves relating renal sympathetic nerve activity and heart rate to mean arterial pressure by producing ramp increases (intravenous phenylephrine) and decreases (intravenous nitroprusside) in mean arterial pressure. Cyclosporin A treatment produced a shift of the midrange of the baroreflex control of heart rate (78.0±4.1 to 84.6±4.7 mm Hg,
P
<.05) and renal sympathetic nerve activity (74.6±3.9 to 87.0±4.8 mm Hg,
P
<.05). Vehicle administration produced no effects on arterial baroreflex curves relating renal sympathetic nerve activity and heart rate to mean arterial pressure. Compared with vehicle treatment, cyclosporin A reduced the maximum gain of heart rate (−5.6±0.6 versus −3.1±0.8 beats per minute per millimeter of mercury,
P
<.05) but had no effect on the maximum gain of renal sympathetic nerve activity. In conscious sinoaortic-denervated rabbits, cyclosporin A had no effect on mean arterial pressure (95.7±7.3 to 91.8±10.8 mm Hg), renal sympathetic nerve activity (100% to 110±6%), and heart rate (287±10 to 279±8 beats per minute). However, when the same sinoaortic-denervated rabbits were anesthetized with sodium pentobarbital, cyclosporin A (20 mg/kg IV) produced increases in renal sympathetic nerve activity (100% to 189±27%). These data indicate (1) that the sympathoexcitatory response to cyclosporin A depends on baroreceptor afferent input in the conscious state and (2) that this response involves an upward resetting of the arterial baroreflex.
Brain ‘Ouabain’ in the Median Preoptic Nucleus Mediates Sodium-Sensitive Hypertension in Spontaneously Hypertensive Rats
Authors: Budzikowski Adam S. , Leenen Frans H.H.
Published: June 2012

Pressor responses to an acute increase in cerebrospinal fluid sodium and exaggeration of the hypertension and sympathetic hyperreactivity in spontaneously hypertensive rats (SHR) by high sodium diet involve release of brain “ouabain” and subsequent activation of the brain renin-angiotensin system. In the present study, we determined whether release of “ouabain” in the median preoptic nucleus participates in these responses. In conscious Wistar rats, the pressor and heart rate responses to central hypertonic saline (0.3 mol/L NaCl, 3.8 μL/min over 10 minutes) and ouabain (0.6 μg) were compared after median preoptic nucleus injection of either γ-globulins or Fab fragments binding ouabain and brain “ouabain” with high affinity. Microinjection of Fab fragments into the median preoptic nucleus abolished the pressor and tachycardic responses to central hypertonic saline and significantly reduced the pressor response to central ouabain. In SHR on high sodium, microinjection of Fab fragments into the median preoptic nucleus significantly decreased baseline blood pressure to a level not different from that in SHR on regular sodium (149±7 versus 145±5 mm Hg), whereas the enhanced responses to air stress were not affected. Our results support the concept that blood pressure responses to central hypertonic saline and exaggeration of the hypertension in SHR by high sodium diet depend on release of brain “ouabain” in the median preoptic nucleus.
Spontaneously Hypertensive Rat Y Chromosome Increases Indexes of Sympathetic Nervous System Activity
Authors: Ely Daniel , Caplea Ann , Dunphy Gail , Daneshvar Hamid , Turner Monte , Milsted Amy , Takiyyuddin Marwan
Published: June 2012

Previous studies from our laboratory have demonstrated that the Y chromosome from the spontaneously hypertensive rat (SHR) is responsible for a significant portion of the elevated blood pressure and also produces an earlier pubertal rise in plasma testosterone. We performed the following studies to determine whether the SHR Y chromosome raises blood pressure by sympathetic nervous system responses as measured by adrenal chromogranin A and plasma and tissue catecholamines. Male SHR from The University of Akron colony were studied from 5 to 20 weeks of age. Blood pressure was measured by tail-cuff, tail artery cannulation, and aortic telemetry (Data Sciences); acute (air stress) and chronic (territorial colony) social stressors were compared; blood was collected for determination of plasma catecholamines; and adrenal glands were analyzed at 15 weeks for catecholamines. Rats with the SHR Y chromosome had higher blood pressure and plasma norepinephrine than those with the normotensive Wistar-Kyoto (WKY) Y chromosome. However, the SHR Y chromosome did not significantly change responsiveness to acute or chronic stressors. Phentolamine and clonidine prevented the stress responses. Adrenal chromogranin A levels were elevated 37% and 40% and adrenal norepinephrine content 29% and 100% at 4 and 10 weeks of age, respectively, in rats with an SHR Y chromosome compared with WKY. Chemical sympathectomy normalized blood pressure in all strains and significantly reduced norepinephrine (36% to 41%) in all strains except in WKY, which already had a normal blood pressure. In conclusion, the SHR Y chromosome appears to increase the chronic sympathetic nervous system. A potential mechanism could be a Y locus that influences chronic sympathetic nervous system activity, which may reinforce neurohumoral factors and structural components of the vessel wall, accelerating the development of hypertension.
Transfer of a Salt-Resistant Renin Allele Raises Blood Pressure in Dahl Salt-Sensitive Rats
Authors: Jiang Jian , Stec David E. , Drummond Heather , Simon Jason S. , Koike George , Jacob Howard J. , Roman Richard J.
Published: June 2012

To evaluate the role of the renin gene in the development of hypertension in Dahl salt-sensitive rats (SS/Jr/Hsd), we derived a congenic strain of rats homozygous for the salt-resistant renin allele (S/ren
rr
) and compared them with a control strain homozygous for the salt-sensitive renin allele (S/ren
ss
). Mean arterial pressure was significantly higher in 12-week-old S/ren
rr
rats fed a high salt (8.0%) diet for 3 weeks than in S/ren
ss
rats or in SS/Jr/Hsd rats rederived from the foundation colony we used to generate the congenic strain (195±3 [n=49] versus 168±3 [n=17] or 161±3 [n=16] mm Hg). Mean arterial pressure was also higher in S/ren
rr
rats than in S/ren
ss
rats raised from birth on either a very low salt (0.1%) diet (119±9 [n=6] versus 100±7 [n=4] mm Hg) or a low salt (0.4%) diet (143±1 [n=22] versus 117±3 [n=10] mm Hg). Plasma renin activity of S/ren
rr
rats was significantly higher than that of S/ren
ss
rats fed a very low salt diet (5.7±2.0 versus 1.8±0.3 ng angiotensin I/mL per hour), a low salt diet (4.4±1.0 versus 1.1±0.3), or a high salt diet (1.5±0.2 versus 0.9±0.1). Urinary protein excretion was greater in S/ren
rr
rats than in S/ren
ss
rats fed a high salt diet (244.2±48.5 versus 43.6±19.5 mg/24 h), and this was associated with significant reductions in renal blood flow (3.3±0.6 versus 4.6±0.5 mL/min per gram kidney weight) and glomerular filtration rate (0.49±0.11 versus 0.82±0.08 mL/min per gram kidney weight). Captopril (20 mg/kg IV) had no effect on blood pressure in S/ren
ss
rats fed a low salt diet, but it lowered blood pressure by 20 mm Hg in S/ren
rr
rats to the same level seen in untreated S/ren
ss
rats. Chronic administration of captopril (5 mg/100 mL drinking water) reduced blood pressure in S/ren
rr
rats fed a high salt diet (170±5 mm Hg) to the same level seen in untreated S/ren
ss
rats, whereas it had no significant effect on blood pressure in S/ren
ss
rats. These results indicate that transfer of a salt-resistant renin allele to SS/Jr/Hsd rats raises plasma renin activity and augments the severity of hypertension and renal disease.
Different Concepts in First-Line Treatment of Essential Hypertension
Authors: Krönig Bernd , Pittrow David Bernhard , Kirch Wilhelm , Welzel Dieter , Weidinger Gottfried
Published: June 2012

Low-dose combination therapy has been proposed as a rational first-line approach to hypertension treatment. We compared the efficacy and tolerability of the fixed combination of reserpine (0.1 mg) plus the thiazide clopamid (5 mg) with its single components and the calcium-antagonist nitrendipine (20 mg) in a randomized, double-blind, parallel study of 273 hypertensive patients with diastolic blood pressure (BP) between 100 and 114 mm Hg. The four groups did not differ regarding baseline characteristics (mean age, 58 years; 51% men; mean BP after a 2-week placebo period, 158 to 160/103 to 104 mm Hg). After 6 weeks of treatment with one capsule daily, mean reductions in sitting BP from baseline at 24 hours after dosing in the reserpine-clopamid combination, reserpine, clopamid, and nitrendipine groups were −23.0/−17.1, −14.0/−11.7, −13.6/−11.9, and −11.6/−12.3 mm Hg, respectively (2
P
<.01). The corresponding normalization rates (diastolic BP <90 mm Hg) were 55%, 40%, 36%, and 33% (2
P
=.11). All patients whose BP had not been normalized at this point received two capsules of the respective medication once daily from weeks 7 to 12. At week 12, mean BP reductions were −25.7/−18.1, −14.6/−12.2, −17.7/−13.4, and −14.9/−15.3 mm Hg in the four groups, respectively (2
P
<.01). The respective normalization rates were 69%, 35%, 39%, and 45% (2
P
<.0001). Linear regression modeling indicated that reserpine and clopamid combined acted more than additively. As regards tolerability, adverse experiences were observed in 27%, 28%, 29%, and 48% of patients, respectively (2
P
<.05). The respective rates of premature discontinuation because of adverse effects were 3%, 3%, 7%, and 13% (2
P
=.06). In conclusion, a low-dose combination of reserpine and clopamid lowered BP significantly more than both the components alone and nitrendipine. Moreover, the combination was tolerated as well as its components and significantly better than nitrendipine. Thus, the use of this low-dose reserpine-thiazide combination appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.
Two-Kidney, One Clip and One-Kidney, One Clip Hypertension in Mice
Authors: Wiesel Philippe , Mazzolai Lucia , Nussberger Jürg , Pedrazzini Thierry
Published: June 2012

Abstract
The mouse remains the animal of choice in transgenic experiments, creating a need for methods of evaluating the physiology of genetically modified animals. We have established and characterized two murine models of renovascular hypertension known as the two-kidney, one clip and one-kidney, one clip models. The appropriate size of the clip lumen needed to induce high blood pressure was determined to be 0.12 mm. Clips with a lumen of 0.11 mm induced a high percentage of renal infarction, and clips with a 0.13-mm opening did not produce hypertension. Four weeks after clipping, two-kidney, one clip hypertensive mice exhibited blood pressure approximately 20 mm Hg higher than their sham-operated controls. After a similar period, this increase reached almost 35 mm Hg in the one-kidney, one clip model. Depending on the model, mice develop either renin-dependent or renin-independent hypertension. Both models are characterized by the development of cardiovascular hypertrophy.
Preliminary Evidence of Linkage of Salt Sensitivity in Black Americans at the β
2
-Adrenergic Receptor Locus
Authors: Svetkey Laura P. , Chen Yuan-Tsong , McKeown Sean P. , Preis Lisa , Wilson Alexander F.
Published: June 2012

Abstract
Salt sensitivity is a heritable trait that is a hallmark of hypertension in black Americans. Genes encoding adrenergic receptors are candidate loci for the inheritance of this hypertension-related trait because of the role of these receptors in the regulation of renal sodium excretion and vascular tone. We performed this study to determine whether these loci are responsible for some of the phenotypic variation in salt sensitivity. Hypertensive black American probands were ascertained, followed by sequential ascertainment of adult sib pairs among the first-, second- and third-degree relatives of the proband. Both hypertensive and normotensive siblings were tested for salt sensitivity by an intravenous sodium-loading, lasix volume-depletion protocol. Genotyping was performed with restriction fragment length polymorphisms in genomic DNA probed with clones containing the β
2
- and α
2c10
-adrenergic receptor genes. A total of 109 sib pairs was evaluated. Salt sensitivity was defined as the change in blood pressure in each individual, comparing the sodium-loaded with the volume-depleted state. Systolic pressure decreased by an average of 9.0±9%, diastolic pressure by 1.5±11%, and mean arterial pressure by 5.0±9%. Neither blood pressure nor salt sensitivity was linked at the α
2c10
-adrenergic receptor locus. No evidence suggested that systolic salt sensitivity and baseline blood pressure were linked at the β
2
-adrenergic receptor locus. Model-independent sib pair linkage analysis suggested that diastolic blood pressure response to sodium loading/volume depletion is linked at the β
2
-adrenergic receptor locus (
P
<.006). Evidence for linkage was significant at the .05 level after adjustment for the number of phenotypic traits examined.
Calcitonin Gene–Related Peptide Is a Depressor of Deoxycorticosterone-Salt Hypertension in the Rat
Authors: Supowit Scott C. , Zhao Huawei , Hallman Diane M. , DiPette Donald J.
Published: June 2012

Abstract
Calcitonin gene–related peptide (CGRP) is a potent vasodilator neuropeptide. We previously demonstrated that neuronal CGRP expression is significantly increased in deoxycorticosterone (DOC)–salt hypertensive rats. To determine the hemodynamic role of CGRP in this setting, we used CGRP
8-37
, a specific CGRP receptor antagonist. DOC-salt hypertension was induced in Sprague-Dawley rats. To control for DOC pellet implantation, left nephrectomy, and/or saline drinking water, we also studied four normotensive groups. Four weeks after the initiation of each protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. Baseline mean arterial pressure was higher in the DOC-salt than normotensive rats (175±5 versus 119±4 mm Hg,
P
<.001). Vehicle administration did not alter mean arterial pressure in any group, and CGRP
8-37
administration (bolus doses of 3.2×10
4
or 6.4×10
4
pmol/L) did not change mean arterial pressure in the four normotensive groups. However, CGRP
8-37
administration to the DOC-salt rats rapidly and significantly increased mean arterial pressure at both the lower dose (9±1 mm Hg,
P
<.001) and higher dose (14±1 mm Hg,
P
<.001). In addition, the increase in mean arterial pressure between the two CGRP
8-37
doses was also significant (
P
<.01), indicating a dose-dependent response. We conclude that the increase in neuronal CGRP expression in DOC-salt hypertension plays a compensatory vasodilator role to attenuate the elevated blood pressure. These results provide the first conclusive evidence that CGRP plays a direct role in DOC-salt hypertension.
Dopamine D
1A
Receptors and Renin Release in Rat Juxtaglomerular Cells
Authors: Yamaguchi Ikuyo , Yao Lynne , Sanada Hironobu , Ozono Ryoji , Mouradian M. Maral , Jose Pedro A. , Carey Robert M. , Felder Robin A.
Published: June 2012

Abstract
Two dopamine D
1
-like receptors have been cloned from mammals, the D
1
and D
5
receptors, also known as D
1A
and D
1B
receptors, respectively, in rodents. Although D
1
-like receptors are known to stimulate renin release, the receptor subtype mediating this action has not been determined. We investigated D
1
receptor subtype expression in rat juxtaglomerular cells obtained after enzymatic dispersion of kidney cortex and differential centrifugation. Juxtaglomerular cells in primary culture were immunocytochemically 85% to 95% renin positive. These cells expressed the D
1A
but not the D
1B
receptor (mRNA and protein). D
1
-like receptor function was demonstrated by a concentration-dependent stimulation of cAMP production by dopamine (n=5-9 per group). Fenoldopam, a D
1
-like receptor agonist, also caused a concentration-dependent increase in cAMP production and renin secretion that was blocked by the selective D
1
-like receptor antagonist
SCH23390
(n=4-13 per group). Although the D
1
ligands do not distinguish between the cloned D
1
-like receptors, the actions of fenoldopam were due to occupancy of the D
1A
receptor: (1) the D
1B
receptor, the only other mammalian D
1
-like receptor, is not expressed in juxtaglomerular cells; (2) antisense but not sense D
1A
oligonucleotides completely blocked the stimulatory effect of fenoldopam on cAMP production and renin secretion. We conclude that there is selective dopamine receptor gene expression in juxtaglomerular cells; the dopamine receptor subtype linked to the stimulation of cAMP and renin secretion in juxtaglomerular cells is the D
1A
subtype.
Calcification of Medial Elastic Fibers and Aortic Elasticity
Authors: Niederhoffer Nathalie , Lartaud-Idjouadiene Isabelle , Giummelly Philippe , Duvivier Claude , Peslin René , Atkinson Jeffrey
Published: June 2012

Abstract
We tested the hypothesis that a simple change in wall composition (medial calcium overload of elastic fibers) can decrease aortic elasticity. Calcium overload was produced by hypervitaminosis D plus nicotine (VDN) in the young rat. Two months later, measurement of central aortic mean blood pressure in the unanesthetized, unrestrained rat showed that the VDN rat suffered from isolated systolic hypertension but that mean blood pressure was normal. Wall thickness and internal diameter determined after in situ pressurized fixation were unchanged, as was calculated wall stress. Wall stiffness was estimated from (1) elastic modulus (determined with the Moens-Korteweg equation and values for aortic pulse wave velocity in the unanesthetized, unrestrained rat and arterial dimensions) and (2) isobaric elasticity (=slope relating pulse wave velocity to mean intraluminal pressure in the phenylephrine-infused, pithed rat preparation). Both increased after VDN, and both were significantly correlated to the wall content of calcium and the elastin-specific amino acids desmosine and isodesmosine. Left ventricular hypertrophy occurred in the VDN model, and left ventricular mass was related to isobaric elasticity. In conclusion, elastocalcinosis induces destruction of elastic fibers, which leads to arterial stiffness, and the latter may be involved in the development of left ventricular hypertrophy in a normotensive model.
Renin-Angiotensin System Components in the Interstitial Fluid of the Isolated Perfused Rat Heart
Authors: de Lannoy Larissa M. , Danser A. H. Jan , van Kats Jorge P. , Schoemaker Regien G. , Saxena Pramod R. , Schalekamp Maarten A. D. H.
Published: June 2012

Abstract
We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the uptake and clearance of exogenous renin, angiotensinogen, and angiotensin I (Ang I) as well as the cardiac production of Ang I. The levels of these compounds in interstitial transudate were considered to be representative of the levels in the cardiac interstitial fluid. During perfusion with renin or angiotensinogen, the steady-state levels (mean±SD) in interstitial transudate were 64±34% (
P
<.05 for difference from the arterial level, n=8) and 108±42% (n=6) of the arterial level, respectively; the levels in coronary effluent were not significantly different from those in interstitial transudate. Ang I was not detectable in interstitial transudate during perfusion with Tyrode’s buffer or angiotensinogen. It was very low in interstitial transudate during perfusion with renin and rose to much higher levels during combined renin and angiotensinogen perfusion. The total production rate of Ang I present in interstitial fluid could be largely explained by the renin-angiotensinogen reaction in the fluid phase of the interstitial compartment. In contrast, the total production rate of Ang I present in coronary effluent and the net ejection rate of Ang I via coronary effluent were, respectively, 4.6±2.2 and 2.8±1.3 (
P
<.01 and
P
<.05 for difference from 1.0, n=6) times higher than could be explained by Ang I formation in the fluid phase of the intravascular compartment. Ang I from the interstitial fluid contributed little to the Ang I in the intravascular fluid and vice versa. These data reveal two tissue sites of Ang I production, ie, the interstitial fluid and a site closer to the blood compartment, possibly vascular surface-bound renin. There was no evidence that the release of locally produced Ang I into coronary effluent and interstitial transudate occurred independently of blood-derived renin or angiotensinogen.
Effects of Enalapril, Losartan, and Verapamil on Blood Pressure and Glucose Metabolism in the Cohen-Rosenthal Diabetic Hypertensive Rat
Authors: Rosenthal Talma , Erlich Yael , Rosenmann Eliezer , Cohen Aharon
Published: June 2012

Abstract
We undertook the present study to examine the effect of the angiotensin-converting enzyme inhibitor enalapril, the angiotensin II antagonist losartan, and calcium antagonist verapamil on systolic pressure and spontaneous blood glucose levels in rats from the Cohen-Rosenthal diabetic hypertensive strain. Genetic hypertension and diabetes developed in this strain after crossbreeding of Cohen diabetic and spontaneously hypertensive rats. The new rat strain was fed their usual copper-poor sucrose diet, which is essential for the development of this model, and for 4 weeks received either enalapril, losartan, or verapamil. Systolic pressure was reduced significantly compared with controls in all treated groups. Chronic treatment with enalapril or verapamil, but not with losartan, succeeded in lowering spontaneous blood glucose, indicating improved diabetic control. Data suggest that angiotensin-converting enzyme inhibition by enalapril, but not angiotensin II antagonism by losartan, can improve glucose metabolism in addition to its hypotensive effect in a genetic diabetic hypertensive rat strain. This confirms that the drop in glucose with converting enzyme inhibition is highly dependent on bradykinin accumulation. Data further suggest that calcium channel blockade by verapamil can also improve glucose metabolism. The question remains whether the reduction in glucose by verapamil was a result of inhibition of glucogenesis.
Lack of Correlation Between Arterial and Venous β-Adrenergic Receptor Sensitivity
Authors: Stein C. Michael , Deegan Robert , Wood Alastair J. J.
Published: June 2012

Abstract
The regulation of vascular β-adrenoceptor responses in humans has been studied in vivo in both arteries and veins. Because venous responses can be studied less invasively than arterial responses, they are an attractive substitute for the measurement of arterial responses, provided that venous responses are representative of responses in resistance arteries. However, although venous, particularly hand vein response, has been extensively studied, arterial and venous β-adrenergic sensitivities, in the same individuals, have not been compared. Measures of venous and arterial β-adrenergic sensitivities were compared in 10 healthy normotensive subjects. Forearm blood flow, after administration of increasing doses of isoproterenol into the brachial artery, was measured by strain-gauge plethysmography and was used for determination of arterial β-adrenoceptor sensitivity, expressed as the IP
500
(the dose of isoproterenol resulting in a fivefold [500%] increase in baseline forearm blood flow). Venous sensitivity to isoproterenol, expressed as the IP
15
(the dose of isoproterenol resulting in 15% venodilation), was measured in a dorsal hand vein using the linear variable differential transformer. Administration of isoproterenol into the hand vein and brachial artery resulted in venodilation and increased forearm blood flow, respectively. However, there was no correlation between the measures of venous (log IP
15
) and arterial (log IP
500
) measures of vascular β-adrenergic sensitivity (
r
=−.12,
P
=.74). We conclude that since arterial and venous sensitivities to isoproterenol in healthy white men did not correlate, venous and arterial β-adrenergic responses are regulated differently and that studies examining vascular β-adrenoceptor sensitivity would most appropriately be performed in a vessel representative of the vascular bed of interest.
Effects of Age on Ca
2+
Currents in Small Mesenteric Artery Myocytes From Wistar-Kyoto and Spontaneously Hypertensive Rats
Authors: Lozinskaya Irina M. , Cox Robert H.
Published: June 2012

Abstract
The purpose of this study was to test the hypothesis that differences in voltage-gated Ca
2+
channels increase with age during the development of sustained hypertension in the spontaneously hypertensive rat (SHR). Using patch-clamp methods, we measured whole-cell Ca
2+
currents in freshly isolated myocytes from small mesenteric arteries of juvenile (5 to 7 weeks), young (10 to 12 weeks), and mature (19 to 23 weeks) Wistar-Kyoto rats (WKY) and SHR. Indirect tail artery systolic pressure increased progressively with age in SHR (from 125±5 to 159±5 to 192±5 mm Hg) but only in the younger WKY (from 107±6 to 130±4 to 136±4 mm Hg). Peak Ca
2+
current density (current per cell capacitance) was larger in SHR than WKY myocytes at all ages (at 6 weeks, 3.5±0.4 versus 2.3±0.2 pA/pF; at 12 weeks, 3.8±0.2 versus 3.1±0.2; at 20 weeks, 4.9±0.4 versus 3.3±0.4). Cell capacitance (surface area) was significantly smaller in 12-week-old SHR than WKY (25.2±1.1 versus 31.8±1.6 pF), but no differences were found in the 6- or 20-week-old groups. There were significant differences in Ca
2+
current with strain, age, and voltage but no significant age-strain interactions. The ratio of peak Ca
2+
current for SHR to that of WKY declined linearly with voltage at all ages, suggesting differences in the voltage dependence of Ca
2+
current activation. The voltage dependence of Ca
2+
current was shifted to the left in SHR compared with WKY at all ages. Activation curves were shifted significantly in the negative voltage direction only in 20-week-old SHR myocytes. We have found differences with age in Ca
2+
current density and its voltage dependence in SHR compared with WKY during the phase of development in which blood pressure becomes established in the SHR. The net effect of these differences predicts a larger Ca
2+
current in SHR at voltages in the physiological range of membrane potential.
Continuous monitoring of arterial pressure indicates sinoaortic denervated rats are not hypertensive.
Authors: Norman R A , Coleman T G , Dent A C
Published: June 2012

The mean arterial pressure (MAP) of nine sinoaortic denervated (SAD) and eight control rats housed in standard-sized metabolic cages was determined continuously via aortic cannulae and computerized data collection over 24 hours. These continuous measurements were compared with direct, mean aortic pressure measurements and indirect, tail-cuff systolic pressure determinations made while these rats were resting in a Lucite restrainer. Denervated rats were studied 1 month after debuffering. Both types of measurements made during restraint indicated that the SAD rats were hypertensive; the MAP averaged 145 +/- 3.4 mm Hg (mean +/- SEM) in SAD rats compared with 119 +/- 2.8 mm Hg in the control group (p less than 0.001), and the tail-cuff pressure in SAD rats was 156 +/- 5.4 vs 121 +/- 2.7 mm Hg in control rats (p less than 0.001). In contrast, continuous monitoring showed that the SAD rats were normotensive; the MAP averaged 119 +/- 4.7 mm Hg in the SAD group and 119 +/- 3.1 mm Hg in the control group. Denervation increased pressure lability; the average 24-hour standard deviation of MAP was 19.0 +/- 1.2 mm Hg in SAD rats vs 8.0 +/- 0.7 mm Hg in control rats (p less than 0.001). Apparently, arterial pressure is elevated during restraint in SAD rats because buffering by the baroreceptor reflex is absent, and pressure measurements made under these conditions give a false indication of hypertension.
Evidence against a role of vasopressin in the maintenance of high blood pressure in mineralocorticoid and renovascular hypertension.
Authors: Rabito S F , Carretero O A , Scicli A G
Published: June 2012

To determine the role of vasopressin in the maintenance of high blood pressure, the antihypertensive effect of the antagonists of the vasopressor effect of vasopressin, [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (dPVDAVP), and [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 4-valine, 8-D-arginine] vasopressin (cyclo dVDAVP), was studied in unanesthetized, nonsurgically stressed rats with adrenal regeneration hypertension, malignant DOCA-salt hypertension, and malignant two-kidney, one clip Goldblatt hypertension. The doses of vasopressin antagonist used blocked the blood pressure (BP) response to vasopressin almost completely, with no changes in the pressor response to norepinephrine and angiotensin II. Administration of the vasopressin antagonists did not induce significant changes in the mean BP in any of the three experimental groups studied. It is suggested that in unanesthetized, nonsurgically stressed rats with adrenal regeneration hypertension, malignant DOCA-salt hypertension, and malignant two-kidney, one clip Goldblatt hypertension, vasopressin does not have a role in the maintenance of high BP.
Norepinephrine and renin activity in chronic renal failure. Evidence for interacting roles in hemodialysis hypertension.
Authors: Textor S C , Gavras H , Tifft C P , Bernard D B , Idelson B , Brunner H R
Published: June 2012

To assess the interaction between adrenergic activity and blood pressure regulation in patients with chronic renal failure, plasma norepinephrine (NE) and plasma renin activity (PRA) were measured before and after vigorous ultrafiltration. The significance of PRA was further assessed by angiotensin blockade with saralasin. Two patterns of response were defined: nine patients had low levels of PRA before and after hemodialysis. These patients showed a net fall in norepinephrine and no angiotensin dependence of any time. Failure to stimulate either PRA or norepinephrine was also observed during periods of marked hypotension. Seven other patients had higher PRA, which rose during hemodialysis. This was associated with an increase in NE and postdialysis angiotensin dependence. Patients experiencing hypotension in this group showed a sharp rise in NE, suggesting baroceptor-mediated adrenergic stimulation. In all patients sustaining hypotension during therapy, postdialysis PRA was closely correlated with NE. These results indicate that hemodialysis mobilizes the renin-angiotensin system to maintain hypertension in a greater proportion of dialysis patients than previously supposed and that impaired renin release following hypotension may represent uremic autonomic dysfunction.
Sodium pump activity in arteries of Dahl salt-sensitive rats.
Authors: Overbeck H W , Ku D D , Rapp J P
Published: June 2012

Decreased activity of the electrogenic sodium pump of vascular smooth muscle has been reported in several forms of experimental hypertension and may play an important role in basic disease mechanisms. It has been proposed that such pump suppression may characterize volume-expanded forms of hypertension. The present investigation tested this latter hypothesis. Sodium pump activity was assessed in vitro in sodium-loaded tail artery and thoracic aorta freshly excised from Dahl salt-sensitive (S) and salt-resistant (R) rats on low (0.4%) or high (8%) NaCl diets for 5 to 7 weeks. Rubidium (86Rb) uptake in the absence (total uptake) and presence (ouabain-insensitive uptake) of 1.0mM ouabain was measured and ouabain-sensitive uptake (nmole/mg dry weight/10 min) was calculated. In S rats, salt feeding was accompanied by elevation of arterial pressure, cardiac hypertrophy, increases of 20% to 30% in total blood volume, and increases in the ouabain-sensitive, ouabain-insensitive, and total uptakes in the aorta, but no significant change in uptakes in the tail artery. However, ouabain-sensitive uptake in the tail artery of all S rats exceeded than in R rats. There was no evidence of a decrease in vascular sodium pump activity accompanying hypertension in either artery. Therefore, the results of this study provide no evidence in support of the hypothesis that pump suppression in vascular smooth muscle characterizes volume-expanded forms of hypertension. It is unlikely that the observed increases in vascular pump activity in S rats reflected intracellular sodium concentrations higher than those in the control rats. Rather, increases in the numbers of pump molecules or in their turnover rate are probably involved.
Effect of hemodialysis on blood volume distribution and cardiac output.
Authors: Chaignon M , Chen W T , Tarazi R C , Bravo E L , Nakamoto S
Published: June 2012

Effects of hemodialysis on extracellular fluid volume distribution, left ventricular volumes, and cardiac output were determined in patients with end-stage renal disease (n = 19). Distribution of extracellular fluid loss from hemodialysis differed widely among patients, so that weight change correlated weakly with contraction of total blood volume (index of determination 29%, p less than 0.05). End-diastolic volume (EDV) decreased from 150 +/- 49 ml (mean +/- SD) to 118 +/- 42 ml, p less than 0.001; stroke volume (SV) decreased from 108 +/- 36 to 86 +/- 33 ml (p less than 0.001) without change in ejection fraction (from 0.73 +/- 0.09 to 0.74 +/- 0.11). A significant correlation was found between total blood volume (TBV) and EDV before (r = 0.66, p less than 0.005) and after dialysis (r = 0.61, p less than 0.001). The correlation between TBV and SV was highly significant before (r = 0.78, p less than 0.001) and after dialysis (r = 0.66, p less than 0.005), but there was no correlation between change in TBV and change in EDV or in SV. The ratio of EDV to TBV (EDV/TBV x 100) was reduced significantly from 3.49 +/- 0.92 to 3.06 +/- 0.97, p less than 0.001). There results suggest that, although intravascular volume was the major determinant of cardiac output in dialyzed patients, the postdialysis reduction in cardiac output might be related more to the relocation of blood volume than to the absolute degree of blood volume contraction.
The antihypertensive mechanism of clonidine in man. Evidence against a generalized reduction of sympathetic activity.
Authors: Wallin B G , Frisk-Holmberg M
Published: June 2012

Recording of multi-unit sympathetic activity were made from muscle branches of the peroneal nerve during i.v. bolus injection of 100 to 275 micrograms clonidine in seven hypertensive patients. Blood pressure was reduced in all patients, but sympathetic activity and heart rate could either increase or decrease. When plasma levels of clonidine were low, sympathetic activity tended to increase, and when plasma levels were high, activity tended to decrease. Irrespective of whether mean level of sympathetic activity increased or decreased with the fall in blood pressure level, transient fluctuations of blood pressure continued to cause dynamic baroreflex modulation of the sympathetic outflow. It is suggested that the drug influences sympathetic outflow by a combination of central and peripheral effects.
Basis for the altered arterial wall mechanics in the spontaneously hypertensive rat.
Authors: Cox R H
Published: June 2012

Carotid and tail arteries from 20-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used to compare mechanics and biochemical properties. Measurements of pressure-diameter relations were made on isolated segments under conditions of active (145 mM K+) and passive (O mM Ca+2 and 2 mM EGTA) smooth muscle. Connective tissue, water and electrolyte contents, and extracellular water spaces were determined. Chemical data were also obtained from segments of thoracic aorta. The passive mechanics of arteries from the SHR were stiffer compared to those from WKY. Total connective tissue content (collagen + elastin) and collagen/elastin ratio were both smaller in the SHR arteries. Differences in the characteristics of the connective tissue matrix other than total content must exist in SHR and WKY arteries. Maximum values of active stress (force/area) developed by SHR arteries were larger and occurred at smaller values of wall strain compared to WKY arteries. The maximum reduction in wall diameter with smooth muscle activation was larger in the WKY arteries, but these constriction responses were better maintained at higher pressures by SHR arteries. Extracellular water space was lower in SHR arteries, while total water content was not different. The fraction of the wall of SHR arteries occupied by smooth muscle cells was larger than that of WKY arteries. When values of maximum active stress were normalized to the relative cell content, no difference was found for SHR and WKY carotids, but SHR tail arteries still produced a significantly larger active cell stress than WKY tail arteries. This suggests that intrinsic differences exist in the properties of smooth muscle cells of SHR and WKY tail arteries.
Cardiovascular characteristics in adolescents who develop essential hypertension.
Authors: Falkner B , Kushner H , Onesti G , Angelakos E T
Published: June 2012

The risk parameters for the development of essential hypertension (EH) were evaluated in a group of adolescents with borderline hypertension. A population comprised of 50 adolescents with systolic or diastolic blood pressure between the 90th and 95th percentile was compared to a normotensive (less than 90%) family history-negative control population. Evaluative parameters included genetic risk, resting blood pressure, resting heart rate, and cardiovascular response to mental stress. In a follow-up period of up to 41 months, 28 borderline hypertensive adolescents (56%) developed fixed EH. At the time of initial evaluation, these 28 hypertensive adolescents had a strong family history of EH, higher resting heart rate (p less than 0.01) and blood pressure (p less than 0.01), and a greater cardiovascular response to mental stress (p less than 0.001) compared to the normotensive family history-negative control population. Time series analysis of the stress phase also demonstrated a rhythmic cardiovascular response in the normotensive group (p less than 0.05) that was not present in the hypertensive group. These results indicate that adolescents with borderline hypertension displaying these characteristics have a greater risk for EH than previously reported.
Alcohol consumption and blood pressure. The lipid research clinics prevalence study.
Authors: Criqui M H , Wallace R B , Mishkel M , Barrett-Connor E , Heiss G
Published: June 2012

The relationship between alcohol consumption and systolic and diastolic blood pressure (BP) was examined in 2482 men and 2301 women 20 years of age or older in nine North American populations. Men at the highest level of alcohol consumption (greater than or equal to 30 ml alcohol per day) had the highest BP, while women either at the highest level of alcohol consumption or consuming no alcohol had the highest BP. Men aged greater than or equal to 35 years of age consuming greater than or equal to 30 ml alcohol per day were 1.5 to 2 times more likely to be hypertensive than non-drinkers. Multivariate analysis showed systolic and diastolic BP in both men and women to be positively and significantly (p less than 0.05) related to alcohol consumption, and this relationship was independent of the potential confounding effects of age, obesity, cigarette smoking, regular exercise, education, and gonadal hormone use in women. The regression coefficients indicated that an average of 30 ml of alcohol per day would produce a 2 to 6 mm Hg increase in systolic BP. Analyses suggested the univariate U-shaped alcohol-BP association in women was confounded by differences in obesity and cigarette smoking in nondrinking women, and by very low alcohol consumption in hypertensive women using medication. Additional analyses indicated that alcohol consumed in the 24 hours prior to the study was much more strongly associated with elevated BP than alcohol consumed in the week prior to the study excluding the previous 24 hours. We conclude that alcohol appears to have a modest but consistent and independent effect on systolic and diastolic BP.
Plasma concentration and acetylator phenotype determine response to oral hydralazine.
Authors: Shepherd A M , McNay J L , Ludden T M , Lin M S , Musgrave G E
Published: June 2012

The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was studied in hypertensive patients. The concentration of hydralazine in plasma was measured both by a newly developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients. The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator phenotyping for individualization of hydralazine dosage regimens merits further evaluation.