bluuebunny/crossref_metadata_2025 huggingface dataset:
Parathyroid hormone analogues inhibit calcium mobilization in cultured vascular cells.
Authors: Hino T , Nyby M D , Fittingoff M , Tuck M L , Brickman A S
Published: June 2012

Parathyroid hormone and parathyroid hormone-related protein lower blood pressure and relax contracted arteries. Parathyroid hormone also attenuates angiotensin II-induced vasoconstriction. To determine the cellular mechanism or mechanisms by which parathyroid hormone analogues antagonize pressor effects, we examined the effect of these peptides on angiotensin II-induced calcium mobilization in fura 2-AM-loaded cultured rat vascular smooth muscle cells. Either 100 nmol/L parathyroid hormone or parathyroid hormone-related protein significantly reduced the amount of calcium mobilized by 100 nmol/L angiotensin II. The attenuating effect of these peptides was mimicked by 10 mmol/L forskolin and 10 mmol/L isobutylmethylxanthine and was not dependent on the presence of extracellular calcium. This effect of the parathyroid hormone analogues was reduced when cells were pretreated with 100 mmol/L 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor. Combined inhibition of cyclic nucleotide-dependent protein kinases eliminated the inhibitory effect of parathyroid hormone, whereas protein kinase C inhibition had no effect. Parathyroid hormone analogues decreased the amount of calcium released by inositol 1,4,5-trisphosphate in digitonin-permeabilized vascular smooth muscle cells. This effect was inhibited by treatment with 2',5'-dideoxyadenosine. These results suggest that these peptides attenuate inositol 1,4,5-trisphosphate-sensitive calcium mobilized by angiotensin II via an adenylate cyclase-dependent mechanism. This may be a mechanism by which acute administration of parathyroid hormone or parathyroid hormone-related peptide antagonizes vasoconstriction.
Regional differences in mortality during 15-year follow-up of 11,936 hypertensive veterans.
Authors: Miller J P , Perry H M , Rossiter J E , Baty J D , Carmody S E , Sambhi M P
Published: June 2012

Several different investigators have reported increased stroke mortality in the southeastern United States, leading to the introduction of the term "Stroke Belt." The results presented here from the Veterans Administration Hypertension Screening and Treatment Program (HSTP) demonstrate an increased all-cause mortality among hypertensive patients seen in HSTP clinics in the southeastern United States when compared with similar patients from other HSTP clinics. Several different groupings of southeastern states were examined and compared with nine states west of the Mississippi River. A total of 11,936 male veterans, 5737 of whom were black, were identified as hypertensive during 1974-1976 in 32 HSTP clinics. Their mean age was 52.4 +/- 10.4 years, and their mean pretreatment blood pressure was 153.8 +/- 19.1/100.4 +/- 9.8 mm Hg. During a minimum of 13.9 years of follow-up, 5360 (44.9%) of these patients died. Proportional hazards modeling was used to fit a basic survival model with terms representing race, age, blood pressure, smoking, and obesity. Risk was increased with higher blood pressure, age, and smoking and with lower body mass index. For 6 HSTP clinics in an 11-state Stroke Belt (defined as states with stroke mortality > 10% above the United States average), the relative risk of death was 1.226 (95% confidence interval, 1.106-1.358) when compared with 9 states west of the Mississippi River. For two different groupings of southeastern states with 10 and 8 HSTP clinics the relative risk of death was 1.231 and 1.295.(ABSTRACT TRUNCATED AT 250 WORDS)
Smooth muscle cell responsiveness to nitrovasodilators in hypertensive and normotensive rats.
Authors: Papapetropoulos A , Marczin N , Snead M D , Cheng C , Milici A , Catravas J D
Published: June 2012

Endothelium-derived relaxing factor and exogenous nitrovasodilators are thought to produce smooth muscle relaxation by activation of soluble guanylate cyclase. To investigate whether diminished cyclic GMP (cGMP) accumulation underlies the differences in vascular reactivity to nitrovasodilators between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we determined cGMP formation in aortic smooth muscle cells from the two strains. Both cultured cells and aortic rings from 12- to 14-week-old SHR accumulated greater amounts of cGMP on stimulation with exogenous nitrovasodilators (ie, sodium nitroprusside) than those from WKY rats, whereas there was no difference observed in cells from prehypertensive animals (5- to 6-week old) between the two strains. Responsiveness of smooth muscle cells to endothelium-derived relaxing factor was investigated in cocultures of bovine aortic endothelial cells (BAE) and smooth muscle cells from SHR and WKY rats. cGMP accumulation elicited by endothelium-derived relaxing factor released either basally or in response to bradykinin and the calcium ionophore A23187 was greater in smooth muscle from 12- to 14-week-old SHR than from age-matched WKY rats (80 +/- 17 versus 11 +/- 2 for basal; 152 +/- 12 versus 80 +/- 26 for A23187; 163 +/- 21 versus 40 +/- 12 pmol/mg protein per 15 minutes for bradykinin) in SHR/BAE and WKY/BAE cocultures, respectively. Northern blot analysis of steady-state messenger RNA levels for the beta 1 subunit of soluble guanylate cyclase revealed higher levels of the message in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults.
Authors: de Simone G , Devereux R B , Roman M J , Alderman M H , Laragh J H
Published: June 2012

Although it is recognized that both hypertension and obesity are associated with increased left ventricular mass, the relative impacts of obesity, arterial hypertension, and gender on the prevalence of ventricular hypertrophy remain uncertain. Accordingly, echocardiographic left ventricular mass normalized for height to the power of the allometric or growth relation between ventricular mass and height was compared in 164 normotensive subjects (85 men [24 obese] and 79 women [28 obese], aged 45 +/- 12 years) and 475 hypertensive patients (325 men [126 obese] and 150 women [85 obese], aged 54 +/- 10 years) from an adult employed population. Gender-specific upper normal limits were used to identify ventricular hypertrophy. Left ventricular mass/height 2.7 was higher in obese than normal-weight normotensive subjects (P < .004) independently of the level of blood pressure and identified a higher prevalence of hypertrophy (mainly eccentric) in obese than in normal-weight normotensive subjects (14% versus 5%, P < .04), a difference that was not detected by left ventricular mass/body surface area. Left ventricular mass/height identified hypertrophy in 52% of obese and 30% of normal-weight hypertensive patients (P < .0001) because of higher prevalences in obese than normal-weight patients of both eccentric (34% versus 20%) and concentric ventricular hypertrophy (18% versus 10%). The increase in left ventricular mass was independent of blood pressure values in obese normotensive women (but not men), and the prevalence of supranormal left ventricular mass/height 2.7 was even higher in hypertensive obese women (58%) than men (49%).(ABSTRACT TRUNCATED AT 250 WORDS)
Sex influence on renal alpha 2-adrenergic receptor density in the spontaneously hypertensive rat.
Authors: Gong G , Dobin A , McArdle S , Sun L , Johnson M L , Pettinger W A
Published: June 2012

Male spontaneously hypertensive rats (SHR) have higher blood pressure than females. We compared renal alpha 2-adrenergic receptor density among intact SHR and Wistar-Kyoto (WKY) rats of both sexes, male and female SHR gonadectomized at 4 weeks of age, and gonadectomized SHR supplemented with testosterone. Additional groups of SHR were treated with enalapril (30 mg/kg per day), an angiotensin-converting enzyme inhibitor, from 5 to 14 weeks of age. Renal alpha 2-adrenergic receptor density was higher in males than females in both SHR and WKY rats. Female SHR and WKY rats had identical low renal alpha 2-adrenergic receptor density. Castration of male SHR reduced the male-female differences in blood pressure and renal alpha 2-adrenergic receptor density by 60%. Treatment with testosterone raised blood pressure and renal alpha 2-adrenergic receptor density to the intact male levels in both gonadectomized males and females. Treatment with enalapril decreased blood pressure but not renal alpha 2-adrenergic receptor density in both male and female SHR. We conclude that (1) both renal alpha 2-adrenergic receptor density and blood pressure are influenced by sex in SHR and WKY, (2) renal alpha 2-adrenergic receptor density like blood pressure is regulated by androgens, and (3) increased renal alpha 2-adrenergic receptor density is not a consequence of high blood pressure in male SHR.
Pressure range for release of renomedullary depressor substance in rabbits.
Authors: Thomas C J , Woods R L , Gao Y , Anderson W P
Published: June 2012

We investigated the relation between renal perfusion pressure and the release of a renal vasodepressor substance in vivo to determine whether this substance was released at physiological pressures. We perfused the left kidneys of anesthetized rabbits using an extracorporeal circuit that allowed renal perfusion pressures to be set at 65 mm Hg (control) and increased to 95, 125, 155, or 185 mm Hg for 30-minute experimental periods. Systemic blood pressure did not change significantly when renal perfusion pressure was maintained at 65 mm Hg throughout. When renal perfusion pressure was increased to 95, 125, 155, or 185 mm Hg, systemic blood pressure fell significantly at rates of 0.17 +/- 0.04, 0.79 +/- 0.31, 0.60 +/- 0.11, and 2.18 +/- 0.79 mm Hg/min, respectively (P < .05). Restoration of renal perfusion pressure to 65 mm Hg abruptly reversed the falls in systemic blood pressure in each group. There was a natriuresis and diuresis that were both pressure related and progressive in the face of each constant level of increased renal perfusion pressure. In summary, there was a continuum of arterial vasodepressor responses across a renal perfusion pressure range from resting pressure to 185 mm Hg. We suggest that the threshold level for the release of significant amounts of a renal medullary depressor substance, probably medullipin, is just above normal arterial blood pressure and that the rate of release increases with increasing arterial pressure.
Mechanism of cyclosporine-induced sympathetic activation and acute hypertension in rats.
Authors: Lyson T , McMullan D M , Ermel L D , Morgan B J , Victor R G
Published: June 2012

Although intravenous cyclosporine A (CsA) previously has been shown to cause a robust sympathetically mediated increase in blood pressure in the rat, the underlying mechanism by which CsA increases the activity of the sympathetic nervous system is unknown. To determine the relative contributions of central neural versus peripheral reflex mechanisms in causing this sympathetic activation, we recorded efferent renal sympathetic nerve activity and blood pressure during intracerebroventricular or intravenous infusion of CsA, the latter performed in intact rats and in those with sinoaortic denervation, cervical or subdiaphragmatic vagotomy, or dorsal rhizotomy (T10 through L1). In intact rats, intravenous CsA (5 mg/kg), as expected, tripled renal sympathetic nerve activity and increased mean arterial pressure by 27 +/- 4 mm Hg (P < .05). The new findings are that this sympathoexcitatory effect of intravenous CsA (1) was not duplicated by central administration (either into the cerebroventricular system or directly onto the ventrolateral surface of the medulla), (2) was unaffected by sinoaortic denervation, but (3) was greatly attenuated by either cervical or subdiaphragmatic vagotomy or by dorsal rhizotomy. In additional experiments, we found that intravenous cyclosporine increased the multiunit activity of subdiaphragmatic but not cardiopulmonary vagal afferents. From these data, we conclude that in the rat CsA-induced increases in sympathetic activity and blood pressure are caused mainly by activation of excitatory neural reflexes arising in the subdiaphragmatic region. These reflex mechanisms use at least two different afferent neural pathways: one involving the subdiaphragmatic vagi and the other involving the low thoracic dorsal spinal roots.
Epidermal growth factor-enhanced human angiotensin II type 1 receptor.
Authors: Guo D F , Inagami T
Published: June 2012

The human angiotensin II type 1 (AT1) receptor gene was isolated and its promoter function analyzed by deletion mutant promoter/luciferase constructs in transfected Cos 7 cells. We found that epidermal growth factor enhanced the human AT1 promoter activity twofold to threefold. The region between -227 and -366 bp from the 5' end of the cDNA was mapped for a base sequence responsive to the epidermal growth factor stimulation. By computer analysis, PEA3 transcription factor was located in this region and was shown to bind to the promoter by gel shift assay in Cos 7 and HepG2 cells. These results indicated that the human AT1 receptor enhanced by epidermal growth factor may be due to PEA3 binding to the human AT1 promoter.
Endothelin mobilizes calcium and enhances glucose uptake in cultured human skeletal myoblasts and L6 myotubes.
Authors: Yang X Y , Fekete Z , Gardner J , Benevenia J , Aviv A
Published: June 2012

In this study we used endothelin as a paradigm to explore the concept that some vasoactive agents, acting through mobilization of Ca2+ and stimulation of protein kinase C, can interact with human skeletal muscle and modify its glucose transport. Cultured human skeletal myoblasts from the vastus lateralis demonstrated two subclasses of high-affinity endothelin receptors and a robust increase in cytosolic free Ca2+ upon exposure to endothelin. The endothelin-evoked rise in cytosolic free Ca2+ primarily resulted from Ca2+ mobilization from intracellular organelles. Both endothelin and insulin enhanced [3H]deoxy-D-glucose uptake in human myoblasts, but their effects were not additive. These findings also were observed in differentiated myotubes of L6 skeletal muscle cells. Moreover, [3H]deoxy-D-glucose uptake in human myoblasts was enhanced by treatment with phorbol 12-myristate 13-acetate. The endothelin- and insulin-mediated increases in [3H]deoxy-D-glucose were totally ablated by treatment with calphostin C. Such observations suggest that endothelin can enhance glucose uptake in human skeletal muscle. This is mediated through mechanisms that are at least partially protein kinase C dependent. Thus, increased levels of endothelin in vascular beds may contribute to altered glucose metabolism in essential hypertension.
Altered protein kinase C regulation of phosphoinositide-coupled receptors in deoxycorticosterone acetate-salt hypertensive rats.
Authors: Calderone A , Oster L , Moreau P , Rouleau J L , Stewart D J , de Champlain J
Published: June 2012

This study examined the contribution of phosphatidylinositol metabolism and the efficacy of protein kinase C-mediated desensitization in the exaggerated alpha 1b-adrenergic receptor-mediated inositol phosphate response in the aorta of the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension. The basal accumulation of inositol phosphates and the basal incorporation of [3H]myo-inositol in the phosphatidylinositol lipid pool were significantly higher in the aorta of these hypertensive rats. A positive correlation (r = .88, P < .01) was demonstrated between basal inositol phosphate levels and the [3H]myo-inositol-labeled phosphatidylinositol lipid pool. In hypertensive rats, alpha 1b-adrenergic receptor-mediated inositol phosphate production in response to phenylephrine was significantly higher compared with normotensive rats. Despite the normalization of phenylephrine-mediated inositol phosphate production to the [3H]myo-inositol-labeled phosphatidylinositol lipid pool, the alpha 1b-adrenergic response remained significantly higher in the hypertensive rats. Phorbol ester activation of protein kinase C attenuated to a lesser extent phenylephrine-mediated inositol phosphate production (40%) in the aorta of hypertensive rats compared with the 80% attenuation observed in the aorta of normotensive rats. This desensitization was inhibited in both groups by the protein kinase C inhibitor staurosporine. The blunted desensitization of the alpha 1b-adrenergic receptor by protein kinase C activation was not associated with a decrease in protein kinase C activity in the hypertensive rats, because aortic strips from these animals were more responsive to phorbol ester activation than aortic strips from normotensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts.
Authors: Isgaard J , Wåhlander H , Adams M A , Friberg P
Published: June 2012

Recent results suggest that insulin-like growth factor-I (IGF-I) may be involved in the transition of a hemodynamic load into cardiac hypertrophy and that the expression of IGF-I seems to be coupled to increased wall stress. The present study investigated the role of growth hormone (GH) and IGF-I in myocardial hypertrophy induced by volume overload. An aortocaval fistula (ACF) was created in male Wistar rats, and experiments were performed 2, 4, and 7 days after the onset of volume overload. Right and left ventricular (RV and LV, respectively) myocardial expression of GH receptor mRNA and IGF-I mRNA were quantitated by a solution hybridization RNase protection assay. RV GH receptor mRNA content was elevated on the fourth and seventh days after the induction of the shunt, with peak levels (0.63 +/- 0.16 versus 0.14 +/- 0.03 amol/microgram DNA for the sham-operated animals; P < .01) after 4 days. Similarly, IGF-I mRNA was significantly increased in the RV of shunted animals (1.26 +/- 0.13 versus 0.56 +/- 0.05 amol/micrograms DNA; P < .01) 7 days after surgery. In the left ventricle, where systolic pressure was reduced in ACF rats, no differences could be detected in GH receptor and IGF-I mRNA content between ACF and sham-operated rats on any of the experimental days. There was no difference in the ratio of RV to LV weight during the experimental period. We have shown that the thin-walled right ventricle responds to volume overload with an increase of GH receptor mRNA content followed by elevated expression of IGF-I mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Intraglomerular expression of alpha-smooth muscle actin in aging mice.
Authors: Romano L A , Ferder L , Inserra F , Ercole L , Gomez R A
Published: June 2012

To determine whether chronic treatment with enalapril initiated early in life prevents glomerular injury secondary to normal aging, CF1 mice received enalapril (20 mg/L, n = 10) or nifedipine (40 mg/L, n = 10) in their drinking water from the time of weaning to 12 months of life. Control mice (n = 10) received tap water ad libitum. Immunocytochemical detection of renin confirmed that angiotensin-converting enzyme inhibition resulted in recruitment of renin-containing cells along the preglomerular vessels. Morphometric analysis of glomeruli included assessment of glomerular diameter and the percentage of mesangial area per glomerulus. Glomerular diameter and mesangial area were higher in control mice (99.7 +/- 0.5 microns, 12.7 +/- 0.3%) than in enalapril-treated mice (88 +/- 0.8 microns, 8.6 +/- 0.6%) (P < .05). Glomerular diameter and mesangial area in the nifedipine-treated group (99.1 +/- 0.9 microns, 12.4 +/- 0.9%) were not different from control mice. These results demonstrate that angiotensin-converting enzyme inhibition prevents the glomerular enlargement and mesangial expansion observed during natural aging. In addition, control glomeruli expressed alpha-smooth muscle actin in a mesangial distribution. This effect was prevented by enalapril treatment but not by nifedipine. We conclude that long-term treatment with enalapril from early life prevents the early changes associated with glomerular injury and expression of alpha-smooth muscle actin in the glomerulus. alpha-Smooth muscle actin may participate in and serve as an early marker of the glomerular injury during the normal aging process.
Hypertension induced by nitric oxide synthesis inhibition is renal nerve dependent.
Authors: Matsuoka H , Nishida H , Nomura G , Van Vliet B N , Toshima H
Published: June 2012

Recent studies have indicated that chronic administration of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, produces marked hypertension. Although the mechanism of this form of hypertension is not well understood, several studies have demonstrated that sympathetic nerve activity is at least acutely elevated after L-NAME administration. To evaluate the potential role of the renal sympathetic nerves in L-NAME-induced hypertension, we compared the blood pressure response to L-NAME in four groups of Sprague-Dawley rats (n = 8 each): (1) sham-operated vehicle-treated, (2) sham-operated L-NAME-treated, (3) denervated vehicle-treated, and (4) denervated L-NAME-treated. After renal denervation or sham surgery, L-NAME was added to the drinking water (70 mg/100 mL) for 4 weeks, and arterial pressure was measured weekly by the tail-cuff method. L-NAME treatment caused a progressive increase in arterial pressure in sham-operated rats, rising to 154 +/- 6 mm Hg by week 4 of treatment compared with 115 +/- 2 mm Hg in the vehicle-treated sham-operated group (P < .005). In contrast, the development of hypertension was significantly delayed and attenuated in renal-denervated rats treated with L-NAME. The results of our study suggest that L-NAME-induced hypertension may be partly mediated by or is at least dependent on the integrity of the renal nerves.
High calcium diet prevents baroreflex impairment in salt-loaded spontaneously hypertensive rats.
Authors: Ono A , Kuwaki T , Cao W H , Kumada M , Fujita T
Published: June 2012

To investigate the role of the sympathetic control mechanism in the antihypertensive effect of dietary calcium supplementation, we examined whether a high calcium diet affected mean arterial pressure, renal sympathetic nerve activity, heart rate, and overall and central properties of the arterial baroreceptor reflex in salt-loaded young spontaneously hypertensive rats (SHR). Six-week-old SHR were fed either a normal (0.66%) or high (8.00%) salt diet with either a normal (1.17%) or high (4.07%) calcium content for 4 weeks. The arterial baroreceptor reflex was elicited with rats under halothane anesthesia by altering mean arterial pressure with nitroprusside or phenylephrine. The overall property of the arterial baroreceptor reflex was assessed by the median mean arterial pressure (MAP50) and maximal gain (Gmax) of the relation between mean arterial pressure and renal sympathetic nerve activity and between mean arterial pressure and heart rate. The central property of the arterial baroreceptor reflex was assessed by reflex inhibition of renal sympathetic nerve activity and heart rate elicited by electrical stimulation of the aortic depressor nerve. Compared with the control group fed a normal salt/normal calcium diet, the high salt/normal calcium group had significantly higher mean arterial pressure and renal sympathetic nerve activity but not heart rate. Moreover, the arterial baroreceptor reflex was impaired in the latter group, as evidenced by an increase in MAP50 and decrease in Gmax of the two relations and an attenuation of reflex inhibition of renal sympathetic nerve activity by aortic depressor nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic patients. Pharmacodynamic effects on beta 2-adrenergic receptors.
Authors: Bauer K , Kaik G , Kaik B
Published: June 2012

This study investigated the effects of an osmotic release oral drug delivery system of metoprolol on the changes induced by cumulative doses of inhaled salbutamol on bronchomotor tone, skeletal muscle, and the circulatory system after single (day 1) and multiple (day 7) dosing in 18 hypertensive asthmatic patients (forced expiratory volume in 1 second > 50% predicted; diastolic blood pressure > 90 mm Hg). The patients were given 14/190 mg metoprolol, 100 mg atenolol, and placebo once daily for a 7-day period each in a randomized, double-blind, crossover design. At the estimated time of peak plasma concentrations, cumulative doses of salbutamol (12.5, 37.5, 112.5, 412.5, 812.5, and 1612.5 micrograms) were applied every 20 minutes. Specific airway conductance, finger tremor amplitude, heart rate, and blood pressure were registered at baseline and at each dose increment. The slopes of the salbutamol dose-response curves of specific airway conductance did not differ on day 1 (P > .05). On day 7, atenolol caused a shift of the dose-response curves of specific airway conductance to the right (P < .05), whereas metoprolol was indistinguishable from placebo (P > .05). The median cumulative salbutamol concentrations causing a 50% increase in specific airway conductance were 416 and 384 micrograms (days 1 and 7, respectively) for placebo, 594 and 444 micrograms for metoprolol, and 562 and 1419 micrograms for atenolol. The median cumulative salbutamol concentrations causing a 35% increase in tremor were 732 and 706 micrograms for placebo, 812 and 1213 micrograms for metoprolol, and 797 and 1323 micrograms for atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of treppe and calcium on intracellular calcium and function in the failing heart from the spontaneously hypertensive rat.
Authors: Brooks W W , Bing O H , Litwin S E , Conrad C H , Morgan J P
Published: June 2012

We studied functional and intracellular calcium responses to treppe and extracellular calcium in spontaneously hypertensive rat (SHR) hearts during the transition from compensated pressure overload to failure. Intracellular calcium was measured using aequorin, a bioluminescent Ca2+ indicator. Experiments were performed with intact, isovolumically contracting, buffer-perfused hearts from three rat groups: (1) aging SHR with evidence of heart failure (SHR-F), (2) age-matched SHR with no evidence of heart failure (SHR-NF), and (3) age-matched normotensive Wistar-Kyoto (WKY) rats. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Hearts were studied at 30 degrees C and paced at a rate of 1.6 Hz while being perfused with oxygenated Krebs-Henseleit solution (95% O2/5% CO2) at 100 mm Hg. At the baseline state, peak systolic pressure was greatest in the SHR-NF group and lowest in the SHR-F group. Peak and resting [Ca2+]i were not significantly different among groups; however, the calcium transient was prolonged in the SHR-NF and SHR-F groups. With increasing perfusate [Ca2+]o from 0.5 to 3.0 mmol/L, the relative increases in peak [Ca2+]i and peak systolic pressure were similar among groups. When stimulation rate was increased from 1.6 to 2.0, 2.4, 2.8, and 3.2 Hz, peak [Ca2+]i, peak systolic pressure, and +/- dP/dt fell in SHR-F hearts. Peak systolic pressure decreased in the SHR-NF group at rates above 2.4 Hz but did not decline in the WKY group. Peak [Ca2+]i increased in the WKY and SHR-NF groups with increasing heart rates. Peak systolic pressure did not fall significantly in the WKY group at any heart rate. Elevation of diastolic [Ca2+]i and/or calcium transient and pressure alternans were present in 8 of 13 SHR-F hearts at the highest stimulation rate, findings that were absent in both the WKY and SHR-NF hearts. We conclude the following: (1) Under baseline conditions, depressed contractile function of failing myocardium cannot be explained by decreased peak [Ca2+]i, (2) relative increases in [Ca2+]i and inotropy with increasing [Ca2+]o are proportional among groups; and (3) although peak systolic [Ca2+]i and inotropy are maintained with increasing stimulation rate in the WKY and SHR-NF groups, peak systolic [Ca2+]i and pressure decrease in parallel in the SHR-F heart with increasing stimulation rate, suggesting that impaired calcium cycling may contribute to compromised pump function in the SHR-F heart.
Reduced sodium-proton exchange activity in lymphocytes from transgenic rats.
Authors: Tepel M , Klaus T , Laukemper S , Zidek W
Published: June 2012

We investigated sodium-proton (Na(+)-H+) exchange activity in transgenic TGR(mRen-2)27 rats, a strain showing fulminant hypertension after the mouse Ren-2d renin gene has been integrated into its genome, in age-matched normotensive Sprague-Dawley (SD) rats, in spontaneously hypertensive rats (SHR) from the Münster strain, and in normotensive Wistar-Kyoto (WKY) rats. From each strain Na(+)-H+ exchange activity was determined in lymphocytes using the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) by measuring the recovery rate of cytosolic pH (pHi) after intracellular acidification. Resting pHi was not significantly different in transgenic rats (n = 10) compared with SD rats (n = 10) (7.305 +/- 0.038 versus 7.337 +/- 0.031; mean +/- SEM), but resting pHi was significantly lower in lymphocytes from SHR (n = 12) compared with their normotensive WKY counterparts (n = 12) (7.232 +/- 0.030 versus 7.377 +/- 0.022; P < .01). Na(+)-H+ exchange activity was significantly lower in lymphocytes from transgenic rats compared with SD rats (5.102 +/- 0.561 versus 7.385 +/- 0.491 x 10(-3) dpHi/s; P < .01), whereas Na(+)-H+ exchange was significantly enhanced in lymphocytes from SHR compared with WKY rats (5.564 +/- 0.432 versus 3.921 +/- 0.433 x 10(-3) dpHi/s; P < .05). The apparent half-maximal activation of Na(+)-H+ exchange was not significantly different in the strains tested. The present study indicates that hypertension in transgenic rats is not related to Na(+)-H+ exchange overactivity.
Cloning of the alpha-subunit of GS protein from spontaneously hypertensive rats.
Authors: Gurich R W , Beach R E , Caflisch C R
Published: June 2012

Enhanced sodium reabsorption by the kidney has a significant role in the development of genetic hypertension. In the spontaneously hypertensive rat (SHR) model of genetic hypertension, the enhanced sodium reabsorption likely arises from abnormal hormonal regulation of tubular transport. Since hormonal signaling pathways are coupled frequently via GTP binding proteins, one explanation for hormonal abnormalities in SHR would be a defect in a GTP binding protein or proteins. Recent work has suggested that the regulation of Na+,K(+)-ATPase activity by cholera toxin-sensitive GTP binding proteins is abnormal in SHR. The purpose of the present studies was to clone the alpha S-subunit, which is the subunit ADP ribosylated by cholera toxin, of GS protein to determine whether it is abnormal in SHR. Reverse transcription-polymerase chain reaction was able to detect mRNA for alpha S in both Wistar-Kyoto (WKY) rats and SHR. Northern analysis indicated that equivalent amounts of alpha S mRNA were present in WKY rats and SHR. S1 nuclease analysis demonstrated that there was no difference in the amount of alpha S short and long forms between WKY rats and SHR. Subcloning and sequencing of polymerase chain reaction products from WKY rats and SHR indicated that the alpha S forms present in renal cortex were identical. ADP ribosylation studies with cholera toxin demonstrated the presence of equivalent amounts of alpha S protein in WKY rats and SHR. Taken together, these results suggest that the abnormal regulation of Na+,K(+)-ATPase activity by a cholera toxin-sensitive pathway in SHR does not arise from a defect in the alpha S subunit.
Dyslipoproteinemic changes in borderline hypertension.
Authors: Lemne C , Hamsten A , Karpe F , Nilsson-Ehle P , de Faire U
Published: June 2012

The present study examined plasma lipoprotein, lipoprotein lipase, hepatic lipase, and insulin levels in men with borderline hypertension (diastolic blood pressure 85 to 94 mm Hg) compared with age-matched normotensive control subjects (diastolic blood pressure less than or equal to 80 mm Hg, n = 75 + 75). High-density lipoprotein (HDL) subclasses were determined in a subset (n = 45 + 45). While total and low-density lipoprotein cholesterol levels were similar, levels of very-low-density lipoprotein (VLDL) cholesterol and triglycerides (0.46 versus 0.41 mmol/L, P = .027, and 1.0 versus 0.85 mmol/L, P = .031) and total triglycerides (1.53 versus 1.33 mmol/L, P = .009) were elevated and HDL cholesterol was reduced in the borderline group compared with the normotensive group (1.17 versus 1.26 mmol/L, P = .043). The HDL subclass HDL2b concentration was lower (0.16 versus 0.24 mmol/L, P = .006), while HDL3b and HDL3c concentrations were higher in the borderline group (0.38 versus 0.32 mmol/L, P = .016, and 0.19 versus 0.16 mmol/L, P = .042). Significantly higher activities of hepatic lipase in the borderline group (282 versus 232 mU/mL, P = .024) and significant correlations between lipoprotein lipase activity and VLDL and HDL concentrations suggest an involvement of these enzymes in the development of these differences. When adjusted for body mass index or insulin level, all differences disappeared, except for HDL3b and HDL3c concentrations, which remained significantly elevated. These results indicate that dyslipoproteinemic changes are present in early hypertension. Although most of these changes are related to obesity, alterations in HDL profile were not explained by influences of body mass index and insulin.
Augmented responses to intrathecal nicotinic agonists in spontaneous hypertension.
Authors: Khan I M , Printz M P , Yaksh T L , Taylor P
Published: June 2012

Abnormal central cholinergic activity has been reported to be responsible in part for the pathogenesis of high blood pressure in spontaneously hypertensive rats (SHR). Administration of cholinergic agonists in brain and spinal cord results in exaggerated pressor responses in SHR. Studies to date have focused largely on the muscarinic cholinergic system. Recently, we demonstrated that intrathecal administration of nicotinic agonists results in pressor, tachycardic, and irritation responses. In the present study we examine the cardiovascular and behavioral responses to nicotine and cytisine administered intrathecally in La Jolla strain (LJ) SHRLJ and age-matched Wistar-Kyoto (WKYLJ) rats. Nicotinic agonists produced augmented pressor, heart rate, and irritation responses in SHRLJ compared with normotensive rats. In both SHRLJ and WKYLJ rats, cytisine elicited a greater nociceptive response and greater spinobulbar component to the pressor response than nicotine. SHRLJ and WKYLJ rats also differ in that the SHRLJ strain shows a diminished tendency for desensitization to cytisine. As in Sprague-Dawley rats, in SHRLJ and WKYLJ rats the cardiovascular and behavioral responses to intrathecal nicotine were significantly inhibited by mecamylamine, dihydro-beta-erthyroidine, and methyllycaconitine. However, methyllycaconitine, which effectively blocked cytisine-elicited cardiovascular and behavioral responses in Sprague-Dawley and WKYLJ rats, was unable to inhibit the maximal rise in cystine-elicited blood pressure, heart rate, and irritation responses in SHRLJ. In contrast to the heightened cardiovascular and behavioral responses, the number of nicotinic binding sites in spinal cord membranes was significantly decreased in the hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Modulatory effects of endogenous adenosine on epinephrine secretion from the adrenal medulla of the rat.
Authors: Tseng C J , Ho W Y , Lin H C , Tung C S , Kuan C J
Published: June 2012

The purpose of this study was to examine (1) whether endogenous adenosine receptors inhibit the release of epinephrine and norepinephrine from adrenal medulla in response to physiological and pharmacological stimuli and (2) whether the renin-angiotensin system modulates this effect of endogenous adenosine. We used a conscious animal model to approximate normal physiological conditions. Male Sprague-Dawley rats were treated with a surface adenosine receptor antagonist, 1,3-dipropyl- 8-(p-sulfophenyl)xanthine (DPSPX) to explore the effect of endogenous adenosine. Plasma epinephrine and norepinephrine levels in response to hydralazine-induced hypotension were measured in these animals. The same protocol was repeated in rats pretreated with either adrenalectomy or captopril. The results showed that DPSPX treatment significantly increased plasma epinephrine and norepinephrine levels at both baseline conditions and after hydralazine-induced hypotension. The results from the adrenalectomized rats showed that the difference in plasma epinephrine level between the control and DPSPX groups originated from the adrenal medulla. Pretreatment with captopril attenuated the rise of plasma epinephrine and norepinephrine levels in DPSPX-treated animals. This result suggests that endogenous adenosine receptors inhibit epinephrine release from the adrenal medulla and suppress plasma norepinephrine levels. When catecholamine release was stimulated by physiological and pharmacological stimuli, this inhibitory function of adenosine receptors was augmented. The renin-angiotensin system is at least partially responsible for the modulatory function of endogenous adenosine on the catecholamine response as demonstrated in this study.
Systematic difference between blood pressure readings caused by cuff type.
Authors: Bovet P , Hungerbuhler P , Quilindo J , Grettve M L , Waeber B , Burnand B
Published: June 2012

In this study we determine whether blood pressure readings using a cuff of fixed size systematically differed from readings made with a triple-bladder cuff (Tricuff) that automatically adjusts bladder width to arm circumference and assessed subsequent clinical and epidemiological effects. Blood pressure was measured with a standard cuff or a Tricuff in 454 patients visiting an outpatient clinic in the Seychelles (Indian Ocean). Overall means of within-individual standard cuff-Tricuff differences in systolic and diastolic blood pressures were examined in relation to arm circumference and sex. The standard cuff-Tricuff difference in systolic and diastolic blood pressures increased monotonically with circumference (from 4.7 +/- 0.8/3.2 +/- 0.7 mm Hg for arm circumference of 30 to 31 cm to 10.0 +/- 1.1/8.0 +/- 0.9 mm Hg for arm circumference > or = 36 cm) and was larger in women than men. Multivariate linear regression indicated independent effects of arm circumference and sex. Forty percent of subjects with a diastolic blood pressure of > or = 95 mm Hg measured with a standard cuff had values less than 95 mm Hg measured with a Tricuff. Extrapolation to the entire population of the Seychelles decreased the prevalence of blood pressure greater than or equal to 160/95 mm Hg by 11.5% and 24.0% in men and women, respectively, aged 35 to 64 years. The age-adjusted effect of body mass index on systolic and diastolic blood pressures decreased twofold using blood pressure readings made with a Tricuff instead of a standard cuff.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased Prevalence of Hypertension and Long-term Arsenic Exposure
Authors: Chen Chien-Jen , Hsueh Yu-Mei , Lai Mei-Shwu , Shyu Mei-Pyng , Chen Shu-Yuan , Wu Meei-Maan , Kuo Tsung-Li , Tai Tong-Yuan
Published: June 2012

Abstract
To examine the association between long-term exposure to inorganic arsenic and the prevalence of hypertension, we studied a total of 382 men and 516 women residing in villages where arseniasis was hyperendemic. Hypertension was defined as a systolic blood pressure of 160 mm Hg or greater, a diastolic blood pressure of 95 mm Hg or greater, or a history of hypertension treated regularly with antihypertensive drugs. The long-term arsenic exposure was calculated from the history of artesian well water consumption obtained through standardized interviews based on a structured questionnaire and the measured arsenic concentration in well water. Residents in villages where long-term arseniasis was hyperendemic had a 1.5-fold increase in age- and sex-adjusted prevalence of hypertension compared with residents in nonendemic areas. Duration of artesian well water consumption, average arsenic concentration in drinking water, and cumulative arsenic exposure were all significantly associated with hypertension prevalence. The higher the cumulative arsenic exposure, the higher the prevalence of hypertension. This dose-response relation remained significant after adjustment for age, sex, diabetes mellitus, proteinuria, body mass index, and serum triglyceride level. The results suggest that long-term arsenic exposure may induce hypertension in humans.
Role of Nitric Oxide in the Regulation of Coronary Vascular Tone in Hearts From Hypertensive Rats
Authors: Kelm Malte , Feelisch Martin , Krebber Thomas , Deußen Andreas , Motz Wolfgang , Strauer Bodo E.
Published: June 2012

Abstract
In arterial hypertension, coronary flow reserve, expressed by the difference between autoregulated and maximal coronary flow, is frequently impaired. Previous experimental and clinical investigations using acetylcholine as a stimulus for the production of endothelium-derived relaxing factor suggested that an impaired endothelium-dependent vasodilation, presumably caused by a decreased formation of nitric oxide (NO), may account for this microvascular dysfunction. However, so far no study has been performed that quantifies the formation of NO within the coronary circulation of hypertensive hearts to assess its role in setting coronary vascular tone in the hypertensive heart. We therefore quantified NO formation within the coronary circulation of constant flow–perfused, isolated hearts from spontaneously hypertensive rats (SHR, 16th to 26th week), as a model for hypertensive heart disease, and from the normotensive control strain (Wistar-Kyoto, WKY) using the oxyhemoglobin technique. Coronary perfusion pressure and vascular resistance were almost 30% higher in SHR compared with WKY hearts. Intracoronarily applied NO decreased coronary vascular resistance by maximally 45% of resting values in a concentration-dependent manner in both groups. The bradykinin-induced decrease in coronary vascular resistance and the parallel increase in NO release were comparable in SHR and WKY hearts and fell within the vasodilator range of exogenously applied NO. Moreover, basal release of NO normalized to heart wet weight was 50% higher in SHR compared with WKY hearts. Rates of basal NO release were correlated inversely with changes in coronary perfusion pressure and vascular resistance in both groups (
r
=−.85 and −.84, respectively,
P
<.05). This relation between resting coronary vascular resistance and NO formation, as a critical determinant of coronary flow, was shifted significantly to higher levels in SHR. From the present data we conclude that in the coronary circulation of SHR, NO formation is preserved under basal and stimulated conditions and critically determines resting coronary resistance. Moreover, the enhanced basal release of NO may serve the purpose of compensating the higher coronary vascular resistance of hypertensive hearts.
Natriuretic Peptides Inhibit DNA Synthesis in Cardiac Fibroblasts
Authors: Cao Li , Gardner David G.
Published: June 2012

Abstract
We have examined the effects of the natriuretic peptides on DNA synthesis in primary cultures of neonatal rat cardiac fibroblasts. Binding analysis using
125
I-labeled atrial natriuretic peptide identified a single class of high-affinity binding sites (
K
d
=0.03±0.01 nmol/L) in these cells. Of these sites, 80% appear to be of the natriuretic peptide C receptor subtype, with the remainder being A and B receptor subtypes. Northern blot analysis confirmed the presence of all three natriuretic peptide receptors in these cells. Atrial natriuretic peptide (10
−7
mol/L) effected a modest but consistent reduction in both agonist- and stretch-stimulated [
3
H]thymidine incorporation (17% to 41%). Moreover, brain natriuretic peptide (10
−7
mol/L), C-type natriuretic peptide (10
−7
mol/L), and des-[Gln
18
,Ser
19
,Gly
20
,Leu
21
,Gly
22
]-ANF 4-23-NH
2
(10
−7
to 10
−6
mol/L) all proved capable of antagonizing growth factor–dependent [
3
H]thymidine incorporation (the inhibition ranged from 14% to 28%) and cell proliferation, suggesting that all three natriuretic peptide receptor subtypes are involved in the regulation of mitogenesis in these cultures. The inhibition by atrial natriuretic peptide was amplified by cotreatment with phosphodiesterase inhibitors. Similar reduction in [
3
H]thymidine incorporation was seen after treatment with 8-bromo-cGMP (10
−4
to 10
−3
mol/L) or nitroprusside (10
−4
to 10
−3
mol/L). These results suggest an important paracrine role for the natriuretic peptides in regulating fibroblast growth during cardiac hypertrophy.
Carotid Artery Mechanical Properties of Dahl Salt-Sensitive Rats
Authors: Benetos Athanase , Bouaziz Hervé , Albaladejo Pierre , Guez David , Safar Michel E.
Published: June 2012

Abstract
We evaluated the mechanical properties of the carotid artery in anesthetized Dahl rats with or without long-term treatment with the diuretic compound indapamide. The mechanical properties of the carotid artery were evaluated by establishing pressure-volume curves in situ in vivo before and after total relaxation of arterial smooth muscle by potassium cyanide. Dahl salt-sensitive and salt-resistant rats were fed either a low (0.4%) or high (7%) NaCl diet for 5 weeks. In each group, half the rats received for the same period of time oral treatment with indapamide (3 mg/kg per day). Blood pressure, heart rate, and pressure-volume curves were studied at the end of the 5-week period. In untreated Dahl salt-sensitive rats, the pressure-volume curve of the carotid artery was shifted to the right compared with that in untreated Dahl salt-resistant rats. The finding was observed even after potassium cyanide and regardless of the NaCl diet (
P
<.01 between Dahl salt-sensitive and -resistant rats). Indapamide was able to prevent the development of hypertension in Dahl salt-sensitive rats receiving a high NaCl diet (185±7 versus 146±8 mm Hg in untreated and treated Dahl salt-sensitive rats with a high NaCl diet,
P
<.0005). In the other groups, indapamide had no effect on blood pressure. Indapamide treatment increased carotid arterial static compliance in Dahl salt-sensitive rats with a high or low NaCl diet and to a lesser extent in Dahl salt-resistant rats. The increase was observed even after total relaxation of carotid arterial smooth muscle by potassium cyanide. These results suggest that (1) the mechanical properties of the carotid arteries were altered in Dahl salt-sensitive rats independently of NaCl diet and transmural pressure changes, and (2) the diuretic compound indapamide prevented the disturbed mechanical properties of the carotid artery in Dahl salt-sensitive rats with a high or low NaCl diet, acting on both arterial structure and function. Sodium sensitivity (and not sodium intake) influences the changes in the carotid artery mechanical properties of Dahl rats.