bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropeptide Y in rat sympathetic neurons is altered by genetic hypertension and by age.
Authors: Gurusinghe C J , Harris P J , Abbott D F , Bell C
Published: June 2012

We have used immunocytochemistry to quantitate neuronal neuropeptide Y in superior cervical ganglia of a strain of normotensive Wistar-Otago rats and a related genetically hypertensive strain over the age range 1-60 weeks. The numbers of neuropeptide Y-immunoreactive cells and total ganglionic cell numbers were both greater in ganglia of young normotensive than in those of hypertensive rats. Between 10 and 60 weeks of age, peptide immunoreactivity and total cell numbers both fell in normotensive rat ganglia but remained constant in ganglia from hypertensive rats. Densitometric analysis showed that the concentrations of neuropeptide Y were similar in neurons of age-matched individuals of both strains, but during aging there was a substantial decline in neuronal peptide content that was similar in both strains and that was not accompanied by any decline in neuronal immunoreactivity for tyrosine hydroxylase. Our results suggest that there is a developmental abnormality of neuropeptide Y in sympathetic neurons of this strain of genetically hypertensive rat and that, furthermore, the aging process is accompanied by a selective loss of neuronal neuropeptide Y that is independent of blood pressure status.
Antirenin immunization versus angiotensin converting enzyme inhibition in rats.
Authors: Lo M , Julien C , Michel J B , Vincent M , Cerutti C , Gomez-Sanchez C E , Sassard J
Published: June 2012

The effects of specific active immunization against renin were compared with those of chronic angiotensin converting enzyme (ACE) inhibition. Male spontaneously hypertensive rats (SHR) were immunized (SHR-I) (n = 10) against pure murine renin (four injections of 30 micrograms/kg s.c.) or received (SHR-P) (n = 11) a converting enzyme inhibitor (perindopril, 2 mg/kg/day per os for 4 weeks). Sham-immunized SHR (SHR-S) (n = 12) and normotensive Wistar-Kyoto (WKY-S) (n = 12) rats served as controls. At 15 weeks of age, 24-hour average blood pressure was obtained in freely moving rats using intra-aortic pressure recording with computer analysis. Antirenin immunization induced high circulating titers of antibodies, a fall in plasma renin activity (-95%), and urinary excretion of mineralocorticoids. Perindopril abolished the pressor response to angiotensin I, whereas plasma ACE was only partly (-56%) decreased. It also increased plasma renin activity and did not alter the urinary excretion of steroids. Both immunization and perindopril allowed the blood pressure of SHR to return to the level of WKY-S rats and reduced the left ventricular weight. These decreases were associated with an elevated sympathetic nervous system activity as indicated by increases in the urinary excretion of catecholamines and their metabolites. It is conclude that, apart from an unaltered steroid synthesis, most of the cardiovascular effects of chronic ACE inhibition are similar to those of antirenin immunization, thus indicating that blockade of the circulating and renal renin-angiotensin system accounts for most of the effects of ACE inhibitors.
Variations in the apparent pH set point for activation of platelet Na-H antiport.
Authors: Tokudome G , Tomonari H , Gardner J P , Aladjem M , Fine B P , Lasker N , Gutkin M , Byrd L H , Aviv A
Published: June 2012

To explore the role of the Na-H antiport in essential hypertension, we studied the kinetics of cytosolic pH and external sodium activation of this transport system in platelets from 65 normotensive and essential hypertensive subjects on and off antihypertensive medications. Subjects included both blacks and whites, as well as men and women. The fluorescent dye 2'7-bis(carboxyethyl)-5,6-carboxyfluorescein was used to monitor the cytosolic pH in these cells. Platelets from black (hypertensive and normotensive) men and hypertensive white men demonstrated a highly significant alkaline shift in the apparent cytosolic pH set point for activation of the Na-H antiport. For the hypertensive subgroups, the cytosolic pH set point values (mean +/- SEM) were: white men, 7.45 +/- 0.052; white women, 7.04 +/- 0.089; black men, 7.66 +/- 0.148; and black women, 7.20 +/- 0.082. For the normotensive subgroups, the cytosolic pH set point values were: white men, 7.13 +/- 0.034; white women, 7.05 +/- 0.036; black men, 7.50 +/- 0.110; and black women, 7.20 +/- 0.176 (p = 0.0016 for race and p = 0.0001 for gender, using a three-way analysis of variance by race, gender, and hypertension). There were no race-, gender-, or blood pressure-related differences among the various cohorts in the kinetics of sodium activation of the Na-H antiport, the cellular buffering power, and basal pH. These results suggest that at basal pH the Na-H antiport is quiescent in platelets from both black and white women and normotensive white men.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension in the spontaneously hypertensive rat is linked to the Y chromosome.
Authors: Ely D L , Turner M E
Published: June 2012

The objective of our study was to determine the genetic influence on blood pressure in spontaneously hypertensive rats (SHR), and normotensive Wistar-Kyoto (WKY) rats using genetic crosses. Blood pressure was measured by tail sphygmomanometry from 8 to 20 weeks of age. Blood pressure was significantly higher from 12 to 20 weeks in the male offspring derived from WKY mothers x SHR fathers as compared with male offspring derived from SHR mothers X WKY fathers (180 +/- 4 versus 160 +/- 5 mm Hg, p less than 0.01). There was no significant difference between the blood pressure of the F1 females, further supporting Y chromosome linkage and not parental imprinting. The blood pressure data from F2 males derived from reciprocal crosses of parental strains were consistent with the presence of a Y-linked locus, but not with an X-linked locus controlling blood pressure. The data strongly suggest that hypertension in the SHR has two primary components of equal magnitude, one consisting of a small number of autosomal loci with a second Y-linked component.
Glucocorticoids and atrial natriuretic factor receptors on vascular smooth muscle.
Authors: Yasunari K , Kohno M , Murakawa K , Yokokawa K , Takeda T
Published: June 2012

The effect of glucocorticoids on the atrial natriuretic factor (ANF)-mediated formation of cyclic guanosine monophosphate (cGMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from the renal arteries of 14-week-old Wistar rats by the explant method. Micromolar concentrations of dexamethasone, given as pretreatment for 48 hours, suppressed the ANF-mediated response. The dexamethasone-induced suppression was detectable at 6 hours and reached a maximum 24 hours after administration in a dose-dependent manner. Inhibitors of protein synthesis blocked this effect of the glucocorticoid. The basal activity of guanylate cyclase in the dexamethasone-treated cells was lower than in the control cells. Other steroids having glucocorticoid action mimicked this suppression of the ANF-mediated response. This suppression was blocked by a glucocorticoid receptor antagonist. The results suggest that glucocorticoids suppress ANF-mediated cGMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis. Suppression of the ANF-mediated response may play a role in glucocorticoid-induced hypertension.
Role of the adrenal renin-angiotensin system on adrenocorticotropic hormone- and potassium-stimulated aldosterone production by rat adrenal glomerulosa cells in monolayer culture.
Authors: Yamaguchi T , Naito Z , Stoner G D , Franco-Saenz R , Mulrow P J
Published: June 2012

The rat zona glomerulosa has a renin-angiotensin system that appears to function as an autocrine or paracrine system in the regulation of aldosterone production. To further investigate dynamic changes of production of renin and aldosterone in vitro we developed a primary monolayer culture of rat adrenal glomerulosa cells in serum-free medium. Collagenase-dispersed glomerulosa cells were incubated in PFMR-4 medium containing 10% fetal calf serum for 48 hours; the medium was then replaced with serum-free PFMR-4 medium. The cell viability and the aldosterone secretion were stable over the additional 48 hours in the serum-free control medium. After incubation for 24 hours in the serum-free medium, the cells were exposed to high K+ or adrenocorticotropic hormone (ACTH) for another 24 hours. ACTH stimulated aldosterone secretion, and this increased secretion was associated with an increase in renin activity (cell active renin, from 15.56 +/- 0.71 to 45.75 +/- 5.69; cell inactive renin, from 0.67 +/- 0.54 to 8.75 +/- 3.40; medium inactive renin, from 5.58 +/- 1.16 to 106.20 +/- 14.01 pg angiotensin I (Ang I)/micrograms protein/3 hr). Aldosterone was also stimulated by high K+. This increase was also associated with an increase in active renin in the cells (from 15.08 +/- 1.80 to 23.26 +/- 2.15 pg Ang I/micrograms protein/3 hr) and an increase in inactive renin in the medium (from 10.87 +/- 1.62 to 21.37 +/- 3.20 pg Ang I/micrograms protein/3 hr). Addition of the angiotensin converting enzyme inhibitor lisinopril attenuated both ACTH- and high K(+)-stimulated aldosterone secretion significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Rapid baroreceptor resetting in chronic hypertension. Implications for normalization of arterial pressure.
Authors: Xie P L , McDowell T S , Chapleau M W , Hajduczok G , Abboud F M
Published: June 2012

The purpose of this study was to examine the ability of baroreceptors of renal hypertensive rabbits to reset rapidly during acute changes in arterial pressure. The carotid sinus (CS) was vascularly isolated and baroreceptor activity was recorded during slow ramp increases in CS pressure in hypertensive (one-kidney, one wrap; 127 +/- 3 mm Hg) and normotensive (one-kidney, no wrap; 85 +/- 3 mm Hg) rabbits anesthetized with chloralose. Control measurements were made after holding pressure for 10-15 minutes at the level of arterial pressure recorded before each experiment. Baroreceptor threshold pressure (Pth) was higher in hypertensives (78 +/- 4 mm Hg) compared with normotensives (55 +/- 3 mm Hg, p less than 0.05), and nerve activity was less in hypertensives over a wide range of pressure. CS distensibility (sonomicrometers) was not significantly different in the two groups. After increasing holding pressure from control by 30 and 60 mm Hg for 10-15 minutes, the extent of baroreceptor resetting (delta Pth/delta holding pressure x 100%) in normotensives was 39 +/- 6% and 33 +/- 2%, respectively, but only 14 +/- 5% and 9 +/- 3% in hypertensives (p less than 0.05). After decreasing holding pressure by 30 and 60 mm Hg, resetting was similar in normotensives (32 +/- 6% and 28 +/- 3%) and hypertensives (34 +/- 3% and 30 +/- 4%). In hypertensive rabbits, acute (10-15 minutes) exposure of baroreceptors to normotension (71 +/- 4 mm Hg) decreased Pth to 62 +/- 4 mm Hg and increased nerve activity to levels not significantly different from those of normotensive animals without altering CS distensibility.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging escalates baroreceptor reflex suppression by the posterior hypothalamus in rats.
Authors: Tanabe S , Buñag R D
Published: June 2012

To examine whether baroreceptor reflex regulation by the posterior hypothalamus becomes modified with age, we compared baroreceptor reflex sensitivity and hypothalamic responsiveness in 2- and 10-month-old rats anesthetized with urethane-chloralose. Hypothalamic regulation of baroreceptor reflex sensitivity was assessed by recording responses to intravenously infused phenylephrine and afferent aortic nerve stimulation after sham operation or electrolytic destruction of the posterior hypothalamus. Regardless of age, reflex bradycardia and sympathoinhibition elicited during pressor responses to phenylephrine, as well as all cardiovascular and sympathetic nerve responses to afferent aortic nerve stimulation, were stronger in rats with bilateral hypothalamic lesions than in age-matched, sham-operated controls. Distinctively, because baroreceptor reflex sensitivity differed with age only in sham-operated controls but not in lesioned rats, we concluded that age-related differences in baroreceptor reflex sensitivity had been abolished by posterior hypothalamic lesions. Other experiments were then performed to compare responses to graded electrical stimulation of the posterior hypothalamus in baroreceptor-intact rats. Pressor and sympathoexcitatory responses to hypothalamic stimulation were larger, and stimulus thresholds were lower at 10 than at 2 months of age thereby suggesting that hypothalamic responsiveness had increased with age. Our results are in accord with the interpretation that aging exacerbates the baroreceptor reflex suppression normally exerted by the posterior hypothalamus.
Protein kinase inhibitors and blood pressure control in spontaneously hypertensive rats.
Authors: Buchholz R A , Dundore R L , Cumiskey W R , Harris A L , Silver P J
Published: June 2012

Considerable evidence suggests that protein kinase C activation participates in the regulation of vascular smooth muscle tone. The objective of the current study was to examine the relations between inhibition of protein kinase C (PKC) and myosin light-chain kinase (MLCK) and vasorelaxation and blood pressure regulation in spontaneously hypertensive rats (SHR). Putative PKC inhibitors from two chemical classes, staurosporinelike (staurosporine and K252A) and isoquinolinesulfonamides (H7 and HA1004), were tested for their ability to 1) inhibit PKC and MLCK from SHR aorta, 2) relax isolated SHR aorta, and 3) lower blood pressure in conscious SHR. A rank order of potency for the inhibition of PKC and MLCK was established, with the staurosporinelike compounds (staurosporine PKC IC50 = 54 nM) clearly more potent than the isoquinolinesulfonamides (H7 PKC IC50 = 128 microM). The rank order of potency for inhibition of PKC was retained for inhibition of MLCK for all compounds. Staurosporine (EC50 = 75 nM) and H7 (EC50 = 2 microM) caused concentration-dependent relaxation of SHR aorta, but only staurosporine produced vasorelaxation at concentrations consistent with the inhibition of PKC or MLCK. Dose-dependent reductions in arterial pressure of SHR were demonstrated after intravenous injection of staurosporine and HA1004. A single intravenous injection of staurosporine (0.3 mg/kg) lowered blood pressure for more than 10 hours. Staurosporine also lowered blood pressure after oral administration. The depressor response to staurosporine was unaffected by sympathetic beta-adrenergic blockade. In conclusion, the vasorelaxant and antihypertensive actions of staurosporine in SHR are consistent with the inhibition of PKC but could also be equally related to inhibition of MLCK. Not all PKC inhibitors produce vasorelaxation and lower blood pressure. Moreover, the lack of correlation between in vitro vasodilation and PKC or MLCK inhibition for the isoquinolinesulfonamide protein kinase inhibitors H7 and HA1004 suggests that these agents do not cause vasorelaxation in SHR by inhibition of these enzymes.
Preservation of renal function by angiotensin during chronic adrenergic stimulation.
Authors: Lohmeier T E , Yang H M
Published: June 2012

The purpose of the present study was to determine the role of angiotensin II (Ang II) in mediating renal responses to chronic intrarenal norepinephrine infusion. Norepinephrine was continuously infused for 5 days into the renal artery of unilaterally nephrectomized dogs at progressively higher daily infusion rates: 0.05, 0.10, 0.20, 0.30, and 0.40 micrograms/kg/min. In three additional groups of dogs, norepinephrine infusion was repeated during chronic intravenous captopril administration to fix plasma Ang II concentration at 1) low levels (no Ang II infused), 2) high levels in the renal circulation (Ang II infused intrarenally at a rate of 1 ng/kg/min), and 3) high levels in the systemic circulation (Ang II infused intravenously at a rate of 5 ng/kg/min). In the control group of animals with intact renin-angiotensin systems, there were progressive increments in mean arterial pressure (from 96 +/- 4 to 141 +/- 6 mm Hg) and plasma renin activity (from 0.4 +/- 0.1 to 10.9 +/- 4.5 ng angiotensin I/ml/hr) and concomitant reductions in glomerular filtration rate and renal plasma flow to approximately 40% of control during the 5-day norepinephrine infusion period. In marked contrast, when captopril was infused chronically without Ang II, mean arterial pressure was 20-25 mm Hg less than that under control conditions, and the renal hemodynamic effects of norepinephrine were greatly exaggerated; by day 3 of norepinephrine infusion, both glomerular filtration rate (16 +/- 2% of control) and renal plasma flow (12 +/- 4% of control) were considerably lower than values in control animals (86 +/- 4% and 80 +/- 8% of control, respectively). Similarly, when a high level of Ang II was localized in the renal circulation during captopril administration, mean arterial pressure was depressed, and again there were pronounced renal responses to norepinephrine. Conversely, when Ang II was infused intravenously during captopril administration, mean arterial pressure was not reduced, and the glomerular filtration rate and renal plasma flow responses to norepinephrine were similar to those that occurred under control conditions. These findings indicate that the renin-angiotensin system prevents exaggerated renal vascular responses to chronic norepinephrine stimulation by preserving renal perfusion pressure.
Small artery resistance increases during the development of renal hypertension.
Authors: Imig J D , Anderson G L
Published: June 2012

Vascular pressures were measured in the principal (A1) arteriole and in upstream small arteries of the rat cremaster muscle to investigate vascular resistance changes associated with one-kidney, one clip Goldblatt hypertension. Pressure measurements were made at a proximal and distal site of each vessel using a servonull micropipette system. Vessel diameters were measured using video microscopy. A1 arteriole and external spermatic artery diameters were both decreased after 2 and 4 weeks of hypertension. Mean arterial pressure was elevated after 2 weeks of hypertension (106 +/- 4 mm Hg versus 140 +/- 5 mm Hg). Likewise, vascular pressures were elevated at every site: pudicepigastric artery (36%), external spermatic artery (47%), and A1 arteriole (38%). The pressure drop along the external spermatic artery was increased (87%) after 2 weeks of hypertension. Mean arterial pressure was further elevated from 2-4 weeks of hypertension (105 +/- 4 mm Hg versus 162 +/- 7 mm Hg) but only the proximal pudic-epigastric artery pressure was further elevated during this time from 2 to 4 weeks (131 +/- 5 mm Hg versus 147 +/- 7 mm Hg) of hypertension development. This was associated with an increased pressure drop (87%) along the artery compared with the situation at 2 weeks. These data indicate that small arteries upstream from the microcirculation contribute significantly to the increase in vascular resistance during hypertension. In addition, these data indicate that the increases in small artery resistance do not develop uniformly throughout all vessel branches.
Recovery of erythrocyte Na(+)-K(+)-Cl- cotransport activity by enalapril.
Authors: Sanchez R A , Gimenez M I , Gilbert B H , Giannone C , Marco E J , Ramirez A J
Published: June 2012

We studied total exchangeable sodium, ion transport activity at maximal rate, and erythrocyte Na+ content in response to angiotensin converting enzyme inhibition in mild-to-moderate essential hypertensive patients with normal renal function. Twenty-five patients (mean age 56 years, range 40-62 years) who had abnormal red blood cell Na(+)-K(+)-Cl- cotransport or red blood cell Li(+)-Na+ countertransport were treated with either enalapril (20 mg daily) or hydrochlorothiazide (50 mg daily) during a 30-day period. During the period of enalapril treatment, Na(+)-K+ pump and Na(+)-K(+)-Cl- cotransport increased significantly from 4,282 +/- 255 to 5,236 +/- 325 mumol/l red blood cell/hr (p less than 0.01) and 166 +/- 21 to 220 +/- 24 mumol/l red blood cell/hr (p less than 0.05), respectively. Mean intracellular Na+ content in erythrocytes decreased from 11.4 +/- 0.40 to 10.0 +/- 0.33 mmol/l (p less than 0.01) and exchangeable Na+ from 39.8 +/- 0.6 mmol/kg to 35.6 +/- 0.6 mmol/kg (p less than 0.001). Sodium reduction correlated with the recovery of Na(+)-K(+)-Cl- cotransport activity (r = -0.65, p less than 0.01). During treatment, systolic and diastolic blood pressures were reduced significantly (p less than 0.01). In 12 patients treated with hydrochlorothiazide, Na(+)-K(+)-Cl- cotransport, Na(+)-K+ pump, Na(+)-Li+ countertransport, and Na+ permeability did not change significantly while Na+ content decreased from 11.7 +/- 0.3 to 10.3 +/- 0.2 mmol/l (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Salt blocks the renal benefits of ramipril in diabetic hypertensive rats.
Authors: Fabris B , Jackson B , Johnston C I
Published: June 2012

To establish if the benefit of angiotensin converting enzyme inhibitor therapy in retarding progressive diabetic renal injury is due to a specific intrarenal effect of the systemic hypotensive effect, we studied the effect of long-term ramipril treatment on blood pressure, glomerular filtration rate, and urinary protein excretion in streptozotocin-diabetic spontaneously hypertensive rats. The hypotensive effect of ramipril was prevented by a high salt diet, which did not alter the degree of renal angiotensin converting enzyme inhibition. Three weeks after uninephrectomy and induction of diabetes, rats were allocated to three groups. Groups 1 and 2 were given 1% NaCl, whereas group 3 was given water as drinking solution. One week later, groups 2 and 3 received 0.4 mg/kg/day ramipril in their drinking solution, which was continued over a 2-month period. Ramipril produced a blood pressure fall only in water-drinking rats (group 3) despite a similar reduction in plasma and renal angiotensin converting enzyme activity in groups 2 and 3. Salt-loaded rats had a progressive increase in urinary protein excretion over the duration of study. Ramipril treatment prevented an increase in protein excretion only in animals given water and with a reduced systolic blood pressure. Glomerular filtration rate was similar in all three groups. Ramipril treatment improved animal survival independently of a reduction in blood pressure or an effect on proteinuria. Although it is possible that angiotensin converting enzyme inhibitors have specific intrarenal effects reducing progression of diabetic proteinuria, concomitant control of systemic blood pressure appears to be necessary to demonstrate a benefit.
Kinin contribution to renal vasodilator effect of captopril in rabbit.
Authors: Hajj-ali A F , Zimmerman B G
Published: June 2012

This study was conducted to examine the role of bradykinin in the persistence of the renal vasodilator effect of captopril during angiotensin II receptor blockade. Blood pressure and renal blood flow were monitored in eight groups of pentobarbital-anesthetized rabbits. In group 4, captopril alone was administered, and it decreased blood pressure by 14 +/- 4 mm Hg and increased renal blood flow by 21 +/- 4 ml/min. After a bolus injection and a constant intravenous infusion of the imidazole derivative angiotensin II receptor antagonist DuP 753 (group 5), captopril decreased blood pressure by 9 +/- 2 mm Hg and increased renal blood flow by 8 +/- 1 ml/min (12 +/- 1% change in renal blood flow, p less than 0.05 versus group 4). In the presence of a constant intravenous infusion of saralasin (group 6), captopril decreased blood pressure by 13 +/- 5 mm Hg and increased renal blood flow by 7 +/- 2 ml/min (17 +/- 5% change in renal blood flow, p less than 0.05 versus group 4). These results did not differ from those in group 5. During a constant intrarenal arterial infusion of a B2 bradykinin receptor antagonist, DArg0, [Hyp3-Thi5,8-DPhe7]-bradykinin (BkA) (group 7), captopril decreased blood pressure by 14 +/- 4 mm Hg and increased renal blood flow by 10 +/- 4 ml/min. Combined administration of DuP 753 intravenously and BkA intra-arterially (group 8) eliminated the effect of captopril. In group 8, captopril caused insignificant changes in blood pressure and renal blood flow. The results indicate that DuP 753 and saralasin antagonize the renin-angiotensin system to a comparable extent in vivo. Although blockade of the latter system accounted for a significant part of the increase in renal blood flow caused by captopril, the remaining component was contributed by endogenous bradykinin.
Effects of alpha 1-blockade on arterial compliance in normotensive and hypertensive rats.
Authors: Levy B I , Poitevin P , Safar M E
Published: June 2012

The effects of blockade of alpha 1-adrenergic receptors on the mechanical properties of the arterial wall were studied in 10 spontaneously hypertensive rats (SHR) as compared with 10 matched normotensive Wistar-Kyoto (WKY) rats. Ascending aortic pressure and flow were recorded in open-chest anesthetized rats, and the systemic arterial compliance was calculated. Intravenous injection (1 mg/kg) of Urapidil, a selective alpha 1-adrenergic antagonist, induced a significant decrease in arterial pressure (-26%, p less than 0.01 and -37%, p less than 0.001 in WKY rats and SHR, respectively) without significant changes in cardiac output. In control conditions, systemic arterial compliance was lower in SHR (3.29 +/- 1.52 microliters/mm Hg) than in WKY rats (4.35 +/- 1.35 microliters/mm Hg, p less than 0.01). Urapidil injection induced significant increases in systemic arterial compliance values in both strains (p less than 0.001). In another set of experiments (15 WKY rats and 15 SHR), the carotid compliance (microliters/mm Hg) was determined from the arterial volume-pressure relation under control conditions, after local incubation with Urapidil, and after total abolition of the vascular smooth muscle by KCN. In WKY rats, the carotid compliance increased markedly after incubation with Urapidil at doses corresponding to 1 mg/kg (+31%, p less than 0.01). A further increase in the carotid compliance was observed after KCN poisoning (+11%, p less than 0.05). In SHR, incubation with Urapidil at doses corresponding to 2 mg/kg were necessary to induce a significant increase in compliance (+38%). At this dosage, there was no further increase in compliance after KCN poisoning.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of ouabain on endothelium-dependent relaxation of human resistance arteries.
Authors: Woolfson R G , Poston L
Published: June 2012

Inhibition of active sodium transport by ouabain was found to cause concentration- and time-dependent impairment of acetylcholine-induced relaxation in human resistance arteries with a significant effect at 100 pM. The reduced acetylcholine response was attributable to inhibition of the NG-monomethyl L-arginine-sensitive but not the indomethacin-sensitive component of relaxation. Relaxation by sodium nitroprusside was not affected by ouabain, suggesting that inhibition of sodium transport, directly or indirectly, must affect synthesis or release of endothelium-derived relaxing factor rather than its effector pathway. These results do not support the existence of an additional endothelium-derived relaxing factor other than endothelium-derived relaxing factor, which is dependent on sodium pump activity. The finding that inhibition of sodium transport has a profound effect on vascular relaxation may have implications in the pathogenesis of certain forms of hypertension.
Red blood cell lithium-sodium countertransport in the tecumseh blood pressure study.
Authors: Weder A B , Schork N J , Krause L , Julius S
Published: June 2012

Human essential hypertension has more than one cause, but to dissect out subtypes, markers are required. The maximal activity of red blood cell lithium-sodium countertransport has been shown to be increased in hypertensive patients in case-control and population-based studies; in the latter, its distribution is a mixture of two overlapping but distinguishable subpopulations. In the present study, we classified 705 participants in the Tecumseh Blood Pressure Study as having either normal (mean, 0.234 mmol/l cells/hr; n = 614) or high (mean, 0.463 mmol/l cells/hr; n = 91) red blood cell lithium-sodium countertransport to determine if the red blood cell marker is associated with distinctive physiological characteristics. We found that subjects with elevated lithium-sodium countertransport have higher average blood pressure and a greater prevalence of hypertension than those with normal countertransport and that elevated blood pressure had been present since youth. Hemodynamically, the high countertransport group is characterized by elevated vascular resistance, whereas sympathetic nervous system activity appears to be slightly depressed. Subjects with increased lithium-sodium countertransport, compared with those with normal countertransport, have significantly lower average left ventricular mass index and only very infrequently demonstrate left ventricular hypertrophy. Our results support the usefulness of measurements of the maximal activity of red blood cell lithium-sodium countertransport as a way of distinguishing subgroups in the population. Our data are consistent with the idea that subjects with an elevated maximal activity for red blood cell lithium-sodium countertransport are a subset of the population with a genetic lesion that predisposes them to the development of essential hypertension.
Body weight is more important than family history of hypertension for left ventricular function.
Authors: Suurküla M B , Wikstrand J , Berglund G , Sivertsson R
Published: June 2012

Left ventricular function was studied in young men with a positive family history of hypertension for two generations (n = 15). The findings were compared with three control groups: one age-, sex-, and weight-matched group with a negative family history of hypertension (n = 14); one normotensive control group unselected as regards family history of hypertension (n = 27); and one group also unselected regarding family history of hypertension but selected with blood pressure criteria to have mild blood pressure elevation (n = 59). The group with a positive family history of hypertension, in comparison with the normotensive control group, was heavier, had higher blood pressure, increased left ventricular wall thickness, increased left ventricular mass, and signs of changes in diastolic and systolic left ventricular function. There were no differences in these variables between the group with a positive family history and the other two control groups. Data clearly indicated that subjects with a positive family history of hypertension, as well as subjects with mild blood pressure elevation, were heavier than the normotensive control group. It is not possible to judge, with available data, if the changes in left ventricular morphology and function in the two groups with a different family history of hypertension and in the group with mild blood pressure elevation occurred as a physiological response to the increase in afterload or if the neurohormonal and metabolic disturbances leading to the condition of slight overweight also affected left ventricular function.
Juxtamedullary afferent arteriolar responses to P1 and P2 purinergic stimulation.
Authors: Inscho E W , Carmines P K , Navar L G
Published: June 2012

We assessed the responsiveness of rat juxtamedullary afferent arterioles to purinergic stimulation using the in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy to allow direct measurement of arteriolar inside diameter. To minimize the contribution of endogenously formed angiotensin II, all rats were pretreated with enalaprilat (2 mg i.v.) for 30 minutes before the right kidney was isolated and prepared for study. Renal perfusion pressure was set at 110 mm Hg and held constant. Afferent arteriolar diameter averaged 20.9 +/- 0.8 microns (n = 41) under control conditions. Exposure to 1.0 microM 2-chloroadenosine induced a significant (11.1 +/- 3.2%) reduction in vessel diameter, whereas a 100 microM concentration induced an afferent vasodilation (7.6 +/- 1.5%; p less than 0.05). These data are consistent with the preferential stimulation of high affinity constrictor adenosine receptors (A1) at lower concentrations and activation of lower affinity vasodilator adenosine receptors (A2) at higher concentrations. In contrast, ATP elicited a significant afferent vasoconstriction of approximately 9.2%, 12.9%, and 10.0% at concentrations in the range of 1-100 microM (p less than 0.05). Treatment with ADP, at concentrations up to 100 microM, failed to alter vessel caliber significantly. Furthermore, the nonhydrolyzable ATP analogue alpha,beta-methylene ATP produced a rapid and potent vasoconstriction, which mimicked the response to ATP. These data reveal the presence of both adenosine-sensitive P1 and ATP-sensitive P2 purinergic receptors on rat juxtamedullary afferent arterioles and demonstrate that ATP can induce afferent arteriolar vasoconstriction directly without first requiring hydrolysis to adenosine.
Role of vasopressin in salt-induced hypertension in baroreceptor-denervated uninephrectomized rabbits.
Authors: Ryuzaki M , Suzuki H , Kumagai K , Kumagai H , Ichikawa M , Matsumura Y , Saruta T
Published: June 2012

To elucidate the contributions of renal, humoral, and arterial baroreceptor reflex components to salt-induced hypertension, we administered 10% NaCl intravenously for 10 days to sinoaortic-denervated rabbits with unilateral nephrectomy (n = 7), sinoaortic-denervated rabbits with intact kidneys (n = 7), and sham-operated sinoaortic-denervated rabbits with unilateral nephrectomy (n = 7). Serial changes in mean arterial pressure (MAP), heart rate, and blood pressure variability were recorded. In sinoaortic-denervated rabbits with unilateral nephrectomy, MAP increased significantly from 109 +/- 2 to 124 +/- 3 mm Hg (day 4) and remained elevated for the rest of the experiment. This elevation of MAP was accompanied by a reduction in the standard deviation of MAP, with significant elevations in plasma vasopressin, norepinephrine, and atrial natriuretic peptide concentrations and in sodium retention. In the other groups, there were no significant changes in these vasoactive hormones. In the sham-operated sinoaortic-denervated rabbits with unilateral nephrectomy, sodium retention was similar to that of sinoaortic-denervated rabbits with unilateral nephrectomy. Continuous infusion (1 microgram/kg/hr) of a V1 antagonist prevented the elevation of blood pressure and plasma norepinephrine, the accumulation of sodium, and the reduction of blood pressure lability, whereas a bolus injection (10 micrograms/kg) on day 4 reduced blood pressure from 128 +/- 3 to 115 +/- 2 mm Hg (p less than 0.005). These results imply that vasopressin plays a crucial role in the expression of salt-induced hypertension in rabbits with compromised baroreceptor and renal function.
Carotid baroreceptor function in dogs with chronic norepinephrine infusion.
Authors: Wang J , Ochoa M , Patel M B , Zucker I H , Loud A V , Zeballos G A , Hintze T H
Published: June 2012

Carotid baroreceptor function, the compliance of the carotid sinus wall, and the structure of the carotid artery were examined in dogs with elevated plasma norepinephrine (2,000-4,000 pg/ml) for 28 days. The dogs with high norepinephrine were normotensive (100 +/- 4.0 versus 98 +/- 4.0 mm Hg; p greater than 0.05) with bradycardia (65 +/- 4.0 versus 87 +/- 16 beats/min; p less than 0.05) compared with normal dogs in the conscious state. However, after pentobarbital anesthesia blood pressure was significantly higher in dogs with chronic norepinephrine infusion (165 +/- 6 mm Hg) compared with normal dogs (132 +/- 6 mm Hg). To assess baroreceptor sensitivity, multiunit carotid baroreceptor activity was recorded from the right carotid sinus nerve, and the carotid sinus wall compliance (sonomicrometers) was measured during nitroglycerin and phenylephrine injections. The threshold and saturation pressures increased from 96 +/- 3.9 to 117 +/- 4.2 mm Hg and from 145 +/- 4.3 to 171 +/- 5.7 mm Hg, respectively, in the normal dogs compared with the high norepinephrine dogs. The most striking differences were the marked increases in sensitivity of carotid baroreceptors (0.47 +/- 0.05 versus 1.99 +/- 0.45 spikes.sec-1.mm Hg-1; p less than 0.01) and maximum firing frequency of the baroreceptors (24 +/- 3.1 versus 48 +/- 4.4 spikes/sec; p less than 0.01), whereas the carotid sinus wall compliance was unchanged (0.014 +/- 0.003 versus 0.012 +/- 0.002 mm/mm Hg; p greater than 0.05). Similar alterations were observed using single fiber recordings, that is, an increase in threshold and saturation pressures and slope of baroreceptor units in dogs with elevated norepinephrine. The wall thickness and area of the carotid artery were determined. Both increased significantly (0.77 +/- 0.06 versus 1.30 +/- 0.12 mm and 9.0 +/- 0.8 versus 11.9 +/- 0.9 mm2; p less than 0.05) in dogs chronically infused with norepinephrine while the dry weight-to-wet weight ratio of left carotid artery tissue also increased from 26.0 +/- 0.73% to 29.0 +/- 0.57%. These studies indicate that 1) one of the possible mechanisms responsible for bradycardia in the conscious dogs with high norepinephrine is enhanced sensitivity of carotid baroreceptors; 2) the enhanced sensitivity of carotid baroreceptors is not due to a change in compliance of the carotid sinus wall; and 3) chronic elevation of norepinephrine causes hypertrophy or hyperplasia of the wall of the common carotid artery.
Effect of NG-monomethyl L-arginine on endothelium-dependent relaxation in arterioles of one-kidney, one clip hypertensive rats.
Authors: Nakamura T , Prewitt R L
Published: June 2012

Dose-response curves to topically applied acetylcholine, bradykinin, and nitroprusside were obtained by intravital microscopy in arcading arterioles of the spinotrapezius muscle of control (n = 9) and one-kidney, one clip hypertensive (1K1C) rats (n = 11) of 4 weeks' duration before and during superfusion with the specific inhibitor of nitric oxide formation NG-monomethyl L-arginine (LNMMA) (10(-4) M) and both LNMMA (10(-4) M) and indomethacin (2.8 x 10(-5) M). Resting arteriolar tone was higher in 1K1C rats than in controls, and vasodilation to acetylcholine and bradykinin, but not to nitroprusside, was reduced (p less than 0.05) in 1K1C rats compared with controls. LNMMA increased arteriolar tone (p less than 0.05) and inhibited the vasodilator responses to acetylcholine and bradykinin (p less than 0.05) in controls but not in 1K1C rats. LNMMA did not alter the response to nitroprusside in either group. Addition of indomethacin to LNMMA increased arteriolar tone and markedly reduced the response to bradykinin, but not to acetylcholine or nitroprusside, in both groups. These findings suggest that resting arteriolar tone is increased in 1K1C rats partially because of the decreased basal release or synthesis of nitric oxide. Responses to the endothelium-dependent vasodilators acetylcholine and bradykinin were attenuated in 1K1C rats, possibly because of changes in synthesis or release of nitric oxide for acetylcholine and of prostacyclin for bradykinin, because the response to the endothelium-independent vasodilator nitroprusside did not differ between the groups.
Role of sympathetic nerve activity in the generation of vascular nitric oxide in urethane-anesthetized rats.
Authors: Lacolley P J , Lewis S J , Brody M J
Published: June 2012

The aim of the present study was to examine the involvement of the sympathetic nervous system in the generation or release of vascular nitric oxide. In urethane-anesthetized rats, the administration of the novel nitric oxide synthesis inhibitor L-N-nitro arginine (LNA) (0.02 mmol/kg i.v.) increased mean arterial pressure and renal, mesenteric, and hindquarter vascular resistances. The intravenous administration of L-arginine (60 mg/kg plus 12 mg/kg/min i.v.) produced small reductions in arterial pressure and vascular resistances and abolished the hemodynamic effects of LNA. Pretreatment with the ganglion blocking agent chlorisondamine lowered mean arterial pressure and vascular resistances, abolished the LNA-induced pressor and renal vasoconstrictor response, and attenuated the increases in mesenteric and hindquarter resistances. In contrast, the vasodilator hydralazine lowered mean arterial pressure and vascular resistances to levels equivalent to that of ganglionic blockade; however, the subsequent administration of LNA still produced significant increases in arterial pressure and regional vascular resistances. In ganglion-blocked rats in which pressure and vascular resistances were returned to normal levels by infusion of arginine vasopressin or phenylephrine, the pressor and vasoconstrictor effects of LNA were restored. However, phenylephrine was significantly more efficacious and markedly exaggerated the action of LNA. These results suggest that the sympathetic nervous system plays an important role in modulating the synthesis or release of vascular nitric oxide through the effects of 1) normal sympathetic discharge, 2) humoral activation of alpha-adrenergic receptors, and 3) vascular tone per se.
Transforming growth factor beta 1 expression and effect in aortic smooth muscle cells from spontaneously hypertensive rats.
Authors: Hamet P , Hadrava V , Kruppa U , Tremblay J
Published: June 2012

Previous studies demonstrated that in addition to an increased response to growth factors, cultured vascular smooth muscle cells derived from spontaneously hypertensive rats (SHRs) grow to a greater density than cells from normotensive Wistar-Kyoto (WKY) rats. Transforming growth factor beta 1 (TGF-beta 1) has a bimodal effect on vascular smooth muscle cell growth, depending on cell density. The present study investigated the relation between cell density and expression of the proto-oncogene c-fos and TGF-beta 1 in cells from WKY rats and SHRs. The results demonstrate an increased accumulation of c-fos mRNA in calf serum-stimulated SHR cells but only at a high cell density. The expression of TGF-beta 1 mRNA was enhanced in growing SHR cells at every density studied as early as 24 hours after inoculation, with a further increase at later times. The effect of exogenous TGF-beta 1 on new DNA synthesis was evaluated by [3H]thymidine incorporation. At a low cell density, TGF-beta 1 had no effect on DNA synthesis in either WKY or SHR vascular smooth muscle cells. At a high cell density, there was a significant increase of DNA synthesis in response to TGF-beta 1 in SHR cells without any effect in WKY cells. In conclusion, contact inhibition of vascular smooth muscle cells from SHRs at a higher cell density is accompanied by an earlier expression of the marker gene c-fos and preceded by an exaggerated expression of TGF-beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)
Structural alterations of microvascular smooth muscle cells in reduced renal mass hypertension.
Authors: Hansen-Smith F , Greene A S , Cowley A W , Lougee L , Lombard J H
Published: June 2012

Loss of microvessels (anatomic rarefaction) occurs in chronic reduced renal mass (RRM) hypertension and is mediated via structural degeneration of vascular smooth muscle (VSM) and endothelial cells. The purpose of the present study was to determine if structural changes occur in VSM cells of the microvessels that remain in the tissue of rats with chronic RRM hypertension. Samples of cremaster muscles were taken from normotensive control rats and rats with acute (3-7 days) and chronic (14-28 days) RRM hypertension (75% reduction in kidney mass with 4% NaCl loading). The samples were fixed in situ and processed for light and electron microscopy. Ultrastructural morphology of VSM cells in terminal arterioles of control animals was normal. Although VSM morphology in many microvessels of RRM hypertensive rats was also normal, some vessels exhibited structural changes that were not present in arterioles of the normotensive animals. The most striking change was the appearance of more extensive dense bodies anchoring the contractile filaments around the outer membrane of the cells. Extreme vasoconstriction was observed in some arterioles of RRM rats as long as 2 weeks after salt loading. Focal areas of VSM cell proliferation were evident. Many of the changes occurring in RRM were detected as early as 1 week after the onset of hypertension. These observations suggest that renal mass reduction-salt loading hypertension is associated with early structural and functional changes in the VSM cells.
Mass spectral characterization of an endogenous digitalislike factor from human plasma.
Authors: Mathews W R , DuCharme D W , Hamlyn J M , Harris D W , Mandel F , Clark M A , Ludens J H
Published: June 2012

A sodium pump inhibitor has been isolated from human plasma and extensively purified. This material, endogenous digitalislike factor, was examined by a variety of mass spectrometric techniques. A low-resolution fast atom bombardment mass spectrometric analysis of a sample of purified endogenous digitalislike factor revealed a single unique molecular ion in the mass range 100-2,500. The accurate mass was determined to be 585.295 Da in a second high-resolution fast atom bombardment mass spectrometric experiment. Based on this accurate mass, the elemental composition of endogenous digitalislike factor was determined and found to be identical to the elemental composition of the known cardenolide ouabain. Direct comparison of ouabain and endogenous digitalislike factor by linked scan tandem mass spectrometry, derivatization with acetic anhydride coupled with fast atom bombardment mass spectrometry, and analytical high-performance liquid chromatography failed to reveal any differences. We conclude that the endogenous digitalislike factor isolated from human plasma is ouabain or a closely related isomer.
Linkage of MN locus and erythrocyte lithium-sodium countertransport in Tecumseh, Michigan.
Authors: Weder A B , Schork N J , Julius S
Published: June 2012

Human essential hypertension is a family of diseases; one subtype has an increased maximum velocity for red blood cell lithium-sodium countertransport activity. To begin the localization of the gene or genes responsible for this phenotype, we examined the association of blood pressure, lithium-sodium countertransport, and two genetic markers previously associated with hypertension--the MN blood group antigen (chromosome 4) and the plasma protein haptoglobin (chromosome 18)--in a population-based sample of 592 young adults from Tecumseh, Mich., the site of an ongoing cardiovascular epidemiological investigation. Our results suggest that the relation between MN phenotype and systolic blood pressure is significantly different and oppositely directed in men and women. Analysis of data available from previous examinations revealed that similar blood pressure differences related to MN phenotype had been present at least a decade earlier in both men and women. There also was a significant relation between systolic blood pressure and haptoglobin phenotype for the combined group of men and women. In addition to having high systolic blood pressure, men with the MM phenotype had significantly elevated red blood cell lithium-sodium countertransport activity. In studies of brother-brother pairs, we found evidence for significant genetic linkage between the MN locus and red blood cell lithium-sodium countertransport activity.