bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of plasma angiotensin concentrations in a comparative study of responses to angiotensin in the maturing newborn lamb.
Authors: Wilson T A , Kaiser D L , Wright E M , Ortt E M , Freedlender A E , Peach M J , Carey R M
Published: September 2013

Plasma angiotensin concentrations were measured in a longitudinal study of the vascular, renal, and adrenal responses to infusions of angiotensin II (AII) in the maturing newborn lamb. Basal plasma concentrations of angiotensin increased with age and correlated with the rising arterial pressure that occurred with maturation. However, age was a stronger determinant of arterial pressure than was plasma angiotensin concentration. For any given dose of AII per kilogram of body weight, the actual plasma angiotensin concentration achieved increased as the lambs matured and gained weight. Therefore, a comparative study of biologic responses to AII in maturing animals must be based on actual plasma angiotensin concentrations achieved rather than on dose of AII infused per kilogram of body weight. When analyzed on the basis of actual plasma angiotensin concentration, the increase in arterial pressure and the suppression of plasma renin activity in response to increasing plasma angiotensin concentrations did not differ significantly as the lambs matured. However, the increment in plasma aldosterone concentrations in response to increasing plasma angiotensin concentrations was diminished in immature lambs (less than 18 days) when compared to the aldosterone responses in the same lambs at older ages.
Etiology of essential hypertension.
Authors: Cruz-Coke R
Published: September 2013

It is not possible to understand the etiology of hypertension without considering the role of inheritance. Epidemiological evidence indicates that the development of high blood pressure in the population at large depends on the interaction of different types of genes and several environmental influences. The sources of genetic variation in blood pressure distribution are polygenes, polymorphic genes, and dominant idiomorphic genes. The main environmental sources are weight gain, excess salt (Na) intake, and psychosocial stress. Only those individuals with a specific genetic predisposition may develop high blood pressure when exposed to excessive environmental influences.
Antiadrenergic therapy: special aspects in hypertension in the elderly.
Authors: Messerli F H , Dreslinski G R , Husserl F E , Suarez D H , MacPhee A A , Frohlich E D
Published: September 2013

The effect of antiadrenergic treatment with methyldopa was studied in 17 patients with established essential hypertension who were subdivided with respect to age in a group younger (n = 10; mean age, 47 +/- 2.4 (SEM) years; and a group older than 60 years of age (n = 7, mean age, 67 +/- 2.8 SEM). The fall in arterial pressure was associated with a significant (p less than 0.05) decrease in cardiac output and heart rate in patients over 60 years of age and no change in total peripheral resistance, whereas a (nonsignificant) fall in resistance occurred in younger patients. In both age groups, a significant (p less than 0.05 and less than 0.01, respectively) decrease in plasma norepinephrine levels was observed, whereas epinephrine and dopamine showed no changes. Pre- and posttreatment values of mean arterial pressure correlated directly with plasma norepinephrine values (r = 0.35 p less than 0.05). Regardless of whether cardiac output was reduced or remained unchanged, renal blood flow, plasma and total blood volume did not change in either group with antiadrenergic treatment. Further, reflexive cardiac changes (responses to isometric exercise and upright tilt) remained qualitatively unchanged. It is concluded that antiadrenergic treatment with methyldopa lowers arterial pressure additionally by decreasing circulating norepinephrine levels. The antihypertensive effect is associated with a fall in peripheral resistance in the younger and a decrease in cardiac output in the older patients, and does not compromise renal blood flow or cardiac reflexive responses.
Hypertension and economic activities in São Paulo, Brazil.
Authors: Ribeiro M B , Ribeiro A B , Neto C S , Chaves C C , Kater C E , Iunes M , Saragoça M A , Zanella M T , Anção M S , Marson O , Kohlmann O , Franco R J , Nunes S F , Ramos O L
Published: September 2013

A study of the prevalence of hypertension was undertaken among workers in 10 subsectors of the economy in São Paulo, a major urban-industrial area of Brazil. Included in the study were 5500 subjects 15-65 years of age, employed in 57 randomly selected firms. Hypertension rates (DBP greater than or equal to 90 mm Hg) were higher among males up to 44 years of age. There was a decreasing gradient from mild to moderate and severe forms in all groups. Severity tended to increase with age in all groups. Black males showed higher rates than whites (29.2% vs 16.7%, p less than 0.05), the excess being partially accounted for by moderate and severe forms (40% vs 20%). Subjects who overworked showed a trend toward higher hypertension rates. Higher rates in four subsectors (metallurgy, finance, transport, and journalism), aside from the distribution of known risk factors and job selection, may reflect a variety of work-related stressors.
Active and inactive kallikrein released by kidney slices from normotensive and hypertensive rats.
Authors: Nolly H , Lama M C
Published: September 2013

The relative rates of release of active and inactive kallikrein were investigated in the rat kidney by studying in vitro kidney slices. The slices were kept in Warburg flasks in a Krebs-Ringer solution for 15 up to 60 minutes, and their kallikrein content and the kallikrein-like activity released by them were measured at different times. Renal kallikrein concentration from two-kidney, one clip hypertensive rats was less than in the sham-operated controls (p less than 0.01). Active kallikrein released into the bathing medium was 4.7 +/- 0.3 ng/mg/hr in normotensive rats (n = 10) and 3.3 +/- 0.3 in two-kidney hypertensive animals (n = 12); the difference between both groups was statistically significant (p less than 0.01). Inactive kallikrein is between 60% and 70% of the total kallikrein released by kidneys of normal and hypertensive rats. Thus, under the conditions of these experiments, the kidney slices were able to release a kallikrein-like enzyme in an active and an inactive form. The rate of active kallikrein released from slices of hypertensive animals was lower than in the normotensive controls.
Renal Na+-K+-ATPase in Okamoto and Dahl hypertensive rats.
Authors: Rodriguez-Sargent C , Cangiano J L , Opava-Stitzer S , Martínez-Maldonado M
Published: September 2013

Plasma renin activity (PRA, ng AI/ml/hr), plasma aldosterone (PA, ng%) and renal Na+-K+-ATPase (micron m PO 4/mg protein/hr) were measured in tow groups of eight spontaneously hypertensive rats (SHR), two groups of eight Dahl salt hypertensive rats (SS), and their controls (16 normal Wistar and 16 salt-resistant rats). Measurements were made in one group after 2 weeks on a normal (0.48% sodium) and in the other group after 2 weeks on a low (0.01% sodium) sodium diet. After a normal sodium diet, PRA and PA were lower in both groups of hypertensive rats than in control normotensive animals. Renal NA+-K+-ATPase was lower in SS than in controls: in SHR it was not different from control. On a sodium-free diet, SHR exhibited a rise in renal Na+-K+-ATPase but PRA and PA remained low. In contrast, under similar conditions PRA, PA, and renal Na+-K-ATPase increased in SS rats, although to a lesser extent than in SR. These results suggest that under basal conditions and after low salt diet, renal Na+-K+-ATPase activity in SHR behaves as it does in normal rats. However, the changes are independent of PA in SHR. The reduction in PRA and PA in SS suggest volume expansion hypertension. IN SHR, volume expansion is not present, and renal Na+-K+-ATPase is not altered. Enzyme activity is lower in SS than in SHR and control. This suggests that some factor that results from volume expansion may be responsible for inhibition of renal Na+-K+-ATPase.
Demographic, dietary, life style, and anthropometric correlates of blood pressure.
Authors: Stanton J L , Braitman L E , Riley A M , Khoo C S , Smith J L
Published: September 2013

The relationships between systolic and diastolic blood pressure, and select demographic, dietary, life-style, and anthropometric variables were examined for a specialized sample of 10,419 adults, 18 years and over, from the National Health and Nutrition Examination Survey (NHANES) I conducted in 1971-1974. The bivariate relationships of blood pressure to each of the measurements above were examined using zero-order correlation coefficients, and Step-wise linear regression. Age and body mass index (BMI) played a major role in accounting for most of the variance in blood pressure. These two indices alone accounted for 94.5% and 89.0% of the variance in systolic and diastolic blood pressure. In contrast, only 5.5% and 11.0% of the changes in systolic and diastolic blood pressure were explained by all other variables combined. Diet explained less than 1% of the total variance observed for blood pressure for whites, and less than 5% for nonwhites. Select dietary variables such as sodium/potassium ratio, calories from fat, and % saturated fat were not significantly (p less than 0.001) correlated to blood pressure. On the other hand, food calcium, sodium/calcium ratio, food vitamin C, and calcium/phosphorus ratio were significantly correlated to both systolic and diastolic blood pressure.
Hypertension and the Department of Health and Human Services.
Authors: Rubin R J , Bladen C
Published: September 2013

Hypertension affects from 17% to 25% of all Americans. Because of its fundamental charge to help protect the public health, the Department of Health and Human Services (HHS) is substantially concerned with the condition. Additionally, hypertension represents a significant source of underwriting risk to which HHS is exposed in its role as health insurer of the poor and the elderly. HHS has invested hundreds of millions of dollars in hypertension research, development and testing of treatment regimens, and education of health care providers and consumers. However, much of the etiology of hypertension still eludes us. Sodium's apparent importance as a "causal" agent to the development of hypertension, and in its treatment, has waxed and waned over the past several generations; research to date has not yet finally settled the issue. Is sodium or some other cation the key? While research on this issue continues, HHS is currently faced with deciding whether and how to require inclusion of sodium content in nutrition labelling. In the debate, attention has to be given not only to the current best evidence on sodium; additional issues of consumer choice, costs, and education are also of importance.
Hemodynamic effects of alterations in potassium.
Authors: Paller M S , Linas S L
Published: September 2013

Potassium is the major intracellular cation. Despite this fact, the systemic and renal hemodynamic effects of alterations in either serum K or in total body K are only partially understood. In isolated preparations acute K excess causes vasodilation while acute K deficiency results in vasoconstriction. Although chronic K excess may decrease arterial pressure in experimental models of hypertension, no definitive conclusions can be stated on the effect of K excess in hypertensive patients. In normotensive animals, chronic K depletion is associated with decreased systemic vascular resistance and increased renal vascular resistance. Although a number of studies have shown that K depletion ameliorates experimental hypertension, no definitive conclusions can be stated on the effect of K depletion in hypertensive patients. The vasodilatory effect of K depletion appears to be a direct effect on vascular smooth muscle since it is associated with an increase in total body Na as well as an increase in cardiac output and in renin ane arginine vasopressin levels. Although renin levels are increased in K deficient rats to a value comparable to na-depleted rats, angiotensin antagonism results in a substantially smaller decrease in arterial pressure than in Na-depleted rats (11 +/- 1.6 vs 24 +/- 3.4 mm Hg, p less than 0.01). This relative resistance to the pressor effect of angiotensin also results in a blunted pressor sensitivity to exogenous angiotensin II. Since changes in K balance appear to have a major effect on the control of hemodynamics, further studies are warranted to determine whether alterations in K balance would be useful in the treatment of hypertension.
beta-Receptors and contractile reserve in left ventricular hypertrophy.
Authors: Ayobe M H , Tarazi R C
Published: September 2013

The inotropic responsiveness to adrenergic stimulation is diminished in hypertension associated with left ventricular hypertrophy (LVH). This was shown in hypertrophied hearts from renal hypertensive rats (RHR) (two-kidney, one clip hypertension, Goldblatt) 6 weeks after renal artery clipping when compared to age-matched normotensive sham-operated controls (NR). The isoproterenol-stimulated inotropic responses (delta peak dP/dt) of isolated hearts perfused at constant pressure were significantly lower in RHR than in NR (p less than 0.001 by analysis of variance and covariance, including repeated measures). This reduction in ventricular responsiveness of isolated hearts from RHR did not extend to other inotropic agents such as calcium ions and the cardiotonic cardiac glycoside scillaren. Assay of beta-adrenergic receptors by binding to (-) [3H] dihydroalprenolol showed that left ventricular beta-receptor numbers (fmol per mg membrane protein) were significantly reduced in RHR compared to NR (28.2 +/- 1.1 vs 36 +/- 2.6, p less than 0.01) with no significant change in affinity (Kd,nM) (1.9 +/- 0.27 vs 2.26 +/- 0.34,NS). The results of this study suggest that LVH in renovascular hypertension is associated with impairment in inotropic responsiveness to beta-receptor stimulation parallel with and, in part, related to, a reduction in ventricular beta-receptor concentrations. Such blunting of inotropic responsiveness to beta-adrenergic stimulation may be one of the mechanisms in the progression from LVH to heart failure in hypertensive disease.
Mechanism of increased renin release in the adrenalectomized rat. Adrenal insufficiency and renin.
Authors: Welch W J , Ott C E , Guthrie G P , Kotchen T A
Published: September 2013

We have previously suggested that inhibition of renin release by sodium chloride is related to absorptive chloride transport in the loop of Henle. Infusion of sodium chloride fails to inhibit renin release in the adrenalectomized (Adx) rat, and dexamethasone restores renin responsiveness to sodium chloride. The purpose of the present study was to evaluate the relationship between loop function (urinary diluting and concentration capacity) and plasma renin concentration (PRC) in the Adx rat. After hypotonic sodium chloride infusion, free water clearance (CH2O) of Adx rats (0.56 ml/hr/100 g +/- 0.17 SE) was decreased (p less than 0.01) compared to controls (2.86 ml/hr/100 g +/- 0.29 SE); PRC of Adx rats (61.9 units/ml +/- 11.2 SE) was increased (p less than 0.01) above controls (6.0 units/ml +/- 1.7 SE). These differences persisted after administration of d(CH2)5Tyr(Et)VAVP, a potent ADH antagonist. In separate groups of animals, after water deprivation, urine concentration of Adx rat (1,401 mOsm/kg +/- 45 SE) was less (p less than 0.01) than that of controls (2,117 mOsm/kg +/- 169 SE). Dexamethasone normalized both CH2O and urinary concentrating ability and also decreased PRC in Adx rats. Thus, in the glucocorticoid deficient rat, increased renin release is associated with impaired loop function. The loop defect may account for high PRC that is not suppressed by sodium chloride.
Effectiveness of combined nifedipine and propranolol treatment in hypertension.
Authors: Yagil Y , Kobrin I , Stessman J , Ghanem J , Leibel B , Ben-Ishay D
Published: September 2013

The long-term antihypertensive effect of combined nifedipine and propranolol therapy was assessed in an open trial in 26 hypertensive patients (19 men, seven women, mean age 53 years). On propranolol alone (160 to 240 mg/day), the patients' average sitting blood pressure was 192 +/- 5/114 +/- 2 mm Hg. Propranolol was continued in a fixed dose and nifedipine was added in a dose that was gradually increased from 30 to 90 mg/day to achieve blood pressure (BP) values below 160/95 mm Hg. Twenty-two patients remained on the combined regimen for 14 to 30 weeks. Their BP decreased to 136 +/- 3/84 +/- 2 mm Hg on an average daily dose of 59.5 mg nifedipine. Seventeen of the 22 subjects were subsequently treated sequentially with propranolol alone, combined therapy, and nifedipine alone, to assess the relative efficacy of each mode of therapy. The combined regimen was found to be more effective than either drug alone. Side effects occurred in 13 of 26 patients. Four dropped out 4 to 11 weeks after starting nifedipine because of either intolerable flushing (2), allergic rash (1), or headache (1). Nine subjects experienced mild reactions that were well tolerated. It is concluded that the combined use of propranolol and nifedipine is effective in the long-term treatment of moderately severe hypertension and offers an alternative therapeutic approach that deserves further evaluation.
Pharmacokinetics and metabolism of nifedipine.
Authors: Raemsch K D , Sommer J
Published: September 2013

Nifedipine is almost completely absorbed from the gastrointestinal tract as shown by plasma levels after sublingual, oral, and rectal administration. Because of presystemic metabolism, the bioavailability is about 56% to 77%. After oral administration of 10 mg, the mean plasma concentration of nifedipine reaches maximum values of 160 +/- 49 micrograms/liter after 30 to 60 minutes. After 8 hours, the mean concentration drops to 3.4 +/- 1.2 micrograms/liter. After intravenous administration (0.015 mg/kg) biphasic elimination occurs, the half-life of the alpha-phase being about 13 minutes and of the beta-phase 1.26 +/- 0.55 hours in healthy volunteers. After oral administration of higher doses (40 mg) and after continuous infusion over 24 hours, a third phase with a half-life of about 8 hours can be seen. The apparent volume of distribution of the central compartment (Vce) is 0.294 +/- 0.1 l/kg, and the total body clearance amounts to 0.45 +/- 0.1 liter/hr . kg. Nifedipine is eliminated from the body by hepatic metabolism to the major metabolites 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid (M I) and the corresponding 2-hydroxymethyl-pyridinecarboxylic acid (M II). Methods for the quantitative detection of unchanged nifedipine in the presence of the pyridine analog in plasma (HPLC) and of the main metabolites in plasma and urine (GLC) have been developed. A simple semiquantitative method for detecting metabolites in urine (HPTLC) can be used to monitor patient compliance.
When and how far should we lower blood pressure?
Authors: Sleight P
Published: September 2013

The accuracy of the diagnosis of mild or borderline hypertension is dubious. Perhaps up to one-third of such patients are wrongly categorized when more accurate measures are taken, largely because of the "defense" reaction. The recent trials of mild hypertension are discussed. Patients with a diastolic blood pressure in the range of 95 to 100 mm Hg should only begin treatment after careful assessment and consideration of other risk factors.
Response to placebo treatment in hypertension.
Authors: Doyle A E
Published: September 2013

In essential hypertension, the blood pressure is variable, with large changes occurring in response to variations in physical and emotional stimuli. Patients given placebo tablets often have short-lived decreases in blood pressure. Placebo-controlled studies are essential for the proper evaluation of antihypertensive drugs. In longer term studies in mild hypertension, many patients given placebos have substantial decreases in blood pressure, often to normal levels, a finding that makes a period of observation desirable before commencing active treatment. Patients given placebos also have a high incidence of symptomatic side effects.
Peripheral large arteries and the response to antihypertensive treatment.
Authors: Safar M E , Bouthier J A , Levenson J A , Simon A C
Published: September 2013

Since systolic pressure is governed by the rate of ventricular ejection and the rigidity of the aortic wall, antihypertensive agents may have different effects on systolic and diastolic pressure. Despite an adequate decrease in diastolic pressure, systolic pressure may remain elevated due to structural alterations of large arteries. In the present study, a procedure is described to distinguish the dilation of small and large arteries. The former is evaluated from the calculation of forearm resistance and the latter from the determination of the arterial diameter of the brachial artery, using a bidimensional pulsed Doppler system. Nitroglycerin dilates the brachial artery, with no change in forearm resistance. Dihydralazine reduces the diameter of the brachial artery but decreases forearm resistance. Only calcium and converting-enzyme inhibitors dilate both small and large arteries and cause an increase in brachial blood flow.
Reduction of cardiovascular disease events by worksite hypertension treatment.
Authors: Alderman M H , Madhavan S , Davis T
Published: September 2013

A retrospective cohort study of hypertensive employees to evaluate the impact of worksite antihypertensive treatment (WST) on cardiovascular disease (CVD) over 8 1/2 years is reported. In a union-sponsored screening from August 1973 to February 1974, 604 hypertensives (greater than or equal to 160 and/or 95 mm Hg, or on medication) were identified. Of these, standardized criteria were met by 344, of whom 150 chose WST and 194 referred care (RC). The study groups were similar in age and sex composition. Union hospitalization and death records through 1982 revealed that CVD rates were fewer in WST than RC (3.0 vs 5.4/100 person-years; p less than 0.01). By contrast, nonCVD rates were similar (8.1 vs 9.6). All-cause mortality rate in WST (0.89) was significantly (p less than 0.05) lower than that in RC (1.81), as was the standard mortality ratio (55.1), based on U.S. mortality in 1978. CVD mortality was also lower (0.48 vs 1.10; NS). Persons with an initial blood pressure (BP) less than 160/95 mm Hg had CVD event rates that were low and similar in WST and RC (3.6 vs 3.5). However, among those with elevated BP at entry, WST subjects fared significantly better than RC (2.8 vs 6.1; p less than 0.001). Furthermore, in WST, previously treated patients with elevated BP at screening experienced one-third the CVD morbidity of their counterparts in RC (3.1 vs 10.8; p less than 0.01). These results extend previous evidence that WST is an effective method to achieve BP control and demonstrate that this approach to the management of hypertension alters health outcomes favorably and significantly.
Malignant hypertension: a syndrome accompanied by plasmatic diminution of low and high molecular weight kininogens.
Authors: Ribeiro A B , Schwarzwalder S R , Saragoça M A , Almeida F A , Voos A , Stella R C , Ramos O L
Published: September 2013

Total kininogen (Kgn), kallikrein, and prekallikrein were measured in patients with malignant hypertension (MH), essential hypertension (EH), normotensive control (NC), and hypertension and chronic renal failure (HRF). These components of the kallikrein-kinin system were related to the levels of creatinine and fibrinogen. High molecular weight Kgn and low molecular weight Kgn were also measured in blood samples from a peripheral vein, arterial blood, and suprahepatic vein in NC, EH, and MH. Results showed that total Kgn levels were diminished in MH and this diminution could not be ascribed to decreases in renal function, hematocrit, or fibrinogen levels. Appropriate antihypertensive treatment for over 1 year did not normalize Kgn levels in 10 of 11 patients. High molecular weight Kgn and low molecular weight Kgn were both diminished in MH (0.26 +/- 0.04 nmol bradykinin/ml and 0.93 +/- 0.12 nmol lysyl-bradykinin/ml, respectively) as compared to NC (0.39 +/- 0.07 and 1.92 +/- 0.16) and EH (0.51 +/- 0.07 and 1.65 +/- 0.13). Higher concentrations of high molecular weight Kgn were demonstrated in the suprahepatic vein as compared to arterial blood, demonstrating its synthesis by the liver. However, patients with MH had a diminished capacity to synthetize high molecular weight Kgn. A decrease in synthesis of high molecular weight Kgn may be a partial explanation for low levels of total Kgn. It is suggested that a lack of Kgn may play a role in the pathogenesis of MH.
Further studies on the development of two-kidney, two clip Goldblatt hypertension in 6-hydroxydopamine-treated rats.
Authors: Kurnjek M L , Mangiarua E , Basso N , Taquini A C
Published: September 2013

The development of two-kidney, two clip Goldblatt hypertension (2K2C) in the rat seems to be unaffected by chemical sympathectomy with 6-hydroxydopamine (6-HODA) and adrenal demedullation. Since this treatment only partially depletes vascular norepinephrine (NE) content, we evaluated the degree of sympathectomy achieved with the 6-HODA treatment and the structural vascular changes in treated and untreated animals. Litters of male Wistar rats were divided in two groups: 6-HODA-treated (6-HODA) animals (group 1) were injected with 6-HODA since the day of birth until the end of the experiment; control group (CG) animals (group 2) received the vehicle solution. When rats reached about 250 g, a silver clip (0.25 mm width) was placed on both renal arteries in half of them in each group; a sham operation was performed on the rest of the animals. Adrenal demedullation and denervation was performed in all 6-HODA animals. Blood pressure was followed weekly by the tail cuff method for 7 weeks. At the 8th week, Silastic cannulas were placed in the carotid artery and jugular vein in all the animals. Pressor responses to tyramine (0.05 and 0.1 mg), angiotensin (10, 40 and 160 ng), and norepinephrine (NE) (25, 100 and 400 ng) and the hypotensive effect of prazosin (1 mg/kg) were determined in the conscious rats. The pressor effect of carotid occlusion was registered 24 hours later. Animals were sacrificed, and the heart and artery weight as well as the nucleic acids and alkali soluble proteins content in the vascular wall were determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Is renin a factor in the etiology of essential hypertension?
Authors: Haber E , Zusman R , Burton J , Dzau V J , Barger A C
Published: September 2013

The widespread clinical study of converting-enzyme inhibitors has shown that they are effective antihypertensive drugs even in patients who may manifest either normal or decreased plasma renin activity. This suggests either that renin in a site other than plasma may play a contributory role in essential hypertension or that the hypotensive effect is caused by increased concentrations of kinins and prostaglandins, both demonstrated consequences of converting-enzyme inhibitor administration. Specific renin inhibitors appropriate for studies in humans would aid in the resolution of this question. Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogens, and peptides that are related to the amino-terminal sequence of prorenin. With the purification of renin, specific polyclonal or monoclonal antibodies have become available. The former have already been used extensively in physiologic studies in intact animals. Pepstatin is an inhibitor of many acid proteases. Its in vivo application has been retarded by its relative insolubility, but recent chemical modifications, particularly the addition of charged amino acids at the carboxy terminus, have rendered it more useful. The minimal substrate for renin is an octapeptide segment of the protein substrate: His-Pro-Phe-His-Leu-Leu-Val-Tyr. Variants of this sequence have resulted in competitive inhibitors that are useful in vivo. Recently, remarkably active inhibitors have been synthesized by reducing the peptide bond that is cleaved by renin, producing what may be a transition state inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Bulbospinal serotonin pressor pathways and hypotensive action of methyldopa in the rat.
Authors: Chalmers J P , Minson J B , Choy V
Published: September 2013

The administration of methyldopa (200 mg/kg i.p.) induced a green fluorescence typical of catecholamine fluorescence, in regions of the brain stem which coincided with all the major serotonin cell groups, including the B1, B2, and B3 cell groups in the medulla. Prior administration of 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin relatively specific for serotonin neurons, prevented the appearance of this methyldopa-induced fluorescence. Electrical stimulation of the ventrolateral medulla in areas that coincided with the lateral elements of the B1 and B3 serotonin cell groups evoked pressor responses recorded via cannulae in the abdominal aorta. The pressor responses were frequency-dependent and could be markedly attenuated by prior administration of 5,7-DHT either intracerebroventricularly (i.c.v.) or directly into the cervical cord to ablate descending serotonin nerve fibers. Microinjection of methyldopa (4-16 micrograms) directly into the region of the B1 and B3 cells in the ventrolateral medulla evoked a dose-dependent fall in arterial pressure observed for 4 hours. Here too, prior administration of 5,7-DHT either intracerebroventricularly or directly into the cervical cord largely prevented the hypotensive action of the microinjections of methyldopa. The administration of 5,7-DHT produced a highly selective depletion of serotonin stores without reducing the concentrations of norepinephrine. These experiments suggest that the activity of serotonin nerves descending into the spinal cord from the B1 and B3 cells in the ventrolateral medulla serves to elevate or maintain arterial pressure. They also suggest that these descending serotonin neurons may contribute to the hypotensive action of methyldopa.
Changes in brain alpha-adrenergic receptors after alpha-methyldopa administration to spontaneously hypertensive rats.
Authors: Freed C R , Wang C H , U'Prichard D C
Published: September 2013

The hypotensive action of methyldopa has been linked to production of the metabolites methyldopamine and methylnorepinephrine in brain. We have studied the effect of long-term (72 hour) intravenous infusions of methyldopa to awake restrained spontaneously hypertensive rats and normotensive Wistar-Kyoto control animals to look for differences in hypotensive effect, differences in concentrations of natural and alpha-methylated catecholamines, and differences in alpha 1 and alpha 2-adrenergic receptor populations. Results described here indicate that hypertensive rats have a greater reduction in blood pressure and a larger increase in hypothalamic and brain stem methylnorepinephrine concentrations than do the normotensive animals. The methylnorepinephrine concentration reached a plateau value in hypothalamus in both strains while pons and medulla showed progressive, dose-related increases in concentration. These regional and strain differences in the metabolism of alpha-methyldopa suggest that the production of methylnorepinephrine in brain stem nuclei is most correlated with the hypotensive action of methyldopa. alpha 2 Agonist binding (p-amino-clonidine) declined in both hypothalamus and brain stem, and the fall was greater in hypertensive than in normotensive rats. alpha 1-Adrenergic receptor binding (prazosin) was increased, again more in hypertensive than in normotensive rats. The down regulation of alpha 2-adrenergic receptors and the up regulation of alpha 1-adrenergic receptors are compatible with increased alpha 2-adrenergic agonist presynaptic inhibition of catecholamine release with resultant postsynaptic alpha 1-adrenergic receptor supersensitivity. Spontaneously hypertensive rats showed greater methylnorepinephrine production, larger up regulation of alpha 1-adrenergic receptors, and greater down regulation of alpha 2-adrenergic receptors than did the normotensive animals; these changes may be physiological markers for the greater antisympathetic action of methyldopa in hypertensive animals.
In summary: satellite symposium on central alpha-adrenergic blood pressure regulating mechanisms.
Authors: Abrams W B
Published: September 2013

This symposium reviewed the fundamental principles, pharmacology, and clinical pharmacology of central alpha-adrenergic blood pressure regulating mechanisms. Fundamental principles Arterial baro- and chemoreceptor signals reach the nucleus of the tractus solitarius (NTS) via vagal and glossopharyngeal afferents. The NTS communicates with sympathetic preganglionic neurons in the spinal cord via centers and tracts in the medulla, pons, and hypothalamus that include an alpha-adrenergic inhibitory network. Descending tracts emphasized in this symposium originate in the C-1 epinephrine cells of the medulla, B-1 and B-3 serotonin cells of the medulla, and A-5 norepinephrine cells of the pons. Transmitters involved are norepinephrine, epinephrine, serotonin, glutamate, and gamma-aminobutyric acid (GABA). Catecholamine enzymes share protein domains in their primary structures and may be coded by linked or single genes. New methods of purifying and locating alpha- and beta-receptors have been developed. Pharmacology Methyldopa, clonidine, and clonidine-like drugs lower blood pressure by stimulating postsynaptic alpha 2-receptors in a brain stem inhibitory network, which down-regulates these receptors. Alpha 1-receptors were found to be higher in normotensive than in hypertensive rats and were increased in the latter by methyldopa administration. Alpha 2-receptors were found to differ in various tissues, which permits the development of highly selective agonists and antagonists. Although alpha-methylnorepinephrine is probably the principal metabolite of methyldopa, alpha-methylepinephrine and alpha-methyldopamine may also contribute. The site of action usually is identified as the NTS. Possible roles for the descending tracts were suggested. Clinical pharmacology Methyldopa, clonidine, guanfacine, and related drugs lower blood pressure principally by CNS mechanisms but peripheral actions may also contribute.(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term hypotensive and renal effects of atrial natriuretic peptide.
Authors: Granger J P , Opgenorth T J , Salazar J , Romero J C , Burnett J C
Published: September 2013

The present study was designed to examine the short-term and long-term effects of increased plasma levels of atrial natriuretic peptide on the glomerular filtration rate, sodium excretion, and arterial pressure. Intravenous infusion of synthetic atrial natriuretic peptide (2 micrograms/kg/bolus, 50 ng/kg/min continuous infusion) for 45 minutes in six conscious dogs increased plasma levels of immunoreactive atrial natriuretic peptide from 69 +/- 10 to 233 +/- 14 pg/ml. Short-term increases in plasma levels of atrial natriuretic peptide increased the glomerular filtration rate from 53 +/- 15 to 82 +/- 16 ml/min and increased sodium excretion from 74.4 +/- 32.6 to 146.9 +/- 38.1 microEq/min. Mean arterial pressure decreased slightly, from 88 +/- 3 to 83 +/- 3 mm Hg, whereas no changes occurred in plasma renin activity (2.0 +/- 0.6 to 1.6 +/- 0.8 ng of angiotensin I per milliliter per hour) or plasma aldosterone concentration (6.9 +/- 2.3 to 8.1 +/- 3.9 ng/dl). To determine whether the short-term effects of atrial natriuretic peptide on the glomerular filtration rate and sodium excretion lead to a sustained reduction in mean arterial pressure, atrial natriuretic peptide (50 ng/kg/min) was infused intravenously for 5 days in six conscious dogs. Long-term infusion increased plasma levels of immunoreactive atrial natriuretic peptide from 27 +/- 5 to 292 +/- 31 pg/ml. The infusion caused only a transient increase in sodium excretion and had no significant long-term effect on the glomerular filtration rate. Mean arterial pressure decreased from 90 +/- 3 to 74 +/- 3 and 75 +/- 4 mm Hg by Days 4 and 5 of the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
The liver converts the antihypertensive hormone of the kidney. The renohepatic axis.
Authors: Muirhead E E , Byers L W , Brooks B , Dowell R
Published: September 2013

The antihypertensive neutral renomedullary lipid, derived from the renal papilla, causes a vasodepressor effect when injected into a peripheral vein, such as the inferior vena cava, after a lag period of 1 to 2 minutes. The blood pressure tracing is skewed (cuplike effect). The lag period is significantly reduced after injection of the antihypertensive lipid into the portal vein. The vasodepressor configuration (cuplike) is the same whether the lipid is injected into the vena cava or portal vein. Removal of the liver from the circulation prevents the depressor effect. Thus, passage through the liver is essential for antihypertensive lipid activity. Renoportal shunting of blood potentiates the antihypertensive function of the kidney after unclipping in the one-kidney, one clip hypertensive rat. Lack of a hepatic circulation prevents the antihypertensive function of the kidney after unclipping. Antihypertensive neutral renomedullary lipid and the renal venous effluent after unclipping have the same biological behavior. We conclude that antihypertensive neutral renomedullary lipid is a promolecule, the putative prohormone of the renal papilla and its renomedullary interstitial cells. The liver converts the antihypertensive prohormone of the kidney to an active antihypertensive substance. A renohepatic axis of blood pressure control appears to exist.
Measurement of left ventricular wall mass in pediatric populations.
Authors: Schieken R M
Published: September 2013

This paper reviews the techniques for obtaining technically adequate echocardiograms for epidemiologic studies. When these techniques were applied to studies of pediatric populations the following objectives were achieved: reproducible echocardiograms, observations about the relationship of echocardiographic variables to cardiovascular variables, and information about the relationship of echocardiographic and electrocardiographic variables to each other and to blood pressure. We documented the precision of M-mode left ventricular chambers and dimensions, interobserver and intraobserver variability, and the day-to-day variability of these measures. Left ventricular wall mass was significantly larger than expected for age and body size in children with persistently elevated blood pressure. The relationship between the echocardiographic and electrocardiographic variables was poor. Moreover, the electrocardiographic measures of ventricular hypertrophy did not correlate with blood pressure.
Cost-effectiveness of echocardiography and electrocardiography for detection of left ventricular hypertrophy in patients with systemic hypertension.
Authors: Devereux R B , Casale P N , Wallerson D C , Kligfield P , Hammond I W , Liebson P R , Campo E , Alonso D R , Laragh J H
Published: September 2013

Although echocardiography is more accurate than electrocardiography for detection of left ventricular hypertrophy, it is also more expensive, making it uncertain whether echocardiography is cost-effective for detection of this abnormality in hypertensive patients. Accordingly, the sensitivity of M-mode echocardiographic and electrocardiographic criteria for left ventricular hypertrophy was determined in necropsied patients with anatomic hypertrophy of mild (n = 26), moderate (n = 21) or severe (n = 46) degree, and the prevalence of each degree of hypertrophy was determined in 561 hypertensive adults drawn from clinical and employed population samples. The sensitivity of echocardiographic left ventricular mass index criteria was 57% in necropsied patients with mild hypertrophy and 98% in patients with moderate or severe hypertrophy. All electrocardiographic criteria exhibited lower sensitivity: 15 to 42% for mild, 10 to 38% for moderate, and 30 to 57% for severe hypertrophy. Cost estimates from three sources were $160 for M-mode echocardiography and $48 to $64 for 12-lead electrocardiography. In populations with a 12 to 40% prevalence of hypertrophy, echocardiography was calculated to cost less than electrocardiography per instance of hypertrophy detected ($390-$1013 vs $800-$1829), yielded better separation in predicted incidence of morbid events between hypertensive patients with or without hypertrophy (3.4-4.7 vs 1.5-2.1 per 100 patient-years as opposed to 3.0-4.4 vs 1.9-2.9 per 100 patient-years), and required smaller case and control samples for hypothetical research studies (n = 254-309 vs 397-3478).(ABSTRACT TRUNCATED AT 250 WORDS)
Systemic and regional hemodynamic effects of calcitonin gene-related peptide.
Authors: DiPette D J , Schwarzenberger K , Kerr N , Holland O B
Published: September 2013

Calcitonin gene-related peptide, a 37-amino-acid neuropeptide, has been shown to be widely distributed in periadventitial nerves throughout the cardiovascular system, particularly in association with coronary arteries. In vivo and in vitro studies have demonstrated that calcitonin gene-related peptide possesses potent vasodilator properties. Circulating calcitonin gene-related peptide is derived primarily from periadventitial nerves, though its systemic and regional hemodynamic effects are unknown. In this study, systemic and regional hemodynamics were determined by the radioactive microsphere technique prior to and following the intravenous administration of 65-pmol and 2.2-nmol doses of calcitonin gene-related peptide and vehicle to three groups of conscious, unrestrained rats. Vehicle administration did not change any systemic or regional organ hemodynamic parameter determined. In contrast, 65 pmol and 2.2 nmol of calcitonin gene-related peptide significantly decreased mean blood pressure and total peripheral resistance and increased heart rate in a dose-dependent manner, while only slightly increasing cardiac output. Both 65-pmol and 2.2-nmol doses of calcitonin gene-related peptide significantly increased blood flow (percentage of cardiac output) to the heart. There was no difference in blood flow to the heart between the two doses. In addition, the 2.2-nmol dose of calcitonin gene-related peptide significantly increased blood flow to the stomach, liver, and skin and decreased it to the brain, kidneys, and spleen. In conclusion, calcitonin gene-related peptide infusion decreases blood pressure in a dose-dependent manner primarily by peripheral vasodilation. In addition, calcitonin gene-related peptide selectively changes regional organ blood flow, particularly to cause coronary vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Electron spin resonance studies of erythrocytes from spontaneously hypertensive rats and humans with essential hypertension.
Authors: Tsuda K , Iwahashi H , Minatogawa Y , Nishio I , Kido R , Masuyama Y
Published: September 2013

The purpose of the present study was to investigate erythrocyte membrane abnormalities in hypertension by means of an electron spin resonance and spin-label technique. The erythrocytes from spontaneously hypertensive rats (SHR) and humans with untreated essential hypertension were examined and compared with their normotensive counterparts, and electron spin resonance spectra were obtained for a fatty spin-label agent (5-nitroxy stearate) incorporated into the erythrocyte membranes. The value of outer hyperfine splitting (2T' parallel) was significantly higher in erythrocytes of SHR and humans with essential hypertension than in erythrocytes of normotensive controls (at 37 degrees C: SHR, 56.14 +/- 0.51 gauss [G], n = 8; Wistar-Kyoto rats, 52.22 +/- 0.86 G, n = 4, p less than 0.01; humans with essential hypertension, 56.94 +/- 0.27 G, n = 11; normotensive subjects, 55.44 +/- 0.36 G, n = 8, p less than 0.01). The order parameter (S) was also increased in the hypertensive rats and humans compared to their respective normotensive controls. When calcium was loaded to erythrocytes with calcium ionophore A23187 (0.9 microM) and CaCl2 (1.0 mM), the parameters of the spectra were increased. These changes were more prominent in the hypertensive groups than in the normotensive controls. These results revealed that the erythrocyte membranes of the hypertensive subjects tolerated different spin motions than those of the normotensive controls in the electron spin resonance study and that membrane fluidity might be decreased in hypertension. Additionally, calcium loading to erythrocytes caused the reduction of membrane fluidity. Therefore, it is suggested that an abnormality of calcium handling at the cellular level might affect physical properties of the biomembranes in hypertension.
Presence of angiotensinogen messenger RNA in various cultured cell lines.
Authors: Fatigati V , Washington J M , Lynch K R , Peach M J , Miller E D
Published: September 2013

The presence of angiotensinogen messenger RNA (mRNA) was assessed in total RNA extracted from hepatoma, glioma, neuroblastoma, and glioma-neuroblastoma hybrid cell lines. Total RNA from 1 X 10(7) cells was extracted, transferred to a membrane, and hybridized with a 32P-labeled, full-length (1650-base pair) rat angiotensinogen complementary DNA (cDNA). Angiotensinogen RNA sequences could be definitively detected only in hepatoma cells. Steroids were used in an attempt to increase the angiotensinogen mRNA level. Dexamethasone (2 X 10(-6) M) or 17 beta-estradiol (1 X 10(-7) M) was added to the cultures 18 to 24 hours prior to harvest. Dexamethasone treatment of the hepatoma cells resulted in a large increase in angiotensinogen mRNA, whereas estradiol had no effect. Steroids failed to induce detectable levels of angiotensinogen mRNA in total RNA from the other cell lines. That the RNA was intact was ensured by hybridizing duplicate Northern blots to a 32P-labeled actin cDNA. Actin mRNA sequences were detected in all cell lines. Blot hybridization of poly(A)+RNA resulted in the visualization of a weak angiotensinogen mRNA signal for a glioma cell line and a glioma-neuroblastoma hybrid line. However, the ability to detect angiotensinogen mRNA in a cell may depend on the phenotype expressed, which can be governed by culture conditions.
Reduced electrogenic sodium-potassium pump in arterioles during renovascular hypertension.
Authors: Lombard J H , Joyner W L , Stekiel W J
Published: September 2013

The goal of this study was to assess the role of the electrogenic Na+-K+ pump in controlling active tone in cremasteric arterioles of normotensive hamsters and hamsters with bilateral (two-kidney, two figure-8) Grollman hypertension. Arterioles of both groups exhibited a large transient dilation when the Na+-K+ pump was stimulated by superfusing the cremaster muscle with physiological salt solution containing 15 mM K+ after 20 minutes of 0 mM K+ superfusion. Arteriolar dilation in response to 15 mM K+ was significantly smaller in the hypertensive animals than in sham-operated controls. Ouabain (10(-5) M and 10(-3) M) inhibited arteriolar dilation in response to 15 mM K+ in both groups of animals. Resting diameters, total active tone (assessed by application of 10(-4) M adenosine), and arteriolar responses to inhibition of the Na+-K+ pump by superfusion with 0 mM K+ or ouabain were not significantly different in normotensive and hypertensive animals. These data indicate that an electrogenic Na+-K+ pump can regulate active tone in cremasteric arterioles, and that the maximum response of this pump to stimulation with 15 mM K+ is reduced in arterioles of hamsters with two-kidney Grollman hypertension.