bluuebunny/crossref_metadata_2025 huggingface dataset:
DOCA test for aldosteronism: its usefulness and implications.
Authors: Rodríguez J A , Lopez J M , Biglieri E G
Published: September 2013

Experience with the DOCA test (measurement of urinary excretion of aldosterone before and after 3 days of administration of 10 mg deoxycorticosterone acetate [DOCA] intramuscularly every 12 hours while on high sodium intake) is presented in 129 hypertensive patients to define its usefulness in discriminating between autonomous and nonautonomous production of aldosterone. All patients who did not have primary aldosteronism had a decrease in urinary excretion of aldosterone to values within the normal range, with a greater than 30% fall from control values. Patients with an aldosterone-producing adenoma had a 5.7% fall and those with idiopathic hyperaldosteronism had a 9.9% fall. Sodium retention was limited in these patients when compared with that in normal subjects. The least retention occurred in patients with an aldosterone-producing adenoma, whereas patients with low-renin essential hypertension retained more sodium than any other hypertensive group; the latter required greater sodium retention than those with normal-renin essential hypertension to produce a similar decrease in urinary aldosterone. Sodium retention correlated significantly with the percent fall in urinary aldosterone only in the low-renin essential hypertension group. Serum potassium levels fell in all groups. Changes in serum potassium levels and plasma renin concentration did not correlate with changes in urinary aldosterone excretion. The DOCA test is effect in discriminating between primary aldosteronism and other causes of hypertension. It also demonstrates that in hypertensive patients small changes in sodium retention reduce aldosterone excretion.
Unconjugated hyperepinephrinemia: a hallmark of hypertension imitating pheochromocytoma?
Authors: Kuchel O , Buu N T , Hamet P , Larochelle P , Bourque M , Genest J
Published: September 2013

Hypertensive patients with elevated and hyperresponsive plasma norepinephrine and epinephrine (NE + E) associated with low conjugated NE + E were previously identified by determination of the sum of NE + E. Because of their excessive E but not NE responses to glucagon and also hypertension corresponding to E excess, we explored whether an elevated unconjugated E resulting from a selective E conjugation defect could be obscured by the sum of NE + E. We found that nine patients with elevated E (reflected by the normal 4:1 ratio of plasma NE to E reversed in favor of E), had, when compared to 31 patients with plasma NE exceeding E:1) lower plasma conjugated E (mean 0.03 vs 0.27 ng/ml, p less than 0.01), lower degree of E conjugation (8 vs 51%, p less than 0.01), and a higher maximum systolic (p less than 0.05), pulse pressure (p less than 0.02) and higher pulse rates (p less than 0.04), but no differences in the unconjugated and conjugated proportions of plasma NE; and 2) an absence of conjugated E throughout the circulation and relative preponderance of E over NE at sampling points close to the peripheral venous blood (p less than 0.05). The absolutely and relatively decreased plasma conjugated E in patients with E exceeding NE (without difference in conjugated NE) is a preliminary indication that a selective sulfoconjugating defect of E results in plasma E higher than NE in accordance with the hyper-beta-adrenergic features of their hypertension. Epinephrine, a circulating hormone, is more dependent on conjugated E reflect better this defect than those measuring the sum of NE and E.
Renin-like activity in the rat brain during the development of DOC-salt hypertension.
Authors: Basso N , Ruiz P , Mangiarua E , Taquini A C
Published: September 2013

Levels and distribution of an angiotensin-forming enzyme, active at the physiological pH (isorenin), were determined in the central nervous system of 24 rats treated with 25 mg/kg of deoxycorticosterone (DOC) subcutaneously, twice a week, plus saline to drink during 30 days and in 14 control animals. Different areas of the brain were excised and homogenized. Renin activity and concentration were determined by incubation of the supernatant of each homogenate at pH 7.2 alone and in the presence of an excess of renin substrate. The angiotensin generated was measured by radioimmunoassay. Concentration of the renin-like enzyme was significantly higher in the posterior hypophysis and in the brain stem of the experimental group; isorenin activity was higher in the hypothalamus, cerebral cortex, cerebellum, and brain stem of the DOC-salt-treated rats than in the control rats. Changes in the angiotensin-forming enzyme in the central nervous system of experimental animals, active at physiological pH, suggest that this isorenin system may play a role in the physiological response to DOC-salt in the rat. The significance of the brain isorenin system in the regulation of blood pressure requires further analysis.
Treatment of hypertension in 1981.
Authors: Freis E D
Published: September 2013

Antihypertensive drugs reduce cardiovascular morbidity and mortality. This was demonstrated by controlled clinical trials. While most complications are dramatically reduced it is not certain whether the incidence of myocardial infarction is decreased by treatment or whether the severity of the infarct is reduced. The prognosis in patients with borderline and mild hypertension varies widely depending on the number of other risk factors present. Patients with mild hypertension and low risk profiles may not obtain enough benefit from treatment to justify the side effects, inconvenience, and expense of such therapy. Such patients should be individually evaluated as to the need and desirability of treatment. Patients who are not treated with drugs should be seen for an annual follow-up to detect progression. Low sodium diets are effective but they are not practical because it is difficult to adhere to the required degree of sodium restriction. Weight-reducing diets also reduce blood pressure but compliance again is difficult, although it is worth advocating for the few patients who will maintain the diet more or less indefinitely. Between 1973 and 1977 in the United States there has been an 8% decline in deaths due to heart disease, a 17% decrease in deaths due to stroke, and an increase in average life expectancy from 71.3 to 72.8 years. Could this be the result of more widespread treatment?
Effect of intracerebroventricular captopril on vasopressin and blood pressure in spontaneously hypertensive rats.
Authors: Crofton J T , Rockhold R W , Share L , Wang B C , Horovitz Z P , Manning M , Sawyer W H
Published: September 2013

In conscious, unrestrained spontaneously hypertensive rats (SHR), mean arterial blood pressure (MAP) increased from a pretreatment value of 150 +/- 4 to 179 +/- 7mm Hg within 10 min (p less than 0.01) following an intracerebroventricular (i.c.v.) injection of captopril (2 mg/kg body weight), and the plasma vasopressin concentration was increased eightfold (p less than 0.01). MAP than fell to 131 +/- 5 mm Hg at 120 minutes (p less than 0.01), and plasma vasopressin concentration returned to pretreatment levels. The initial increase in MAP was due in large part to increased plasma vasopressin levels since this increase was reduced 50% by pre-treatment with a specific antagonist of the pressor action of vasopressin. The reduction in MAP at 120 minutes in captopril-treated rats may been nonspecific, since a similar effect was observed in SHR given an i.c.v. injection of a control solution. In (Wistar-Kyoto) WKY rats, i.c.v. captopril was without a statistically significant effect on MAP, but the plasma vasopressin concentration increased three-fold (p less than 0.01). These findings may reflect an increased sensitivity of the control system for vasopressin release in the SHR.
Sodium intake and essential hypertension.
Authors: Luft F C , Weinberger M H
Published: September 2013

This review briefly considers the hypothesis that a generous dietary sodium intake contributes to the development or maintenance of essential hypertension. Three lines of evidence are presented that are not mutually exclusive. Epidemiological studies examining sodium intake, prevalence of hypertension, and increases of blood pressure with age provide circumstantial support for the concept that hypertension is related to sodium intake. Analyses of cellular electrolyte transport suggest that hypertensives and their relatives are at a disadvantage with respect to extruding sodium from cells. A conceptual framework indicates that blood pressure is determined by a balance between the natriuretic effect of increased blood pressure and the pressor effect of sodium retention. Clinical studies in humans support the sodium hypothesis. The kidney's ability to excrete sodium and its sodium regulatory system are genetically determined. In hypertensive humans, blood pressure is directly correlated with total body and exchangeable sodium, a relationship that increases with age. Groups at risk for hypertension excrete sodium less well then those at less risk. Yet both hypertensives and normotensives exhibit heterogeneous blood pressure responses when sodium-loaded or -depleted. It has not been shown that sodium restriction will prevent the development of hypertension in normal individuals; however, it is clear that sodium restriction is an important aspect of management. In three prospective randomized controlled trials, practical sodium restriction lowered blood pressure by 8 mm Hg. Such a decrease would lower cardiovascular morbidity by 10% to 15%. Were means available to detect "salt-sensitive" hypertensives, sodium restriction could be conducted in a more appropriate fashion.
Human nutrition and blood pressure regulation: an integrated approach.
Authors: McCarron D A , Henry H J , Morris C D
Published: September 2013

This review highlights the complex interactions that constitute the disciplines of nutrition and cardiovascular physiology. Nutritional factors have long been considered as critical in the pathogenesis of human hypertension. Theoretical and established contributions of various nutrients to blood pressure regulation are presented. A brief historical perspective of sodium's dominance in this area is provided. "Accepted" principles of nutrient interaction are then applied to cardiovascular research. First, the interrelationships among all macronutrients and diet composition, nutrient absorption, renal elimination, and ultimate bioavailability to the vascular tissue are assessed. An analysis of dietary recall data from human studies is provided to illustrate such nutrient interaction. Second, associated factors that influence nutrition are considered in relation to both human and animal investigations of blood pressure regulation. Finally, the development and interpretation of future studies are assessed in light of these principles. Examples from both the human and animal investigations of blood pressure regulation. Finally, the development and interpretation of future studies are assessed in light of these principles. Examples from both the human and animal literature are provided to show why it is necessary to incorporate fully the established principles of nutrition into our current concepts of the pathogenesis of hypertension. Future progress in terms of nutrition, food, and health will be dependent upon such an integrated approach.
Calcium, magnesium, and phosphorus balance in human and experimental hypertension.
Authors: McCarron D A
Published: September 2013

The thesis that primary disturbances of divalent ion metabolism contribute to the development and maintenance of hypertension is addressed. Representative interactions of calcium, magnesium, and phosphorus with normal cardiovascular physiology are presented. Established and postulated abnormalities of divalent ion metabolism associated with human and experimental hypertension are reviewed. The influence of calcium balance on blood pressure development in the young spontaneously hypertensive rat is demonstrated by the results of a diet intervention study. Twelve male SHRs were randomized at 4 weeks of age to one of three diets that differed only in the calcium content (0.25%, 0.5%, and 4.0% by weight). The SHRs' blood pressures stratified inversely (p less than 0.001) based upon the calcium content. The low calcium animals experienced a more rapid and greater rise in blood pressure between 4 and 20 weeks of age (p less than 0.01). Blood pressures of the supplemented SHRs (4%) peaked at a lower value (174 vs 192 mm Hg, p less than 0.01). After maturity, the 4% SHRs experienced an attenuation (p less than 0.01) of their hypertension (154 +/- 7 mm Hg, 4% SHR vs 176 +/- 7 mm Hg, 0.5% SHR). It is proposed that membrane-associated bioavailable Ca2+ is reduced in the SHR, and possibly in human, hypertension. Dietary calcium supplementation may reverse this defect, resulting in cell membrane stabilization and vascular smooth muscle relaxation.
Response of the renal kallikrein-kinin system, intravascular volume, and renal hemodynamics to sodium restriction and diuretic treatment in essential hypertension.
Authors: O'Connor D T
Published: September 2013

The renal kallikrein-kinin system, distinct from the plasma system, is an enzyme sequence producing kinins, principally lysyl bradykinin. While the functions of the system have not been conclusively established, it has been implicated in renal vasodilation and natriuresis, although the evidence is often conflicting. Measurement of urinary kallikrein excretion is the most common way to assess the system, although kallikrein excretion and kinin excretion are often dissociated. Kallikrein excretion is influenced by several hormonal systems, as well as dietary alterations, disease states (including hypertension), and numerous drugs. Kallikrein excretion is diminished in hypertension (especially hypertension with reduced renal function), suggesting involvement in the pathogenesis of the disease. Dietary sodium restriction increases kallikrein excretion while lowering blood pressure, but the blood pressure reduction correlates with plasma volume contraction rather than the increase in kallikrein. Thiazide diuretics lower blood pressure and renal vascular resistance while increasing kallikrein excretion, and blood pressure "responders" to thiazides have a greater kallikrein increment than the "nonresponders," suggesting a role for renal kallikrein in the hypotensive response to thiazides.
Beta adrenergic receptor response coupling in hypertrophied hearts.
Authors: Kumano K , Upsher M E , Khairallah P A
Published: September 2013

Reports in the literature have indicated that inotropic responsiveness to isoproterenol (ISO) of hypertrophied rat myocardium is decreased. We have studied possible biochemical mechanisms to explain this. Adenylate cyclase activity in myocardial membranes from 13-week-old spontaneously hypertensive rats (SHR) was unchanged compared to enzyme activity in Wystar-Kyoto (WKY) when measured under basal conditions or following NaF, a guanosine triphosphate analog, MnCl2, or forskolin stimulation. However, ISO-stimulated cyclase activity was decreased as were beta-adrenergic receptor density with no change in receptor affinity. On the other hand, hearts from two-kidney, one clip renal hypertensive rats 6 weeks after initiation of hypertension showed decreased basal, ISO, NaF, and GTP analog-stimulated cyclase activity with no change in Mn++ or forskolin-stimulated activity. In this model, receptor density increased. When the clipped kidney was removed, these changes returned toward normal as did the blood pressure and heart weight. We interpret these data to indicate that in SHR the biochemical defect leading to decreased inotropic responsiveness of hypertrophied hearts is due to decreased beta-adrenergic receptor density, leading to decreased ISO-stimulated cyclase activity. The nucleotide regulatory protein component (N) and the catalytic subunit (C) are not changed. In the renal hypertensive rat, on the other hand, although the C is unchanged, there is a decrease in the activity of N, and this is probably the primary reason why inotropic responsiveness to ISO is decreased. Increases in receptor density seen in this model may possibly be compensatory.
Effect of anteroventral third ventricle lesions on vascular sodium-pump activity in two-kidney Goldblatt hypertension.
Authors: Songu-Mize E , Bealer S L , Caldwell R W
Published: September 2013

We studied the effects of anteroventral third ventricle (AV3V) lesions on the vascular Na+-pump activity and blood pressure of rats prepared by the two-kidney Goldblatt procedure. Blood pressures and Na+-pump activity of the isolated tail arteries, measured as ouabain-sensitive 86Rb+-uptake were determined in rats with renal artery clips, rats with AV3V lesions, and rats with AV3V lesions. Rats with renal artery clips developed higher blood pressures (40%) and higher vascular Na+-pump activity (20%-35%) than rats with no renal clips. Placement of AV3V lesions prior to the placement of renal clips prevented the increase in blood pressure and the increase in vascular Na+-pump activity. Plasma potassium and creatinine concentrations, nonspecific 86Rb+-uptake, and hematocrit were not different among these groups. Plasma sodium concentration was elevated in the AV3V lesioned control group. These experiments suggest a possible role of this CNS region in the regulation of vascular Na+-pump function during hypertensive states.
Treatment of hypertension in hemodialysis patients with nifedipine.
Authors: Kubo K , Shiraishi K , Muto H , Suzuki T , Sugino N
Published: September 2013

The hemodynamic effects of nifedipine were studied in nine patients with acute or chronic renal failure undergoing hemodialysis. Arterial blood pressure was lowered within 15 minutes of oral administration of nifedipine 10 mg. Mean arterial pressure and total systemic peripheral resistance were significantly decreased, whereas cardiac index and heart rate revealed slight but statistically insignificant changes. Changes in pulmonary artery diastolic pressure and mean right atrial pressure which were closely related to cardiac preload were not significant. However, the antihypertensive effect was enhanced in patients with lower pretreatment preload. Results show that oral nifedipine is effective in rapidly reducing blood pressure during or following hemodialysis.
Long-term efficacy of calcium antagonists in resistant hypertension.
Authors: Robinson B F , Bayley S , Dobbs R J
Published: September 2013

Verapamil and nifedipine are calcium-blocking agents that have a selective dilator effect on resistance vessels. Both drugs have been shown to lower arterial pressure when given in long-term therapy under conditions of a double-blind controlled trial. Both agents may be effective as sole therapy or when given in combination with a diuretic; nifedipine has been used successfully in conjunction with beta-adrenoceptor antagonist/diuretic combinations. Calcium-blocking agents do not evoke tolerance in long-term treatment; in contrast to other directly acting dilator drugs, they do not consistently lead to a rise in plasma renin activity and they induce little or no sodium retention. Calcium-blocking agents do not all share the same mechanism of action, and they vary considerably in their effect on the heart. These differences may be important in determining which compound is best suited for use in particular clinical situations.
Pharmacokinetic studies of nifedipine tablet. Correlation with antihypertensive effects.
Authors: Taburet A M , Singlas E , Colin J N , Banzet O , Thibonnier M , Corvol P
Published: September 2013

A tablet form of nifedipine was given to eight hypertensive hospitalized men (Stage I or II WHO, 45 +/- 10 years old). After an initial placebo test, 20, 40, and 60 mg of nifedipine were given at 8.00 a.m. in random order at 72-hour intervals in a single administration double-blind crossover study. Blood pressure and heart rate were measured twice by the same observer every 20 minutes from 7.00 a.m. to 8.00 a.m. and then hourly until 8.00 p.m., first with the patients recumbent and again after 1 minute of standing. Plasma nifedipine levels were assayed in samples drawn hourly from 8.00 a.m. to noon, every 2 hours from noon to 8.00 p.m., and at 24 and 48 hours after drug ingestion. The three doses all lowered blood pressure significantly. The reduction during recumbency was significantly larger (-18%) and lasted longer (12 hours) after 60 mg than after 20 mg (-11% at 7 hours). The three doses caused similar increases in heart rate (+29% to +38%), the maximum occurring at the second hour and lasting for 5 hours. The peak plasma concentrations and areas under the plasma concentration time curve were dose-dependent; kinetics were linear between 20 and 60 mg, and the half-life of nifedipine tablets was close to 10 hours. The decrease in mean arterial blood pressure correlated strongly with plasma nifedipine levels (r = 0.61; n = 190; p less than 0.001). Four patients experienced mild side effects (headaches, flushes, drowsiness, or weakness). The tablet form of nifedipine had a potent antihypertensive action that lasted longer than that of the capsule formulation.
Factors involved in the antihypertensive action of calcium antagonists.
Authors: Garthoff B , Kazda S , Knorr A , Thomas G
Published: September 2013

The main mechanism underlying the antihypertensive action of calcium antagonists is believed to be the vasodilation of peripheral vessels. To compare the effects of calcium antagonists with those of other vasodilators, nifedipine or its antihypertensive analog nitrendipine were tested in different normotensive and hypertensive rat strains and situations. The acute blood-pressure-lowering effect of nifedipine in the Dahl salt-sensitive rat was characterized by a rapid onset of action, the minimal effective oral dosage (0.1 mg/kg) being effective for up to 6 hours. Nifedipine was approximately 3 times more potent than hydralazine and equipotent to, but of shorter duration of action than, minoxidil. Natriuretic activity in normotensive Wistar and hypertensive Dahl salt-sensitive rats was observed with nitrendipine after an acute saline load (30 ml/kg by mouth), whereas vasodilators such as minoxidil and hydralazine decreased renal function under these conditions. Treatment of spontaneously hypertensive rats (SHR) with nifedipine in food (315 parts per million) for 60 weeks prevented the development of hypertension and resulted in decreased plasma renin activity and plasma aldosterone concentration in comparison to untreated SHR controls. Moreover, absolute and relative heart weights were reduced in the treated rats. Results suggest that the antihypertensive action of calcium antagonists, at least those of the dihydropyridine type, is not only due to peripheral vasodilation, since in contrast to other vasodilators a hyperdynamic circulation is not induced, the renin-angiotensin-aldosterone system is not activated, and sodium/volume retention cannot be expected because of a primary natriuretic effect. Therefore, a reduced volume load in addition to the decrease in afterload contributes to the antihypertensive effect of calcium antagonists and their prevention of heart hypertrophy.
Epidemiological study of the relationship between calcium and blood pressure.
Authors: Kesteloot H , Geboers J , Van Hoof R
Published: September 2013

During an epidemiological survey of 9321 male Belgian subjects, a highly significant positive correlation was found between the serum calcium level and blood pressure. The slope of the equation relating serum calcium level to blood pressure was higher in subjects who restricted their sodium intake than in subjects who did not. The slope was also significantly higher in subjects who did not take medication for hypertension compared to those who did. There was a significant and positive correlation between urinary calcium measured from 24-hour samples and blood pressure, both in the Belgian study and in a further epidemiological survey in Korea. In the Korean study, no significant correlation was found between 24-hour urinary magnesium excretion and blood pressure.
Calcium and blood pressure regulation in normal and hypertensive subjects.
Authors: Bianchetti M G , Beretta-Piccoli C , Weidmann P , Link L , Boehringer K , Ferrier C , Morton J J
Published: September 2013

To elucidate the mechanisms involved in calcium-mediated blood pressure (BP) control, plasma norepinephrine (NE), epinephrine, renin activity, and angiotensin II (AII) levels and the cardiovascular pressor responsiveness to NE and AII were assessed before and during acute mild hypercalcemia or short-term calcium (Ca) inhibition with nifedipine in 20 normal and five borderline hypertensive subjects. In normal subjects, systolic BP and plasma NE and epinephrine concentrations were increased significantly (p less than 0.05) during an acute rise in serum Ca of 3.1 mg/dl (intermediate rate Ca infusion, 0.05 mg/kg/min for 3 hours), but not following an increase of 1 mg/dl (low rate Ca infusion, 0.034 mg/kg/min for 2 hours). In the borderline hypertensive group, low-rate Ca infusion elevating serum Ca by 1 mg/dl was associated with a slight increase in systolic BP (p less than 0.05) and plasma catecholamines. In both groups, the pressor responses to infused NE and AII, and plasma renin and AII levels, were unchanged during mild to moderate hypercalcemia. Nifedipine given for 2 weeks (average dose, 48 mg/d) reduced BP significantly (p less than 0.05) in the borderline hypertensive subjects only and NE pressor responses in both groups (p less than 0.025), but had no significant effect on plasma catecholamines, renin, or AII levels. These findings suggest that the adrenergic BP control mechanism may be more dependent on clinical variations in calcium metabolism than the angiotensin BP regulatory mechanism. Acute hypercalcemia may increase BP at least in part by causing an increase in adrenergic activity without an equivalent decrease in cardiovascular reactivity. Calcium inhibition with nifedipine may modify noradrenergic BP control by lowering the NE pressor reactivity without causing an equivalent increase in adrenergic activity.
Pharmacology of calcium entry blockers: interaction with vascular alpha-adrenoceptors.
Authors: van Zwieten P A , van Meel J C , Timmermans P B
Published: September 2013

The pharmacology of calcium entry blockers (CEB), as used in various types of cardiovascular disease, is reviewed. Their vasodilator potency is analyzed, which is the most common therapeutic characteristic of all CEB, apart from the antiarrhythmic activity of verapamil. All CEB relax vascular smooth muscle, particularly in arteriolar beds, thus reducing peripheral vascular resistance. Arteriolar relaxation appears to be associated with inhibition of transmembrane calcium influx. Recent studies have demonstrated that vasoconstriction induced by stimulation of vascular postsynaptic alpha 2-adrenoceptors, using selective agonists, is reduced by CEB through a noncompetitive mechanism. However, vasoconstriction evoked by selective excitation of vascular alpha 1-adrenoceptors remains virtually uninfluenced by CEB. The selective interference of CEB with alpha 2-adrenoceptor stimulation suggests that calcium movement is associated with alpha 2-adrenoceptor stimulation. This mechanism may further contribute to the vasodilator effect of CEB by inhibiting that part of vascular tone evoked by the stimulation of alpha 2-adrenoceptors by endogenous catecholamines.
Low-dose captopril therapy in mild and moderate hypertension. Randomized comparison of twice daily vs three times daily doses.
Authors: Corea L , Bentivoglio M , Verdecchia P
Published: September 2013

We have investigated the antihypertensive activity of relatively low daily doses of captopril in patients with mild and moderate arterial hypertension. In a first trial, at the end of a 2-week placebo washout period, 18 patients with essential hypertension WHO Stage I or II were treated with captopril, 25 mg three times daily (t.i.d.), 25 mg twice daily (b.i.d.), 50 mg t.i.d., and 50 mg b.i.d., according to a randomized within-patient open design, with each regimen lasting for a 2-week period. In a second trial, 12 hypertensive patients not adequately controlled by chlorthalidone 25 mg daily as monotherapy (supine diastolic blood pressure at rest greater than 95 mm Hg), continued the diuretic treatment in combination with captopril, 25 mg t.i.d. and 25 mg b.i.d. according to a randomized within-patient open design. Analysis of variance did not reveal differences between the four captopril dosing schedules (1st trial), or between the two captopril dosing schedules (2nd trial). Both the patients on captopril monotherapy (1st trial) and those cotreated with chlorthalidone (2nd trial) showed lower systolic and diastolic blood pressure values on each captopril regimen compared to prerandomization values (all p less than 0.01). No relevant unwanted effects were noted. We conclude that in patients with mild or moderate essential hypertension, either untreated or resistant to chlorthalidone, captopril is effective in reducing blood pressure even at daily doses not exceeding 150 mg, without differences between a t.i.d. and a b.i.d. dosing schedule.
Causes of inadequate response to antihypertensive drugs. Volume factors.
Authors: Dustan H P
Published: September 2013

Diuretic therapy, by producing a negative salt and water balance, eliminates the false tolerance to sympatholytic drugs that often occurs during long-term monotherapy. This tolerance results from salt and water retention produced by the drugs. Review of published results suggests a primacy for arterial pressure reduction in this fluid because suppressed renal sympathetic activity should facilitate salt and water excretion through lessened alpha-adrenergic influence on tubular reabsorption, and beta-adrenergic inhibition would diminish renin release thus promoting natriuresis. The return of hypertension that characterizes the false tolerances seems paradoxical because these drugs cause venodilation, which should provide ample storage of expanded blood volume without affecting cardiac output. However, animal studies have suggested that dilated veins have decreased compliance; if that is so, in humans it would mean that fluid retention would be accompanied by a redistribution of blood into the central circulation, with a rise in cardiac output.
Methods for assessing blood pressure values in humans.
Authors: Mancia G
Published: September 2013

In clinical medicine and epidemiology, measurements of blood pressure largely rely upon the use of cuff inflation and Korotkoff sounds. Although still the most practical, this method has been recognized to have important limitations. This paper focuses on two limitations of the cuff method that have been found while recording 24-hour intraarterial blood pressure in free-living normotensive and hypertensive patients. First, the 24-hour blood pressure is characterized by large long- and short-term variabilities whose magnitudes vary according to the patient's basal blood pressure and age. This is likely to reduce the possibility that a few isolated cuff measurements are accurate and representative of the patient's average blood pressure. Second, during cuff blood pressure assessment by the doctor (and to a lesser degree by the nurse), the patient's blood pressure normally rises due to an alarm reaction, with a large peak within the first 4 minutes and a subsequent decline. The magnitude of the peak rise, as well as its large and unpredictable difference among subjects may be responsible for seriously and variably overestimating the blood pressure. A 10-minute wait from the beginning of the doctor's visit usually avoids this inconvenience. Finally, the paper briefly considers alternative methods to the cuff method, including invasive intraarterial 24-hour recording in ambulatory subjects, which provides a large amount of information but is impractical, and noninvasive automatic blood pressure devices, which offer a promising practical approach but must wait for technical validation.
Severe hypertension in the Spanish population. Association with specific HLA antigens.
Authors: Luque Otero M , Martell Claros N , Llorente Pérez L , Fernández Pinilla C , Fernández-Cruz A
Published: September 2013

There is now increasing evidence for immunological changes in essential hypertension. Immunological response is determined in part by genes linked to the HLA system. It has been reported a positive association between HLA B15 and the risk for cerebral events in essential hypertensive (EH) patients. We studied the distribution of HLA antigens in 128 EH (age range, 13-85 years) and 1000 normotensive controls. EH were classified in accordance with the World Health Organization (WHO) criteria: in WHO Stages I and II, there were 100 patients; in WHO Stage III, there were 28 patients. HLA-A and B antigens of peripheral blood lymphocytes were studied according to the microlymphocytotoxicity test. The results were compared by chi-square analysis, and the p value was multiplied by the number of antigens studied at each locus, to avoid overestimation of an association. Frequency of HLA-BW 22 was higher in EH compared with controls (5.4% vs 1.2%, p less than 0.01). Frequency of HLA-B12 in EH with WHO Stage III hypertension (64.2%) was significantly increased compared either with EH in WHO Stage I or II (29%, p less than 0.01) or the control group (26.9% p less than 0.001). The incidence of HLA-B15 antigen in the whole hypertensive group was 3.1%, lower than in normotensive controls (6.4%, p less than 0.8). None of the patients with WHO Stage III hypertension had the HLA-B15 antigen. In conclusion, the results seemed to indicated that the Spanish population had an association between HLA-B12 and severe hypertension.
Abnormalities of membrane transport in hypertension.
Authors: Haddy F J
Published: September 2013

In this review, postulated passive and active fluxes of sodium, potassium, and calcium across the sarcolemma of the normal vascular smooth muscle cell are first summarized. Some practical problems encountered in their measurement are also mentioned. The review then considers how these fluxes appear to be altered in various forms of hypertension in animals and humans. Emphasis is given to abnormal fluxes of sodium and potassium due to altered sodium pump activity and permeability. Increasing evidence indicates that sodium retention due to increased sodium intake or decreased sodium excretion causes hypertension by releasing a humoral pressor substance from brain. This substance, which may be the putative natriuretic hormone, inhibits Na+, K+-ATPase and sodium pump activities in blood vessels and heart, thereby increasing contractile activity. In the genetic models of hypertension, the primary defect appears to be increased permeability of the vascular smooth muscle cell wall to sodium; pump activity increases to compensate for the increased inward leak of sodium. This may also be the case in patients with heritable essential hypertension. The possible consequences of super-imposing the sodium pump inhibitor on the primary defect are also considered. This may occur when animals with genetic hypertension or patients with heritable essential hypertension retain sodium subsequent to increased sodium intake and/or decreased ability to excrete sodium. Such superimposition should raise intracellular sodium concentration to high levels since now the pump would not fully compensate for the increased inward leak of sodium.
Neurogenic actions of angiotensin II.
Authors: Ferrario C M
Published: September 2013

It has become increasingly evident that blood-borne angiotensin II has major effects upon brain cardiovascular centers. With the discovery of an angiotensin I-forming enzyme or isoenzymes in the central nervous system of mammals, alternative concepts have emerged regarding the role of this peptide in the regulation of central adrenoreceptor activity, pituitary function, and hydromineral metabolism. These concepts are reviewed, and a framework for future research is suggested by the author.
Effect of centrally acting alpha-adrenergic agonists on sympathetic nervous system function in humans.
Authors: Brown M J , Harland D , Murphy M B , Struthers A D
Published: September 2013

Three studies were undertaken to reevaluate whether there is a peripheral component in the reduction of sympathetic activity caused by centrally acting drugs; and whether the antihypertensive effect of these drugs is due entirely to this reduction. Plasma growth hormone and norepinephrine concentrations were used as respective markers of central alpha-adrenoceptor stimulation and peripheral sympathetic activity. In six normal volunteers, intravenous infusion of 0.2 mg clonidine and 2 mg guanfacine was compared. The falls in systolic blood pressure and plasma norepinephrine concentration were slightly greater after clonidine (18 mm Hg and 0.22 ng/ml) than after guanfacine (12 mm Hg and 0.13 ng/ml) administration. These falls occurred earlier than the rise in growth hormone, which rose to a maximum of 23 and 20 IU/ml respectively at 45 minutes after dosing. In six patients with essential hypertension clonidine and alpha-methyldopa caused similar falls in blood pressure and plasma norepinephrine concentration although these changes occurred later with alpha-methyldopa. Plasma growth hormone levels remained undetectable in most patients. In Wistar rats the effect of central and peripheral alpha 2-blockade on clonidine-induced changes was compared. Two groups of six rats received intravenous RX 781094, 0.3 mg/kg, or vehicle 10 minutes before receiving clonidine, 5 micrograms/kg i.v. In the latter, control group, clonidine reduced mean blood pressure by 30.7 +/- 1.9 mm Hg and heart rate by 46 +/- 6.7 beats/min. Plasma norepinephrine fell from 0.22 +/- 0.023 ng/ml to 0.116 +/- 0.013 ng/ml. After pretreatment with RX 781094, blood pressure did not change and heart rate fell by 18 +/- 2.7 beats/min.(ABSTRACT TRUNCATED AT 250 WORDS)
Withdrawal reactions following cessation of central alpha-adrenergic receptor agonists.
Authors: Reid J L , Campbell B C , Hamilton C A
Published: September 2013

Interruption of long-term treatment with alpha 2-adrenergic receptor agonists may be associated with reversal of their hemodynamic effects, clinical and biochemical evidence of increased peripheral sympathetic activity, and behavioral responses similar to those seen after narcotic or alcohol withdrawal. Reactions are most commonly observed after short-acting imidazoline drugs such as clonidine and tiamenidine. Reactions are less common after longer acting agents such as guanfacine. A new management approach to withdrawal has been evaluated, which uses a combination of alpha 1-blockade (prazosin) and cardioselective beta-blockade (atenolol) together with a benzodiazepine (chlordiazepoxide). Withdrawal reactions were not observed in eight patients in whom clonidine was withdrawn under cover of these agents. The mechanism of the withdrawal reaction may involve agonist-induced down regulation of alpha 2-adrenergic receptor affinity, number, or both. Experimental studies with the irreversible alpha-antagonist phenoxybenzamine on the turnover of alpha 2-receptors suggest that recovery of receptor number may be much slower in the brain than in the periphery.
Statine-containing dipeptide and tripeptide inhibitors of human renin.
Authors: Kokubu T , Hiwada K , Nagae A , Murakami E , Morisawa Y , Yabe Y , Koike H , Iijima Y
Published: September 2013

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
High salt diet sensitizes cardiopulmonary baroreflexes in Dahl salt-resistant rats.
Authors: Victor R G , Morgan D A , Thorén P , Mark A L
Published: September 2013

Compared with Dahl salt-resistant (R) rats, Dahl salt-sensitive (S) rats on a low salt diet have impaired cardiopulmonary baroreflex control of sympathetic nerve activity. The purpose of this study was to examine the sensitivity of cardiopulmonary baroreflex function in both strains of Dahl rats when they are challenged with a high salt diet. We studied Dahl R and S rats after 6 weeks of low and high salt diets. To assess cardiopulmonary baroreflex function, we measured decreases in splanchnic sympathetic nerve activity produced by increases in left ventricular end-diastolic pressure during graded volume expansion (dextran 75) after bilateral sinoaortic denervation. A given amount of infused volume produced comparable increases in left ventricular end-diastolic pressure in Dahl R rats on low and high salt diets but significantly greater decreases in sympathetic nerve activity in the high salt group than in the low salt group. Thus, the high salt diet augmented the sympathoinhibitory response to volume expansion in the Dahl R rats. In contrast, among the Dahl S rats equivalent increases in left ventricular end-diastolic pressure during volume expansion produced smaller sympathoinhibitory responses in the high salt group than in the low salt group. The gain of the cardiopulmonary baroreflex, expressed as the percentage decrease in sympathetic nerve activity per mm Hg increase in left ventricular end-diastolic pressure, was significantly increased by a high salt diet in Dahl R rats but tended to be decreased by a high salt diet in Dahl S rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelium-dependent responses to platelets and serotonin in spontaneously hypertensive rats.
Authors: Lüscher T F , Vanhoutte P M
Published: September 2013

We studied endothelium-dependent responses to substances released from aggregating platelets in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rings of thoracic aorta with and without endothelium were taken from adult rats and suspended for isometric tension recording in organ chambers containing modified Krebs-Ringer bicarbonate solution. Aggregating platelets caused statistically similar contractions in rings without endothelium in both strains. In rings with endothelium from SHR the contractions were significantly more pronounced than in rings with endothelium from WKY. In contracted rings with endothelium, serotonin caused a slight relaxation at lower concentrations but contraction at higher concentrations; only contractions were seen in rings without endothelium. The higher concentrations of the monoamine caused contractions, which in the SHR but not in the WKY were larger in the presence than in the absence of endothelium. In both strains adenosine diphosphate induced concentration-dependent relaxation in rings with endothelium but not in those without it; at high concentrations of adenosine diphosphate, the relaxation responses were significantly smaller in the SHR than in the WKY. Endothelium-dependent relaxation in response to thrombin did not differ in the two strains. The increased contraction in response to aggregating platelets and serotonin and the decreased relaxation in response to adenosine diphosphate in the SHR suggest that functional changes occur in the endothelium in this model of hypertension, possibly because of the release of one or more endothelium-derived contracting factors.
The loss of endothelium-dependent vascular relaxation in hypertension.
Authors: Lockette W , Otsuka Y , Carretero O
Published: September 2013

We investigated endothelium-dependent relaxation in rat aortae, using three models of experimental hypertension: deoxycorticosterone and salt; one-kidney, one clip renovascular hypertension; and coarctation. Isolated aortae were contracted with phenylephrine, and relaxation was subsequently induced with acetylcholine or calcium ionophore A23187. Blood vessels denuded of endothelium did not relax in response to acetylcholine or A23187. Blood vessels from animals with high blood pressure had decreased relaxation responses to acetylcholine and A23187, and also to the endothelium-independent vasodilator sodium nitroprusside. Unlike acetylcholine and A23187, however, nitroprusside completely relaxed the blood vessels from the hypertensive animals, though the sensitivity to nitroprusside was much lower in these vessels. Subsequent reversal of hypertension caused a return of endothelium-dependent relaxation. Loss of endothelium-dependent relaxation occurs readily in the aortae with the development of hypertension; this phenomenon appears to be related to elevated pressure.
Extrarenal prorenin in plasma requires an activator of renal origin.
Authors: Wilczynski E A , Osmond D H
Published: September 2013

Plasma prorenin may be of renal or extrarenal origin, and its conversion to renin may be catalyzed by renal or extrarenal enzymes. We tested the effect of bilateral nephrectomy and sham bilateral nephrectomy on plasma renin and prorenin in dogs, using low (3 mg/ml) and high (5 mg/ml) concentrations of trypsin to activate the prorenin. In the nephrectomized dogs, active plasma renin quickly disappeared, whereas plasma prorenin (inactive renin) increased by up to 300% during the first 24 hours after surgery, suggesting that it was released rapidly from a major extrarenal source but not converted to renin in the absence of the kidneys. In the sham surgery (control) group, plasma renin activity increased by up to 400% in the first 24 hours but returned almost to baseline by 48 hours, whereas prorenin remained at the preoperative value or fell below it. The quantity of prorenin varied greatly between the groups according to the time after surgery and the different concentrations of trypsin used. In the nephrectomy group, low and high trypsin levels resulted in similar prorenin values during the first 3 hours, but later on, the high trypsin level resulted in about twice as much prorenin. In the control group, high trypsin levels generally produced lower prorenin values than did low trypsin levels. Since trypsin is believed to interact with endogenous convertase enzymes in converting prorenin, a high requirement for it after bilateral nephrectomy suggests that removal of the kidneys causes a deficiency of such convertases. Conversely, the low requirement for trypsin after the stress of sham surgery suggests enhanced plasma convertase activity in the presence of the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
Application of echocardiography to population-based research projects.
Authors: Schoenberger J A
Published: September 2013

The value of echocardiography as a tool for the epidemiologic investigation of hypertension has not yet been determined. Since echocardiography is considerably more sensitive than electrocardiography in the detection of left ventricular hypertrophy, the development and regression of left ventricular hypertrophy assessed by echocardiography may be extremely useful in determining prognosis in hypertension and the efficiacy of therapeutic interventions. Its use may free clinical trials of dependence on total mortality and coronary incidence as the only end points.