Plasma epinephrine concentration in healthy men: correlation with systolic pressure and rate-pressure product.

Relations among plasma epinephrine, norepinephrine and renin activity and systolic pressure, diastolic pressure, heart rate and the product of heart rate and systolic pressure (rate-pressure product) were evaluated in 31 healthy men whose arterial pressure spanned the range from normal to mildly elevated. Measurements were made during 60 minutes with the patient in the supine position and during 10 minutes of quiet standing. In the supine position, highly significant regressions were found between systolic pressure or rate-pressure product and plasma epinephrine, but not between these variables and norepinephrine or renin activity. A weakly significant correlation was also found between heart rate and norepinephrine. On standing, norepinephrine and epinephrine increased significantly. In this position, rate-pressure product was significantly related by regression analysis only with plasma epinephrine. Weakly significant correlations between systolic pressure and epinephrine and between heart rate and norepinephrine and epinephrine were also found. Plasma renin activity was not significantly correlated with arterial pressure, heart rate or rate-pressure product in either position. These results suggest that plasma epinephrine is a determinant of systolic pressure when postural reflexes are minimized and that epinephrine may participate in control of cardiac work load, as reflected by rate-pressure product in the absence of exercise or definable stress.

Normalization of left ventricular mass and associated changes in neurohormones and atrial natriuretic peptide after 1 year of sustained nifedipine therapy for severe hypertension.

Sixteen patients with severe hypertension were treated for 1 year with extended release nifedipine, during which time serial changes in left ventricular mass index and associated alterations in left ventricular systolic function, left ventricular filling, plasma renin activity, atrial natriuretic peptide and catecholamines were evaluated. Mean seated blood pressure (+/- SE) was significantly reduced from 200 +/- 8/122 +/- 3 to 144 +/- 5/89 +/- 2 mm Hg (p less than 0.0001) at 1 year. After 6 months, left ventricular mass index was significantly reduced by 19% from 121 +/- 8 to 96 +/- 7 g/m2 and this reduction was sustained at 1 year. Septal and posterior wall thickness were reduced from 13.4 +/- 0.1 to 11.2 +/- 0.04 mm and from 12.8 +/- 0.1 to 10.0 +/- 0.03 mm (p less than 0.001), respectively. The prevalence of left ventricular hypertrophy decreased from 63% to 25%. Left ventricular fractional shortening increased from 34 +/- 2% to 41 +/- 3% (p less than 0.05) and the relation between fractional shortening and end-systolic stress did not change. Over the year of sustained blood pressure reduction, the peak velocity of early filling increased from 57 +/- 3 to 63 +/- 4 cm/s (p = 0.07), peak velocity of late filling did not change and the ratio of late to early peak left ventricular filling velocity significantly decreased (p less than 0.05). Plasma atrial natriuretic peptide levels, markedly elevated at entry, decreased from 70 +/- 15 to 41 +/- 8 pg/ml at 1 year (p less than 0.05). Plasma renin activity and catecholamine levels were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Doppler echocardiographic analysis of left ventricular filling in treated hypertensive patients.

Early detection and prevention of cardiac dysfunction is an important goal in the management of hypertensive patients. In this study, Doppler echocardiography was used to evaluate the pattern of left ventricular diastolic filling in 38 subjects: 18 treated hypertensive patients (blood pressure 141 +/- 17/83 +/- 10 mm Hg, mean +/- SD) without other coronary risk factors and 20 risk-free normotensive subjects of similar age (47 +/- 10 and 49 +/- 13 years, respectively). Peak velocity of late left ventricular filling due to the atrial contraction was greater in hypertensive compared with normotensive subjects (69 +/- 14 versus 52 +/- 13 cm/s; p less than 0.001). Peak velocity of late filling was significantly greater in hypertensive versus normotensive subjects in those aged 50 years or younger and those older than age 50 (65 +/- 12 versus 50 +/- 11; p less than 0.01 and 75 +/- 15 versus 56 +/- 15 cm/s; p less than 0.05, respectively). In hypertensive subjects, peak velocity of late filling did not correlate with routine indexes of hypertensive heart disease (including posterior wall thickness and left ventricular mass), systolic and diastolic blood pressure or duration of hypertension. These results indicate that increased velocity of late left ventricular filling may be independent of left ventricular hypertrophy and persist despite effective blood pressure control.

Determinants of abnormal left ventricular filling in early hypertension.

Thirty-seven untreated subjects with borderline or mild hypertension were studied to establish the prevalence and clinical characteristics associated with abnormal left ventricular filling in this disorder. Subjects were referred to this study because of casual office blood pressure measurements of greater than or equal to 140/90 mm Hg; all were less than 50 years old, had no other cardiovascular or systemic disease and had not received antihypertensive medication for at least 1 year. To precisely determine blood pressure, measurements were made over 30 min with the patient in the supine position and during awake hours with ambulatory monitoring. Left ventricular mass was determined echocardiographically, and Doppler echocardiography was used to assess left ventricular filling. No subject had increased left ventricular mass, but 8 (22%) of the 37 had abnormal left ventricular filling. All eight subjects with abnormal left ventricular filling had an ambulatory systolic blood pressure greater than 130 mm Hg and a supine systolic blood pressure greater than 122 mm Hg. Abnormal filling was not related to left ventricular mass or heart rate. In multivariate analysis, the degree of abnormal filling could best be predicted from a combination of age and supine systolic blood pressure (r = 0.69; p less than 0.001). This study suggests that in untreated early essential hypertension, abnormal left ventricular filling is present in greater than 20% of subjects, precedes detectable left ventricular hypertrophy and is related to age and prevailing level of blood pressure.

Hypertensive crisis caused by hypoglycemia and propranolol.

In a patient with severe hypertension in association with insulin-induced hypoglycemia and prior therapy with propranolol hydrochloride, intravenous 50% dextrose significantly reduced arterial pressure on two occasions. Subsequent reduction of arterial pressure was observed with prazosin hydrochloride, an alpha-receptor antagonist. The hypertensive episode may have been caused by hypoglycemia stimulating excessive release of epinephrine. In the presence of vascular beta 2-receptor blockade by propranolol, the hypertensive action of epinephrine was mediated by vascular alpha-receptors. When beta-antagonists must be used in insulin-dependent diabetic patients, beta 1-selective antagonists appear to be a better choice.

Restoration of renal function after bilateral renal artery occlusion.

Five patients had anuric renal failure caused by occlusion of the main renal arteries. All had a background of controlled hypertension, but in three patients, hypertension accelerated in the months before anuria. Extensive atherosclerotic disease was clinically evident in the peripheral (3/5), coronary (4/5), and cerebral (1/5) vessels. Identifiable precipitating events preceded the development of anuria in four patients. Although the use of renal ultrasonogram and scintiscan was suggestive, angiography was essential to establish the diagnosis after a brief period of maintenance hemodialysis. Renal artery revascularization performed as long as 38 days after the onset of anuria resulted in restoration of kidney function.

Measurement of plasma renin substrate by radioimmunoassay of angiotensin. I. Concentration in syndromes associated with steroid excess.

PIP: Plasma renin substrate (PRS) and plasma renin activity (PRA) were measured by radioimmunoassay of generated angiotension I in normal subjects and patients with steroid excess syndromes. In subjects with Cushing's syndrome, glucocorticosteroid therapy and oral contraceptive agents or estrogens, significant elevations of plasma renin substrate was observed. Only in subjects with primary aldosteronism was the plasma renin activity significantly supressed. The significance of elevations of PRS was assessed by determining the Km of the plasma renin-substrate reaction at physiologic pH. The apparent Km for the reaction was 1000 ng Angiotension I in PRS units. Correction of measured PRA to a standardized PRA was achieved by calculation of the reaction rate that would occur at the mean normal PRS concentration of 1100 ng/ml. Results indicate that elevations of PRS which occur in Cushing's syndrome or with administration of glucocorticoids, oral contraceptive agents, or estrogens are sufficient to significantly elevate the renin substrate reaction in plasma. In contrast, glucocorticoid excess appears not to suppress plasma renin activity even when reaction rates are corrected for increased PRS.^ieng

The differential effect of aldosterone and dexamethasone on pressor responses in adrenalectomized rats.

The effect of selective glucocorticoid or mineralocorticoid replacement on pressor responses to angiotensin I and II and norepinephrine was studied in adrenalectomized rats given high salt intake. Four groups were prepared by 1) adrenalectomy only (n = 5); 2) adrenalectomy plus aldosterone, 6 micrograms/24 hr i.p. (n = 5); or 3) adrenalectomy plus dexamethasone, 10 micrograms/24 hr i.p. (n = 5), using miniosmotic pumps; and 4) sham adrenalectomy (controls; n = 5). Plasma corticosterone was undetectable in all three adrenalectomized groups. Plasma aldosterone concentration was similar in aldosterone-replaced and sham-operated controls. Pressor responses to various doses of angiotensin I, angiotensin II, and norepinephrine were determined in unanesthetized, undisturbed rats. Compared with both control and dexamethasone-replaced rats, pressor responses to all three agonists were significantly reduced in both nonreplaced adrenalectomized and aldosterone-replaced groups. Comparing the ratios of the pressor responses to angiotensin I and angiotensin II in the four groups over the entire dose range suggests that a greater fraction of injected angiotensin I was converted to angiotensin II in nonreplaced adrenalectomized rats than in the other three groups. We conclude that glucocorticoid action markedly contributes to the systemic pressor effect of angiotensin and norepinephrine. However, glucocorticoid deficiency does not impair in vivo conversion of angiotensin I to angiotensin II.

Diuretic treatment alters clonidine suppression of plasma norepinephrine.

The effect of short-term diuretic treatment on the action of clonidine was evaluated in eight subjects with mild, uncomplicated hypertension. A single oral dose of clonidine (0.3 mg) was given before and after 1 week of therapy with hydrochlorothiazide, 50 mg, and amiloride, 5 mg, taken daily. Changes in mean arterial pressure, heart rate, plasma norepinephrine and epinephrine levels, and plasma renin activity were assessed. Diuretic treatment caused a significant weight loss, increased plasma renin activity, and reduced serum potassium concentration but did not significantly alter the absolute reduction in mean arterial pressure caused by clonidine. Absolute clonidine-induced reduction in plasma renin activity after diuretic treatment was three times greater than before treatment, although percent changes were similar. Before diuretic therapy, clonidine significantly reduced the level of norepinephrine (absolute and percent change). After diuretic treatment, clonidine failed to suppress norepinephrine, and the difference from prediuretic changes was significant. The level of epinephrine was not altered significantly either by diuretic treatment or clonidine. These results indicate that diuretic therapy alters the clonidine-activated mechanism for reduction of arterial pressure through a shift from overall suppression of sympathetic tone to pathways that are more restricted to renal tone. This shift may be due to changes in fluid or electrolyte balance that alter the action of alpha 2-adrenergic receptor-mediated pathways. Use of the clonidine suppression test for the diagnosis of pheochromocytoma may give false-positive results in diuretic-treated patients.

Confirmation or exclusion of stage I hypertension by ambulatory blood pressure monitoring.

Criteria for the diagnosis or exclusion of hypertension using ambulatory blood pressure monitoring have not been agreed upon. We designed this study to provide a statistically based guide for using results of ambulatory blood pressure monitoring to resolve this issue. To generate this information, we used a database of 228 subjects (135 men, 93 women; average age, 45 years) referred by their primary physicians over the past 7 years for evaluation of borderline or stage I hypertension (average blood pressure, 148/92 mm Hg; SD, +/-17.5/12.2 mm Hg). In this population, the pooled SDs of systolic and diastolic ambulatory blood pressures were 13.8 and 11.6 mm Hg, respectively. Using the pooled SD, we calculated the probability that a patient's blood pressure falls within the hypertensive range (> 140/90 mm Hg). The 95% confidence interval for each subject's blood pressure was also determined. For example, if 40 ambulatory blood pressure measurements are performed on a subject and the average systolic ambulatory blood pressure is 137 mm Hg, then there is a 10% probability that the patient's "true" average blood pressure is actually in the hypertensive range. By contrast, if the systolic pressure is 143 mm Hg, there is a 90% probability that the patient is hypertensive. This approach may be useful for clinical decision making and also for the design of clinical trials.

Maintenance of arterial pressure by vasopressin and angiotensin II after adrenalectomy.

Participation of vasopressin and the renin-angiotensin system in the maintenance of systemic arterial pressure was evaluated in unanesthetized adrenalectomized rats. Adrenalectomized and sham-operated rats with implanted arterial and venous catheters were given 1% sodium chloride and 2.5% glucose as drinking fluid for 72 hours following adrenalectomy. Serum and urine samples were obtained for measurement of electrolyte and solute concentration. The pattern of serum electrolytes, serum osmolality, and renal excretion of electrolytes, solute, and water observed in the adrenalectomized rats was entirely consistent with previous observations in this model. Mean arterial pressure of unanesthetized unrestrained adrenalectomized rats was significantly lower than controls. In adrenalectomized rats, dPMeTyrAVP reduced mean arterial pressure 9 +/- 1 mm Hg, p less than 0.001; captopril then caused an additional reduction of 17 +/- 2 mm Hg, p less than 0.01. Neither antagonist altered arterial pressure in the control group. Our results indicate that vasopressin and the renin-angiotensin system play a compensatory pressor role in adrenal insufficiency, preventing a larger decrease of arterial pressure in this model of chronic hypotension.

Relation among left ventricular mass, insulin resistance, and blood pressure in nonobese subjects.

Because left ventricular (LV) mass (LVM) is a powerful predictor of future cardiovascular events, it is important to identify hemodynamic and nonhemodynamic factors that increase LVM. We studied the separate contribution to LVM of daily arterial blood pressure (BP) and insulin resistance in a consecutive series of 29 (mean+/-SD age, 43+/-13 yr) nonobese (body mass index, 24+/-1.8 kg/m2), nondiabetic, glucose-tolerant subjects with untreated borderline or mild hypertension. The insulin sensitivity index (SI) was quantitatively determined from the frequently sampled iv glucose tolerance test. BP was characterized by ambulatory 24-h BP monitoring, and LVM index (LVMI) was determined by two-dimensional directed M-mode echocardiography. LVMI was directly related to 24-h mean BP (r=0.47; P=0.01). LMVI was also significantly related to Si (r=-0.43; P=0.02). In this nonobese group, neither LVMI nor Si was related to body mass index or age. After adjustment for the influence of BP on LVMI, a significant relation remained between LVMI and Si (P < 0.05). We conclude that in nonobese subjects with high normal BP, insulin sensitivity is related to LVM independently of BP and may be an important modulator of LV growth. In addition to a reduction of arterial BP, optimal prevention of LV hypertrophy in hypertensives may require improved insulin sensitivity.

Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance.

It has been hypothesized that insulin resistance and hyperinsulinemia contribute to the development of arterial hypertension. To further investigate this relationship, we compared arterial blood pressure in controls and women with polycystic ovary syndrome (PCO), an insulin-resistant state. Fourteen PCO women and 18 normal control women of similar age, body mass index, and race were studied. Plasma glucose and insulin levels were determined in an oral glucose tolerance test. The insulin sensitivity (SI) index was determined by the minimal model method. Systolic and diastolic blood pressure were measured by 24-h ambulatory monitoring. Left ventricular mass was assessed by echocardiography. The two groups had comparable fasting glucose levels, but the 2-h postload glucose was higher in PCO (8.0 +/- 0.5 vs. 5.6 +/- 0.3 mmol/L; P less than 0.001). Compared to controls, PCO women were significantly more insulin resistant by fasting insulin, 2-h insulin concentrations, and SI (28.3 +/- 6.7 vs. 68.3 +/- 10.0 min-1/nmol.mL; P less than 0.01). Average ambulatory systolic (121 +/- 2 vs. 118 +/- 2 mm Hg) and diastolic (76 +/- 2 vs. 73 +/- 2 mm Hg) blood pressures were similar for PCO and control women. No difference was found in left ventricular mass. Therefore, despite profound insulin resistance and hyperinsulinemia, women with PCO do not have increased arterial pressure or left ventricular mass.

Antihypertensive effects of tolamolol.

The antihypertensive and renin-lowering efficacy and side effects of tolamolol, a beta adrenergic blocking drug with cardioselectivity, were examined in 10 patients with mild essential hypertension while on regular diet. Tolamol, at a dose of 300 to 900 mg per day, given over a period of 2 to 4 wk significantly decreased systolic and diastolic blood pressures in both the recumbent and standing positions. Normal blood pressure (140/90 mm Hg or less) was attained in 8 subjects. Mean heart rate and ambulatory midday plasma renin activity (PRA) decreased significantly; however, there was no significant correlation between blood pressure decrease and either the pretreatment PRA or decrease in PRA. Body weight did not change significantly. No adverse side effects were detected and no changes in the liver or renal function or in the blood count were observed. It is concluded that tolamolol is effective in lowering blood pressure and PRA in patients with hypertension.

Addition of acebutolol to diuretics in hypertension.

The effect of acebutolol as an antihypertensive beta receptor-blocking drug was evaluated in 15 patients that remained hypertensive while on diuretics. Observations were made in a small randomized double-blind trial in which the drug was compared to placebo and subsequently during a single-blind phase when the drug was given to those who had not responded to placebo. The dose range for acebutolol was 200 to 600 mg twice daily. Pretreatment plasma renin activity (PRA) and the response to intravenous saralasin infusion were assessed as predictors of the antihypertensive effect of acebutolol. None of six patients receiving placebo had a response of goal blood pressure or below; six of nine receiving acebutolol did respond (P less than 0.01). Acebutolol treatment induced reduction in diastolic pressure, heart rate, and PRA pooled from both phases of the study. There were no significant correlations between acebutolol therapy. Our data indicate that acebutolol is effective in diuretic-resistant hypertensive patients and that indices of the renin-angiotensin system are not predictors of the therapeutic response.

Effect of guanabenz on blood pressure responses to posture and exercise.

A single dose of guanabenz was examined for effects upon blood pressure, heart rate, plasma catecholamines, and plasma renin activity in a randomized, double-blind, crossover design. Eight patients were studied when supine, standing, and during submaximal exercise. Guanabenz reduced blood pressure in subjects who were supine or standing. Heart rate was lowered only in the supine subjects. Guanabenz induced reduction in plasma catecholamines subjects in all positions and the reduction correlated with the placebo level for both norepinephrine and epinephrine. Plasma renin activity was not significantly affected by guanabenz. The results indicate that the central alpha-agonist action of guanabenz reduces sympathoadrenal function to a greater extent in hyperadrenergic hypertensive patients than in those without this disorder.

Activation of the renin system in acute pancreatitis.

Activity of the renin-angiotensin system was assessed in patients with acute pancreatitis. Measurements of active plasma renin and inactive plasma renin were made in normal subjects, patients with acute pancreatitis, and patients with acute abdominal pain syndromes exclusive of pancreatitis. Active plasma renin values were significantly increased in acute pancreatitis, nearly 500 percent higher than in the other two groups. Inactive plasma renin values were similar in the three groups. In a subgroup of patients with acute pancreatitis, measurements were made on presentation and after recovery. The elevated active plasma renin values on admission fell significantly with recovery, in parallel with changes in serum amylase values. Inactive plasma renin values changed variably; there was a significant inverse regression relationship between the changes in active and inactive plasma renin values with recovery. The results indicate that the renin-angiotensin system is activated in acute pancreatitis to a significantly greater extent than in other syndromes with acute abdominal pain. The increased active plasma renin in acute pancreatitis is most likely due to renal release secondary to the reduced circulating volume and hypotensive effect of this disease. However, changes in the relationship between active and inactive plasma renin in some patients suggest that activation of inactive renin by proteolytic enzymes released in acute pancreatitis might play an additional role.

Saralasin infusion in screening patients for renovascular hypertension.

The usefulness of screening patients for renovascular hypertension by infusion of saralasin, a competitive antagonist of angiotensin II, was evaluated. Responses were compared in 19 patients with proved renovascular hypertension and in 34 without renovascular hypertension, as indicated by renal arteriography and renal venous renin studies. Saralasin infusion was carried out in the morning after furosemide, 80 mg by mouth, had been given the previous evening. Seventy-five percent of patients with and 12 percent of those without renovascular hypertension had a reduction in diastolic pressure of 5 mm Hg or more during saralasin infusion; only 45 percent of patients with and 6 percent of those without renovascular hypertension had a reduction of 10 mm Hg or greater during infusion. In comparison, 80 percent of patients with and 18 percent of those without renovascular hypertension had a positive intravenous pyelogram. The predictive value of a positive saralasin test (5 mm Hg or greater reduction in diastolic pressure) was calculated for varying prevalence rates of renovascular hypertension with use of Bayes theorem. The results indicate that when the prevalence rate of renovascular hypertension among hypertensive patients is 5 percent only 25 percent of positive saralasin tests will correctly predict its presence.

Comparison of ambulatory blood pressure and amounts of left ventricular hypertrophy in men versus women with similar levels of hypertensive clinic blood pressures.

The purpose of this study was to assess several indexes of cardiovascular risk in men and women with moderate to severe hypertension. We found that women with moderate and severe hypertension have lower ambulatory blood pressure and less cardiac hypertrophy than men with similar clinic blood pressure.

Noninvasive ambulatory blood pressure monitoring in patients with recently detected systemic hypertension.

Noninvasive ambulatory blood pressure monitoring and Doppler echocardiography were used in a recent study evaluating persons aged 18 to 50 years who were initially found to have mild hypertension by casual blood pressure determination. Ambulatory blood pressure recordings were performed on a day of usual activity in 54 subjects; a subgroup of 24 patients had evaluation of left ventricular dimensions and diastolic filling patterns by Doppler echocardiography. Average ambulatory systolic pressures of 42% of subjects were greater than or equal to 130 mm Hg. Only 35% had average diastolic pressures greater than or equal to 85 mm Hg, and 57% had either systolic or diastolic pressures greater than or equal to 130/85 mm Hg. Correlation between casual and ambulatory pressures was not significant. No subject had left ventricular hypertrophy determined by echocardiography. Abnormal left ventricular diastolic filling was noted in 38% of those patients with average ambulatory pressures greater than or equal to 130/85 mm Hg, but in no patients with average pressures less than 130/85 mm Hg (p less than 0.05). These results suggest that ambulatory blood pressure monitoring may be a specific method for detecting those patients with mild hypertension who may have early and potentially reversible cardiac abnormalities.