R. A. Stone

Baroreflex sensitivity and heredity in essential hypertension.

BackgroundAbnormalities in baroreflex control of heart rate may be important in the pathogenesis of essential hypertension. Methods and ResultsTo investigate the influence of heredity on baroreflex function, we measured baroreflex sensitivity in 40 untreated patients with essential hypertension grouped by the presence (FH+) or absence (FH−) of a family history of hypertension and in 24 normotensive counterparts. Baroreflex sensitivity was assessed by both high-pressure (phenylephrine bolus) and low-pressure (amyl nitrite inhalation) stimuli. Subject groups were matched for age, blood pressure, body weight, and race. Baroreflex sensitivity (in milliseconds per millimeter of mercury) assessed by amyl nitrite inhalation was 24.3 2.8 in FHnormotensives, 12.3±1.7 in FH+ normotensives, 15.4±3.3 in FH− hypertensives, and 8.1±1.2 in FH+ hypertensives. Baroreflex sensitivity assessed by phenylephrine bolus was 28.8±5.6 in FH− normotensives, 19.3±2.8 in FH+ normotensives, 19.1±2.0 in Fl− hypertensives, and 13.6±1.3 in FH+ hypertensives. Two-factor analysis of variance showed significant effects on baroreflex sensitivity for blood pressure status (normotensive versus hypertensive) and for family history of hypertension. After control line (controlling) for the effects of several variables, including age, mean arterial pressure, body weight, and race through multiple linear regression analysis, the effect of family history of hypertension on baroreflex sensitivity was still highly significant. Indeed, of all variables investigated, family history of hypertension was the strongest unique baroreflex sensitivity predictor. ConclusionsThese data suggest that the impairment in baroreflex sensitivity in hypertension is in part genetically determined and may be an important hereditary component in the pathogenesis of essential hypertension.

Psychotherapeutic Control of Hypertension

We conducted a six-month trial to determine the effect of psychologic relaxation on blood pressure. Alterations of peripheral sympathetic-nervous-system activity, as reflected by changes of dopamine-beta-hydroxylase in plasma, were evaluated, and plasma volume and plasma renin activity were measured. Treated patients exhibited significant (P less than 0.05) reductions of blood pressure when supine and upright, and of plasma dopamine-beta-hydroxylase activity, and furosemide-stimulated renin activity when upright. Blood-pressure changes after six months correlated best with differences in plasma activity of dopamine-beta-hydroxylase with patients supine (r = 0.54; P less than 0.05) and upright (r = 0.62; P less than 0.05). These results suggest that reduction of peripheral adrenergic activity contributes importantly to the improvement of hypertension observed with this form of therapy. Furthermore, the decrease of furosemide-stimulated plasma renin activity suggests that alterations of the renin-angiotensin system may help lower blood pressure in certain patients.

Renal hemodynamics in essential hypertension. Racial differences in response to changes in dietary sodium.

Previous studies have suggested striking racial differences in hypertension-related renal disease. To explore potential mechanisms responsible for these differences, we investigated changes in renal hemodynamics in white and black essential hypertensive patients in response to alterations in dietary sodium. Patients were untreated, age-matched, and blood pressure-matched white (n = 59) and black (n = 22) males with essential hypertension. Studies were conducted on an inpatient metabolic ward and included assessment of blood pressure, urinary sodium excretion, glomerular filtration rate, renal plasma flow, and renal blood flow after 5 days each of high and low salt diets. In response to high dietary salt intake, both white and black patients demonstrated significantly higher mean arterial pressure, renal plasma flow, and renal blood flow, and there were no racial differences in the changes in these parameters. However, whites and blacks differed significantly in glomerular filtration rate, with black hypertensive patients showing an increase in glomerular filtration rate (+17.3 +/- 5.3 mL/min per 1.73 m2, F = 7.586, P = .007) and white hypertensive patients showing no change (-0.2 +/- 3.3 mL/min per 1.73 m2) in response to high dietary sodium. These data demonstrate racial differences in the autoregulation of glomerular filtration rate in response to changes in dietary sodium. These differences suggest that glomerular hyperfiltration in response to a high salt diet may be a mechanism contributing to the racial disparity in hypertension-related renal disease.

Racial Disparity of Plasma Volume in Hypertensive Man

Excerpt Many pathophysiologic mechanisms have been proposed to explain the role of plasma volume in human hypertension (1-3). Although most authorities agree that volume is an important factor in i...

Autonomic function in hypertension. Are there racial differences

Previous biochemical assessment of sympathetic nervous system activity including plasma catecholamines, plasma renin activity, and plasma dopamine-beta-hydroxylase levels has suggested racial differences in the contribution of the sympathetic nervous system to the pathogenesis or maintenance of hypertension. We, therefore, performed physiological and pharmacological studies in white and black subjects with essential hypertension and their age-matched normotensive counterparts to assess autonomic and sympathetic nervous system function. One hundred one male subjects (47 white hypertensive, 17 black hypertensive, 22 white normotensive, and 15 black normotensive subjects) were evaluated for baroreceptor reflex sensitivity to low-pressure (amyl nitrite inhalation) and high-pressure (phenylephrine infusion) stimuli; cold pressor test heart rate and blood pressure responses; and blood pressure response to phentolamine alpha-adrenergic blockade. Hypertensive subjects exhibited an increase in resting heart rate, a decrease in baroreceptor reflex sensitivity, and an exaggerated decline in mean arterial pressure in response to phentolamine. These abnormalities were present to a comparable degree in black and white hypertensive subjects. Cold pressor testing revealed greater increases in heart rate in blacks as compared with whites; however, this racial difference was present regardless of blood pressure status, occurring in black normotensive and black hypertensive subjects to a comparable degree. Cold pressor test blood pressure increments were similar in the four groups. We conclude that both white hypertensive and black hypertensive subjects demonstrate similar abnormalities in autonomic and sympathetic nervous system function including blunting of baroreceptor reflex sensitivity and an increased alpha-adrenergic receptor participation in blood pressure maintenance. The results do not suggest major racial differences in autonomic pathogenetic mechanisms in hypertension.

Chromogranin a immunoreactivity in human cerebrospinal fluid: Properties, relationship to noradrenergic neuronal activity, and variation in neurologic disease

Although measurement of chromogranin A in the bloodstream is of value in sympathoadrenal investigations, little is systematically known about chromogranin A in cerebrospinal fluid, despite substantial knowledge about its occurrence and distribution in brain. We therefore applied a homologous human chromogranin A radioimmunoassay to cerebrospinal fluid, in order to evaluate the properties and stability of cerebrospinal fluid chomogranin A, as well as its relationship to central noradrenergic neuronal activity, to peripheral (plasma) chromogranin A, and to disease states such as hypertension, renal failure and Parkinsonism. Authentic, physically stable chromogranin A immunoreactivity was found in cerebrospinal fluid (at 37-146 ng/ml; mean, 87.0 +/- 6.0 ng/ml in healthy subjects), and several lines of evidence (including 3.39 +/- 0.27-fold higher chromogranin A in cerebrospinal fluid than in plasma) indicated that it originated from a local central nervous system source, rather than the periphery. Cerebrospinal fluid chromogranin A values were not influenced by administration of effective antihypertensive doses of clonidine or propranolol, and were not related to the cerebrospinal fluid concentrations of norepinephrine, methoxyhydroxyphenylglycol, or dopamine-beta-hydroxylase; thus, cerebrospinal fluid chromogranin A was not closely linked to biochemical or pharmacologic indices of central noradrenergic neuronal activity. Cerebrospinal fluid chromogranin A was not changed (P > 0.1) in essential hypertension (84.2 +/- 14.0 ng/ml) or renal failure (72.2 +/- 13.4 ng/ml), despite a marked (7.1-fold; P < 0.001) increase in plasma chromogranin A in renal failure, and a modest (1.5-fold; P = 0.004) increase in plasma chromogranin A in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary kallikrein activity and renal vascular resistance in the antihypertensive response to thiazide diuretics.

SUMMARY To evaluate the mechanism of chronic thiazide diuretic action in hypertension, we treated 19 essential hypertensive white men for 1-month periods on placebo alone and hydrochlorothiazlde alone. During therapy, mean arterial pressure (MAP) fell, but radioisotopically determined intrarascular volume remained unchanged, suggesting other mechanisms of thiazide action upon blood pressure. In the renal circulation, thiazides did not change renal plasma flow or glomerular filtration rate, but renovascuiar resistance was diminished, probably at the afferent arteriole. Concomitant with the decline in blood pressure and renovascuiar resistance, urinary kallikrein excretion increased, from subnormal (hypertensive) levels back into the normal range. The kallikrein increase did not correlate with changes in plasma aldosterone. In addition, patients with blood pressure responses (reduction £ 10%) to thiazides (n = 12) had greater increases in kallikrein excretion than those without such a blood pressure decrement (n = 7), suggesting a role for renal kallikrein in the hypotensive response to thiazide diuretics.

Hypertension in adult onset diabetes mellitus: abnormal renal hemodynamics and endogenous vasoregulatory factors.

We evaluated 10 adult onset diabetics who developed hypertension well after the onset of glucose intolerance. Systemic and renal hemodynamics, intravascular volume, the renin-angiotensin-aldosterone axis, and the renal kallikrein-kinin system were examined at extremes of sodium intake, and compared to results from matched normotensive and essential hypertensive subjects. On unrestricted sodium diet, the diabetics, compared to normotensives, had significantly decreased blood volume (p less than 0.01), and preservation of renal plasma and blood flow, but significantly elevated renal vascular resistance (p less than 0.05), decreased creatinine clearance (p less than 0.01), and decreased filtration fraction (p less than 0.01). On restricted sodium intake, diabetics, compared to normotensives, had reduced urinary kallikrein activity (p less than 0.01) and reduced ambulatory plasma renin activity (p less than 0.01). Essential hypertensives were similar to diabetics in that both had reduced intravascular volume, elevated renal vascular resistance, and reduced levels of stimulated urinary kallikrein and ambulatory renin activities, but plasma aldosterone concentrations were reduced in diabetics compared to both normotensives and essential hypertensives under all dietary conditions. The ratio urinary kallikrein activity/supine plasma renin activity in diabetics correlated with renal blood flow (p less than 0.05), and inversely with renal vascular resistance (p less than 0.05). We conclude that these hypertensive diabetics have multiple abnormalities in intrarenal hemodynamics that may be related, in part, to abnormal activities of the renal enzymes renin and kallikrein. The kallikrein defect may be an etiologic factor in their hypertension.

PLASMA DOPAMINE-β-HYDROXYLASE ACTIVITY AND BLOOD PRESSURE VARIABILITY IN HYPERTENSIVE MAN

It has been proposed that measurements of plasma dopamine‐β‐hydroxylase (DBH) may allow for assessment of adrenergic tone and may elucidate a possible neurogenic contribution to essential hypertension. We performed a series of measurements of DBH in fifty‐seven normotensive and fifty hypertensive black and white men in order (1) to compare DBH to selected blood pressure patterns and (2) to evaluate the influence of salt intake, posture and race on plasma DBH. Plasma DBH, measured on unrestricted salt intake with subjects supine, was 42 ± 4 Units/L in white normotensives, greater (P< 0.05) than black normotensives (26 ± 6 Units/L). White hypertensives had greater plasma concentrations of DBH than black (35 ± 3 vs. 24 ± 5, P< 0.05). Normotensives did not differ from hypertensives. Dietary salt restriction and upright ambulation increased plasma DBH activity in hypertensives. Although DBH did not correlate directly with blood pressure, high DBH values were associated with lability of blood pressure in hypertensives but not in normotensives. There are two possible explanations for our results: (1) multiple factors influence plasma DBH activity and plasma levels reflect more than adrenergic function, or (2) essential hypertension is a multifactorial disease and excess sympathetic neuronal activity alone is not sufficient to produce sustained hypertension.

PLASMA DOPAMINE-BETA-HYDROXYLASE ACTIVITY IN PHAEOCHROMOCYTOMA

Plasma dopamine‐beta‐hydroxylase (DßH) activity, a marker of catecholamine secretion that occurs via exocytosis, was determined preoperatively in eight patients with phaeochromocytoma. Despite very elevated urinary catecholamine concentrations, mean plasma DßH activity was 32.6±3 u/1 and was not significantly different from apparently healthy subjects. Seven days after surgery, one subject exhibited a 60% postoperative decrease of enzyme activity. These results suggest that diffusion across plasma membranes is the predominant mechanism of catecholamine release from phaeochromocytomas. The postoperative change in one patient suggests tumour heterogeneity and that exocytosis may contribute to the process of catecholamine release in some patients.