Changes in plasma noradrenaline concentration following sympathetic stimulation by gradual tilting.

Plasma noradrenaline concentration was determined by a radioenzymatic method in 10 normal individuals who were subjected to a stepwise tilt through 45 degrees. A gradual increase in noradrenaline was observed with maximal values occurring in most subjects following the full 45 degrees of tilt. Maximal levels were sustained for up to 30 min. In two subjects who fainted, the syncopal episode followed an initial sympathetic postural response as shown by a rise in plasma noradrenaline. For the remaining subjects a significant correlation was found between changes in plasma noradrenaline and mean arterial pressure.

Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans.

To determine whether venous plasma norepinephrine concentrations consistently reflect changes in sympathetic nervous activity, the influence of mental arithmetic, static handgrip, and submaximal bicycle exercise on intra-arterial blood pressure, heart rate, and plasma norepinephrine was studied in 51 subjects with untreated essential hypertension (mean age, 46 years; range, 16-69 years). At rest, plasma norepinephrine was unrelated to age or blood pressure. Mental arithmetic increased mean arterial pressure from 108 +/- 18 to 127 +/- 18 mm Hg (mean +/- S.D.; p less than 0.001) and heart rate from 69 +/- 7 to 93 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (547 +/- 297 to 518 +/- 250 pg/ml). Isometric exercise raised mean arterial pressure from 115 +/- 18 to 148 +/- 21 mm Hg (p less than 0.001) and heart rate from 76 +/- 9 to 95 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (683 +/- 253 to 741 +/- 253 pg/ml). Bicycle exercise increased mean arterial pressure from 114 +/- 20 to 146 +/- 26 mm Hg (p less than 0.001), heart rate from 77 +/- 9 to 128 +/- 19 beats/min (p less than 0.001), and plasma norepinephrine from 645 +/- 228 to 1151 +/- 462 pg/ml (p less than 0.001). Both the maximum mean arterial pressure and the peak heart rate attained during bicycle exercise were related to the exercise plasma norepinephrine level (r = 0.33, p less than 0.02 and r = 0.28, p less than 0.03, respectively). Increases in plasma norepinephrine with exercise were not greater in older or more hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors influencing blood pressure and heart rate variability in hypertensive humans.

We examined the influence of baroreceptor reflex sensitivity (the increase in pulse interval in response to a phenylephrine-induced increase in blood pressure), age, blood pressure, and beta-adrenergic receptor blockade on the variability of blood pressure and heart rate in essential hypertension. Fifty-six subjects were studied before treatment; intra-arterial blood pressure was recorded outside the hospital for 24 hours. Variability was defined (from all beats occurring while subjects were awake) as the standard deviation about the average waking value for mean arterial pressure (MAP) or pulse interval. The correlation (r) between baroreceptor reflex sensitivity and blood pressure variability was -0.47 (p less than 0.0002). Baroreceptor reflex sensitivity was the only independent determinant of blood pressure variability on multiple regression analysis. Thirty subjects were restudied after 5 months of beta-adrenergic receptor blockade. Ambulatory blood pressure was lower during treatment, whereas pulse interval, its variability, and baroreceptor reflex sensitivity were higher. Blood pressure variability was unchanged. The variability of MAP was inversely correlated with baroreceptor reflex sensitivity before (r = -0.42, p less than 0.02) and during (r = -0.45, p less than 0.02) treatment, but it was unrelated to the average ambulatory MAP or to the variability of pulse interval either before or during beta-blockade. Sixteen subjects whose average waking ambulatory blood pressure was 140/90 mm Hg or less were not treated. This group of borderline hypertensive subjects had less variable MAP than did the remaining 40 subjects (12.4 +/- 2.3 [SD] vs 14.5 +/- 2.5 mm Hg; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Consequences of impaired arterial baroreflexes in essential hypertension: effects on pressor responses, plasma noradrenaline and blood pressure variability.

In 62 untreated patients with essential hypertension, arterial baroreflex sensitivity (BRS) for heart rate, i.e. the change in pulse interval in response to a phenylephrine-induced increase in blood pressure, was compared with (1) haemodynamic changes during mental arithmetic, a reaction time test, isometric and bicycle exercise; (2) plasma noradrenaline (PNA) concentrations at rest, and during bicycle exercise and; (3) the variability of ambulatory intra-arterial blood pressure. Subjects with diminished BRS showed the following responses: (1) higher mean arterial blood pressure (MAP) during all four stimuli; (2) a greater pressor response to cycling; (3) tended to have higher PNA concentrations during bicycle exercise and; (4) greater variation in ambulatory blood pressure. Furthermore, an increased pressor response to the reaction time test and increased ambulatory blood pressure variability was seen in younger subjects with reduced BRS. When subjects were subgrouped according to their WHO stage of hypertension, there were significant inverse relationships between BRS and the pressor responses to mental arithmetic, the reaction time test and cycling, and with ambulatory blood pressure variability only in those subjects without ECG or radiographic evidence of left ventricular enlargement (WHO stage I hypertension; n = 42). None of these correlations were present in subjects with one or both of these clinical findings (WHO stage II; n = 20). Pressor responses to the four laboratory stimuli and ambulatory blood pressure variability were similar in both groups, despite significantly higher arterial pressure and significantly lower BRS in WHO stage II subjects. These results suggest that differing mechanisms may be responsible for the regulation of blood pressure variation in these two groups. The arterial baroreflex can buffer acute changes in blood pressure in subjects with WHO stage I hypertension, but this ability is attenuated with progressive reduction of BRS. With the development of clinically evident cardiac adaptation to hypertension (WHO stage II), the contribution of the arterial baroreflex to the regulation of blood pressure is no longer detectable and the influence of cardiac and somatic afferents to reflex circulatory adjustments to activity may predominate.

Unequivocal synthesis and characterisation of dopamine 3- and 4-O-sulphates.

The major metabolic products of the endogeneous catecholamine dopamine are its 3- and 4-O-sulphates which have also been implicated as intermediates in noradrenaline biosynthesis. Because of the unsatisfactory status of the literature concerning the synthesis, isolation, purity and characterisation of the dopamine O-sulphates we describe both a one-step synthesis and definitive separation and characterisation procedures for these metabolites. High-performance liquid chromatography (HPLC) combined with high-field nuclear magnetic resonance techniques were employed. The chemical sulphonation of dopamine gave three synthetic products, whose relative amounts depended critically upon the reaction conditions employed. Dopamine 3- and 4-O-sulphates together with dopamine 6-sulphonic acid, a hitherto undescribed derivative of dopamine, were for the first time isolated and characterised unequivocally. It should now prove possible to reappraise critically the biological significance of the major metabolite products of dopamine.

Plasma-noradrenaline in essential hypertension.

Plasma-noradrenaline (P.N.A.) has been determined in normotensive controls and in patients with essential hypertension while resting and after postural stimulation. A linear relationship was found between age and P.N.A. in normotensives during recumbency and in the upright posture. This relationship did not occur in the hypertensives and was due to raised P.N.A. levels in many younger patients. On standing, ten out of thirty-four patients under the age of 50 years with essential hypertension had significantly greater P.N.A. than the age-matched controls. No differences were found, however, between controls and patients in the older age-group. It is proposed that stimulation of the sympathetic nervous system by postural challenge provides a means for identifying a subgroup of younger patients with essential hypertension in whom sympathetic overactivity may play an important rule.

Cuff and ambulatory blood pressure in subjects with essential hypertension.

Clinic cuff blood-pressure measurements, obtained on at least three occasions, were compared with mean arterial pressures in 59 patients with borderline or essential hypertension who underwent direct ambulatory monitoring of blood pressure. In 22 patients (group I) mean cuff and ambulatory pressures were similar (+/- 10 mm Hg) while in 32 subjects (group II) cuff pressures were more than 10 mm Hg higher. Groups I and II could not be distinguished on the basis of clinical examination, indices of sympathetic nerve activity, or blood-pressure variability, or by the magnitude of pressure rise during physical or mental exercise. Group II had less cardiovascular target organ damage and better baroreflex sensitivity but there was considerable overlap. There was no reliable way of telling which subjects would have lower ambulatory than cuff pressures. 20 out of 59 subjects classified as hypertensive by cuff measurements had awake ambulatory pressures or less than 140/90 mm Hg.

Expression and regulation of the Na+-K+-2Cl- cotransporter NKCC1 in the normal and CFTR-deficient murine colon.

Defective regulation and/or reduced expression of the Na+-K+-2Cl- cotransporter NKCC1 may contribute to the severe secretory defect that is observed in cystic fibrosis, but data concerning the expression and function of NKCC1 in cystic fibrosis transmembrane conductance regulator (CFTR)-deficient cells are equivocal. We therefore investigated NKCC1 mRNA expression, Na+-K+-2Cl- cotransport activity and regulation by cAMP in crypts isolated from the proximal colon of CFTR-containing (CFTR (+/+)) and CFTR-deficient (CFTR (-/-)) mice. mRNA expression levels were determined by semiquantitative PCR, transport rates were measured fluorometrically in 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein acetomethylester (BCECF)-loaded crypts, cytoplasmic volume changes were assessed by confocal microscopy, and [Cl-]i changes were examined by N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) quenching. NKCC1 mRNA expression levels were not significantly reduced in CFTR (-/-) crypts compared to controls. Azosemide-sensitive NH4+ influx (used as a measure of Na+-K+-2Cl- cotransport) was 2.23 +/- 0.72 vs. 1.56 +/- 0.16 mM min-1, and increased by 63.6 % in (+/+) and 87.3 % in (-/-) crypts upon stimulation for 5 min with forskolin. After 20 min of stimulation with forskolin, the Na+-K+-2Cl- cotransport rates in (-/-) and (+/+) crypts were identical. Crypt cross-sectional area and [Cl-]i decreased only in (+/+) crypts upon stimulation. In conclusion, normal NKCC1 expression levels, somewhat reduced Na+-K+-2Cl- cotransport rates, but preserved activation by cAMP were found in colonic crypts from CFTR (-/-) mice, ruling out a severe dysfunction of the Na+-K+-2Cl- cotransporter in the CF intestine. Furthermore, these studies establish the existence of a direct, cell-volume- and [Cl-]i-independent activation of colonic NKCC1 by an increase in intracellular cAMP.

Renal function, body fluid volumes, renin, aldosterone, and noradrenaline during treatment of hypertension with pindolol.

Sixteen hypertensive patients received pindolol (10-45 mg/day); mean +/- SD, 28.75 +/- 15.22) for 3-8 weeks in a placebo-controlled, single-blind, crossover study. Supine and standing blood pressures (BP) were lowered, whereas effective renal plasma flow and glomerular filtration rates (estimated from the clearances of Hippuran and EDTA during oral water loading) did not change consistently. "Blood volume" (calculated from 125I-human serum albumin space and microhaematocrit) increased, with a corresponding reduction in serum albumin but without a change in body weight or "total body water" (T2O space). The results suggest a transfer of water from the interstitial to the intravascular compartment. This was supported by estimates of "extracellular fluid volume" (EDTA space) and "interstitial volume" (EDTA) minus human serum albumin spaces) in 3 subjects. The changes produced in "blood volume" correlated with those in BP. Plasma levels of noradrenaline, renin activity, and aldosterone were reduced, as was renal aldosterone excretion. There was no correlation between the changes produced by pindolol in BP and these hormone levels. Pindolol treatment reduced serum calcium concentration. There was a strong positive correlation between changes in BP and serum calcium and renal calcium excretion.

Baroreflex control of blood pressure and plasma noradrenaline during exercise in essential hypertension.

1. Twelve subjects (mean age 46.3 +/- 12.5 years) with mild to moderate hypertension were studied before, during and after bicycle ergometer exercise. 2. Baroreflex sensitivity was determined by the Oxford phenylephrine method; sensitivity at rest was inversely related to intra-arterial pressure and age. Age and resting arterial pressure were not related. 3. Exercise for 5 min at 50 W and 5 min at 75 W raised the mean arterial pressure from 116.4 +/- 18.0 to 150.0 +/- 25.4 mmHg, the heart rate from 73.2 to 126.7 beats/min and the plasma noradrenaline from 541 +/- 142.7 to 1309.8 +/- 543.5 pg/ml (P less than 0.001). 4. The increase in noradrenaline during exercise and the maximum mean pressure achieved were inversely related to resting baroreflex sensitivity (r = -0.68 and -0.77 respectively). Resting values of noradrenaline were not related to baroreflex sensitivity, age, or resting blood pressure. 5. It is possible that the rise in both plasma noradrenaline and arterial blood pressure produced by exercise is controlled by the baroreceptor reflexes; these are less effective in hypertensive subjects and thus the increases in noradrenaline and arterial pressure during exercise are greater in subjects with raised blood pressure.