Search

Clinical studies have shown that aldosterone and salt are independently related to hypertension, cardiovascular morbidity and mortality. More recently, studies in humans have demonstrated that, similarly to animals, endogenous aldosterone and dietary salt intake have not only separate, but also combined effects to accelerate target-organ deterioration. The aldosterone-salt interaction has important clinical implications, because combined effects of both can be minimized, if not avoided, by reducing salt intake. This interaction could also be interrupted by blocking the effects of aldosterone, with use of mineralocorticoid receptor antagonists, or by reducing aldosterone effects by adrenalectomy, in patients with aldosterone producing adenoma. Furthermore, aldosterone reduction or blockade may reduce salt appetite.

Gordon's syndrome is a rare condition characterized by hypertension and hyperkalemia despite normal renal glomerular function. We report the administration of an anaesthetic to one such patient for an urgent surgical procedure. The patient's serum potassium was only marginally raised at the outset of the procedure. During surgery the serum potassium rose significantly, but responded to conventional management. Hyperkalaemia is a specific electrolyte disturbance that has numerous implications for the administration of an anaesthetic. Most importantly, there is a danger that further acute elevations may occur, caused by the surgery, the anaesthetic, or the condition itself

Familial hyperaldosteronism type II (FH-II) is caused by adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted in an autosomal dominant fashion. Unlike FH type I (FH-I), which results from fusion of the CYP11B1 and CYP11B2 genes, hyperaldosteronism in FH-II is not glucocorticoid remediable. A large family with FH-II was used for a genome wide search and its members were evaluated by measuring the aldosterone:renin ratio. In those with an increased ratio, FH-II was confirmed by fludrocortisone suppression testing. After excluding most of the genome, genetic linkage was identified with a maximum two point lod score of 3.26 at theta=0, between FH-II in this family and the polymorphic markers D7S511, D7S517, and GATA24F03 on chromosome 7, a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II; its molecular elucidation may provide further insight into the aetiology of primary aldosteronism.

Primary aldosteronism (PAL) has been traditionally regarded as a rare cause of hypertension and not worth looking for in the absence of hypokalemia. However, the availability of the aldosterone/renin ratio as a screening test and its application to a wider population of hypertensives has resulted in a marked increase in detection rate, suggesting that PAL is common, with most patients being normokalemic. The spectrum of PAL has been expanded further by the study of familial varieties, in which family screening efforts have permitted the recognition of earlier, sometimes even pre-clinical, stages of disease. Familial hyperaldosteronism type I(FH-I) In FH-I, inheritance of a 'hybrid' 11beta-hydroxylase/aldosterone synthase gene causes adrenocorticotrophic hormone (ACTH)-regulated aldosterone and 'hybrid steroid' (18hydroxy-cortisol and 18-oxo-cortisol) overproduction. Genetic testing, by Southern blot or polymerase chain reaction-based techniques, has greatly facilitated detection, being more convenient and more reliable than dexamethasone suppression testing, and has led to a fuller appreciation of the marked phenotypic variability in this disorder. The demonstration of excessive, abnormally regulated aldosterone production in normotensive subjects with FH-I suggests that absence of hypertension in such individuals cannot merely be attributed to lack of expression of the hybrid gene. Determinants of hypertension severity may include patient gender, gender of affected parent, degree of hybrid gene expression, and interactions with other genetic and environmental factors. Detailed biochemical studies, including analyses of aldosterone/PRA/cortisol 'day-curve' levels, have led to a fuller understanding of aldosterone regulation both before and in response to glucocorticoid treatment in this condition, and prompted a re-examination of current approaches to treatment Unless ACTH is completely suppressed by glucocorticoid treatment, the hybrid gene dominates over the wild-type aldosterone synthase genes in terms of aldosterone production, both in untreated and treated FH-I. This may in part be due to an abnormality affecting the functional expression of the 'wild-type' genes. Demonstration of persisting hybrid gene expression in patients rendered normotensive by very low doses of glucocorticoids suggests that currently recommended doses, aimed at normalizing aldosterone regulation (rather than blood pressure), may be too high, and may therefore place patients at unnecessary risk of developing Cushingoid side effects. Familial hyperaldosteronism type II (FH-II) Like FH-I, FH-II is associated with hyperaldosteronism and probable autosomal dominant inheritance. Unlike FH-I, hyperaldosteronism in FH-II is not dexamethasone suppressible, and is not associated with the hybrid gene mutation. Detection of adrenal mass lesions, which are frequently (17 of 57 patients in the Greenslopes Hospital series) responsible for PAL in FH-II, does not help to differentiate FH-II from FH-I, since mass lesions may also be common in that condition (detected in seven of 21 patients). Biochemically and morphologically, FH-II is indistinguishable from apparently non-familial PAL, and demonstrates similar variability even among individuals of the same family. In one informative family available for linkage analysis, FH-II does not segregate with either the AT1 gene or the CYP11B2 gene, or any other genetic defect in the chromosome 8q21-8qtel region. A genome-wide search is in progress. As has already occurred in FH-I, the elucidation of underlying genetic mutations in FH-II is likely to facilitate early detection, thereby helping to broaden its spectrum and to permit close follow-up and appropriately timed institution of specific therapy, and wider detection among patients with hypertension of potentially curable or specifically treatable forms.

In familial hyperaldosteronism type I, inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene leads to ACTH-regulated overproduction of aldosterone (causing hypertension) and of "hybrid" steroids, 18-hydroxy- and 18-oxo-cortisol. To determine whether complete suppression of the hybrid gene is necessary to normalize blood pressure, we sought evidence of persisting expression in eight patients who were rendered normotensive for 1.3-4.5 yr by glucocorticoid treatment. At the time of the study, six patients were receiving dexamethasone (0.125-0.25 mg/day) and two patients were taking prednisolone (2.5 or 5 mg/day). Urinary 18-oxo-cortisol levels during treatment demonstrated close correlation with mean "day curve" (blood collected every 2 h for 24 h) cortisol (r = 0.74), consistent with regulation by ACTH. Although urinary 18-oxo-cortisol levels were lower during than before treatment (mean 12.6 +/- 2.4 SEM vs. 35.0 +/- 5.6 nmol/mmol creatinine; P < 0.01), they remained above normal (0.8-5.2 nmol/mmol creatinine) in all eight patients. Although mean upright plasma potassium levels during treatment were higher, aldosterone levels lower, PRA levels higher, and aldosterone to PRA ratios lower than before treatment, PRA levels were uncorrected (< 13 pmol/L x min) and aldosterone to PRA ratios were uncorrected (>65) during treatment in four patients. For each of the eight patients, day curve aldosterone levels during treatment correlated more tightly with cortisol (mean r for the eight patients, 0.87 +/- 0.05 SEM) than with PRA (mean r = 0.36 +/- 0.10 SEM). Hence, control of hypertension by glucocorticoid treatment was associated, in all patients, with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production is not a requisite for hypertension control and, if used as a treatment goal, may unnecessarily increase the risk of Cushingoid side effects.

In familial hyperaldosteronism type I (FH-I), inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene causes ACTH-regulated aldosterone overproduction. In an attempt to understand the marked variability in hypertension severity in FH-I, we compared clinical and biochemical characteristics of 9 affected individuals with mild hypertension (normotensive or onset of hypertension after 15 yr, blood pressure never >160/100 mm Hg, < or = 1 medication required to control hypertension, no history of stroke, age >18 yr when studied) with those of 17 subjects with severe hypertension (onset before 15 yr, or systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg at least once, or > or = 2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs. 6 of 13 females; P < 0.05). All 4 subjects still normotensive after age 18 yr were females. Of 10 other affected, deceased individuals (7 males and 3 females) from a single family, all six who died before 60 yr of age (4 by stroke) were males. Biochemical studies were conducted in 6 mild and 16 severe subjects. The 2 groups were similar in terms of urinary sodium excretion. Mild subjects tended, although not significantly, to have lower urinary 18-oxo-cortisol (mean +/- SD, 27.4 +/- 9.0 vs. 35.2 +/- 12.9 nmol/mmol creatinine x day), higher plasma potassium (4.0 +/- 0.3 vs. 3.6 +/- 0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency) plasma aldosterone levels (498 +/- 279 vs. 744 +/- 290 pmol/L). Upright (midmorning after 2-3 h of upright posture) plasma aldosterone levels were similar (mild, 485 +/- 150; severe, 474 +/- 188 pmol/L). In 1 normotensive female, upright PRA was much higher, and the upright aldosterone/PRA ratio was much lower than that in the other subjects. The remaining mild subjects had similar upright PRA levels (mild, 2.8 +/- 1.4; severe, 3.7 +/- 3.2 pmol/ L x min) and aldosterone/PRA ratios (mild, 199.5 +/- 133.4; severe, 200.6 +/- 150.9) as severe subjects. During angiotensin II (AII) infusion studies (n = 6 mild and 10 severe), performed during recumbency, aldosterone levels were lower in the mild group both basally (404 +/- 144 vs. 843 +/- 498 pmol/L; P < 0.05) and after 60 min AII (2 ng/kg x min; 261 +/- 130 vs. 520 +/- 330 pmol/L; P < 0.05). Aldosterone was unresponsive (rose by <50%) to AII in all subjects. Day curve studies (blood collected every 2 h for 24 h; n = 2 mild and 7 severe) demonstrated abnormal regulation of aldosterone by ACTH rather than by AII in both groups. In conclusion, in this series of patients with FH-I, males had more severe hypertension, and the degree of hybrid gene-induced aldosterone overproduction may have contributed to the severity of hypertension.

Gordon's syndrome (GS) is a salt-sensitive, hyperkalaemic, familial hypertension syndrome which may masquerade in milder forms as essential hypertension. The response of hyperakalaemia to dietary salt restriction and to mineralocorticoids is heterogeneous, suggesting genetic heterogeneity. In a recently published study using small pedigrees, possible linkage of GS to chromosomes 1 and 17 was described. Studying the largest pedigree so far reported with GS, and using fluorescent-labelled microsatellite markers, we sought evidence of linkage to chromosomes 1 and 17. In this family there was no segregation of GS with any of the markers for chromosome 1. On chromosome 17, however, evidence of linkage was found with a maximum multipoint LOD score of 2.4 (the maximum LOD possible from the pedigree) over markers D17S250 and D17S934. This represents strong evidence in this pedigree for a responsible gene mutation on the long arm of chromosome 17. Recent reports of linkage for essential hypertension and, especially, familial essential hypertension within the same area of chromosome 17 containing the D17S934 marker raise the possibility that the same gene may be responsible for familial essential hypertension and for Gordon's syndrome.

Aim: Since detection of familial hyperaldosteronism type I (glucocorticoid-suppressible hyperaldosteronism) allows specific treatment of hypertension with dexamethasone, we compared clinical, biochemical and genetic approaches to detection., Patients and Methods: We studied 22 affected patients, 21 from a single, large family and an additional adopted male. Plasma aldosterone, plasma renin activity and urinary 18-oxo-cortisol were measured by radioimmunoassay. The hybrid gene was demonstrated using either Southern blotting or a long polymerase chain reaction technique., Results: Thirteen out of 22 (59%) patients with familial hyperaldosteronism type I, but only four out of 12 (33%) under 20 years of age, were hypertensive. Plasma potassium and aldosterone were each normal in 20 out of 22 (91%), and unhelpful in diagnosis. Plasma renin activity, the aldosterone: plasma renin activity ratio and 18-oxo-cortisol were more sensitive, being abnormal in 20 out of 22 (91%), 19 out of 22 (86%) and 20 out of 20 (100%) patients, respectively. Aldosterone was unresponsive (<50% rise) to 2 h of upright posture following overnight recumbency in 15 out of 15 (100%) patients studied, and to angiotensin II infusion (2 ng/kg per min for 1 h) in 14 out of 14 patients (100%). Whereas all the abovementioned abnormalities are also characteristic of angiotensin II-unresponsive aldosterone-producing adenoma, marked aldosterone suppression following 4 days of dexamethasone (0.5 mg every 6 h) was sensitive and specific for familial hyperaldosteronism type I (n = 11). The hybrid gene was detectable in peripheral blood leucocyte DNA in all 22 affected patients by Southern blotting, and by a faster, long polymerase chain reaction method developed in our laboratory, both methods requiring only a single blood collection., Conclusions: Should studies in other families confirm its universal applicability, long polymerase chain reaction should prove to be the most practical means of detecting familial hyperaldosteronism type I in laboratories equipped with this technique.

The effects on blood pressure (BP) and heart rate (HR), at rest and during bicycle exercise, of the vascular selective calcium antagonist felodipine, the cardio-selective beta-blocker metoprolol, and of the two drugs in combination, were assessed in a double-blind, three-way cross-over study comprising 23 patients with essential, mild to moderate hypertension. All three treatment regimens were given to each patient in randomised order for 4 weeks after a 4 week placebo run-in period. Felodipine 10-20 mg daily, metoprolol 100-200 mg daily and the combination of felodipine 10-20 mg plus metoprolol 100 mg daily were all effective antihypertensive treatments both at rest and during exercise. The two drugs seemed to have additive effects and the effect on BP of the combination was greater than that of either drug given as monotherapy. The mean sitting BP was 148/103 mmHg at randomisation, after 4 weeks of placebo treatment, and 134/88, 134/94 and 121/84 mmHg, respectively, after 4 weeks' treatment with felodipine, metoprolol and the combination. Maximal exercise capacity was similar irrespective of treatment regimen, and the normal response to exercise BP and HR was maintained during all active treatments. Changes observed in volume regulatory hormones (PRA, aldosterone and ANP) were consistent with a direct tubular natriuretic-diuretic effect of felodipine and of beta-blocker attenuated release of renin. All treatment regimens were well tolerated and adverse events reported were usually mild and transient.

1. In a 19 month period from June 1993 to December 1994, 60 patients (mean age 54.8 +/- 1.5 years s.e.m.; 32 males, 28 females) underwent unilateral laparoscopic adrenalectomy by one of us (JCR) for the treatment of hypertension due to primary aldosteronism (n = 48), phaeochromocytoma (n = 3) and cortisol-producing adenoma (n = 1) or to remove adrenal massess incidentally discovered on abdominal computerized tomography scanning ('incidentaloma') performed for other reasons (seven adenomas without biochemical evidence of excessive steroid hormone or catecholamine secretion and one carcinoma autonomously producing cortisol). 2. Compared with conventional open procedures, laparoscopic adrenalectomy was associated with reduced recovery time and a low complication rate (one pulmonary embolus and one port site incisional hernia). 3. Operation time with experience approximates that of open procedures (60 min), but is significantly longer in obese than in non-obese patients, and in males than in females. 4. Patients with adrenal causes of hypertension were cured or significantly improved by laparoscopic unilateral adrenalectomy. 5. Because of our concern regarding malignant potential of incidentalomas and high patient acceptance of laparoscopic techniques, we have reduced our size criteria for removal of incidentalomas.

In Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-suppressible hyperaldosteronism), a curable form of hypertension inherited in an autosomal dominant fashion, the underlying genetic defect is a "hybrid gene" in which 11 beta-hydroxylase gene regulatory elements are fused to the coding region of the aldosterone synthase gene. The detection of this hybrid gene by Southern blotting is time consuming and involves the use of radioactive isotopes. We describe a new, long polymerase chain reaction-based method for detecting the hybrid gene which greatly reduces the time required to obtain a result, avoids exposure of laboratory workers to radioactive materials, and will thereby facilitate the screening of patients for the presence of FH-I.

1. This study sought to assess the incidence of primary aldosteronism in 199 hypertensives who were normokalaemic and in whom the question of primary aldosteronism had never been raised. 2. The screening test applied was the aldosterone to renin ratio in plasma, which was raised in 40 and normal in 159 patients. A second ratio was normal in 14 of these 40. 3. Twenty-two patients with two further raised ratios required fludrocortisone suppression testing. This has been completed in 17, and failure to suppress led to a diagnosis of primary aldosteronism in all. 4. A dexamethasone suppression test (DST) excluded ACTH-dependent hyperaldosteronism and laterality of aldosterone production was determined by adrenal vein sampling. 5. Unilaterality in five patients led to adrenalectomy in four and spironolactone in one. Bilaterality in six patients led to spironolactone. 6. This study so far provides a proven (minimum) incidence for primary aldosteronism of 8.5%, a probable incidence of 12.0% (including two raised ratios) and a possible (maximum) incidence of 13.0% (leaving out those with second ratio normal). Exclusion of hypokalaemic hypertensives will lead to an underestimation of the true incidence of primary aldosteronism. 7. Based on this and other evidence, it is estimated that the incidence of primary aldosteronism in the 'essential hypertensive' population is between 5 and 15%, and is probably around 10%.

1. The effects of 6 h infusion of adrenaline (INF-A) or dextrose (INF-D) and of post-infusion cold pressor test (CPT) were compared in normal subjects, with (FH+) and without (FH-) a family history of hypertension. 2. Increased urinary excretion rates suggested facilitated noradrenaline (NA) release during and after INF-A in both FH+ and FH-. 3. Urinary adrenaline (UADR) excretion increased during INF-A, as expected, and was also slightly higher after INF-A than INF-D. 4. The effect of INF-A on systolic blood pressure (SBP) was greater in FH- than in FH+ but diastolic blood pressure (DBP) did not fall as quickly with nocturnal recumbency after INF-A in FH+. 5. A significantly greater response in plasma NA to CPT was seen in FH+ than in FH- after INF-A. A similar trend was also seen after INF-D. 6. Increases in DBP due to CPT were higher in FH+ than in FH- after both infusions. 7. This study provides evidence of increased noradrenergic activity during and after INF-A, and also of a difference in response to sympathetic stimulation between FH+ and FH-.

Non drug treatment of hypertension is being given increasing attention. In this article the role of salt restriction is evaluated.

1. Six (12%) out of 52 respondents to newspaper advertisements for antihypertensive drug trials had elevated aldosterone to renin ratio, confirmed by repeated measurement. 2. Failure to suppress aldosterone with fludrocortisone acetate administration and oral salt loading confirmed the presence of primary aldosteronism in all six patients. 3. Two of the six patients have already had aldosterone-producing adenomas removed, one has commenced spironolactone, and one has an adrenal mass on computerized tomography but investigation is incomplete. 4. None of the six patients with primary aldosteronism had unprovoked hypokalaemia. 5. Plasma aldosterone levels did not distinguish those patients with subsequently proven primary aldosteronism from the others. Plasma renin activity (PRA) was a better discriminator, but not as good as the aldosterone to renin ratio. 6. The incidence of primary aldosteronism is probably much higher than the 1% currently quoted in texts, with earlier, normokalaemic forms accounting for the majority of cases.

The levels of plasma atrial natriuretic peptide in response to graded adrenaline infusion were determined in six patients with essential hypertension and six healthy normotensive subjects (controls). Basal plasma adrenaline concentration was similar in both groups and rose progressively and to a similar level during adrenaline infusion. Plasma noradrenaline rose in both groups and to the same extent during the 26 and 39 ng/kg/min adrenaline infusion rates. Basal plasma atrial natriuretic peptide levels were higher in the hypertensives than in the controls. Graded adrenaline infusion had no effect on atrial natriuretic peptide levels in the controls but significantly raised atrial natriuretic peptide levels in the hypertensives. Systolic blood pressure rose progressively during adrenaline infusion at a lower infusion rate in the hypertensives than in the controls. Similarly, while heart rate rose during adrenaline infusion in both groups, there was a greater rise in the hypertensives. The increased cardiovascular responsiveness to adrenaline infusion in patients with essential hypertension may explain why plasma atrial natriuretic peptide levels rose only in this group and not the normotensive subjects.

Exciting developments in knowledge of primary aldosteronism include description of new subtypes and elucidation of the genetic basis of one variety. Furthermore, relatively simple biochemical screening (aldosterone/renin ratio) has disclosed that primary aldosteronism is more common than previously thought, by diagnosing patients at an earlier, normokalaemic stage. The mutant gene discovered in the glucocorticoid-suppressible variety (FHI) codes for an aldosterone biosynythetic enzyme normally controlled by angiotensin II, and now controlled by corticotropin. The zona fasciculata is hyperplastic and makes aldosterone and "hybrid steroids" 18-oxocortisol and 18-hydroxycortisol in excess, in response to ACTH but not to angiotensin II. Adrenal tumours have not yet been described in this condition. Aldosterone-producing adenomas (Conn's syndrome) are also commonly composed of zona fasciculata-like cells, make "hybrid steroids" in excess and are very sensitive to ACTH but not to angiotensin II. We have described a new variety of aldosterone-producing adenoma which is responsive to angiotensin II (AII-responsive APA), consists of at least 20% zona glomerulosa-like cells, and does not make "hybrid steroids" in excess. We have also described a new familial variety of primary aldosteronism that includes tumours and is not glucocorticoid-suppressible (FHII). We propose that primary aldosteronism is a spectrum of genetic diseases expressed as either hyperplasia or neoplasia, and that morphological and genetic diversity explains biochemical and clinical behaviour.

The syndrome of hypertension and hyperkalemia, hyperchloremic acidosis with normal glomerular filtration rate (Gordon's syndrome) is characterised by volume expansion, suppressed renin and reduced mineralocorticoid-induced renal clearance of potassium. The clinical and biochemical defects are aggravated by high salt diet and corrected by low salt diet, leading to the hypothesis of excessive sodium reabsorption in the nephron proximal to where aldosterone acts. In this study, we used lithium clearance as a marker of proximal sodium reabsorption in three patients with Gordon's syndrome, in order to further localise the site in the nephron of defective sodium handling. Fractional excretion of lithium was decreased, and absolute and fractional proximal reabsorption of sodium was increased compared to normal controls. In addition, absolute distal reabsorption of sodium was decreased, consistent with decreased mineralocorticoid activity. Fractional excretion of potassium was markedly decreased and did not rise with increased distal delivery of sodium during saline infusion. However, after severe dietary sodium restriction had elevated plasma aldosterone (lowering plasma potassium levels to normal), fractional excretion of potassium was raised by saline infusion. Reduced lithium clearance in patients with Gordon's syndrome supports the hypothesis of increased proximal sodium reabsorption in this condition.

1. Significant increases in arterial noradrenaline (NA) of similar magnitude were seen in normotensive (NT) and hypertensive humans (HT) during adrenaline (ADR) infusion. 2. Significant falls in plasma potassium (K+) were observed in both NT and HT during ADR infusion, even at rates equivalent to minor stress. Levels achieved were significantly lower in HT than in NT. 3. Plasma glucose increased significantly in HT at all ADR infusion rates but only at higher rates of infusion in NT. 4. Basal insulin levels were significantly higher in NT than in HT. After cessation of infusion, insulin increased three-fold in HT and two-fold in NT. 5. Infusion of ADR to produce levels seen during mild to moderate stress resulted in significant increases in plasma NA, falls in plasma K+ and increases in plasma glucose. The expected large insulin response to rising glucose was not seen until after ADR was ceased, confirming the inhibitory effect of ADR on glucose stimulated insulin release.

1. Clonidine resulted in significant suppression of both noradrenaline (NA) and adrenaline (ADR) in essential hypertensives (EHT) without any false positive findings. That is, every patient who failed to suppress had phaeochromocytoma (PH). 2. The clonidine suppression test (CST) produced minimal suppression of NA in NA-secreting PH (NA-PH) and correctly identified two NA-PH with normal basal plasma NA. 3. In ADR-secreting PH (ADR-PH) the CST did not result in significant suppression of ADR levels, whether elevated or normal basally. 4. The CST proved to be an accurate discriminator of PH from other forms of hypertension.

1. In Gordon's syndrome (GS; a syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate), excessive proximal sodium reabsorption leads to suppression of renin and aldosterone, hyperkalaemia and hyperchloraemic acidosis. 2. Low urinary levels of vasodilator prostaglandins (PG) have been reported in GS, suggesting renal hypoprostaglandinism as a pathophysiological mechanism. 3. In four cases of GS, levels of vasodilator prostaglandins PGE2 and 6-keto-PGF1 alpha were low. 4. In one case of GS, low PGE2 levels were normalized by dietary salt restriction or diuretic therapy.

Twelve hypertensive patients who were classified as pseudoephedrine-sensitive in a preliminary trial were selected for further investigation with single doses of pseudoephedrine 60 mg, a combination of chlorpheniramine 4 mg with paracetamol 650 mg and placebo. A double-blind, randomised, crossover study design was followed. Treatment with pseudoephedrine produced significant effects on all the four variables measured (systolic, diastolic and mean arterial blood pressure, and heart rate). Effects of the chlorpheniramine/paracetamol combination were found to be not significantly different from placebo. It was concluded that the combination may be useful as a medication for 'colds' in hypertensive patients, since it does not induce cardiovascular effects such as those observed with pseudoephedrine.

1. Arterial adrenaline (ADR) levels were measured during graded ADR infusions in normotensives (NT) and in mild hypertensives (HT), in order to test the hypothesis that ADR enhances its own clearance in NT. 2. Although infusion of ADR resulted in similar arterial ADR levels in NT and HT, increases in systolic blood pressure (SBP) and heart rate (HR) and decreases in diastolic blood pressure (DBP) were greater during ADR infusion in HT than in NT. 3. Twenty minutes after cessation of infusion, SBP and HR remained elevated in HT but not in NT. 4. No evidence was found supporting enhanced ADR clearance during increasing ADR levels in NT or HT.

1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities.

The ratio of aldosterone to renin in plasma was measured in samples collected from 79 hypertensive patients. Eighteen patients with primary aldosteronism had ratios ranging from 25 to 677 (mean 183) when measured on 34 occasions, while 16 normal subjects had ratios of 3.3-21 (mean 11.3). Of the remaining 61 patients with ratios ranging from 1.8 to 184, 15 patients have ratios greater than 25 and are under investigation for primary aldosteronism, which appears highly likely in five and has been excluded in two. The aldosterone/renin ratio appears promising as a screening test for primary aldosteronism. Consistency and the effects of sodium and potassium balance and of antihypertensive medications require further study.

1. The decision whether arterial blood pressure (BP) is elevated or normal is usually based on inadequate data: few readings in the presence of great variability of BP; levels higher in the presence of the doctor; and diastolic BP often higher sitting and standing than lying. 2. Assessments of response and of the need for increases in drug dosage are also based on insufficient data. 3. Increased morbidity and mortality from stroke and heart attack, and incomplete correction with treatment have been interpreted as suggesting further benefit from aggressive reduction of BP to 'normal' in all patients. 4. The emergence of powerful drugs with few side-effects, and the promise of lowering office BP to 'normal' as monotherapy, has removed the hesitation to treat 'mild' hypertension. 5. Attempts to lower sitting office diastolic BP to 'normal' have led to increasing drug dosage, dose-related, drug-specific side-effects, and lethargy due to hypotension. 6. Newer self-measurement BP units can be used easily by most patients, cost less than five visits to the doctor and provide a cheap method of obtaining sufficient data on which to base informed management decisions. Supported by normal echocardiographic left ventricular mass, normal 'home BP' (including lying diastolic) permits many mild hypertensives to remain off medications. 7. Non-drug therapy avoids or reduces long-term drug therapy, with its side-effects.

Twenty hypertensive patients received single oral doses of pseudoephedrine 60 mg or placebo in a double-blind, randomised, crossover trial. Systolic, diastolic, mean arterial blood pressure, and heart rate were measured at 5 min intervals for 30 min prior to and 210 min after the administration of pseudoephedrine or placebo. Statistically significant differences between the two treatments were observed with changes in systolic blood pressure (P less than 0.03) and heart rate (P less than 0.01) but not in diastolic (P greater than 0.03) and mean arterial blood pressure (P greater than 0.1). Minor differences in the number of reported side effects between the two treatments were not statistically significant.

1. Nine men aged 20-33 years with essential hypertension measured their own blood pressure at home, lying and standing, three times daily, under conditions of everyday living. The last 14 days' readings (eighty-four observations) from control and treatment periods of at least 4 weeks' duration were used to calculate mean pressures. 2. In eight patients, propranolol (40 mg thrice daily with meals) significantly lowered "mean blood pressure" (diastolic+1/3[systolic-diastolic]) but methyclothiazide (5 mg with breakfast) did not. In five subjects, prindolol (5 mg thrice daily with meals) significantly lowered "mean blood pressure" but methyclothiazide (5 mg with breakfast) did not. 3. In six subjects there was no significant difference between "mean blood pressure" when taking propranolol doses 120 mg with breakfast, 60 mg with breakfast and with the evening meal, and 40 mg with each meal. In five subjects there was no significant difference between "mean blood pressure" when taking metoprolol 200 mg with breakfast and 100 mg with breakfast and with the evening meal. In four subjects there was no significant difference between "mean blood pressure" when taking prindolol 30 mg with breakfast, 15 mg with breakfast and with the evening meal, and 10 mg with each meal. 4. In young males with essential hypertension, beta-adrenoreceptor blockers were more effective than a thiazide diuretic in lowering blood pressure, and were effective in a single daily dose.

1. A significant positive correlation was found between changes in circulating noradrenaline (NA) levels and changes in atrial natriuretic peptide (ANP) levels during NA infusion and clonidine administration. 2. A significant positive correlation was also found between changes in arterial blood pressure and changes in ANP level during infusion of angiotensin II and of NA. 3. Two patients with very high circulating NA levels due to phaeochromocytoma, but receiving alpha- and beta-blockade, did not have clearly elevated ANP. A third not receiving medications and aged 73 years had elevated levels. 4. Atrial natriuretic peptide response to NA and angiotensin II may be mediated by changes in blood pressure levels or increased noradrenergic and angiotensinergic receptor activity in the atria or both. Atrial natriuretic peptide may have a role in blood pressure regulation in both normotensive and hypertensive man.

1. Urinary noradrenaline (NA) and adrenaline (ADR) determinations are a more sensitive index than plasma measurements for the diagnosis of phaeochromocytoma (phaeo). 2. Even though urinary NA excretion serve as a sufficient single diagnostic test for the majority of phaeos, it is necessary to measure urinary ADR excretion if ADR-only secreting phaeos are not to be missed, particularly in patients with multiple endocrine neoplasia (MEN) syndrome. 3. The clonidine suppression test confirmed all tumour diagnoses, and in this series was not responsible for any false negative or false positive results.

If rising plasma catecholamine levels enhance their own clearance, such a mechanism could be protective, and its absence predispose to hypertension. In normal subjects and in mild essential hypertensives serial increases in plasma noradrenaline (NA) and adrenaline (ADR) generated by intravenous infusion were used to test the effect of rising plasma levels on clearance. Plasma NA and ADR were measured radio-enzymatically, venous clearance of NA by isotopic infusion and clearance of ADR by increment in arterial plasma levels. Serial increases in NA and ADR through the physiological range did not lead to increased plasma clearance: in fact, NA and NA clearance were significantly negatively correlated. For ADR, a circulating hormone, any effect on clearance may be biologically important. Chronic increases in circulating ADR due to mental stress have been suggested as an etiological factor in essential hypertension, working through enhanced noradrenergic transmission. The significance of these findings for NA, a local neurotransmitter rather than a circulating hormone, depends on the extent to which changes in plasma clearance reflect changes in tissue clearance.

A family with the syndrome of hypertension and hyperkalaemia affecting six members in two generations is reported from Australia, where the first two sporadic cases were described. All family members had hyperkalaemia, hyperchloraemia and normal creatinine clearance. Only one affected adult and no affected children were hypertensive, possibly because of habitual low-salt diets. Plasma potassium fell significantly during fludrocortisone acetate administration, and urine potassium increased during saline infusion, consistent with renal tubular responsiveness to mineralocorticoid. Low plasma renin activity and pressor hyper-responsiveness to angiotensin II suggested sodium volume overload, but atrial natriuretic factor (ANF) was normal or only slightly elevated when compared with clearly elevated levels in primary aldosteronism. Plasma ANF was unresponsive to the usually reliable stimulus of angiotensin infusion in the two brothers affected and to saline infusion in one of them. These findings are consistent with a renal tubular avidity for sodium, leading to volume expansion, suppression of renin, and, depending on dietary sodium intake, hypertension. A role for dysregulation of ANF in the pathophysiology is possible.

Home blood pressure measurements were used to assess the effect of methyclothiazide in young essential hypertensive and normotensive males. Although plasma volume was reduced by approximately 10 percent, blood pressure was not reduced in either group. The lack of effect on blood pressure was probably not attributable to dosage employed, as doubling the dose (5 to 10 mg) in the normal subjects (who were equilibrated on constant diet) did not significantly increase changes in plasma volume, plasma renin activity, aldosterone excretion, urine sodium or blood pressure. The higher dose did result in greater changes in plasma potassium and uric acid. Homeostatic mechanisms which limit the volume mediated and other antihypertensive effects of methyclothiazide apparently achieved complete compensation in these young males. This suggests that thiazide diuretics may not be the drug of first choice in the treatment of hypertension in young adults. Further studies with other diuretics are clearly necessary before the significance of these findings can be fully assessed.

Based on 28 reported patients, constant features of the syndrome of hypertension and hyperkalaemia are hyperkalaemia, hyperchloraemia, normal renal glomerular function and, in all adult patients, hypertension. Inconstant features include short stature, intellectual impairment and muscle weakness. Levels of renin and aldosterone are low, but respond to dietary salt restriction and diuretic therapy, both of which reverse the hypertension and hyperkalaemia. The basic abnormality is excessive renal sodium retention, leading to chronic suppression of renin and aldosterone; the latter is then hyporesponsive to the hyperkalaemic stimulus. Dietary salt loading or impaired production of any natriuretic or chloriuretic factor (for example atrial natriuretic peptide or renal natriuretic prostaglandins) would predispose to development of the syndrome. With normal GFR, this appears to be a unique mechanism for hypertension and hyperkalaemia.

In a within-patient comparison of conventional oxprenolol administered twice daily with slow-release oxprenolol administered once daily in the treatment of hypertension, twenty patients previously responsive to beta-blockers took each formulation for 4 weeks, after wash-out periods off beta-blocker of 2 weeks' duration. The order of administration of the two forms was randomized, and sixteen patients continued medication with cyclopenthiazide 0.5 mg daily. Blood pressure levels at the end of the 4-week treatment periods were compared with levels at the end of the preceding 2-week wash-out periods. Both formulations lowered blood pressure and pulse rate significantly. There was no difference in their effects on pulse rate or on blood pressure, whether measured by the doctors using standard sphygmomanometers or by the hypertension sister using a random-zero sphygmomanometer. In four patients who measured their own blood pressures at home each morning (before medications), afternoon and night, mean levels were similar with the two formulations. Both formulations were very well tolerated.

1. In normal subjects and essential hypertensives, plasma noradrenaline (NA) levels, and NA clearance (3H-NA constant infusion), were measured during graded infusion of NA. 2. Plasma levels of NA were similar in both groups, with parallel increases to levels approximately three times basal, but still in the upper normal range. 3. Clearance did not increase in either group with increasing plasma NA levels. There was no correlation between plasma NA achieved and NA clearance, which was similar in hypertensives and normotensives. 5. Insofar as plasma clearance reflects tissue clearance, these studies provide no support for the contention that altered NA metabolism might predispose to elevated NA levels in essential hypertension.

An excellent response to treatment with thiazide diuretic for twelve years is described in a patient with Gordon's Syndrome, the first to be reported from Scotland, and only the second to manifest the full clinical picture of short stature, hypertension, hyperkalaemia and hyperchloraemic acidosis without renal failure. The hypertension and biochemical abnormalities were reversed during therapy. Temporary withdrawal after seven years was followed by the immediate return of all the biochemical abnormalities, but not of the hypertension.

In many applications of discriminant analysis in medicine, data of known origin which can be reasonably assumed to be a random sample from the entire class may not be available for each of the possible classes. In this paper we note how such situations can be handled by using finite mixture models to formulate the estimation problem. This approach is adopted to model the distribution of the renal venous renin ratio (RVRR) between left and right kidneys in patients with hypertension. This distribution is used in the formation of a probabilistic allocation rule as an aid in the diagnosis of renal artery stenosis, which is potentially curable by surgery.

Plasma levels of ANP were measured in normal subjects and in three conditions associated with disturbed volume homeostasis. Levels of ANP were appropriately raised in seven patients with primary aldosteronism, and fell to normal following removal of an aldosterone-producing adenoma in six and dexamethasone treatment in one patient with glucocorticoid-suppressible hyperaldosteronism. The level of ANP in one patient with Gordon's syndrome (a condition associated with plasma volume expansion) was lower than in the patients with primary aldosteronism, both before and after saline infusion. This is consistent with reduced ANP responsiveness in this condition. responsiveness in this condition. Levels of ANP were inappropriately elevated in three patients with Bartter's syndrome (a condition with plasma volume contraction) and rose further during saline infusion. This is consistent with primary hypersecretion of ANP.

In five males with mild essential hypertension, simultaneous hemodynamic and arterial and venous plasma catecholamine responses to three stimulation tests (mental arithmetic, isometric handgrip exercise, and cold) were studied. Plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) were measured radioenzymatically. Isometric exercise was the best stimulus for systolic and diastolic blood pressure and NE. Mental arithmetic produced the highest levels of plasma EPI, but there was great intersubject variability. Dopamine levels did not increase with any of these stimuli. Consistent arterio-venous differences across the forearm were seen for EPI but not NE, consistent with local production of NE. Isometric exercise produced the closest correlations between peripheral plasma catecholamine levels, blood pressure, and heart rate. Good correlations were seen with mental arithmetic, but with the stimulus of cold correlation was poor.