Direct and sympathetically mediated venoconstriction in essential hypertension. Enhanced responses to endothelin-1.

Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide. Although circulating concentrations are not increased in essential hypertension, enhanced sensitivity to endothelin-1 has been observed in animal models of hypertension. We investigated dorsal hand vein responses to local infusion of endothelin-1 and norepinephrine in 12 patients with essential hypertension who had never received treatment and in 12 age and sex matched normotensive control subjects. The maximal venoconstriction and the geometric mean of the dose of norepinephrine that caused 50% of maximal venoconstriction were similar in hypertensive (mean +/- SE; 80 +/- 4%; 31 +/- 8 pmol/min) and normotensive subjects (87 +/- 5%, 22 +/- 9 pmol/min). In contrast, mean venoconstriction to endothelin-1 was significantly greater in hypertensive (49 +/- 5%) than in normotensive subjects (27 +/- 2%; P = 0.004). Sympathetically mediated venoconstriction elicited by deep breath was substantially potentiated by endothelin-1 in hypertensive (67 +/- 7% at 90 min) but not normotensive subjects (11 +/- 3% at 90 min; P = 0.001). Venoconstriction to endothelin-1 correlated positively with mean arterial pressure in the hypertensive subjects (r = 0.82; p = 0.001) but negatively in the normotensive subjects (r = -0.58; p = 0.047). Endothelin-1 may contribute to the reduction of venous compliance occurring in the early stages of essential hypertension and to the altered systemic hemodynamics in this condition.

Does a hospital formulary influence prescribing practice in an acute medical admissions unit?

AIM: To assess the extent to which prescribing of cardiovascular medications in a busy medical unit deviates from the local joint primary and secondary care drug formulary guidelines. METHOD: A retrospective audit of the case notes, prescription charts and discharge summaries of 150 randomly selected emergency medical admissions over a 4 month period. RESULTS: No patient receiving a non-formulary cardiovascular drug on admission had the choice reviewed in line with formulary recommendations. One third of new cardiovascular medications commenced in hospital were not compliant with formulary recommendations. Decisions about drug therapy were rarely justfied in the written hospital record. CONCLUSIONS: Our results demonstrate that in a busy acute medical admissions' unit there is a clear failure to amend or query non-formulary prescribing at the time of admission and a tendency to exacerbate it during the inpatient period. This potentially undermines the purpose of a joint drug formulary as a guideline for safe, evidence-based and cost-effective prescribing.

Diabetic nephropathy is associated with an increased familial risk of stroke.

OBJECTIVE: To test the hypothesis that genetic susceptibility to diabetic nephropathy is associated with an increased familial risk of vascular disease, we have examined the causes and rates of death of parents of individuals with type 1 diabetes complicated by diabetic nephropathy compared with the causes and rates of death of parents of control subjects with diabetes uncomplicated by nephropathy. RESEARCH DESIGN AND METHODS: Individuals with at least a 14-year duration of type 1 diabetes complicated by diabetic nephropathy were identified and matched for age, sex, and duration of diabetes to control subjects. A total of 118 patients and 118 matched control subjects were identified and approached to obtain information on parental age and cause of death. For parents who had died, the cause of death was ascertained from the death certificate. RESULTS: Kaplan-Meier curves showed that parents of subjects with nephropathy (PN) had reduced survival compared with parents of diabetic subjects without nephropathy (PC) (log rank test P < 0.05). There was an excess of all vascular deaths and, in particular, strokes in the parents of subjects with nephropathy (PN: 20 of 103 deaths, 19% vs. PC: 3 of 66 deaths, 4%; Fisher's exact test P < 0.01). CONCLUSIONS: Parents of diabetic patients with nephropathy have reduced survival. This seems to be largely explained by an increase in vascular deaths and, in particular, a four-fold increase in the number of strokes. This supports the hypothesis that a common hereditary risk factor predisposes to both vascular death and diabetic renal disease.

Angiotensin II-induced aldosterone stimulation in man is not dependent upon adrenocorticotropin.

To document a possible role of ACTH in the aldosterone response to angiotensin II, we measured plasma aldosterone levels during physiological increments in plasma angiotensin II in normal male volunteers on two occasions, once with suppression of endogenous ACTH secretion (dexamethasone or hydrocortisone) and again without ACTH suppression. The subjects were studied under standardized conditions of dietary sodium (40 mmol/day) and potassium (100 mmol/day) intake and controlled body posture. Glucocorticoid pretreatment did not alter the plasma levels of angiotensin II attained during incremental infusions (0.5, 1, 2, and 4 ng/kg . min) of the octapeptide. Baseline plasma aldosterone levels were significantly lowered by glucocorticoid pretreatment. However, aldosterone responsiveness to infused angiotensin II (change and percentage of change from baseline levels) was not altered by suppression of endogenous ACTH production. Serum potassium levels were not increased by the administration of angiotensin II. The results demonstrate that in normal males on a sodium-restricted diet, baseline aldosterone levels are controlled in part by ACTH. The aldosterone response to angiotensin II, however, is not dependent upon endogenous ACTH secretion, an action of angiotensin II on the pituitary to release ACTH, or a rise in serum potassium.

Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase in hypertension.

Exogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase (e.g. glycyrrhetinic acid, a constituent of licorice) raise blood pressure by allowing cortisol to activate mineralocorticoid receptors. Endogenous 11 beta-dehydrogenase inhibitors called glycyrrhetinic acid-like factors (GALFs), have been extracted from urine. Increased GALFs could explain the impairment of 11 beta-dehydrogenase in essential hypertension and ectopic ACTH syndrome. We extracted urine on Sep-Paks and quantified GALFs by their inhibition of 11 beta-dehydrogenase bioactivity in microsomes from rat liver. GALFs have no diurnal rhythm and were no different after dexamethasone treatment, in patients with low ACTH, on in 4 patients with ectopic ACTH secretion. In 79 subjects, GALF excretion did not correlate with blood pressure. In 17 subjects, GALF excretion did not correlate with indices of mineralocorticoid receptor activation on 11 beta-dehydrogenase activity. We conclude that GALFs are not ACTH dependent and have no measurable effect on 11 beta-dehydrogenase in vivo. In hypertension associated with impaired 11 beta-dehydrogenase activity GALFs are unlikely to play a pathophysiological role.

Increased vasoconstrictor sensitivity to glucocorticoids in essential hypertension.

Glucocorticoids raise blood pressure but were thought not to play a pathophysiological role in essential hypertension when it was demonstrated that cortisol secretion rates and circulating concentrations are normal in this disease. However, recent observations suggest that increased tissue sensitivity to cortisol, mediated by either abnormal glucocorticoid receptors or impaired inactivation of cortisol by 11 beta-dehydrogenase, may allow cortisol to raise blood pressure despite normal circulating concentrations. We studied 11 patients with essential hypertension and 11 matched normotensive control subjects. Dermal vasoconstriction after topical application of both cortisol (16 +/- 4 versus 32 +/- 5 U, control subjects versus hypertensive patients; P < .02) and beclomethasone dipropionate (75 +/- 10 versus 100 +/- 7 U; P < .05) was increased in the hypertensive patients. Hypothalamic-pituitary glucocorticoid receptor sensitivity was normal, as judged by basal cortisol secretion rates and suppression of plasma cortisol during sequential overnight dexamethasone suppression tests. 11 beta-Dehydrogenase activity was impaired in essential hypertension, as judged by prolonged half-lives of [11 alpha-3H]cortisol (44 +/- 4 versus 58 +/- 4 minutes, control subjects versus hypertensive patients; P < .02). However, this did not correlate with the dermal vasoconstrictor response. We conclude that vasoconstrictor sensitivity to glucocorticoids is increased in essential hypertension and that this may initiate and/or sustain the increased peripheral vascular resistance that characterizes this disease. The mechanism of increased sensitivity remains uncertain, but it will be important to establish whether it relates to genetic abnormalities of the glucocorticoid receptor that have been observed in animal models and young individuals who are predisposed to essential hypertension.

A case of hypopituitarism with diabetes insipidus and loss of thirst. Role of antidiuretic hormone and angiotensin II in the control of urine flow and osmolality.

A 20-yr-old male was found to have diabetes insipidus is association with panhypopituitarism but without any focal neurological lesion being identified. He was initially treated with steroid supplements, the features of diabetes insipidus being controlled with a thiazide diuretic. Eighteen months later the patient lost thirst sensation and stopped treatment, subsequently being re-admitted with severe dehydration, oliguria and focal neurological signs. Further investigation, including brain biopsy, confirmed the presence of an atypical pinealoma which was considered inoperable. Measurements of plasma antidiuretic hormone (ADH) and angiotensin II (AII) concentrations during the severe dehydration showed very high levels of AII, but inappropriately low plasma ADH levels for the severity of dehydration. We consider that the evidence obtained from this case supports the view that the oliguria with hypertonic urine present during severe dehydration was due to a direct renal action of the very high AII levels, possibly supplemented by the residual ADH secretion.

Plasma arginine vasopressin in the syndrome of antidiuretic hormone excess associated with bronchogenic carcinoma.

A study of plasma arginine vasopressin in 17 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with bronchogenic carcinoma, revealed that the arginine vasopressin levels were distinctly elevated in most. In 14 patients with bronchogenic carcinoma, but without overt SIADH, plasma levels of arginine vasopressin were significantly higher than in normal subjects (p less than 0.001). This, together with the finding of a lower than normal plasma osmolality in this group, suggests that inappropriate ADH excess might be much more common in patients with bronchogenic carcinoma than previously thought. The normal positive correlation between plasma osmolality and plasma arginine vasopressin was found to be reversed in SIADH. Seven of nine patients with overt SIADH, studied after fluid deprivation, showed an increase in plasma arginine vasopressin coincident with an increase in plasma osmolality (r = +0.8, p less than 0.01); in one patient, plasma arginine vasopressin returned to the original level following rehydration. The possibility that this might imply a degree of physiologic control to what is generally considered an autonomous secretion is discussed. It is, however, considered more likely that other factors, including changes in plasma volume and glomerular filtration, might explain the increase in plasma levels of arginine vasopressin.

The accuracy of automated blood pressure measuring devices in patients with controlled atrial fibrillation.

OBJECTIVE: To determine whether automated blood pressure measuring devices can measure blood pressure accurately in patients with atrial fibrillation. DESIGN: Comparison of the accuracy of two electronic sphygmomanometers [Takeda UA-751 (Takeda) and Copal UA-251 (Copal)] and two ambulatory blood pressure monitors [Accutracker 1 (Accutracker) and SpaceLabs 90207 (SpaceLabs)] with that of a trained observer using a Hawksley random-zero sphygmomanometer (Hawksley), using the sequential same-arm technique. SETTING: University teaching hospital: medical wards and outpatient department. SUBJECTS: Twenty-eight patients, mean +/- SD age 72 +/- 9 years, blood pressure range 90-158/40-96 mmHg, in atrial fibrillation with a controlled ventricular rate. MAIN OUTCOME MEASURES: The proportion of machine readings > 5 mmHg different from the Hawksley reading was compared with that obtained by three sequential Hawksley measurements. The variability of each measuring method was assessed by determining the SDD for the paired readings from each device. RESULTS: Five per cent of Takeda, 5% of Copal, 14% of Accutracker and 21% of SpaceLabs readings could not be obtained. Sequential testing with the Hawksley resulted in an accuracy at the 5-mmHg level of (systolic/diastolic) 79/79%, compared with 64/54% (P < 0.05 for diastolic) for the Takeda, 68/75% (NS) for the Copal, 50/36% (P < 0.01 for both) for the Accutracker and 50/29% (P < 0.01 for systolic, P < 0.001 for diastolic) for the SpaceLabs. Intrapatient variability, as assessed by SDD, was 8.3/8.6 mmHg for the Hawksley, similar to that for the Copal (7.7/7.3 mmHg) but higher for the Takeda (11.2/19.7 mmHg), the Accutracker (22.4/26.3 mmHg) and the SpaceLabs (7.5/14.8 mmHg). CONCLUSIONS: Accurate measurement of blood pressure with an electronic device is possible in patients who have atrial fibrillation; the Copal UA-251 provides a satisfactory level of accuracy. However, the marked difference between devices and the limited accuracy of the other machines tested here demonstrates the need to ensure that such devices are of proven accuracy in this patient group.

The British Hypertension Society protocol for the evaluation of automated and semi-automated blood pressure measuring devices with special reference to ambulatory systems.

With the increasing manufacture of expensive systems for the measurement of ambulatory blood pressure there is a need for potential purchasers to be able to satisfy themselves that the systems have been evaluated according to agreed criteria. The British Hypertension Society has, therefore, drawn up a protocol of requirements for the evaluation of these devices. This protocol incorporates many features of the American National Standard for Non-Automated Sphygmomanometers but includes many additional features, such as strict criteria for observer training, interdevice variability testing before and after a month of ambulatory use, and a new system of analysis which permits the test system to be graded. It is recommended that manufacturers of ambulatory blood pressure measuring devices should obtain an unbiased evaluation according to a recognized standard before a device is marketed.

Effects of angiotensin II on arginine-vasopressin in physiological and pathological situations in man.

Studies were designed to determine whether angiotensin II has a direct stimulatory effect on arginine-vasopressin in man and to determine the role, if any, played by angiotensin II in the control of vasopressin release in physiological and pathological conditions. Acute infusion of angiotensin II in normal volunteers produced small but definite increases in plasma levels of arginine-vasopressin (5-4+/-0-3(S.E.M.) to 6-4+/-0-2 pg/ml) only when plasma angiotensin II levels were supraphysiological. Concurrent measurements of plasma arginine-vasopressin and angiotensin II were made during acute changes in fluid balance and posture in normal volunteers and in clinical conditions characterized by high plasma levels of angiotensin II (Addison's disease and Bartter's syndrome). The results of these studies allow us to conclude that there is little to suggest a direct effect of angiotensin II which is likely to be relevant to the normal physiological control of arginine-vasopressin in man.

A radioimmunoassay for plasma arginine-vasopressin in man and dog: application to physiological and pathological states.

A radioimmunoassay has been developed for plasma arginine-vasopressin in man and dog. The mean recovery of added arginine-vasopressin (AVP) was 60 +/-6.9 (S.D.)% and the lower threshold of detection 2.0 pmol/1. A close correlation was found between concurrent radioimmunoassay and bioassay values. The mean concentration found in peripheral venous blood in healthy men after overnight fasting was 5.3 pmol/1 (range 4.6-6.2 pmol/1.) In man, significant increases in plasma AVP occurred after dehydration (5-9-9-5 pmol/1) and significant decreases after oral water-loading (5.9-9.5 pmol/1). During i.v. infusion of graded doses of synthetic AVP in normal men, plasma levels were closely correlated with infusion rate. On stopping the infusion, plasma vasopressin fell exponentially with a half-life of between 7 and 8 min. In man, plasma AVP was unaffected by tilting head-up for 2 h, or by a non-hypotensive bleeding of 500 ml in 10 min. In the dog, haemorrhage of 5 ml/kg and over caused proportionate increases in AVP in the circulation. In normal men, plasma vasopressin was significantly correlated with concurrent urinary osmolality. Five patients with oat-cell bronchial carcinoma and hyponatraemia showed a marked increase of plasma vasopressin. Five patients with diabetes insipidus had significantly reduced, but detectable, levels of plasma AVP. The plasma concentration in these patients did not increase after water restriction.

Ambulatory blood pressure on and off continuous positive airway pressure therapy for the sleep apnea/hypopnea syndrome: effects in "non-dippers".

Ambulatory blood pressure (BP) monitoring was performed in 13 patients with the sleep apnea/ hypopnea syndrome (SAHS) during a randomized, placebo controlled crossover trial of the effects of continuous positive airway pressure (CPAP) therapy. BP was monitored at half-hourly intervals for a 24-hour period both on CPAP and on an oral placebo, each given for a minimum of 3 weeks. Objective effective CPAP use averaged 4.3 hours per night. Weight and anti-hypertensive medications remained stable over the study period. Systolic, diastolic and mean arterial BP for 24-hour, daytime and nighttime periods were not significantly different on placebo compared to CPAP. Those patients with no significant overnight fall in BP on placebo ("non-dippers") showed a significant improvement in daytime mean arterial BP on CPAP (98 +/- 4 mm Hg) compared to placebo (102 +/- 4 mm Hg; p = 0.01). These findings, in a well-controlled trial, suggest that BP is not reduced by CPAP in a heterogeneous group of SAHS patients, but it may be selectively improved in those patients most at risk for cardiovascular morbidity and mortality.

Can simultaneous ambulatory blood pressure and activity monitoring improve the definition of blood pressure?

In this study we measured activity and sleep time, using a wrist actigraph, in a population of 319 patients referred for ambulatory blood pressure monitoring (ABPM). Mean waking and sleeping blood pressure (BP) and the diurnal BP variation derived with this technique were compared to daytime (defined variously as 7 AM to 8 PM, 7 AM to 10 PM, or 7 AM to midnight) and nighttime pressure. To study the relationship of actigraph-derived activity data to BP variability in more detail, 30 patients underwent paired monitoring 1 to 18 (mean 8) days apart. Mean waking BP was then corrected for activity to determine whether this technique could improve reproducibility. Statistically but not clinically significant differences between waking and daytime BP were seen, with larger and potentially clinically relevant differences between sleeping and nighttime BP. The midnight to 7 AM time period gave the best estimate of observed sleeping time and the nocturnal dip of BP. The average correlation between activity and BP was 0.25 for systolic and 0.34 for diastolic BP, but with wide variation in the strength of the relationship both between and within individual patients. On average, activity accounts for 20% of systolic and 26% of diastolic BP variation. Correcting the mean waking BP to a standard activity level reduced within-patient variation by 6%/9%. This made no significant difference to overall reproducibility, perhaps because variability in this sample was low before adjustment, with the standard deviation of the difference equal to 8/4 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

The renal pathology in a case of lithium-induced diabetes insipidus.

A case of lithium-induced diabetes insipidus is reported. At necropsy microscopy shoed unique and extensive damage to cells lining the distal nephron. It is suggested that these changes represent a specific toxic effect of lithium, reported here for the first time in man.

Maximizing the benefit of treatment in mild hypertension:three simple steps to improve diagnostic accuracy.

BACKGROUND: Most patients only have three measurements of blood pressure before being labelled as hypertensive. This may lead to inaccurate classification, unnecessary treatment and dilution in treatment benefit for the population. AIM: To examine the accuracy of current methods of diagnosing mild hypertension, and to explore ways to improving targeting of antihypertensive treatment without entailing lengthy observation. DESIGN: Re-analysis of published data. METHODS: We tested current diagnostic methods using the data for 3965 individuals who were followed for a year in the placebo arm of the MRC Mild Hypertension Trial. We calculated the proportion selected for treatment by current methods and the diagnostic accuracy, using average blood pressure beyond 6 months as representing 'true' long-term blood pressure. We examined the benefit of averaging blood pressures, of prolonging observation modestly and of estimating within-person blood pressure variability. RESULTS: Prolonging observation to 3 months selects a smaller (by about 12%) proportion of the sample for treatment, a proportion similar to that defined as 'truly' hypertensive. The diagnostic accuracy of current methods is poor, with up to 69% discrepancy in classification. This discrepancy was improved by up to 18% in absolute terms by prolonging observation to 3 months and using average blood pressures. Identifying those individuals with low within-person variability allows marked improvement in the prediction of 'true' hypertension. DISCUSSION: Although some inaccuracy in the diagnosis of hypertension is inevitable, observation for 3 months, averaging blood pressures and estimating within-person blood pressure variability can markedly improve upon current practice.

Reduced levels of PGE2 uptake by intact reno-medullary collecting tubule cells isolated from the spontaneously hypertensive rat and the identification of an intracellular PGE2 receptor/binding protein.

Prostaglandin E2 (PGE2) is thought to be involved in the control of NaCl loading in the kidney. Since the ability to balance salt concentrations across the nephron appears to be impaired in the Spontaneously Hypertensive Rat (SHR), the uptakes of PGE by isolated medullary collecting tubule cells (MCT) from both SH and normotensive (NT) rats were compared. A rabbit antiserum directed against PGE2 revealed by flow cytometry the active internalisation of exogenous ligand by a high density fraction of intact MCT cells from NT tissue. Conversely, PGE2 uptake by the same fraction was markedly reduced. The monoclonal antibodies (MoAbs) W2.44 and SH6.6 raised against a 45,000 X g fraction of medullary tissue and which blocked binding of the anti-PGE2 serum, identified by Western blotting, an intracellular PGE2 receptor or binding protein (PGER) of 16 k daltons. No alteration in the structure or level of expression of this antigen could be detected in the MCT fractions isolated from the SHR. It is suggested that an impairment of PGE2 membrane transport in the renal medulla may be a contributory factor to the SH condition.

Primary aldosteronism, a common entity? the myth persists.

Primary aldosterone excess or hyperaldosteronism is an important cause of hypertension which, when associated with an aldosterone secreting adenoma, is amenable to surgical cure. The biochemical hallmarks of the condition are a relative excess of aldosterone production with suppression of plasma levels of renin (a proxy for angiotensin II, the major trophic substance regulating aldosterone secretion). This combination of a high aldosterone and a low renin is however more commonly associated with 'nodular hyperplasia' of the adrenal glands, a condition not improved by surgery and variably responsive to the effects of the mineralocorticoid antagonist, spironolactone. Until recently the prevalence of either form of secondary hypertension has been thought to be low such that few clinicians 'hunted' for it in the absence of hypokalaemia (the traditional clue for the syndrome). This view has been challenged, firstly by the realisation that no more than 50% of such patients will have a low plasma potassium and secondly by the assumption that a 'normal' plasma aldosterone is in fact inappropriately elevated if the renin level is low. A single measurement of the ratio of aldosterone to renin levels is claimed to be highly predictive of patients who will have primary aldosterone excess. This paper examines the logic behind such claims and presents evidence from the literature that an abnormal ratio is simply a different description of the low renin state and that such patients do not necessarily have mineralocorticoid hypertension. Most patients 'discovered' by this test will have what many call low-renin hypertension, a condition not amenable to specific therapy. Claims that they are peculiarly sensitive to the hypotensive effects of spironolactone have not been tested in controlled trials. The test would however be expected to pick up those individuals with true Conn's syndrome but such patients remain too few in number to justify widespread use of an expensive screening test.

Ambulatory blood pressure monitoring: from research to clinical practice.

Evidence from the medical literature is reviewed to indicate that ambulatory monitoring of blood pressure (ABPM) is a better predictor of target organ damage and clinical outcome in the hypertensive patient than clinic measurements of blood pressure (BP). A re-analysis of the documented BPs from the placebo limb of the Medical Research Council's treatment trial of mild hypertension is presented to indicate the difficulties inherent in the advice given by the various published guidelines on the diagnosis and management of hypertension. Finally, it is argued that because ABPM identifies a similar proportion of patients for treatment as a more prolonged follow-up, its use should be considered in the evaluation of all patients with mild hypertension as they can be categorised rapidly with less risk of being 'lost to follow-up'.

Stability of home blood pressure over time.

In the initial assessment of mild hypertensive patients a prolonged period of repeated measurement is necessary to ensure accurate diagnosis. Home monitoring of blood pressure (BP) may accurately predict those patients whose hypertension will be 'sustained' in a clinic environment and it is important therefore to establish whether average home BP is stable on repeated assessment. Seventeen patients found to be hypertensive on screening were recalled after two weeks and again after four weeks for further BP measurement. All patients monitored home BP over 3 days following each clinic visit. Clinic BP fell from the first to last visit (181 +/- 4/97 +/- to 162 +/- 5/93 +/- 2 mmHg, P less than 0.05) with no change in home BP over the same period (153 +/- 3/89 +/- 3 to 154 +/- 4/89 +/- 3 mmHg). It is clear therefore that an average home BP produced during three days of monitoring is a stable measurement at least over a four week period and thus in the initial assessment of a hypertensive patient this technique may allow for greater diagnostic accuracy.