EVIDENCE FOR A ROLE FOR THE CARDIOVASCULAR AMPLIFIERS IN HUMAN PRIMARY HYPERTENSION

1. Hypertrophy of vascular and cardiac smooth muscle is present in human primary hypertension. The amplifier properties associated with hypertrophy play a major role in maintaining hypertension. 2. Long-term antihypertensive drug therapy causes substantial regression of the structural changes, assessed by the non-autonomic component of vascular resistance, and by left ventricular mass. The latter occurs more slowly. 3. The more complete the reversal of left ventricular hypertrophy, the more slowly hypertension redevelops if long-term antihypertensive therapy is discontinued. 4. Subjects who redevelop hypertension more rapidly tend to have higher cardiac output, suggesting that the cardiac amplifier may play a role in the pathogenesis. 5. Studies of small arteries and of veins from patients with primary hypertension suggest that there may be a general disturbance of vascular smooth muscle function, independent of the mechanical effects of elevated systemic blood pressure.     

ACTH HYPERTENSION IN THE RAT: ROLE OF KIDNEY AND GONADS

1. Adrenocorticotrophin (ACTH) administration produces an adrenally dependent rise in blood pressure in rats. 2. The haemodynamic and metabolic effects of ACTH were examined in nephrectomized, 5/6 nephrectomized and orchidectomized male Sprague-Dawley rats and sham operated controls. 3. Reduction in renal mass did not increase the blood pressure rise produced by ACTH. 4. Gonadectomy did not reduce the blood pressure rise produced by ACTH, which was slightly higher in castrated animals.     

ABNORMAL KIDNEY FUNCTION AS A CAUSE AND A CONSEQUENCE OF OBESITY HYPERTENSION

1. Obesity is the most common nutritional disorder in the US and is a major cause of human essential hypertension. Although the precise mechanisms by which obesity raises blood pressure (BP) are not fully understood, there is clear evidence that abnormal kidney function plays a key role in obesity hypertension. 2. Obesity increases tubular reabsorption and this shifts pressure natriuresis towards higher BP. The increased tubular re-absorption is not directly related to hyperinsulinaemia, but is closely linked to activation of the sympathetic and renin-angiotensin systems, and possible changes in intrarenal physical forces caused by medullary compression due to accumulation of adipose tissue around the kidney and increased extracellular matrix within the kidney. 3. Obesity is also associated with marked renal vasodilation and increased glomerular filtration rate, which are compensatory responses that help overcome the increased tubular re-absorption and maintain sodium balance. However, chronic renal vasodilation causes increased hydrostatic pressure and wall stress in the glomeruli which, along with increased lipids and glucose intolerance, may cause glomerulosclerosis and loss of nephron function in obese subjects. Because obesity is a primary cause of essential hypertension as well as type II diabetes, there is good reason to believe that obesity may also be the most frequent cause of end-stage renal disease. 4. Future research is needed to determine the mechanisms by which excess weight gain activates the neurohumoral systems and alters renal structure and function. Because of the high prevalence of obesity in most industrialized countries, unravelling these mechanisms will likely provide a better understanding of the pathophysiology of human essential hypertension and chronic renal failure.     

DIABETIC RENAL MICROVASCULAR DISEASE: THE ROLE OF HYPERTENSION AND ACE INHIBITORS

1. It has been suggested that hypertension may be an important determinant of the rate of progression of diabetic microangiopathy.
2. Renal microvascular disease as assessed by urinary albumin excretion and glomerular ultra-structure was evaluated in a model in which streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR).
3. Diabetes was associated with increases in urinary albumin excretion, and hypertension resulted in a further increase in albuminuria.
4. Various antihypertensive regimens were administered to diabetic SHR, with the angiotensin-converting enzyme inhibitor perindopril and triple therapy (hydralazine, reserpine and hydrochlorothiazide) being more effective than the calcium antagonist (lacidipine) in retarding the increase in albuminuria in diabetic SHR.
5. Antihypertensive therapy appears to ameliorate the development of diabetic renal disease.     

POTASSIUM EXCRETION IN RENAL FAILURE IN THE RAT: THE ROLE OF DISTAL TUBULE FLOW AND ALDOSTERONE

1. This study examines the contribution of an increased distal tubule flow and of aldosterone to the handling of a potassium load in conscious rats with renal failure induced by subtotal nephrectomy or by gentamicin on a control of high K+ diet. 2. Glomerular filtration rate was reduced by subtotal nephrectomy to 40% and by gentamicin treatment to 60% of control. Subtotal nephrectomy induced significant hypertrophy of glomeruli and proximal and distal tubules, but gentamicin did not. Both experimental groups had a normal iothalamate space and plasma potassium after a 20 h fast. 3. Two hours after an acute KCl load rats with renal failure excreted less potassium than control rats. There was also a lesser natriuretic effect of KCl in the renal failure groups. 4. A high K+ diet, given for 5-7 days, increased excretion of an acute KCl load in control rats and rats with renal failure. 5. (UNaV + UKV) was used as an estimate of distal tubule flow. Potassium excretion, related to distal tubule flow, was similar in the renal failure and control rats when on the same diet. This is consistent with potassium excretion being strongly, but not necessarily solely, dependent on distal flow. 6. Adrenalectomy reduced, and aldosterone restored, potassium excretion in the renal failure and control groups. This suggests a role for aldosterone in excretion of an acute potassium load with this degree of renal failure.     

URAEMIA IS NECESSARY FOR ERYTHROPOIETIN-INDUCED HYPERTENSION IN RATS

1. There is no experimental proof that renal insufficiency is a necessary condition for hypertension during erythropoietin treatment. 2. The present study compares the effect of 3 weeks treatment with r-hu EPO (50i.u./kg) on systolic blood pressure (SBP), haematocrit and plasma cGMP in an animal model of chronic renal failure (remnant kidney model excision) and sham-operated rats. 3. Sub-total nephrectomy induced a significant fall in haematocrit and a significant increase in plasma creatinine levels. Treatment with r-hu EPO resulted in a significant haematocrit increase in uraemic as well as in non-uraemic rats. Despite this effect, r-hu EPO treatment had no effect on SBP in sham-operated rats. On the contrary, this treatment caused significant SBP elevation in uraemic ratq in these rats, SBP increase did not correlate with haematocrit increase. 4. Plasma cGMP concentrations were significantly higher in uraemic compared to sham-operated rats and were not modified by r-hu EPO treatment. 5. This study provides evidence that renal insufficiency in rats is a prerequisite for the development of hypertension during erythropoietin treatment.     

ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN HYPERTENSION PRODUCED BY UNILATERAL RENAL ARTERY CONSTRICTION IN THE RAT

1. Conscious rats which had undergone unilateral renal artery constriction were infused for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113). 2. There was a highly significant correlation between the change in blood pressure induced by P-113 and the pre-infusion plasma renin concentration (PRC), regardless of initial blood pressure or the duration of stenosis. However, the blood pressure fall was not significantly greater in nineteen hypertensive rats than in eleven which remained normotensive. P-113 did not abolish the hypertension. 3. The extent to which angiotensin II supports blood pressure in rats with renal artery constriction is directly related to the PRC.     

ALTERATIONS IN CEREBROSPINAL FLUID SODIUM AND OSMOLALITY IN RATS DURING ONE-KIDNEY, ONE-WRAP RENAL HYPERTENSION

Measurements of plasma and cerebrospinal fluid (CSF) sodium and osmolality were made throughout the course of one-kidney, one-wrap Grollman renal hypertension. Although the plasma sodium and osmolality did not rise after 28 days, CSF sodium and osmolality was increased significantly at 3 days postwrap. As a result, the CSF to plasma ratio for both sodium and osmolality was significantly elevated during the initial postwrap period. These observations suggest that an increase in CSF sodium may provide an initiating stimulus for an elevated arterial pressure in one-kidney, one-wrap renal hypertension.     

CYCLOSPORIN HYPERTENSION IN THE WISTAR RAT: ROLE OF UNINEPHRECTOMY

1. The effects of cyclosporin A (CyA) solution (1–50 mg/kg per day), CyA powder (5–20 mg/kg per day) and vehicle, and the effects of renal mass reduction on CyA induced hypertension, were examined in conscious Wistar rats. 2. CyA solution consistently increased blood pressure at 5–20 mg/kg per day and the powder at 10–20 mg/kg per day. The vehicle had no consistent effect. 3. Both CyA solution and powder inhibited gain in bodyweight. There was no consistent effect on food intake, water intake or urine volume. Plasma sodium (Na⁺), and Na⁺ and potassium (K⁺) excretion were reduced by CyA 20 mg/ kg per day. 4. Renal function was impaired by CyA powder at 20 mg/kg per day and plasma renin activity (PRA) was increased by all doses of CyA powder. 5. Thus, uninephrectomy did not potentiate CyA solution (5 mg/kg per day) induced increases in blood pressure and the effects of CyA do not appear to be a consequence of nephrotoxicity in Wistar rats.     

IS A HYPERTENSINOGENIC FACTOR PRESENT IN THE KIDNEY OF HYPERTENSIVE DAHL RATS?

1. Early studies suggest that hypertension in Dahl salt-sensitive (S) rats is related to an uncommon humoral factor that may be released from the kidney. 2. To investigate whether the kidney releases a hypertensino-genic factor for developing salt-induced hypertension in S rats, we examined a pressor effect, or vascular contractive activity of a kidney extract from S rats using a conscious recipient rat or an isolated aortic ring. 3. Donor S and Dahl salt-resistant (R) rats were fed a 0.4 or 8% NaCl diet for 4 weeks and were then used to provide four kinds of kidney extracts (S-0.4%, S-8%, R-0.4%, R-8%). The systolic arterial pressure (SAP) was significantly increased in donor S rats fed an 8% NaCl diet compared with other donor rat groups. 4. All four types of kidney extract increased mean arterial pressure (MAP) in a recipient rat fed a 0.4% NaCl diet. However, the increase in MAP observed following infusion of the S-8% extract was the least of all groups. An angiotensin AT₁ receptor antagonist, CV-11974, abolished any pressor effect of all kidney extracts. In an in vitro experiment, all four types of kidney extract evoked contractile responses in aortic rings, but elicited no significant difference in aortic ring contractile force. 5. These results suggest that the kidney of S rats may not release an active hypertensinogenic factor that would cause salt-induced hypertension.     

VASCULAR SMOOTH MUSCLE POLYPLOIDY IN THE DEVELOPMENT AND REGRESSION OF HYPERTENSION

1. Two groups of spontaneously hypertensive rats (SHR) were treated with enalapril (25-30 mg/kg per day): Group I received treatment from 4 to 14 weeks of age to inhibit development of hypertension and Group R received the drug from 14 to 20 weeks of age to reverse established hypertension. 2. Systolic blood pressure, ploidy of aortic smooth muscle cells (flow cytometric DNA analysis) and aortic hypertrophy (medial cross-sectional area) were determined at times both during and after enalapril treatment (up to 30 weeks). 3. Enalapril treatment normalized blood pressure to that of age-matched Wistar-Kyoto rats in both groups. Blood pressure rose again following cessation of treatment. 4. In untreated SHR the incidence of polyploid cells increased concomitantly with increasing pressure throughout the time studied, whereas in Group I the incidence remained low. In Group R, the incidence of polyploidy directly paralleled both the decrease (normalization) and the rise in blood pressure following cessation of treatment. 5. Hence, the incidence of vascular smooth muscle cell polyploidy is not simply a result of growth of the vessel with increasing age of the SHR, but parallels inhibition, reversal, and redevelopment of hypertension.     

ROLE OF CARDIAC AND VASCULAR AMPLIFIERS IN THE MAINTENANCE OF HYPERTENSION AND THE EFFECT OF REVERSAL OF CARDIOVASCULAR HYPERTROPHY

Changes in amplifying capacities of the hypertrophied heart and resistance vessels account for the characteristic evolution of haemodynamic patterns in the course of essential hypertension. Reversal of hypertrophy in established essential hypertension requires prolonged control of blood pressure. Redevelopment of hypertension on stopping drug therapy is slowest if there has been reversal of both vascular and cardiac hypertrophy. It may be possible to subsequently maintain normal blood pressure in a proportion of patients by non-pharmacological means following the initial period of drug therapy. Preliminary findings suggest that in a majority of patients the sympathetic nervous system may be overactive, whilst a smaller subset may have dysfunction of volume regulation.     

METABOLIC STUDIES OF URIDINE IN RATS WITH DOCA-SALT HYPERTENSION AND ON HIGH SODIUM DIET

1. The steady-state metabolic clearance and calculated secretion rate of the pyrimidine nucleoside uridine were studied by equilibrium infusion in normal rats, rats on a high sodium diet, rats made hypertensive by subcutaneous injection of deoxycorticosterone acetate (DOCA), unilateral nephrectomy and high sodium drinking fluid, and two control groups of rats for the hypertensive group. 2. Basal plasma uridine concentration in DOCA-salt hypertension rats was found to be significantly reduced to 3.99 ± 0.31 pmol/L (mean ± s.e.m.) compared with control rats (11.98 ±1.64 μmol/L). Metabolic clearance (MCR) in DOCA-salt hypertensive rats was significantly raised (200.54±10.77 mL/kg per min) compared with control rats (65.17 ± 1.99 mL/kg per min). No difference was found in plasma uridine concentration and MCR among the other two control groups and high sodium diet rats. Calculated secretion rate was unchanged in all animals. No significant differences were found between different groups of rats in blood pressure responses to uridine. 3. The raised metabolic clearance and reduced plasma uridine concentration in DOCA-salt hypertension may be consistent with increased intracellular transport and phosphorylation of uridine to the physiologically active compound uridine monophosphate (UMP) which would lead to arteriolar constriction, hypertension and natriuresis. The results contrast with those in humans with extracellular fluid (ECF) expansion from endstage renal failure and rats with one-kidney, one-clip (1K1C) hypertension but are not due to the pharmacological effects of deoxycorticosterone. The difference may be due to the haemodynamic consequences of reduced renal perfusion pressure or reduced renal mass compared with DOCA-salt model.     

POINT OF VIEW: WHY HYPERTENSION IS OVERDIAGNOSED AND OVERTREATED IN 1987

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.     

ON THE ROLE OF SEROTONIN IN THE PATHOGENESIS OF PULMONARY HYPERTENSION INDUCED BY ANORECTIC DRUGS; AN EXPERIMENTAL STUDY IN THE ISOLATED PERFUSED RAT LUNG II. FENFLURAMINE, MAZINDOL, MEFENOREX, PHENTERMINE AND R 800

1. The influence of the anorectic drugs fenfluramine, mazindol, mefenorex, phentermine and R 800, an experimental compound, on pulmonary vascular resistance has been studied in the isolated, perfused rat lung. 2. R 800 caused a strong vasoconstriction, which was not antagonized by methysergide or phentolamine; the other drugs listed did not alter vascular resistance. 3. Mazindol and phentermine significantly prolonged the vasoconstrictive effect of serotonin due to inhibition of its metabolic breakdown. 4. Although fenfluramine inhibited serotonin metabolism it also prevented the vasoconstrictive effect of serotonin, due to its ability to act as a serotonin antagonist. 5. Mefenorex did not affect pulmonary vascular resistance, either directly or indirectly via a serotoninergic mechanism.     

THE EFFECT OF THE ''HYPERTENSINOGENIC STEROID, 9α-FLUORO-CORTISOL ON BLOOD PRESSURE IN SHEEP WITH ACTH-INDUCED HYPERTENSION

The effect of treatment with 9 alpha-fluorocortisol (9 alpha FF), a steroid which causes hypertension in sheep, was examined in sheep with ACTH-induced hypertension. ACTH treatment alone increased mean arterial pressure (MAP), plasma Na concentration, water intake and urine volume and decreased plasma K concentration. 9 alpha FF treatment, for 3 days during continuing ACTH administration, did not change blood pressure but increased heart rate, water intake and urine volume and decreased urinary K excretion. As 9 alpha FF did not cause a further increment in blood pressure in sheep with ACTH-induced hypertension it is possible that both ACTH and 9 alpha FF may produce hypertension by similar mechanisms.     

EFFECTS OF NG-NITRO-l-ARGININE ON PRESSURE NATRIURESIS IN ANAESTHETIZED RABBITS

1. We tested the effects of blockade of nitric oxide synthesis on renal function under conditions of controlled renal artery pressure. Our hypothesis was that endogenous nitric oxide plays a role in the natriuresis that accompanies increased renal perfusion pressure. We used a novel technique which employed an extracorporeal circuit to produce step changes over a wide range of renal artery pressures in pentobarbitone-anaesthetized rabbits. 2. Rabbits were treated with either N^G-itro-l-arginine (NOLA, 20 mg/kg, i.v.; n = 8) or its vehicle (n= 8). Renal artery pressure was set (by adjusting the extracorporeal circuit) at 65, 80, 95, 110 and then 130mmHg respectively, at the beginning of each of five 30 min experimental periods. 3. NOLA treatment caused profound renal vasoconstriction that was largely independent of the level of renal artery pressure, renal blood flow being 35–43% lower in NOLA-treated than in vehicle-treated rabbits across the range of renal artery pressures tested (P= 0.002). NOLA treatment increased filtration fraction (P = 0.02), and tended to reduce glomerular filtration rate (P= 0.09). 4. NOLA-treatment affected sodium excretion in a manner dependent on the level of renal artery pressure, with the slope of the relationship between sodium excretion and renal artery pressure being lower in NOLA-treated than in vehicle-treated rabbits (P= 0.006). 5. These data provide direct evidence that in anaesthetized rabbits endogenous nitric oxide (i) tonically dilates the renal vasculature across a wide range of renal perfusion pressures, and (ii) enhances sodium excretion to a progressively greater degree as renal artery pressure is increased. It may therefore play a role in pressure-induced natriuresis.     

THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA WITH NORMAL GFR. A UNIQUE PATHOPHYSIOLOGICAL MECHANISM FOR HYPERTENSION?

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.