Renin-angiotensin-aldosterone system

Summary There is increased activity of the renin, angiotensin, aldosterone (RAA) system in infancy and childhood. An inverse relationship between plasma renin, aldosterone and age has been demonstrated. In childhood hypertension due to renovascular disease or pyelonephritic scarring peripheral plasma renin is increased. Renal vein renin measurements in children with renal hypertension have proved valuable in predicting surgical curability of the underlying lesion. The upper limit of normal for the renal venous renin ratio in normotensive children without renal disease is 1.5. Pharmacological blockade of the RAA system has a place in diagnosis and treatment of hypertensive children. The plasma renin aldosterone profile is diagnostically useful in the investigation of salt-wasting disease and can easily distinguish between aldosterone biosynthetic defects and pseudohypoaldosteronism.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

Renal and adrenal function following acute administration of urapidil in hypertensive patients with normal and impaired renal function

The effects of i.v. injection of urapidil (Ebrantil) (25 mg) on arterial blood pressure, renal function and renin-aldosterone system were studied in a group of patients with hypertension and normal renal function, in patients with hypertension and chronic renal failure and in normotensive controls. The pharmacokinetics of urapidil were evaluated simultaneously by measuring blood levels of the compound and its main metabolite. In the controls and in patients with hypertension, systolic and diastolic blood pressure were lowered few minutes after injection. Minimal blood pressure values were reached after 15-20 min. Hypotensive action was more pronounced in hypertensive patients as compared to controls. In contrast, increment in heart rate was greater in the controls. Despite the fall in blood pressure, renal plasma flow and glomerular filtration rate remained unchanged. Following the injection of urapidil, plasma renin activity increased with no change in plasma aldosterone levels. Plasma half-life of urapidil averaged 1.96 +/- 0.17 h in controls, 3.31 +/- 0.75 h in patients with hypertension and normal renal function and 2.52 +/- 0.46 h in patients with hypertension and chronic renal failure. Urapidil effectively lowers arterial blood pressure in patients with normal and impaired renal function with no deterioration in renal function.     

Plasma renin concentration in hypertension produced by unilateral renal artery constriction in the rat

1. Plasma renin concentration (PRC) and blood pressure were studied sequentially, 24 h to 42 days post-operatively, in rats subjected to unilateral renal artery constriction without contralateral nephrectomy. 2. The PRC of rats failing to develop hypertension remained normal, whereas the mean PRC of twenty-two rats that became hypertensive was five times normal on day 14 of the study when the hypertension was becoming established. 3. In eleven of the twenty-two rats that became hypertensive, PRC did not exceed the upper limit of normal. In the remaining hypertensive rats, the increase in PRC was not always temporally related to the increase in blood pressure. A significant correlation between PRC and blood pressure did not emerge until day 35 of the study. 4. Despite these anomalies, linear regression analysis of 169 pairs of PRC and blood pressure measurements during the 42 day period of development of hypertension in twenty-two rats revealed a highly significant correlation between log PRC and blood pressure (P smaller than 0.001). 5. It is concluded that factors other than the plasma concentration of renin are involved in the early stages of development of hypertension induced by renal artery constriction. Nevertheless, PRC and blood pressure are intricately related.     

Valsartan Effective for Malignant Hypertension after Aortic Dissection with Renal Artery Involvement

When aortic dissections extend to the renal arteries, reductions in renal blood flow can cause marked increases in renin production. The resultant rise in angiotensin II can lead to difficult‐to‐control blood pressure, despite normal postdissection antihypertensive agents. We highlight a case of a postdissection patient with malignant hypertension refractory to eight different enteral antihypertensives. Angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers had been held due to postoperative acute kidney injury. A single dose of valsartan, administered on day 12, produced a marked drop in blood pressure, alleviation of encephalopathy, and allowed for cancellation of a planned tracheostomy. A serum renin level was found to be 50 times the normal upper limit. In patients with aortic dissection and renal artery involvement, angiotensin‐modifying agents may warrant earlier administration to combat this unique cause of hypertension.     

Effect of amlodipine on renin secretion and renin gene expression in rats.

1. This study was done to characterize the influence of calcium channel blockade on renin secretion and renin gene expression in normal rats and rats with renovascular hypertension. To this end we studied the effects of the 1,4-dihydropyridine derivative, amlodipine, on plasma renin activity and renal renin m-RNA levels in normal rats and rats with unilateral renal hypoperfusion induced by applying 0.2 mm left renal artery clips over four days. 2. In normotensive rats, amlodipine significantly decreased basal blood pressure by about 20 mmHg when applied in a concentration of 5, 15 and 45 mg kg-1. Plasma renin activity and also renin mRNA levels were not changed after application of 5 mg kg-1 of amlodipine. However, at a concentration of 15 or 45 mg kg-1, amlodipine, significantly increased not only plasma renin activity by about 250% and 300%, but also renin mRNA levels by about 100% and 500%. The action of amlodipine on all these parameters was maximal after 24 h. Treatment with amlodipine in a concentration of 15 mg kg-1 also increased renin immunoreactive areas in the kidney cortex by retrograde recruitment of renin expressing cells in the afferent arterioles. 3. In 2kidney-1 clip rats, systolic blood pressure rose continuously whilst plasma renin activity and renin m-RNA in the clipped kidney increased transiently and renin m-RNA in the contralateral kidney was constantly suppressed. Amlodipine at a concentration of 15 mg kg-1 markedly attenuated the increase of blood pressure in 2kidney-1 clip rats, produced an almost additive effect on plasma renin activity and showed a tendency to increase renin m-RNA levels in the clipped kidneys. Renin m-RNA levels in the contralateral kidney were also significantly suppressed in the animals receiving additional treatment with amlodipine. 4. These findings suggest that inhibition of calcium channels by amlodipine stimulates renin secretion and renin gene expression in vivo. These stimulatory effects are almost additive to the changes of renin secretion occurring after an unilateral fall of renal perfusion pressure.     

Captopril: pharmacology, metabolism and disposition

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Potential side effects of renin inhibitors--mechanisms based on comparison with other renin-angiotensin blockers

Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.     

Alpha- and beta-adrenoceptors in hypertension. II. Platelet alpha 2- and lymphocyte beta 2-adrenoceptors in children of parents with essential hypertension. A model for the pathogenesis of the genetically determined hypertension

To study whether changes in alpha- and beta-adrenoceptors in human essential hypertension (EHT) might be genetically determined, we assessed platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children of normotensive parents (NT) and in 41 normotensive children with one EHT-parent. Both groups did not differ in age, body weight and height, blood pressure, heart rate, plasma catecholamine levels, plasma renin activity (PRA), and lymphocyte beta 2-adrenoceptor density. Platelet alpha 2-adrenoceptor density, however, was in EHT-children significantly higher than in NT-children. In NT-children, platelet alpha 2-adrenoceptors were significantly, inversely correlated with PRA, indicating that they might mirror renal alpha 2-adrenoceptors which inhibitorily regulate renin release. In contrast, in EHT-children PRA was not at all related to platelet alpha 2-adrenoceptors, suggesting an early (even in the normotensive stage) disturbance of the alpha 2-adrenoceptor-mediated regulation in renin release. From these results and those obtained in the experimental rat models of acquired hypertension, a model for the pathogenesis of the genetically determined hypertension is proposed in which a very early step in the development of hypertension is a genetically determined increase in renal alpha-adrenoceptors that causes enhanced sodium retention. This initiates a chain of events that finally results in increased peripheral vascular resistance and, hence, blood pressure. On the other hand, beta-adrenoceptor changes seem to be secondary phenomena due to the elevation in blood pressure.     

Primary hyperaldosteronism due to adrenal microadenoma: a curable cause of refractory hypertension.

The diagnosis of primary hyperaldosteronism due to microadenoma or unilateral adrenal hyperplasia can be challenging, since hypokalaemic alkalosis, high plasma aldosterone and a definite adenoma on imaging may all be absent. METHOD AND RESULT: We describe three cases of resistant hypertension (on > or = 5 antihypertensives) where hyperaldosteronism was suspected because of a suppressed plasma renin level despite treatment with multiple drugs which normally elevate renin. Renin mass was measured by a double-site chemi-immunoluminometric assay. All patients had normal plasma aldosterone levels. Hypokalaemia was present in the first two cases but computed tomography did not show clear cut adenomas. Adrenal vein sampling (AVS) revealed lateralisation (> 4 times higher aldosterone to cortisol ratio (ACR) on the affected than contra-lateral side). The third patient was normokalaemic and AVS showed only minimal lateralisation (ACR 1.3:1). The severe hypertension in all cases was reversed by adrenalectomy, with blood pressure falling to target despite withdrawal of all but one to two drugs. CONCLUSIONS: The robotic assay of renin mass permits rapid detection of patients in whom plasma renin is suppressed below the normal range. A suppressed plasma renin indicates abnormal Na+-retention, and--when not overcome by drugs such as angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers--may be the only clue to a curable adrenal adenoma. AVS is required to demonstrate lateralisation of aldosterone secretion, justifying adrenalectomy.     

Influence of streptozotocin-induced diabetes on blood pressure and on renin formation and release

Summary I.v. injection of 40 mg/kg or 65 mg/kg streptozotocin reliably induced diabetes in female Sprague-Dawley rats, but failed to induce hypertension within the following 42 days. In most animals injected with the higher dose and in some animals injected with the lower dose, the tail blood flow was permanently impaired so that no blood pressure signals could be obtained by tail plethysmography. This phenomenon occurred also when the drug was injected into the jugular vein and thus was not due to a local effect of streptozotocin. 15 days after 65 mg/kg streptozotocin, the mean arterial pressure of the rats was similar to that of controls, when measured in the awake state (carotid cannula) or under ether anaesthesia. 42 days after streptozotocin, under pentobarbital anaesthesia, the blood pressure was again normal in the animals given 40 mg/kg of the drug and depressed in the animals given 65 mg/kg of the drug 42 days previously. The increase of blood pressure induced by 1 g/kg (–)-noradrenaline i.v. was similar in the latter group of animals and in controls.The renal cortical renin concentration was much lower than in controls 42 days after either dose of streptozotocin, while the plasma renin activity was normal (40 mg/kg) or increased (65 mg/kg). The low renal renin content may have been due to the diabetic state, rather than to the drug itself. Adrenal medullary dopamine-beta-hydroxylase activity was increased 42 days after the higher dose of streptozotocin.Supported by the Swiss National Science Foundation, grant Nr. 3.410.078     

A RENIN-SECRETING TUMOUR SENSITIVE TO CHANGES IN CENTRAL BLOOD VOLUME (PRESUMABLY VIA SYMPATHETICS) BUT NOT TO CIRCULATING ANGIOTENSIN II

1. A 17 year old female presented with severe hypertension, hypokalaemia and elevated levels of plasma renin activity due to a renin-secreting tumour. 2. Renin was responsive to posture, low sodium diet, saline infusion and frusemide, but relatively unresponsive to raising or lowering circulating levels of angiotensin II. 3. Renal venous renin levels lateralized to the side of the tumour with good contralateral suppression when measured with control of posture and avoidance of prior stimulation, with and without angiotensin converting enzyme inhibition. 4. Levels of atrial natriuretic peptide were elevated and responsive to posture, saline infusion and angiotensin infusion. 5. The tumour was evident on computerized tomography, but not on intravenous pyelography or renal angiography. 6. Responsiveness of renin secretion to normal stimuli in reninoma may make diagnosis difficult, and renal vein sampling under controlled conditions is necessary.     

Studies with fenoldopam, a dopamine receptor DA1 agonist, in essential hypertension.

A series of studies were undertaken to assess the effect of oral fenoldopam, a specific DA1 dopamine receptor agonist on blood pressure and renal function in patients with mild essential hypertension. Six patients with essential hypertension were entered into a dose-ranging study and received either placebo, 25, 50 or 100 mg fenoldopam. A significant, dose-related reduction in diastolic blood pressure, and increase in heart rate was demonstrated (both P less than 0.05), maximal at 45 min to 1 h. Fenoldopam increased plasma renin activity. In a double-blind study, seven patients received a single dose of fenoldopam 100 mg or placebo. Fenoldopam produced a significant fall in systolic (P less than 0.05) and diastolic (P less than 0.01) blood pressure and renal vascular resistance (P less than 0.01). Urine flow rate (P less than 0.05), sodium excretion (P less than 0.01), plasma renin activity (P less than 0.05) and plasma aldosterone (P less than 0.05) increased. Five patients underwent measurement of the above parameters following a single dose of fenoldopam 100 mg with a repeat of these measurements after they had taken fenoldopam 100 mg four times daily for 1 month. The acute response of blood pressure to the single dose appeared unchanged but tachyphylaxis was evident in the responses of heart rate, plasma renin activity and plasma aldosterone.     

Renovascular hypertension due to bilateral renal artery stenosis treated with stent implantation in a 12-year old girl

Renovascular hypertension (RVH) in children is a relatively rare disease, but it is important in that it is a treatable condition when properly diagnosed. Percutaneous transluminal renal angioplasty (PTRA) with or without stenting is widely applied to adult patients with RVH. However, limited information is available as to PTRA with stenting in pediatric patients. We experienced a case of RVH in a 12-year-old girl, who had severe hypertension (180/110 mmHg). Bilateral renal artery stenosis was demonstrated by 3D-CT, MR angiography and selective renal arteriography. Renal function and plasma renin activity were normal. Angiotensin blockade was refrained for fear of functional deterioration of the kidney. Medical treatment with amlodipine insufficiently lowered the pressure to 140-160/80-100 mmHg, so we performed PTRA. Stenotic lesion and pressure gradient was still present after balloon angioplasty on both sides, prompting us to place LUMINEXX? stents on both renal arteries. Blood pressure dropped dramatically after the intervention. Amlodipine was discontinued, and then, enalapril and warfarin were administered to prevent neointima and thrombus formation. Her blood pressure and renal function was stable 18 months after PTRA. Oversized self-expanding stent such as LUMINEXX? stent could be used for renal artery stenting even in pediatric patients with RVH.     

Is Primary Aldosteronism Underdiagnosed In Clinical Practice?

1. Primary aldosteronism is a syndrome consisting of hypertension, suppressed renin activity or concentration and high aldosterone levels in plasma or urine. The main steps in diagnosis are the determination of renin and aldosterone levels, the demonstration of renin-aldosterone dissociation and discrimination between idiopathic hyperplasia and Conn's adenoma, with only Conn's adenoma amenable to surgery. 2. Patients with resistant hypertension and/or hypokalaemia should be screened for primary aldosteronism with simple, redundant hormonal tests. The aldosterone to renin ratio is a logical initial screening test, a high ratio demonstrating renin-aldosterone dissociation. Criteria for a high ratio should be determined in each laboratory. 3. In patients with documented primary aldosteronism, computed tomography scan and adrenal vein sampling help to distinguish between idiopathic hyperplasia and Conn's adenoma. 4. Patients with low renin hypertension, idiopathic hyperplasia and Conn's adenoma have overlapping values for plasma concentrations of potassium, renin and aldosterone and the aldosterone to renin ratio. Because primary aldosteronism subtypes are quantitative diseases, the true prevalence of primary aldosteronism cannot be defined. 5. The use of sensitive screening tests (e.g. aldosterone to renin ratio) gives a higher prevalence of diagnosed cases of primary aldosteronism, but not of surgically correctable forms. Therefore, there is no clinical evidence that primary aldosteronism is underdiagnosed. 6. There is a need for tests to predict the postoperative blood pressure outcome of surgery in subjects with Conn's adenoma.     

Immediate plasma renin response to propranolol: differentiation between essential and renal hypertension.

The immediate short-term effect on plasma renin activity of intravenous injection of propranolol was studied in 31 normal subjects and 166 hypertensive patients. In patients with essential hypertension and normal subjects plasma renin activity fell considerably within 15 minutes; the fall was directly proportional to initial plasma renin levels. In contrast, in patients with renal hypertension the fall was much less pronounced or totally absent. These differences in response to propranolol provide, though presently only on a group basis, a biochemical means of differentiating between patients with renal hypertension and those with essential hypertension. The observations also indicate that, unlike normal subjects and patients with essential hypertension, in patients with renal hypertension sympathetic activity plays no part in the control of basal plasma renin levels.     

Study of renovascular hypertension in rats. IV. Renal arterial blood velocity in one-clip, two-kidney hypertensive rats

In one-clip, two-kidney hypertensive models of rats, the renal arterial blood velocity was recorded using the bidirectional Doppler velocimeter before and at various times after clipping of the renal arteries. In all the rats, immediately after placement of a clip, the blood velocity of the stenosed artery was lowered significantly. Although the blood velocity remained low 2 weeks after clipping, it recovered to the pre-clip level at 6 and at 11 to 13 weeks after clipping. The plasma renin activity tended to decrease following the acute, high-renin stage of hypertension. If it can be assumed that the blood velocity is one of the indexes representing blood flow, its return to the pre-clip normal level in the chronic stage of renovascular hypertension may signify recovery of blood flow to the clipped kidney leading to a reduction in renal renin synthesis and consequently a decrease in plasma renin activity.     

The role of the kidney in essential hypertension

1. Many forms of human and experimental hypertension begin with compromised renal function. Essential hypertension may be another such case. 2. The kidneys of subjects with essential hypertension excrete normal amounts of salt and water at higher-than-normal renal perfusing pressures. Other overt signs of renal dysfunction are few; renal disease is excluded by definition. However, renal blood flow and glomerular filtration rate are usually less than normal in essential hypertension. 3. Renal afferent resistance can be calculated from arterial pressure, renal blood flow, and an estimate of glomerular capillary pressure. These calculations indicate that afferent resistance is increased to two or more times normal in essential hypertension. 4. It is not clear whether afferent constriction causes hypertension or results from it. The ability of high pressure to produce vascular damage points to the latter. But, most essential hypertensives show low-to-normal plasma renin levels and a marked afferent dilation after saline loading. These observations do not suggest nephrosclerosis: they are consistent with a causal role for afferent constriction. 5. We can speculate that, in essential hypertension, there is a defect in one of the mechanisms that sets afferent resistance. Afferent constriction could result from extrinsic influences (neural or humoral) or something totally within the kidney, such as abnormal handling of information from the macula densa. 6. The effect of afferent constriction on salt-and-water excretion would theoretically be offset by elevated arterial pressure so that the actual salt-and-water excretion would be normal, but only so long as the arterial pressure remained elevated.     

Pharmacodynamics and kinetics of etozolin/ozolinone in hypertensive patients with normal and impaired kidney function

Summary The effect on urinary electrolyte excretion, renin release and plasma norepinephrine of single oral doses of 400 mg etozolin (E) and of 40 mg furosemide (F) were studied in hypertensive patients with normal (n=6) and impaired kidney function (n=6). E caused a marked saluresis up to 24 hours, showing its long duration of action. F, however, displayed a brief, brisk peak diuresis, followed by a rebound from the 4th to the 24th hours. The brisk peak diuresis induced by F was associated with pronounced release of renin, almost twice that induced by E. In chronic renal failure the renin release in relation to the magnitude of the diuresis was increased, i.e. the sensitivity of these patients to changes in water homeostasis was increased. E and F stimulated the sympathetic system to roughly the same extent. Patients with essential hypertension had higher plasma levels of norepinephrine than hypertensive patients with chronic renal failure. In addition, hypertensive patients with normal renal function (n=4) and varying degrees of renal impairment (n=11) were also given 400 mg daily for 2 weeks. Effects on blood pressure and electrolyte homeostasis were monitored, as well as the plasma kinetics of metabolite I, ozolinone. At the end of the 2 week treatment E had significantly lowered systolic (–12 mm Hg) and diastolic (–9 mm Hg) blood pressure, and had produced a significant loss of body weight, without altering plasma electrolytes or blood chemistry. There was no accumulation of the effective metabolite ozolinone under conditions of severe impairment of kidney function. It is concluded that E can effectively control high blood pressure in patients with normal and impaired kidney function. Its effective metabolite ozolinone did not accumulate in chronic renal failure.     

ACUTE CHANGES IN BLOOD PRESSURE AND VASOACTIVE HORMONES AFTER CAPTOPRIL IN HYPERTENSIVE PATIENTS

1. The acute effects of captopril on blood pressure, renin, angiotensin, bra-dykinin and catecholamines were examined in patients with essential (n= 10, Group 1), accelerated (n=6, Group 2) and renal hypertension (n= 14, Group 3). 2. Blood pressure showed little change in Group 1, fell significantly in Group 2, with a marked fall in Group 3. Heart rate did not change. 3. The fall in blood pressure was positively correlated with pretreatment renin and angiotensin II. 4. Angiotensin II fell, with reciprocal increases in renin and angiotensin I. No changes occurred in bradykinin or catecholamines. 5. The rise in renin after captopril was greatest in renovascular hypertension which may prove useful as a screening test for such patients.     

LONG-TERM INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY AND HYPERTENSION

1. Essential hypertensive patients have been characterized by increased sympathetic nerve activity, increased peripheral vascular tone, decreased plasma volume and normal cardiac output when compared with normotensive subjects. Bilateral renal denervation reduces the magnitude or delays the onset of the blood pressure response in numerous models of experimental hypertension regardless of the aetiology of the elevation in arterial pressure. 2. Using a servocontrolled intrarenal infusion system, we have elevated intrarenal noradrenaline concentration via intermittent renal artery infusion without decreasing renal blood flow as a method of simulating selective elevation of renal sympathetic outflow. 3. Chronic intrarenal adrenergic stimulation increased arterial pressure within 24 h and this hypertension persisted for 28 consecutive days. The elevated arterial pressure was not associated with sustained increases in plasma renin activity, aldosterone, circulating catecholamines, arginine vasopressin or significant renal vasoconstriction. Urinary sodium excretion was chronically elevated and the dogs remained in negative sodium balance for the duration of the intrarenal noradrenaline infusion. 4. After 2 weeks of elevated intrarenal neurotransmitter coupled with hypertension, renal vascular reactivity to further adrenergic stimulation was significantly increased because the hypertension was maintained during continual reductions in the daily dosage of neurotransmitter allowed to be infused by the servocontroller. After only 28 days of noradrenaline infusion, renal vascular hypertrophy developed in vessels from 150–300 μm. 5. We conclude that selective and intermittent increases in intrarenal adrenergic neurotransmitter are sufficient to elicit chronic hypertension in the absence of volume expansion. This intrarenal neuroadrenergic hypertension is closely associated with the haemodynamic parameters which characterize a major subset of human essential hypertensives.