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Phaeochromocytomas and paragangliomas (PPGLs) release catecholamines leading to catecholamine-induced hypertensive (CIH) crises, with blood pressure greater than or equal to 180/120 mm Hg. CIH crises can be complicated by tachyarrhythmias, hypotension, or life-threatening target organ damage while treatment remains undefined, often requiring co-management between endocrinologists and cardiologists. Furthermore, biochemical diagnosis of a PPGL as a cause of a CIH crisis can be difficult to identify or confounded by comorbid conditions, potentially resulting in misdiagnosis. Here, we combine relevant evidence, 60 years of collective clinical experience, insights derived from assessing over 2600 patients with PPGL, and supplementary outcomes from 100 patients (treated at the National Institutes of Health) with a CIH crisis to inform diagnosis and treatment of CIH crises. Recognising that disparities exist between availability, cost, and familiarity of various agents, flexible approaches are delineated allowing for customisation, given institutional availability and provider preference. A CIH crisis and its complications are readily treatable with available drugs, with effective intervention defining an avenue for mitigating consequent morbidity and mortality in patients with PPGL.

Discovered more than 30 years ago, the angiotensin AT2receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research.

The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

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Doctors should be alert to the possibility of adrenal insufficiency developing in conjunction with several conditions. These conditions include AIDS, brain-centered or peripheral nerve-centered adrenoleukodystrophy, autoimmune polyendocrine syndrome type I and II, or familial glucocorticoid deficiency. Adrenal insufficiency may develop in response to different factors involved with each condition including bacterial infections, stress, medications, diet, autoantibodies, or internal bleeding at the adrenal gland.

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Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Angiotensin II receptors regulate muscle microvascular recruitment and the delivery of nutrients, oxygen, and insulin to muscle. Although angiotensin type 1 receptor antagonism increases muscle microvascular perfusion and insulin action, angiotensin type 2 receptor blockade markedly restricts muscle microvascular blood volume and decreases muscle delivery of insulin. To examine the effects of direct type 2 receptor stimulation using Compound 21 (C21) on microvascular perfusion, insulin delivery and action, and tissue oxygenation in muscle, overnight-fasted adult male rats were infused with C21 systemically. C21 potently increased microvascular blood volume without altering microvascular flow velocity or blood pressure, resulting in a net increase in microvascular blood flow in muscle. This was associated with a substantial increase in muscle interstitial oxygen saturation and insulin delivery into the skeletal and cardiac muscle. These effects were neutralized by coinfusion of the type 2 receptor antagonist or nitric oxide synthase inhibitor. Superimposing C21 infusion on insulin infusion increased insulin-mediated whole body glucose disposal by 50%. C21 significantly relaxed the preconstricted distal saphenous artery ex vivo. We have concluded that direct type 2 receptor stimulation markedly increases muscle microvascular perfusion through nitric oxide biosynthesis and enhances insulin delivery and action in muscle. These findings provide a physiologic mechanistic insight into type 2 receptor modulation of insulin action and suggest that type 2 receptor agonists might have therapeutic potential in the management of diabetes and its associated complications.

Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome.

Objective:To develop clinical practice guidelines for the management of patients with primary aldosteronism.Participants:The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration.Evidence:We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used “recommend” for strong recommendations and “suggest” for weak recommendations.Consensus Process:We achieved consensus by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. With the help of a medical writer, the Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and Council successfully reviewed the drafts prepared by the Task Force. We placed the version approved by the Clinical Guidelines Subcommittee and Clinical Affairs Core Committee on the Endocrine Society's website for comments by members. At each stage of review, the Task Force received written comments and incorporated necessary changes.Conclusions:For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions and recommend that a commonly used confirmatory test should confirm/exclude the condition. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist.

The renin-angiotensin system (RAS) is a well-studied hormonal cascade controlling fluid and electrolyte balance and blood pressure through systemic actions. The classical RAS includes renin, an enzyme catalyzing the conversion of angiotensinogen to angiotensin (Ang) I, followed by angiotensin-converting enzyme (ACE) cleavage of Ang I to II, and activation of AT1receptors, which are responsible for all RAS biologic actions. Recent discoveries have transformed the RAS into a far more complex system with several new pathways: the (des-aspartyl1)-Ang II (Ang III)/AT2 receptor pathway, the ACE-2/Ang (1-7)/Mas receptor pathway, and the prorenin-renin/prorenin receptor/mitogen-activated protein kinase pathway, among others. Although the classical RAS pathway induces Na+reabsorption and increases blood pressure, several new pathways constitute a natriuretic/vasodilator arm of the system, opposing detrimental actions of Ang II through Ang II type 1 receptors. Instead of a simple circulating RAS, several independently functioning tissue RASs exist, the most important of which is the intrarenal RAS. Several physiological characteristics of the intrarenal RAS differ from those of the circulating RAS, autoamplifying the activity of the intrarenal RAS and leading to hypertension. This review will update current knowledge on the RAS with particular attention to the intrarenal RAS and its role in the pathophysiology of hypertension.

Adrenal-mediated hypertension (AMH) has been increasingly treated by laparoscopic adrenalectomy (LA). Metabolic derangements in patients with AMH could result in perioperative complications and mortality. Long-term operative and clinical outcomes after laparoscopic treatment of AMH have not been evaluated using large clinical databases. The institutional National Surgical Quality Improvement Program (NSQIP) data for patients undergoing adrenalectomy for AMH between 2002 and 2012 were reviewed. Patient demographics, perioperative variables, and outcomes were analyzed and compared with national NSQIP adrenalectomy data. Improvement in AMH was recorded when discontinuation or reduction of antihypertensive medication occurred or with a decrease of blood pressure on the preoperative antihypertensive regimen. Ninety-four patients underwent adrenalectomy. There were 48 patients with pheochromocytoma (PHE) and 46 patients with aldosterone-producing adenoma (APA). Eighty-five patients (90%) were taking antihypertensive medications preoperatively compared with 36 patients (38%) post-operatively (P< 0.0001). Patients with PHE were more likely to discontinue all medications compared with the patients with APA (80 vs20%, respectively, P< 0.0001). Patients with PHE and APA, respectively, took an average of 2.0 and 3.2 antihypertensive medications preoperatively compared with 0.3 and 1.2 postoperatively. There were no conversions to open procedures or 30-day mortality. Our results were 0 per cent for cerebral vascular accident, 0 per cent for myocardial infarction, and 0.5 per cent for transfusions compared with the national NSQIP data of 0.2, 0, and 6.7 per cent, respectively. Patients presenting with significant AMH including PHE and APA can be effectively and safely treated with LA with minimal complications and with a significant number of patients eliminating or decreasing their need for antihypertensive medications.

Cardiac overexpression of the angiotensin II type 2 receptor (AT2R) attenuates left ventricular (LV) remodeling after myocardial infarction (MI) in transgenic mice. We hypothesized that a novel nonpeptide AT2R agonist, compound 21 (C21), would attenuate post-MI LV remodeling. Fifty-nine mice were studied for 28 days after 1-hour surgical occlusion–reperfusion of the left anterior descending coronary artery. Immediately thereafter, 23 mice received 0.3 mg·kg−1·d−1of C21 via Alzet osmotic minipump, 16 received 10 mg·kg−1·d−1of the AT1R antagonist candesartan in drinking water, and 20 were untreated controls. Cardiac magnetic resonance imaging measured ejection fraction (EF), LV end-systolic, and end-diastolic volumes (ESVI and EDVI) indexed to weight serially post MI. Infarct size was measured on day 1 by late gadolinium-enhanced cardiac magnetic resonance imaging. At baseline, heart rate, blood pressure, EDVI, ESVI, and EF were similar between groups. Mean infarct size (42–45 of LV mass) was similar between groups. C21-treated animals demonstrated adverse LV remodeling (increased EDVI and ESVI at all post-MI time points) compared with control. Candesartan therapy preserved left ventricular EF at day 28 compared with the C21-treated group. Thus, direct stimulation of the AT2R by C21 at 0.3 mg·kg−1·d−1does not attenuate post-MI LV remodeling in reperfused MI in mice.

The aim of this study was to compare the single-dose effects of thiazide-type diuretics cicletanine and hydrochlorothiazide (HCTZ), on natriuresis and kaliuresis in prehypertensive and treatment-naïve, stage 1 hypertensive patients and to explore the impact of GRK4gene polymorphisms on thiazide-induced urinary electrolyte excretion.

Renal dopamine receptor function and ion transport inhibition are impaired in essential hypertension. We recently reported that caveolin-1 (CAV1) and lipid rafts are necessary for normal D1-like receptor-dependent internalization of Na-K-ATPase in human proximal tubule cells. We now hypothesize that CAV1 is necessary for the regulation of urine sodium (Na+) excretion (UNaV) and mean arterial blood pressure (MAP) in vivo. Acute renal interstitial (RI) infusion into Sprague-Dawley rats of 1 μg·kg−1·min−1fenoldopam (FEN; D1-like receptor agonist) caused a 0.46 ± 0.15-μmol/min increase in UNaV (over baseline of 0.29 ± 0.04 μmol/min; P< 0.01). This increase was seen in Na+-loaded rats, but not in those under a normal-sodium load. Coinfusion with β-methyl cyclodextrin (βMCD; lipid raft disrupter, 200 μg·kg−1·min−1) completely blocked this FEN-induced natriuresis (P< 0.001). Long-term (3 day) lipid raft disruption via continuous RI infusion of 80 μg·kg−1·min−1βMCD decreased renal cortical CAV1 expression (47.3 ± 6.4%; P< 0.01) and increased MAP (32.4 ± 6.6 mmHg; P< 0.001) compared with vehicle-infused animals. To determine whether the MAP rise was due to a CAV1-dependent lipid raft-mediated disruption, Na+-loaded rats were given a bolus RI infusion of CAV1 siRNA. Two days postinfusion, cortical CAV1 expression was decreased by 73.6 ± 8.2% (P< 0.001) and the animals showed an increase in MAP by 17.4 ± 2.9 mmHg (P< 0.01) compared with animals receiving scrambled control siRNA. In summary, acute kidney-specific lipid raft disruption decreases CAV1 expression and blocks D1-like receptor-induced natriuresis. Furthermore, chronic disruption of lipid rafts or CAV1 protein expression in the kidney induces hypertension.

AbstractBackground:Hypertension is one of the world’s leading risk factors for morbidity and mortality. Most affected individuals have primary hypertension, while the most common cause of secondary hypertension is primary aldosteronism (6–10). Primary Aldosteronism:Clinical manifestations include hypertension, hypokalemic alkalosis, renal dysfunction, nephrogenic diabetes insipidus, muscle weakness, paresthesias, tetany and, in severe cases, paralysis. The cardiovascular risks for patients with primary aldosteronism are greater than those for patients with primary hypertension. Compared with normotensive subjects, patients with primary aldosteronism have a 4.2-fold greater risk of stroke, a 6.5-fold greater risk of myocardial infarction and a 12.1-fold greater risk of atrial fibrillation. Diagnosis:Patients with hypertension are screened for primary aldosteronism based on the plasma aldosterone to plasma renin activity ratio. A value >30 constitutes a positive result. The diagnosis must be confirmed using one of four available aldosterone suppression tests. Lateralization of aldosterone hypersecretion is documented by adrenal venous sampling. Management:The foundation of primary aldosteronism management is normalization of circulating aldosterone and/or mineralocorticoid blockade. Optimal treatment of unilateral disease is adrenalectomy; spironolactone is the treatment of choice for bilateral disease.Copyright © 2009 S. Karger AG, Basel

The renin-angiotensin system is a coordinated hormonal cascade of critical importance to the regulation of blood pressure and cardiovascular function. The major effector peptide, angiotensin II, binds to two major receptors, angiotensin type-1 and angiotensin type-2. Most of the actions of angiotensin II are mediated by the angiotensin type-1 receptor, but recent evidence strongly suggests that the angiotensin type-2 receptor opposes the angiotensin type-1 receptor, particularly by promoting vasodilatation instead of vasoconstriction.

The renin-angiotensin system is a coordinated hormonal cascade important to the regulation of the renal sodium excretion and blood pressure. The major effector peptide, angiotensin II, binds two major receptors, AT1and AT2. While the majority of angiotensin II actions are mediated via the AT1receptor, evidence has accumulated that the AT2receptor opposes the AT1receptor, especially by inducing vasodilation instead of vasoconstriction.

Diabetes mellitus is associated with increased incidence of cardiovascular complications. Lack of nitric oxide production may exacerbate these complications. We hypothesized that diabetes decreases renal nitric oxide (NO) production, an effect that is reversed via inhibition of angiotensin subtype-1 receptor.

The aims of this study were to assess the renal expression of angiotensin type 1 (AT1) and type 2 (AT2) receptors in diabetic spontaneously hypertensive rats (SHR) and the effect of AT1 receptor blockade on the expression of these receptors.

Angiotensin II-receptor blockers are an established class of antihypertensive agents, but the differences between individual members of the class are largely unknown. The present study employed an animal model to demonstrate angiotensin II-receptor blocker-specific effects and to quantify these differences by comparing two common agents, losartan and valsartan.

Recently, the renin-angiotensin system (RAS) was implicated in organ fibrosis. However, few studies have examined the localization of RAS components, such as angiotensin II receptors, renin (REN), angiotensinogen (AGTN), and angiotensin-converting enzyme (ACE), in the fibrosing kidney. To localize these components in the fibrosing kidney, we used a murine model of renal fibrosis that shows an enhanced expression of angiotensin II type 1A receptor (AT1AR) and AGTN. Our results indicate that the overall expression of angiotensin II type 2 receptor (AT2R) and ACE was attenuated in this model, whereas REN expression was unchanged. In addition to tubular epithelial cells that were positive for AT1AR, AT2R, REN, and AGTN, interstitial fibroblast-like cells expressed AT1AR, REN, AGTN, and ACE in the fibrosing kidney. The interstitial fibroblast-like cells that were positive for AT1AR mRNA were further characterized as positive for the expression of vimentin and transforming growth factor-β1. These data provide strong evidence for a tubulointerstitial RAS within the fibrosing kidney, and a linkage between the RAS and renal fibrogenesis.

The aim of this study was to investigate the relative role of the angiotensin type 1 (AT1) and type 2 (AT2) receptors in mediating angiotensin II-induced regulation of AT2receptor in mesenteric artery.

The interaction of ANG II with intrarenal AT1receptors has been implicated in the progression of diabetic nephropathy, but the role of intrarenal AT2receptors is unknown. The present studies determined the effect of early diabetes on components of the glomerular renin-angiotensin system and on expression of kidney AT2receptors. Three groups of rats were studied after 2 wk: 1) control (C), 2) streptozotocin (STZ)-induced diabetic (D), and 3) STZ-induced diabetic with insulin implant (D+I), to maintain normoglycemia. By competitive RT-PCR, early diabetes had no significant effect on glomerular mRNA expression for renin, angiotensinogen, or angiotensin-converting enzyme (ACE). In isolated glomeruli, nonglycosylated (41-kDa) AT1receptor protein expression (AT1Aand AT1B) was increased in D rats, with no change in glycosylated (53-kDa) AT1receptor protein or in AT1receptor mRNA. By contrast, STZ diabetes caused a significant decrease in glomerular AT2receptor protein expression (47.0 ± 6.5% of C; P< 0.001; n= 6), with partial reversal in D+I rats. In normal rat kidney, AT2receptor immunostaining was localized to glomerular endothelial cells and tubular epithelial cells in the cortex, interstitial, and tubular cells in the outer medulla, and inner medullary collecting duct cells. STZ diabetes caused a significant decrease in AT2receptor immunostaining in all kidney regions, an effect partially reversed in D+I rats. In summary, early diabetes has no effect on glomerular mRNA expression for renin, angiotensinogen, or ACE. AT2receptors are present in glomeruli and are downregulated in early diabetes, as are all kidney AT2receptors. Our data suggest that alterations in the balance of kidney AT1and AT2receptor expression may contribute to ANG II-mediated glomerular injury in progressive diabetic nephropathy.

The angiotensin type 2 receptor is one of two major angiotensin II receptors that has been identified, cloned and sequenced. The other major receptor, the angiotensin type 1 receptor, is thought to mediate most of the biological responses to the peptide. The angiotensin type 2 receptor is expressed heavily in fetal tissues, but only at a low level in the adult. Documented angiotensin type 2 receptor expression sites in the adult include kidney, heart and mesenteric blood vessels. The function of the angiotensin type 2 receptor is just beginning to be explored. Most of the evidence suggests that the angiotensin type 2 receptor mediates a vasodilator signalling cascade that includes bradykinin, nitric oxide and cyclic guanosine 5-monophosphate. At least some of the beneficial actions of angiotensin type 1 receptor blockade, such as hypotension, are mediated by stimulation of the angiotensin type 2 receptor. Several recent papers suggest that angiotensin type 2 receptors, presumably located in systemic blood vessels, mediate vasodilation and hypotension. The angiotensin type 2 receptor may be a new therapeutic target and candidate gene for the pathophysiology of hypertension.

The development of renin-containing cells and nerve fibers was studied in Sprague-Dawley rat kidneys during the last third of gestation and the first 15 days of postnatal life. Kidney tissue sections were stained for nerve fibers or double stained employing an anti-rat renin polyclonal antibody and a monoclonal antibody (TUJ1) directed against a neuron-specific class III beta-tubulin isotype. Renin-containing cells and nerve fibers were detected at 17 days of gestation, in close spatial relationship along the main branches of the renal artery. During fetal life, renin-containing cells and nerve fibers were spatially associated along arcuate and interlobular arteries, renincontaining cells being also present throughout the entire length of afferent arterioles supplying juxtamedullary glomeruli. During postnatal life the distribution of renincontaining cells progressively shifted to a restricted juxtaglomerular position in afferent arterioles. Simultaneously, density and organization of nerve fibers increased with age along the arterial vascular tree. Our results suggest that innervation of renin-containing cells is present in fetal life and follows the centrifugal pattern of renin distribution and nephrovascular development.

After acute blood volume expansion (BVE) in the rat, diuresis and natriuresis are reported to be minimal in rats 20 to 30 d of age, but increase to mature levels by 40 d of age. To evaluate the role of atrial natriuretic peptide (ANP) and its renal action in BVE, anesthetized Sprague-Dawley rats were studied at 25 to 30 (group I) and 45 to 50 d of age (group II). Hematocrit, mean arterial pressure, glomerular filtration rate, urine flow rate, urine sodium excretion, urine cyclic GMP excretion, and plasma ANP concentration (ANP) were measured before and after infusion of donor littermate whole blood, 2.5 body wt (BVE), and in time controls (no BVE) in each group. Baseline hematocrit, mean arterial pressure, and glomerular filtration rate were greater in group II than group I, but urine flow rate, urine sodium excretion, urine cyclic GMP excretion, and ANP did not differ. BVE caused a prompt increase in urine flow rate, urine sodium excretion, and ANP, but not urine cyclic GMP excretion, in both groups, but there was no difference in the response between groups. Additional groups of rats of the same ages as groups I and II studied using a protocol similar to that of a previous report also showed the “mature” diuretic and natriuretic response even in the younger animals. We conclude that there is no further maturation of the renal response to acute BVE in the euvolemic rat after 25 d of age. The increase in ANP after acute BVE in the immature weanling rat is consistent with a role for ANP in mediation of the renal response.

The population of a community of 29,608 adults was screened door-to-door for elevated blood pressure. A questionnaire was administered and analyzed to profile the hypertensive person who is most likely to be unaware of his problem.

Acute bromocriptine administration reduced sitting and standing blood pressure and produced severe orthostatic hypotension in 12 normal subjects. Concomitantly, there was an increase in venous distensibility and basal blood flow, and a decrease in peripheral vascular resistance, as determined by forearm plethysmography. After administration of bromocriptine, plasma norepinephrine concentration decreased. Bromocriptine lowers blood pressure by dilating arterioles and veins, at least in part by means of dopaminergic inhibition of sympathetic nervous system activity.

Patients with pulmonary dysfunction and CO2retention have renal hemodynamic abnormalities accompanied by increased plasma renin activity. To determine if hypercapnia impairs renal function, particularly through the renin-angiotensin system, the effects of acute hypercapnic acidosis (HC), using 8.5 CO2, were measured in five unanesthetized dogs during (a) the intact state; (b) renin-angiotensin antagonism using either 1-sarcosine, 8-glycine angiotensin II ([Sar1, Gly8]AII) or SQ 14,225; and (c) exogenous angiotensin II infusion. As partial arterial carbon dioxide pressure (PaCO2) increased (p < 0.05) from control (C) of 35 ± 1 (SEM) to 48 ± 1 mm Hg during HC, arterial pH fell (p < 0.05) from 7.36 ± 0.01 to 7.24 ± 0.005. Renal function was uncompromised with HC, and glomerular filtration rate (GFR) and urinary sodium excretion increased (p < 0.05) despite a fourfold rise in plasma renin activity from C of 0.6 ± 0.3 to 2.2 ± 0.8 ng AI ml-1h-1during HC. Administration of [Sar1, Gly8]AII during HC did not consistently alter systemic or renal hemodynamic responses, and effects of SQ 14,225 during HC were also observed during normocapnia. Although systemic vascular responses to exogenous AII infusion were similar, the renal vasoconstrictor response was antagonized during HC with unchanged GFR and renal blood flow. These findings indicate that despite activation of the renin—angiotensin system, acute hypercapnic acidosis is unassociated with impairment of renal function in unanesthetized dogs. This may be related to diminished renal vascular AII responsiveness during hypercapnia.

In order to evaluate the role of the α-adrenergic system in the systemic and renal hemodynamic changes of the acute combined blood gas derangement, seven conscious mongrel dogs in careful sodium balance (80 mEq/day for 4 days) were evaluated. Each animal was evaluated during combined acute hypoxemia (PaO2= 35 ± 1 mm Hg) and hypercapnic acidosis (PaCO2= 56 ± 2 mm Hg; pH = 7.18 ± 0.01) with (i) vehicle (D5W) alone and (ii) α1-adrenergic blockade with prazosin, 0.1 mg/kg iv. Mean arterial pressure increased during the combined blood gas derangement with vehicle. In contrast, mean arterial pressure fell during combined acute hypoxemia and hypercapnic acidosis with α1-adrenergic blockade. The mechanism for abrogation of the rise in mean arterial pressure during the combined blood gas derangement by α1-adrenergic blockade appeared to be through attenuation of the rise in cardiac output rather than an exaggerated fall in total peripheral resistance. These observations suggest that the α-adrenergic system is important in circulatory homeostasis during the combined blood gas derangement.

Dopamine produced by renal proximal tubules acts as an intrarenal natriuretic factor by direct tubular action; this paracrine effect is influenced by the state of sodium balance. Up to 60% of sodium excretion with volume (2%–10%) expansion may be mediated by D1-like receptors. The renal paracrine effect of dopamine is impaired in genetic hypertension; this is due to defects in renal dopamine production or transduction of the dopamine signal. The Dahl salt sensitive rat and the spontaneously hypertensive rat (SHR), which have normal renal dopamine production and expression of dopamine receptors, have a defect in the coupling of a D1-like receptor to G-protein/effector enzyme complex. A consequence of the defective D1-like receptor/effector enzyme coupling in SHR is a decreased ability of D1agonists to inhibit Na+/H+exchange and Na+/K+-ATPase activity. The defect is 1) genetic, since it precedes the onset of and cosegregates with the hypertension; 2) receptor specific, since it is not shared by other humoral agents; and 3) confined to the renal proximal tubule. Two of the cloned dopamine receptors in mammals are D1-like (D1Aand D1B). The D1Areceptor gene is expressed to a greater extent in renal proximal tubules than the D1Breceptor gene. The D1-like receptor is important in the pathogenesis of hypertension. Chronic blockade of dopamine receptors accelerates the development of hypertension in normotensive and hypertensive rats. Moreover, disruption of the D1Areceptor gene in mice increases systolic blood pressure and results in diastolic hypertension. The abnormal D1-like receptor in SHR may be the D1Areceptor; its uncoupling from the G-protein/effector enzyme complex in renal proximal tubules of SHR may be due to mistargeting. The mechanism for this “mistargeting” of the D1Areceptor is not due to a mutation in the primary sequence and remains to be determined.

Since publication of the 1980 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure,1 several events have occurred that affect successful management of hypertension: publication of major clinical trial results, introduction of new antihypertensive agents, evidence concerning effectiveness of nonpharmacologic treatment, and further analysis of the epidemiologic data-base relating BPs with the risk of premature morbidity and mortality. These events led the director of the National Heart, Lung, and Blood Institute (NHLBI), as chairman of the National High Blood Pressure Education Program Coordinating Committee, to establish a new Joint National Committee to revise earlier recommendations.This report includes recommendations on the following topics: (1) screening and referral procedures, (2) classification according to BPs, (3) use of nonpharmacologic therapies, (4) revised stepped-care approach, (5) management of mild hypertension, (6) patient-professional interaction, and (7) management of BP in special groups, including blacks, children, and pregnant

The immature kidney appears to be less responsive to atrial natriuretic peptide (ANP) than the mature kidney. It has been proposed that this difference accounts for the limited ability of the young animal to excrete a sodium load. To delineate the effects of age on the renal response to exogenous ANP, Sprague-Dawley rats were anesthetized for study at 31–32 days of age, 35–41 days of age, and adulthood. Synthetic rat ANP was infused intravenously for 20 min at increasing doses ranging from 0.1 to 0.8 μg/kg/min, and mean arterial pressure, glomerular filtration rate, plasma ANP concentration, urine flow rate, and urine sodium excretion were measured at each dose. Since cyclic GMP acts as a second messenger for ANP action, urinary cyclic GMP excretion also was measured. Increasing doses of ANP caused a similar decrease in MAP at all ages studied, and increased glomerular filtration rate in adult but not young rats. Increasing the dose of ANP from 0.1 to 0.4 μg/kg/min caused a greater rise in urine flow and urinary cyclic GMP excretion in adult than young rats, and urine sodium excretion increased more in adults at all doses (p< 0.05). However, the rise in plasma ANP concentration also was greater in adults than in young rats (p< 0.05), indicative of greater systemic clearance of ANP in young animals. Increasing levels of plasma ANP concentration were correlated with a greater rise in urine flow in adult than young (31–32 day old) rats (p< 0.05), but there was no differential effect on urinary cyclic GMP excretion. We conclude that although the diuretic effect of ANP increases with age, the guanylate cyclase response to ANP does not change after 30 days of age in the rat. Decreasing clearance of ANP as rats age may be due to decreased enzymatic degradation of the peptide or reduced removal as a result of altered receptor binding. (Pediatr Res24: 333–337, 1988)

Bioactive SNOs are found in many tissues. We speculated SNOs might be misidentified in conventional assays which reduce NO−3to NO.S-Nitrosothiols were exposed to saturated VCl3in HCl, 1% KI in acetic acid, photolysis, or CuCl and CSH in He; NO was measured by chemiluminescence.S-Nitrosothiols were readily detected in VCl3but not in KI. Reduction in CuCl/cysteine was linear (r2= 1.0,n= 6), sensitive to 10 pmol, and eliminated by HgCl2; it did not detect NO−2, NO−3, or 3-nitrotyrosine.S-Nitrosothiols represented ∼2.9% of NOxassayed by VCl3in human serum, of which <5% were low-mass species. In summary, (i) conventional assays may misidentify NO−3, but not NO−2, as SNOs; and (ii) chemiluminescence/reduction systems may be sensitive and specific as SNO assays. We suggest that assay of the SNO fraction in biological NOxmay be more relevant and feasible than is now appreciated.

Renal juxtaglomerular (JG) cells are specialized myoepithelioid cells located in the afferent arteriole at the entrance to the glomerulus. Their main function and distinctive feature is the synthesis and release of renin, the key hormone-enzyme of the renin-angiotensin system that regulates arterial blood pressure. Despite their relevance to health and disease, not much is known about factors that confer and/or maintain JG cell identity. To identify genes uniquely expressed in JG cells, we used a cell culture model and RNA differential display. JG cells cultured for 2 days express renin and renin mRNA, but after 10 days in culture they no longer contain or release renin and renin mRNA is reduced 700-fold. We report one cDNA differentially expressed in the 2-day JG cell culture that detects a 2.6-kb mRNA expressed at higher levels in newborn than adult kidney. Screening a 2-day culture JG cell cDNA library yielded clones representing differentially spliced transcripts. These cDNAs encode one unique protein (Zis) containing zinc fingers and domains characteristic of splicing factors and RNA binding proteins. Northern blot analysis confirmed Zis mRNA expression in differentiated JG cells, and identified an additional unique 1.5-kb transcript. The Zis transcripts are developmentally regulated in kidney and a number of other organs. The features of the Zis protein and its organ distribution suggest a possible role in regulation of transcription and/or splicing, both important steps for controlling developmentally expressed genes.

In recent years, both molecular biological and immunohistochemical techniques, utilizing receptor subtype-specific probes and antibodies to cloned central nervous system dopamine receptors, have revealed their presence in a number of peripheral organs and tissues. Molecular techniques have been hindered by the low abundance of receptor mRNA in these sites, and reverse transcription-polymerase chain reaction (RT-PCR) has been utilized to address this problem. However, RT-PCR is most often employed on either isolated mRNA or microdissected tissue samples, thereby limiting interpretation of whole tissue distribution. The present paper describes the use of a novel self-sustained sequence replication system (3SR) to amplify a target mRNA sequence in situ within the tissue or cell of interest that is then detected with the use of an internal labeled probe, using standard nonisotopic in situ hybridization. Specifically, D1Areceptor mRNA was amplified and detected in kidney sections of Wistar-Kyoto rats (WKY). The amplified D1Areceptor mRNA was localized to renal arterioles, juxtaglomerular apparatus, and both proximal and distal tubules. mRNA was colocalized to regions shown also to contain D1Areceptor protein. D1Areceptor mRNA was predominantly localized in the cortex. Specificity of D1Areceptor mRNA detection was confirmed by appropriate localization in rat brain sections known to express D1Areceptor mRNA. In addition, we confirmed the presence of renal D1Areceptor mRNA by RT-PCR. We conclude that D1Areceptor mRNA is expressed in a site-specific manner in the WKY kidney. The use of 3SR in situ permits elucidation of site specific mRNA localization in a manner not reported previously.

The population of a community of 29,608 adults was screened door-to-door for elevated blood pressure. Of 12,371 adults screened, 20% were classified as hypertensive. After repeated blood-pressure measurement, however, there were only 9% with sustained hypertension, while 11% had labile hypertension. Sixty percent of the cases of sustained hypertension had been either undiagnosed, untreated, or inadequately treated. Eighty-two percent who initially were unaware of hypertension had labile hypertension after repeated blood-pressure measurement, and 18% were unaware of having, sustained hypertension. Labile hypertension was most prevalent in the young and decreased with age. In contrast, sustained hypertension was least prevalent in the young and increased with age. Labile hypertension was most prevalent in white men, and sustained hypertension was more prevalent in blacks than in whites.Labile hypertension represents a large segment (52%) of the population initially identified as having hypertension in a home blood-pressure survey.(JAMA 236:847-851, 1976)