Robert M. Carey

Resistant Hypertension: Diagnosis, Evaluation, and Treatment A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Resistant Hypertension: Diagnosis, Evaluation, and Treatment. A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.

The renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Virtually all of the biological actions of the principle effector peptide angiotensin II (ANG II) have been attributed to an action at the type 1 (AT(1)) ANG receptor. Until recently, the functional role of the type 2 (AT(2)) receptor, if any, has been unknown, possibly because the AT(2) receptor has a low degree of expression compared with that of the AT(1) receptor. Evidence has now accumulated that the AT(2) receptor opposes functions mediated by the AT(1) receptor. Whereas the AT(1) receptor stimulates cell proliferation, the AT(2) receptor inhibits proliferation and promotes cell differentiation. These differences in growth responses have been ascribed to different cell signaling pathways in which the AT(1) receptor stimulates protein phosphorylation and the AT(2) receptor dephosphorylation. During the past 5 years, studies have demonstrated that the AT(2) receptor is responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor and antinatriuretic effects of ANG II mediated through the AT(1) receptor. Work from our laboratory and others indicates that the AT(2) receptor stimulates vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric oxide, and cyclic GMP. The AT(2) receptor also has been found to control vasodilator prostaglandins, which have a role in blood pressure regulation. The AT(2) receptor appears to play a counterregulatory protective role in the regulation of blood pressure and sodium excretion that opposes the AT(1) receptor.

Protective Role of the Angiotensin AT2 Receptor in a Renal Wrap Hypertension Model

We evaluated the role of the renal angiotensin II type 2 (AT2) receptor in blood pressure regulation in rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension. Renal wrapping increased systolic blood pressure (SBP). Renal interstitial fluid (RIF) bradykinin (BK), nitric oxide end-products (NOX), and cGMP were higher in the contralateral intact kidney than in the wrapped kidney. In rats with Grollman hypertension, losartan normalized SBP and increased renal function, RIF BK, NOX, and cGMP only in contralateral kidneys. In contrast, PD 123319, a specific AT2-receptor antagonist, significantly increased SBP and decreased RIF BK, NOX, and cGMP in both kidneys. Combined administration of losartan and PD 123319 prevented the decrease in SBP and the increase in RIF BK, NOX, and cGMP levels observed with losartan alone. BK-receptor blockade caused a significant increase in RIF BK and a decrease in RIF NOX and cGMP in both kidneys similar to that observed during administration of PD 123319. In rats that underwent sham operation, RIF BK increased in response to angiotensin II, an effect that was blocked by PD 123319. These data demonstrate that angiotensin II mediates renal production of BK, which, in turn, releases nitric oxide and cGMP via stimulation of AT2 receptors. The increase in blood pressure and the decrease in renal BK, nitric oxide, and cGMP during AT2-receptor blockade suggests that the AT2 receptor mediates counterregulatory vasodilation in Grollman hypertension and prevents a further increase in blood pressure.

Ectopic Secretion of Corticotropin-Releasing Factor as a Cause of Cushing's Syndrome: A Clinical, Morphologic, and Biochemical Study

Corticotropin-releasing factor, a hypophyseo-tropic hormone that stimulates adrenocorticotropic hormone (ACTH) secretion, has recently been isolated, characterized, and synthesized in the sheep and rat. We report on a patient with metastatic carcinoma of the prostate presenting with anterior and posterior pituitary hormone deficiency together with ACTH-dependent Cushings syndrome. At postmortem examination, large areas of the median eminence and pituitary stalk were replaced by tumor, but the corticotrophs were markedly hyperplastic. Immunostaining of tumor cells was positive for corticotropin-releasing factor and was negative for ACTH and a wide range of other hormones. Radioimmunoassay and bioassays showed that tumor extracts and further purified fractions were active in corticotropin-releasing factor, and the tumor material coeluted with corticotropin-releasing factor on high-pressure liquid chromatography. These studies demonstrate that ectopic secretion of corticotropin-releasing factor is a cause of Cushings syndrome in human beings. The features of this syndrome include hypercortisolism, pituitary corticotroph hyperplasia, elevation of circulating ACTH levels, and failure to suppress the pituitary-adrenal axis with exogenous glucocorticoids.

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Essential hypertension has a heritability as high as 30–50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4γ, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4γA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.

Effects of Metoclopramide and Bromocriptine on the Renin-Angiotensin-Aldosterone System in Man: DOPAMINERGIC CONTROL OF ALDOSTERONE

This study was designed to investigate the possible role of dopaminergic mechanisms in the control of the renin-angiotensin-aldosterone system in normal man. Six normal male subjects in metabolic balance at 150 meq sodium, 60 meq potassium constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. or placebo followed by angiotensin II infusion 1 h later on 2 consecutive days. Metoclopramide increased plasma aldosterone concentration from 8.2+/-2.2 to 21.0+/-3.3 ng/100 ml (P < 0.005) and plasma prolactin concentration from 18.0+/-4.0 to 91.7+/-4.0 ng/ml (P < 0.001) within 15 min of its administration. At 1 h, plasma aldosterone and prolactin concentrations remained elevated at 16.8+/-2.1 ng/100 ml (P < 0.01) and 86.8+/-15.9 ng/ml (P < 0.005), respectively. Angiotensin II at 2, 4, and 6 pmol/kg per min further increased plasma aldosterone concentration to 27.2+/-3.4, 31.9+/-5.7, and 36.0+/-6.7 ng/100 ml (P < 0.02), respectively. Placebo did not alter plasma aldosterone or prolactin concentrations, but angiotensin II increased plasma aldosterone concentration to 13.7+/-2.4, 19.0+/-1.9, and 23.3+/-3.2 ng/100 ml (P < 0.005). The increment of plasma aldosterone concentration in response to angiotensin II was similar after metoclopramide or placebo. The six subjects also received the dopamine agonist, bromocriptine, 2.5 mg or placebo at 6 p.m., midnight, and 6 a.m. followed by angiotensin II infusion on 2 consecutive d. Bromocriptine suppressed prolactin to <3 ng/ml. After placebo, plasma aldosterone concentration increased from 5.2+/-1.4 to 12.3+/-1.7, 17.2+/-2.2, and 21.8+/-3.5 ng/100 ml (P < 0.01) and after bromocriptine from 7.2+/-1.0 to 14.7+/-3.0, 19.8+/-3.2, and 23.4+/-1.6 ng/100 ml (P < 0.001) with each respective angiotensin II dose. No difference in the response to angiotensin II after bromocriptine or placebo was observed. Plasma renin activity, free 11-hydroxycorticoid concentration, and serum potassium concentration were unchanged by metoclopramide or bromocriptine. The results suggest that aldosterone production is under maximum tonic dopaminergic inhibition which can be overridden with stimulation by angiotensin II in normal man.

The renin–angiotensin–aldosterone system, glucose metabolism and diabetes

In diabetes mellitus (DM), the circulating renin-angiotensin system (RAS) is suppressed, but the renal tissue RAS is activated. Hyperglycemia increases tissue angiotensin II (Ang II), which induces oxidative stress, endothelial damage and disease pathology including vasoconstriction, thrombosis, inflammation and vascular remodeling. In early DM, the type 1 Ang II (AT(1)) receptor is upregulated but the type 2 Ang II (AT(2)) receptor is downregulated. This imbalance can predispose the individual to tissue damage. Hyperglycemia also increases the production of aldosterone, which has an unknown contribution to tissue damage. The insulin resistance state is associated with upregulation of the AT(1) receptor and an increase in oxygen free radicals in endothelial tissue caused by activation of NAD(P)H oxidase. Treatment with an AT(1) receptor blocker normalizes oxidase activity and improves endothelial function. An understanding of the tissue renin-angiotensin-aldosterone system, which is a crucial factor in the progression of tissue damage in DM, is imperative for protection against tissue damage in this chronic disease.

Dopaminergic Inhibition of Metoclopramide-induced Aldosterone Secretion in Man: DISSOCIATION OF RESPONSES TO DOPAMINE AND BROMOCRIPTINE

This study was designed to investigate the role of dopaminergic mechanisms in the control of aldosterone secretion in man. Five normal male subjects in metabolic balance at 150 meq sodium/d and 60 meq potassium/d constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. on 2 consecutive d. On the 1st d, the subjects received an infusion of 5% glucose solution (vehicle) from 60 min before to 60 min after metoclopramide administration; on the 2nd d, an infusion of dopamine 4 mug/kg per min was substituted for vehicle. Metoclopramide in the presence of vehicle increased plasma aldosterone concentrations from 2.4+/-1.1 to a maximum of 17.2+/-2.8 ng/100 ml (P < 0.01) and serum prolactin concentrations from 7.5+/-5.0 to a maximum of 82.2+/-8.7 ng/ml (P < 0.01). Dopamine 4 mug/kg per min did not alter basal plasma aldosterone concentrations, but blunted the aldosterone responses to metoclopramide significantly; in the presence of dopamine, plasma aldosterone concentrations increased from 3.1+/-0.5 to 6.2+/-1.4 ng/100 ml (P < 0.05) in response to metoclopramide. The incremental aldosterone responses to metoclopramide were significantly lower in the presence of dopamine than with vehicle. Dopamine 4 mug/kg per min suppressed basal prolactin to <3 ng/ml and inhibited the prolactin responses to metoclopramide; serum prolactin concentrations increased to a maximum of 8.5+/-2.3 ng/ml with metoclopramide in the presence of dopamine. The subjects were studied in the same manner except that dopamine 2 mug/kg per min was administered instead of the 4-mug/kg per min dose. Dopamine 2 mug/kg per min attenuated the aldosterone and prolactin responses to metoclopramide, but was less effective than the 4-mug/kg per min dose of dopamine. Metoclopramide 10 mg i.v. was administered to five additional subjects after pretreatment with the dopamine agonist, bromocriptine, 2.5 mg or placebo at 6 p.m., midnight, and 6 a.m. before study. Bromocriptine suppressed basal serum prolactin levels and completely inhibited the prolactin responses to metoclopramide. In contrast, bromocriptine did not alter basal plasma aldosterone concentrations or the aldosterone responses to metoclopramide. Plasma renin activity, plasma cortisol, and serum potassium concentrations were unchanged by metoclopramide, dopamine, or bromocriptine. The results of this study suggest that the aldosterone response to metoclopramide is mediated by metoclopramides antagonist activity at the dopamine receptor level. The results further suggest dissociation of the responses to the dopamine agonists, dopamine and bromocriptine, and indicate that a new type of dopamine receptor may inhibit aldosterone secretion.

The intrarenal renin–angiotensin system and diabetic nephropathy

The renin-angiotensin system (RAS) is a coordinated cascade of proteins and peptide hormones, the principal effector of which is angiotensin II (ANG II). Evidence now indicates that the kidney regulates its function via a self-contained RAS in a paracrine fashion. In diabetic nephropathy, the intrarenal generation of ANG II is increased, in spite of suppression of the systemic RAS. This increase can contribute to the progression of diabetic nephropathy via several hemodynamic, tubular and growth-promoting actions. ANG II induces insulin resistance. ANG II type-1 (AT(1)) and type-2 (AT(2)) receptors are downregulated in chronic diabetes, but decreased AT(2) receptor expression might contribute to early diabetic nephropathy by reducing AT(2) receptor-mediated beneficial actions that are counter-regulatory to those of the AT(1) receptor. AT(2) receptor stimulation might account for part of the renal protection seen with AT(1) receptor blockade. A rat model of accelerated diabetic nephropathy is the (mREN-2) 27 renin transgenic rat treated with streptozotocin in which both the intrarenal and extrarenal RAS is activated.