piperidines and Hypertension--Renal

Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non-steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP-5074 and finerenone) have been developed with an improved benefit-risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non-steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

Topics: Heart Failure; Humans; Hypertension, Renal; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Nephritis; Piperidines; Pyrazoles; Quinolines

Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.. We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4+/-2%, CRF -13+/-2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8+/-23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5+/-11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.. ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

Topics: Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Proteinuria; Renal Circulation; Sodium

Topics: Amides; Antihypertensive Agents; Clopamide; Diuretics; Humans; Hypertension; Hypertension, Renal; Piperidines; Reserpine

Endothelin 1 (ET-1) and its receptors, ETA and ETB, play important roles in regulating renal function and blood pressure, and these components are expressed in sensory nerves. Activation of transient receptor potential vanilloid (TRPV) 1 channels expressed in sensory nerves innervating the renal pelvis enhances afferent renal nerve activity (ARNA), diuresis, and natriuresis. We tested the hypothesis that ET-1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in wild-type (WT) but not TRPV1-null mutant mice. ET-1 alone or with BQ123, an ETA antagonist, perfused into the left renal pelvis increased ipsilateral ARNA in WT but not in TRPV1-null mutant mice, and ARNA increases were greater in the latter. [Ala1, 3,11,15]-endothelin 1, an ETB agonist, increased ARNA that was greater than that induced by ET-1 in WT mice only. [Ala1, 3,11,15]-endothelin 1-induced increases in ARNA were abolished by chelerythrine, a protein kinase C inhibitor, but not by H89, a protein kinase A inhibitor. Chelerythrine, H89, and BQ788, an ETB antagonist, did not affect ARNA triggered by capsaicin in WT mice. Substance P release from the renal pelvis was increased by [Ala1, 3,11,15]-endothelin 1 in WT mice only, and the increase was abolished by chelerythrine but not by H89. Chelerythrine, H89, and BQ788 did not affect capsaicin-induced substance P release. Our data show that ET1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in WT but not in TRPV1-null mutant mice, suggesting that TRPV1 mediates ETB-dependent increases in ARNA, diuresis, and natriuresis possibly via the protein kinase C pathway.

Topics: Animals; Antihypertensive Agents; Cyclic AMP-Dependent Protein Kinases; Diuresis; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Renal; Isoquinolines; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Natriuresis; Neurons, Afferent; Oligopeptides; Peptides, Cyclic; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Substance P; Sulfonamides; TRPV Cation Channels

As yet, there are only limited data available on the exact role of endothelin (ET) acting through endothelin-A (ETA) receptors in renal sodium and water regulation and the potential functional implications of an interaction of the renal ET system with renal nerves in normotensive and spontaneously hypertensive rats.. Experiments were carried out in 64 male conscious spontaneously hypertensive rats and in 56 normotensive Wistar-Kyoto (WKY) rats. Bilateral renal denervation (BRD) was performed in 32 spontaneously hypertensive rats and 28 WKY rats 7 days before the experiments. The ETA receptor antagonist, BQ-123 (16.4 nmol/kg x min intravenously) or the endothelin-B (ETB) receptor antagonist, BQ-788 (25 nmol/kg x min intravenously) were infused at a rate of 25 microL/min for 50 minutes.. Renal papillary ET-1 concentration in intact spontaneously hypertensive rats was 67.8% lower than in intact WKY rats (154 +/- 40 fmol/mg protein vs. 478 +/- 62 fmol/mg protein, P < 0.01). BRD decreased papillary ET-1 by 73.5% in WKY rats to 127 +/- 19 fmol/mg protein (P < 0.001), but had no effect in spontaneously hypertensive rats (122 +/- 37 fmol/mg protein). BRD, BQ-123, or BQ-788 did not affect glomerular filtration rate (GFR) or renal blood flow (RBF) in any of the groups. In intact WKY, BQ-123 decreased urine flow rate (V) from 4.65 +/- 0.44 microL/min.100 g body weight to 2.44 +/- 0.35 microL/min.100 g body weight (P < 0.01), urinary excretion of sodium (UNaV) from 238.2 +/- 27.4 to 100.2 +/- 17.0 (P < 0.01) and potassium (UKV) from 532.1 +/- 62.6 nmol/min.100 g body weight to 243.0 +/- 34.2 nmol/min.100 g body weight (P < 0.001), whereas BQ-788 decreased only V and UNaV. In renal denervated WKY, BQ-123 or BQ-788 did not alter V, UNaV, or UKV. In intact spontaneously hypertensive rats BQ-123 but not BQ-788 decreased V from 3.94 +/- 0.48 microL/min.100 g body weight to 2.55 +/- 0.44 microL/min.100 g body weight (P < 0.05). In renal denervated spontaneously hypertensive rats neither BQ-123 nor BQ-788 affected V, UNaV, or UKV.. An interaction between ET and renal nerves is involved in the control of renal function. Moreover, renal nerves participate in the regulation of ET-1 production within the kidney. Finally, decreased synthesis of ET-1 in the renal papilla of spontaneously hypertensive rats may contribute to development and/or maintenance of hypertension due to modulation of renal excretory function.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Denervation; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Renal; Kidney Cortex; Kidney Medulla; Male; Natriuresis; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A; Urine

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Piperidines; Quinolones

The synthesis of a series of 1-aralkyl-4-ureidopiperidines is reported. These compounds are related to the benzamidopiperidines exemplified by indoramin. Some of the ureidopiperidines are more potent antihypertensive agents than their benzamidopiperidine counterparts. Two examples, 1-(2-thenoyl)-3-[1-[2-(3-indolyl)ethyl]piperid-4-yl]urea and 1-(2-thenoyl)-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperid-4-yl]urea (19 and 58), emerged as the most potent antihypertensive agents in this series.

Topics: Animals; Antihypertensive Agents; Desoxycorticosterone; Hypertension; Hypertension, Renal; Piperidines; Rats; Structure-Activity Relationship

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Aorta; Benzamides; Blood Pressure; Guinea Pigs; Histamine H1 Antagonists; Hypertension, Renal; Ileum; In Vitro Techniques; Indoles; Muscle Contraction; Piperidines; Rats; Receptors, Adrenergic; Structure-Activity Relationship

Topics: Animals; Antihypertensive Agents; Benzamides; Blood Pressure; Guinea Pigs; Histamine H1 Antagonists; Hypertension, Renal; Ileum; In Vitro Techniques; Indoles; Muscle Contraction; Piperidines; Rats

1 Intraventricular administration of clonidine (5-30 mug) and an analogue, BAY 1470 (15-30 mug) to conscious renal hypertensive cats produced a fall in mean blood pressure lasting for approximately 3 hours. This fall in blood pressure was accompanied by a marked bradycardia.2 Pretreatment with intraventricular phentolamine (100-200 mug), piperoxan (40-200 mug) or tolazoline (75-200 mug) abolished the cardiovascular effects of intraventricular clonidine (20 mug).3 The cardiovascular effects of intraventricular clonidine (20 mug) were not modified by the pretreatment with either haloperidol (1 mg/kg i.p.) or desmethylimipramine (1 mg/kg i.p.).4 Emesis was observed 1-2 min after the administration of either clonidine (5-20 mug) or BAY 1470 (30 mug). This preceded the cardiovascular actions and was still seen after pretreatment with haloperidol, desmethylimipramine, phentolamine, piperoxan or tolazoline.5 It is concluded that the centrally mediated cardiovascular responses observed after intraventricular administration of small doses of clonidine are due to stimulation of central alpha-adrenoceptors and are independent of central catecholamine uptake mechanisms and dopamine receptors.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Cats; Clonidine; Desipramine; Dioxanes; Dopamine Antagonists; Haloperidol; Heart Rate; Hemodynamics; Hypertension, Renal; Phentolamine; Piperidines; Thiazines; Time Factors; Xylazine

Topics: Adult; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiomegaly; Diuretics; Electrocardiography; Female; Heart; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Minoxidil; Nephrectomy; Piperidines; Posture; Propranolol; Pyrimidines; Vasodilator Agents

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Child; Child, Preschool; Clopamide; Depression, Chemical; Diabetes Complications; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Hyperthyroidism; Infant; Liver Function Tests; Male; Middle Aged; Piperidines; Potassium; Reserpine; Urine

Topics: Adult; Aged; Amides; Blood Pressure; Clopamide; Diuresis; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Potassium Deficiency; Reserpine; Water-Electrolyte Balance

Topics: Animals; Antihypertensive Agents; Female; Hypertension, Renal; Indoles; Methods; Piperidines; Rats

Topics: Adult; Aged; Amides; Clopamide; Diuretics; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Ambulatory Care; Amides; Antihypertensive Agents; Arteriosclerosis; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Antihypertensive Agents; Arteries; Arteriosclerosis; Blood Pressure; Clopamide; Depression, Chemical; Diuretics; Ergot Alkaloids; Hemodynamics; Humans; Hypertension, Renal; Kidney Diseases; Kidney Function Tests; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Aged; Amides; Antihypertensive Agents; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adolescent; Adult; Aged; Amides; Blood Pressure; Clopamide; Diuretics; Drug Synergism; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Amides; Antihypertensive Agents; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Piperidines; Potassium; Reserpine

Topics: Amides; Clopamide; Diuretics; Ergot Alkaloids; Hypertension; Hypertension, Renal; Hypokalemia; Piperidines; Reserpine

Topics: Animals; Antihypertensive Agents; Cats; Dogs; Guanidines; Hypertension; Hypertension, Renal; Kidney; Pharmacology; Piperidines; Rats; Research

Topics: Alkaloids; Hypertension; Hypertension, Renal; Piperidines; Research; Solanine; Spectrophotometry