Ambrisentan,a Non‐peptide Endothelin Receptor Antagonist

Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET)‐system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Ambrisentan (LU 208075), a selective ET_A‐receptor antagonist, is an orally active diphenyl propionic acid derivative. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. The pharmacological properties and data from the experimental investigations suggest additional possible uses of ambrisentan in the prevention of reperfusion injury after organ transplantation and in restenosis following coronary artery dilatation. Furthermore, the pharmacological profile of ambrisentan indicates that this drug may also be suitable in the treatment of cerebrovascular disorders. In the present article basic investigations, animal studies and clinical trials with ambrisentan are reviewed. This review may help to define pathophysiological conditions, in which ambrisentan could be indicated and further evaluated in appropriate preclinical and clinical trials.     

内皮素B受体对肾近曲小管上皮细胞Na~ -K~ -ATP酶活性的影响

目的探讨内皮素B(ETB)受体对肾脏近曲小管(RPT)上皮细胞Na -K -ATP酶活性的影响和机制。方法以WKY(Wistar-Kyoto)大鼠RPT细胞为研究对象,Na -K -ATP酶活性采用哇巴因法进行测定。结果ETB受体激动剂BQ3020能明显降低Na -K -ATP酶的活性,这一抑制作用呈浓度和时间依赖性,BQ302010-8mol/L刺激15min达最大效应,下降幅度达36.1%;用细胞膜钙通道阻断剂尼卡地平预先刺激细胞后,能够阻断ETB受体对Na -K -ATP酶的抑制效应;在无钙状态下,ETB受体激动剂BQ3020对Na -K -ATP酶的抑制效应丧失。结论ETB受体在RPT处通过降低Na -K -ATP酶活性调节离子转运;细胞外钙内流参与了ETB受体对Na -K -ATP酶活性抑制作用的信号途径。     

Eplerenone: A Selective Aldosterone Receptor Antagonist (SARA)

Aldosterone, the final product of the renin‐angiotensin‐aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin‐converting enzyme (ACE) inhibitors and angiotensin type 1 (AT₁) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels — a phenomenon termed “aldosterone synthesis escape.” Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone — the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) — is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24‐h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.     

An Overview of SR121463, a Selective Non‐Peptide Vasopressin V2 Receptor Antagonist

SR121463 is a selective, orally active, non‐peptide antagonist of vasopressin (AVP) V₂ receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free‐water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V₂ receptors and exhibits a remarkably selective V₂ receptor profile. SR121463 and [³H]SR121463 are used, therefore, as selective probes for characterization and labeling of V₂ receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP‐stimulated human renal adenylyl cyclase and dDAVP (1‐desamino, 8‐D arginine‐vasopressin)‐induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V₂ receptor mutant. In vitro, SR1 21463 rescued misfolded V₂ AVP receptor mutants by increasing cell surface expression and restoring V₂ function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose‐dependent aquaresis with no major changes in urinary Na⁺ and K⁺ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10‐day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V₂ (or V₂‐like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V₂ receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V₂ receptors. Pure V₂ receptor antagonists are likely to be therapeutically useful in several water‐retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V₂ receptors (e.g., glaucoma).     

A Review on Telmisartan: A Novel,Long‐Acting Angiotensin II‐Receptor Antagonist

Telmisartan is a potent, long‐lasting, nonpeptide antagonist of the angiotensin II type‐1 (AT₁) receptor that is indicated for the treatment of essential hypertension. It selectively and insurmountably inhibits stimulation of the AT₁ receptor by angiotensin II without affecting other receptor systems involved in cardiovascular regulation. Very high lipophilicity, a unique feature of telmisartan, coupled with a high volume of distribution, indicate that the compound offers the clinically important advantage of good tissue penetration. Telmisartan is not a prodrug and has a longer terminal elimination half‐life than other commercially available sartans (～24 h), making it suitable for once‐daily dosing. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450‐based drug interactions. In animal models, telmisartan exhibits pronounced cardio‐and renoprotective effects in animals with severe, essential hypertension. In clinical studies, telmisartan shows comparable antihypertensive activity to members of other major antihypertensive classes, such as ACE inhibitors, beta blockers and calcium antagonists. These trials have confirmed the placebo‐like safety and tolerability of telmisartan in hypertensive patients. Based on these data, telmisartan offers advantages over other sartans and represents an important new treatment option for hypertension.     

In Vivo Pharmacology of L-159,913, A New Highly Potent and Selective Nonpeptide Angiotensin II Receptor Antagonist

The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2′-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazcl-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED₅₀) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, PO) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-l59,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.     

Prolonged Anti-Hypertensive Effects of Oral Sitaxsentan, a Selective ETA Endothelin Receptor Antagonist, in Spontaneoulsy Hypertensive Hamsters

Introduction The purpose of this study was to determine whether prolonged oral therapy with sitaxsentan, a potent selective ET_A endothelin receptor antagonist, normalizes systolic blood pressure in spontaneously hypertensive hamsters, a new rodent model of high-renin genetic hypertension. Materials and Methods Spontaneously hypertensive hamsters received either oral sitaxsentan (15 mg kg⁻¹ day⁻¹) dissolved in high purity water or saline for 7 weeks. Systolic blood pressure was monitored in lightly anesthetized animals using the leg-cuff method. Results We found that sitaxsentan elicited a significant decrease in systolic blood pressure in spontaneously hypertensive hamsters from 175 ± 6 mmHg at baseline to 109 ± 7 mmHg after 7 weeks (p < 0.05). Although treatment of spontaneously hypertensive hamsters with saline was also associated with a significant decrease in systolic blood pressure from baseline, the magnitude of response was significantly less than that observed with sitaxsentan (p < 0.05). Discussion Collectively, these proof-of-principle data indicate that prolonged oral sitaxsentan therapy normalizes systolic blood pressure in spontaneously hypertensive hamsters. We suggest that selective ET_A endothelin receptor blockade could be beneficial in the treatment of essential hypertension associated with high renin plasma levels.     

RWJ‐58259: A Selective Antagonist of Protease Activated Receptor‐1

Protease activated receptor‐1 (PAR‐1) is a key mediator of the cellular actions of α‐thrombin. Thus, antagonism of this unique G‐protein coupled receptor with a small molecule represents a means of selectively inhibiting thrombin's cellular actions without inhibiting its proteolytic activity. RWJ‐58259 ((αS)‐N‐[(1S)‐3‐amino‐1‐[[(phenylmethyl)‐amino]carbonyl]propyl]‐α‐[[[[[1‐(2,6‐dichlorophenyl)methyl]‐3‐(1‐pyrrolidinylmethyl)‐1H‐indazol‐6‐yl]amino]carbonyl]amino]‐3,4‐difluorobenzenepropanamide) is a potent and selective inhibitor of PAR‐1 identified as part of a synthetic chemistry program based upon a de novo design approach. RWJ‐58259 inhibited thrombin‐induced platelet aggregation in human platelets with an IC₅₀ of 0.37 μM without inhibiting thrombin's proteolytic activity or aggregation induced by other agonists. RWJ‐58259 was not effective in guinea pig models of thrombosis. This reflected the presence of a second thrombin‐sensitive receptor system in guinea pigs (PAR‐3/4) and the selectivity of RWJ‐58259 for PAR‐1. However, RWJ‐58259 was effective in a non‐human primate model of thrombosis. Because human platelets have a PAR expression profile similar to the non‐human primate, PAR‐1 antagonism has the potential to be antithrombotic in humans. RWJ‐58259 also inhibited thrombin‐induced intracellular calcium signaling and proliferation in rat vascular smooth muscle cells. Perivascular application of RWJ‐58259 in vivo significantly inhibited arterial injury‐induced stenosis in a rat model of balloon angioplasty. These preclinical results suggest a potential clinical utility of RWJ‐58259 for treatment of thrombotic disorders and vascular injury associated with acute coronary interventions and atherosclerosis. Given the potential role of PAR‐1 in thrombin's actions in other cell types and disease states, RWJ‐58259 provides a means for assessing additional clinical utilities of PAR‐1 antagonism in disease conditions such as inflammation, cancer and neurodegeneration.     

CVT‐510: A Selective A1 Adenosine Receptor Agonist

Adenosine is an endogenous nucleoside that has potent antiarrhythmic effects on paroxysmal supraventricular tachycardia (PSVT) due to its negative dromotropic effects on the atrioventricular node. In addition to its electrophysiologic effects, adenosine has important effects on vascular smooth muscle cells, inflammatory cells, the central nervous system, and the kidney. Four known adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃) mediate the pleiotropic effects of adenosine in humans. These receptors are coupled to a wide range of second messenger cascades. Activation of the A¹ adenosine receptor accounts for the negative chronotropic and dromotropic effects of adenosine, whereas A_2A, A_2B and A₃ adenosine receptor activation are responsible for such effects as coronary vasodilation, bronchospasm, inhibition of platelet aggregation, and neuronal stimulation. Elucidation of the specific properties of each of the adenosine receptor subtypes has led to the development of selective ligands as potential therapeutic agents. CVT‐510, N‐(3(R)‐tetrahydrofuranyl)‐6‐aminopurine riboside, was developed as a selective A¹ adenosine receptor agonist that specifically targets the atrioventricular node for termination of PSVT. Preliminary clinical trials have shown that CVT‐510 is effective in terminating PSVT and eliminating many of the undesirable adverse effects of adenosine. CVT‐510 is also being explored as a potential agent for controlling the ventricular rate of atrial fibrillation and flutter.     

Pharmacology of the Thromboxane Receptor Antagonist and Thromboxane Synthase Inhibitor BM‐531

BM‐531 (N‐tert‐butyl‐N'‐[(2‐cyclohexylamino‐5‐nitrobenzene)sulfonyl]urea), a torasemide derivative, is a novel noncarboxylic thromboxane receptor antagonist and thromboxane synthase inhibitor. Indeed, its affinity for human washed platelet TXA₂ receptors labeled with [3H]SQ‐29548 (IC₅₀= 0.0078 μM) is higher than sulotroban (IC₅₀= 0.93 μM) and SQ‐29548 (IC₅₀= 0.021 μM). Moreover, BM‐531 is characterized by a potent antiaggregatory property. Indeed, on one hand, in human citrated platelet‐rich plasma BM‐531 prevents platelet aggregation induced by arachidonic acid (600 μM) (ED₁₀₀= 0.125 μM), U‐46619, a stable TXA₂ agonist (1 μM) (ED₅₀= 0.482 μM) or collagen (1 μg/mL) (percentage of inhibition: 42.9% at 10 μM) and inhibits the second wave of ADP (2 μM)‐induced aggregation. On the other hand, when BM‐531 is incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA‐100®) is significantly prolonged. In addition, at the concentrations of 10 and 1 μM, BM‐531 totally prevents the production of TXB₂ by human platelets activated by arachidonic acid. Finally, at 10 μM, BM‐531 significantly prevents rat fundus contractions induced by U‐46619 but not by prostacyclin. These results suggest that BM‐531, which is devoid of the diuretic property of torasemide, can be regarded as a promising antiplatelet agent.     

Ramatroban (BAY u 3405): A Novel Dual Antagonist of TXA2 Receptor and CRTh2, a Newly Identified Prostaglandin D2 Receptor

It is known that thromboxane A₂ (TXA₂) contributes to various diseases such as bronchial asthma, ischemic heart disease, cerebrovascular disorders and allergic rhinitis. A number of TXA₂ synthase inhibitors and TXA₂ receptor (TP receptor) antagonists have been developed to treat these diseases. Ramatroban (BAY u 3405) was developed as a potent TP receptor antagonist with excellent efficacy against allergic rhinitis in many animal models and patients. Recent studies also revealed that ramatroban can block the newly identified PGD₂ receptor, chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTh2). PGD₂ induces migration and degranulation of eosinophils through CRTh2 and contributes to late‐phase inflammation and cell damage. Accordingly, it was considered that ramatroban suppresses the late‐phase inflammation via TP receptor and CRTh2 blockade. In terms of the efficacy on vascular systems, it was revealed that ramatroban can suppress the expression of monocyte chemoattractant protein‐1 (MCP‐1) and adhesion molecules in endothelial cells and prevent exacerbation of inflammation by blocking these responses. According to our recent studies in hypercholesterolemic rabbits ramatroban prevents macrophage infiltration through MCP‐1 downregulation and neointimal formation after balloon injury and attenuates vascular response to acetylcholine. Therefore, ramatroban may be beneficial in the treatment of atherosclerosis.     

The Effect of a Combination of Inhaled Nitric Oxide and an Endothelin<Subscript>A</Subscript>-Receptor Antagonist onHemodynamic Dysfunction in Experimental AcutePulmonary Thromboembolism

Although either inhaled nitric oxide (NO) or endothelin_A receptor antagonist has been tried in the treatment of various forms of pulmonary hypertension, the effects of combination therapy have not been reported. We evaluated the effects of inhaled NO alone or a combination of inhaled NO and ZD2574 (an endothelin_A receptor antagonist) in an experimental canine acute pulmonary thromboembolism model. Forty parts per million of inhaled NO alone, or a combination of inhaled NO and 10 mg/kg of ZD2574 was administered 1 hour after embolization with an autologous blood clot. We compared the hemodynamic and gas exchange parameters between the two treatment groups. Two treatment regimens decreased mean pulmonary arterial pressure and pulmonary vascular resistance and attenuated decrease in cardiac output. Moreover, systemic arterial hypotension or worsening of hypoxemia did not occur in either of the treatment groups. In the combined group, more favorable hemodynamic outcomes were maintained than in the inhaled NO alone group. And hemodynamic deterioration shown after NO withdrawal was attenuated in the combined group. These findings suggest that when inhaled NO is concomitantly administered with an ET_A receptor antagonist, more favorable hemodynamic outcomes can be expected during and after NO inhalation in acute pulmonary thromboembolism.