eprosartan and candesartan

Candesartan is a novel high-affinity type 1 AT(1)-receptor blocker characterized by prolonged binding to and slow dissociation from the receptor. Pharmacokinetic properties of candesartan explain its pronounced and lengthy (24-36 hours) antihypertensive action which does not depend on patients sex, age and body mass. Long term use of candesartan has been associated with regression of left ventricular hypertrophy, renoprotective effect and lowered risk of stroke. Candesartan is well tolerated. All these features make the drug suitable for wide application in the management of hypertension. Preliminary results suggest that candesartan can be useful in the treatment of diabetic nephropathy.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Diabetic Nephropathies; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Tetrazoles; Thiophenes; Valine; Valsartan

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Growth Hormone; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Models, Molecular; Receptor, Angiotensin, Type 1; Tetrazoles; Thiophenes; Thromboxane A2

The angiotensin (II) receptor (1) blockers are known first of all as antihypertensive drugs, however, due to the role of the tissue renin-angiotensin system (RAS) in different pathological conditions, their clinical importance became more pronounced and are at present more widely used. The article gives an overview of the recent knowledge in this field. Beside of summarizing physiological and the most important pathophysiological aspects of the RAS, as well as pharmacokinetic properties of the different angiotensin receptor blocker drugs used at present in Hungary, the potential differences in blocking of the converting enzyme and the angiotensin II receptors are also reviewed.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Pressure; Humans; Imidazoles; Irbesartan; Losartan; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

Angiotensin II type 1 receptor blockers (AT1RBs) share the effect of attenuating angiotensin II actions with angiotensin-converting enzyme inhibitors (ACEIs) but differ in other respects. Notably, the impact of unopposed angiotensin type 2 receptor stimulation and the absence of augmentation of bradykinin through inhibition of the kininase pathway may lead to differences between the effects of AT1RBs and ACEIs. ACEIs have been shown to improve endothelial dysfunction in many clinical settings.. To review current evidence regarding the effects of AT1RBs on endothelial dysfunction in patients.. MEDLINE and Current Contents searches, augmented by careful analyses of the bibliographies in the identified papers, were used to identify studies assessing the effects of chronic, oral use of AT1RBs on endothelial function and related inflammatory markers in patients. Animal studies and human studies using single doses or intravenous infusions were excluded.. Clinical studies are available pertaining to the elderly and patients with coronary artery disease, hypertension and diabetes. The effect on endothelial dysfunction induced by postprandial lipemia has also been assessed. In general, AT1RBs improve vasomotor endothelial dysfunction and some inflammatory markers, but a few studies comparing ACEIs directly with AT1RBs suggest that AT1RBs may be inferior. AT1RB activity on endothelial dysfunction in patients with type I diabetes has not been shown.. AT1RBs are an important addition to the therapy of endothelial dysfunction and vascular inflammation in patients. Further research is necessary to determine which AT1RBs and which dosing regimens are optimal.

Topics: Acrylates; Aged; Antihypertensive Agents; Benzimidazoles; Biomarkers; Biphenyl Compounds; Coronary Artery Disease; Data Interpretation, Statistical; Diabetes Mellitus; E-Selectin; Endothelium, Vascular; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Tetrazoles; Thiophenes; Vasculitis

Hypertension means a basic public health problem in many countries in the world. The therapeutic attempts of the last years did not fulfill the hopes pinned on them, and most of the patients live with blood pressure above the goal value. This is why there is a need for new, more efficient antihypertensive drugs. On the 1st of July, 2001 irbesartan (Aprovel) was introduced in practice in Hungary. The drug belongs to the family of the angiotensin II receptor inhibitors. Several clinical studies were made with irbesartan in order to evaluate its efficiency, tolerability and safety. In other studies it was compared with other antihypertensive treatments and it was found that irbesartan decreases the systolic and diastolic blood pressure as effectively as other first line medicaments. The author summarizes the most important characteristics of irbesartan as well as the results of those clinical studies which show evidence that irbesartan deserves a special place among antihypertensive drugs.

Topics: Acrylates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Atenolol; Benzimidazoles; Benzoates; Biological Availability; Biphenyl Compounds; Controlled Clinical Trials as Topic; Drug Administration Schedule; Enalapril; Half-Life; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

The ARBs are a new class of drugs with broad therapeutic potential in cardiovascular disease. These agents act by selectively inhibiting the AT1 subtype of the angiotensin II receptors. They are effective antihypertensive agents with promise, theoretically, in the prevention and regression of ventricular hypertrophy. They are safe and well tolerated in patients with CHF and might be effective in improving survival and reducing morbidity. ARBs also might have a similar role in improving the clinical outcomes of patients with coronary artery disease and chronic nephropathy. Their precise role in the treatment and prevention of cardiovascular and renal disease should be established by several ongoing clinical trials.

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biological Availability; Biphenyl Compounds; Cardiovascular Diseases; Humans; Imidazoles; Irbesartan; Kidney Diseases; Losartan; Metabolic Clearance Rate; Patient Selection; Renin-Angiotensin System; Telmisartan; Tetrazoles; Thiophenes; Treatment Outcome; Valine; Valsartan

Angiotensin receptor antagonists (ARB) are equally effective but better tolerated than all the other blood pressure lowering agents. The reason, why they are not subscribed as first line drugs for uncomplicated hypertension, is the higher price for these products. What the real difference in costs is, remains unclear because calculations are missing to what extent lesser controls of therapy would shift the balance in favour of the ARBs. For other indications than hypertension, but often associated with that condition, be it per se or as a consequence of it, the effects of the ARBs are studied in large trials these days. For some of them the benefit, which has been proven for ACE inhibitors, is not yet established for the ARBs, but evidence emerges that they are also useful in the treatment of cardiac failure, left ventricular hypertrophy and diabetic and other kinds of nephropathy. A large percentage of hypertensive patients can be treated effectively with ARBs without considerable side effects, thus increasing adherence and minimizing the necessity of safety controls.

Topics: Acrylates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Austria; Benzimidazoles; Benzoates; Biphenyl Compounds; Humans; Hypertension; Imidazoles; Losartan; Prodrugs; Telmisartan; Tetrazoles; Therapeutic Equivalency; Thiophenes; Valine; Valsartan

Topics: Acrylates; Aldosterone; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Drug Therapy, Combination; Heart; Humans; Hypertension; Imidazoles; Irbesartan; Kidney; Losartan; Renin-Angiotensin System; Telmisartan; Tetrazoles; Thiophenes

The efficacy of ACE-inhibitors and beta blockers is well documented in the therapy of heart failure. As pharmacological mechanisms of ATI-receptor-antagonists differ, an additional positive effect can be expected when combining these drugs.. Eighty patients (67.9 +/- 9.9 years) with severe chronic heart failure receiving long-term medication with diuretics, ACE-inhibitors and partially beta blockers (72.5%), were randomized after clinical recompensation to eprosartan (477.5 +/- 143.7 mg/d), telmisartan (65.9 +/- 17.7 mg), candesartan (11.9 +/- 4.0 mg) or no sartan, according to a prospective study. Haemodynamic measurements by impedance cardiography were performed (mean observation time 15.8 days).. Additional sartan treatment resulted in an improvement of cardiac output from 2.32 +/- 0.69 to 3.12 +/- 1.24 l/min (P = 0.003) in the eprosartan group, from 2.24 +/- 0.59 to 2.76 +/- 0.91 l/min (P = 0.001) in the telmisartan group and from 2.76 +/- 0.84 to 3.11 +/- 0.94 l/min (P = 0.02) in the candesartan group. Furthermore, a significant decrease of the total peripheral resistance was measured under eprosartan (23%; P = 0.002), telmisartan (18%; P = 0.002) and candesartan treatment (11.5%; P = 0.049); in the subgroup of combined therapy with beta blockers, ACE-inhibitors and ATI-antagonists a significant increase in cardiac output was also observed. No change was observed in the control group without additional sartan treatment concerning cardiac output and resistance reduction.. The additional treatment with different ATI-receptor-antagonists resulted in an increase of the cardiac output and a decrease of the peripheral resistance. This beneficial effect may be due to the additional property of sartans to block the interaction of locally and not-ACE-generated angiotensin II with their vascular and myocardial ATI-receptors.

Topics: Acrylates; Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Biomarkers; Biphenyl Compounds; Blood Pressure; Cardiac Output; Chronic Disease; Drug Therapy, Combination; Female; Heart Failure; Heart Rate; Humans; Imidazoles; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Telmisartan; Tetrazoles; Thiophenes; Treatment Outcome; Vascular Resistance

Pharmaceuticals and other anthropogenic trace contaminants reach wastewaters and are often not satisfactorily eliminated in sewage treatment plants. These contaminants and/or their degradation products may reach surface waters, thus influencing aquatic life. In this study, the behavior of five different antihypertonic pharmaceuticals from the sartan group (candesartan, eprosartan, irbesartan, olmesartan and valsartan) is investigated in lab-scale sewage plants. The elimination of the substances with related structures varied broadly from 17 % for olmesartan up to 96 % for valsartan. Monitoring data for these drugs in wastewater effluents of six different sewage treatment plants (STPs) in Bavaria, and at eight rivers, showed median concentrations for, e.g. valsartan of 1.1 and 0.13 μg L(-1), respectively. Predicted environmental concentrations (PEC) were calculated and are mostly consistent with the measured environmental concentrations (MEC). The selected sartans and the mixture of the five sartans showed no ecotoxic effects on aquatic organisms in relevant concentrations. Nevertheless, the occurrence of pharmaceuticals in the environment should be reduced to minimize the risk of their distribution in surface waters, ground waters and bank filtrates used for drinking water.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biodegradation, Environmental; Biphenyl Compounds; Chromatography, Liquid; Environmental Monitoring; Germany; Imidazoles; Irbesartan; Mass Spectrometry; Molecular Structure; Rivers; Tetrazoles; Thiophenes; Valine; Valsartan; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical

About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II receptor subtype 2) receptor subtypes. In this paper, partial least squares discriminant analysis is applied to derive the chemical features guiding AT(1) and AT(2) selectivity or mixed AT(1)/AT(2) receptor binding. The method can be used to modulate AT(1) versus AT(2) selectivity. Concerns that unopposed stimulation of the AT(2) receptor might produce adverse effects initiated a search for new balanced antagonists. Moreover, it can serve as a fast filtering procedure in database searches. Finally, some relevant pharmacokinetics and metabolic properties of the database of 53 compounds are calculated using the VolSurf and MetaSite software to allow the simultaneous characterization of pharmacodynamic and pharmacokinetics properties of the chemical space of angiotensin II receptor antagonists.

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Binding Sites; Biphenyl Compounds; Kinetics; Losartan; Models, Molecular; Molecular Conformation; Oxidation-Reduction; Pharmaceutical Preparations; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Structure-Activity Relationship; Tetrazoles

Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities.. The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists.. Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan.. In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II.. Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (-42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity.. AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

Topics: Acrylates; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Electric Stimulation; Imidazoles; Irbesartan; Losartan; Male; Norepinephrine; Rats; Rats, Inbred SHR; Sympathetic Fibers, Postganglionic; Sympatholytics; Tetrazoles; Thiophenes; Time Factors; Treatment Outcome

The aim of the present study was to determine the inhibitory potency of two selective angiotensin AT(1) receptor antagonists, eprosartan and candesartan, at the level of the sympathetic nerve terminal and the vascular smooth muscle. Male New Zealand White rabbits, weighing 2100-2550 g, were used. To study eprosartan and candesartan at the neuronal angiotensin AT(1) receptor, we investigated their influence on the angiotensin II-enhanced, electrical field stimulation-evoked sympathetic transmission in the rabbit isolated thoracic aorta in a noradrenaline spillover model. To study both antagonists at the vascular angiotensin AT(1) receptor, concentration-response curves for angiotensin II were constructed in the presence or absence of the two angiotensin AT(1) receptor antagonists. Angiotensin II (10 nM) caused a significant increase by 107+/-11.1% of the stimulation-evoked sympathetic outflow, which was concentration-dependently inhibited by both eprosartan (pIC(50) 7.91+/-0.12) and candesartan (pIC(50) 10.76+/-0.13). Angiotensin II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force (E(max) 20.62+/-2.24 mN, pD(2) 8.16+/-0.04). Both eprosartan (pA(2) 8.90+/-0.11, pIC(50) 8.87+/-0.12 (10 nM angiotensin II)) and candesartan (pD(2)' 10.80+/-0.13) counteracted the contractions evoked by cumulative concentrations of angiotensin II. Candesartan proved a more potent antagonist than eprosartan at both the pre- and postjunctional angiotensin AT(1) receptor. For eprosartan, vascular inhibitory concentrations were 10-fold lower than sympatho-inhibitory concentrations, whereas for candesartan, inhibitory concentrations at both sites were similar. The results may be explained by differences between the pre- and postjunctional angiotensin AT(1) receptor subtype.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Benzimidazoles; Biphenyl Compounds; Dose-Response Relationship, Drug; Imidazoles; In Vitro Techniques; Male; Presynaptic Terminals; Rabbits; Receptor, Angiotensin, Type 1; Tetrazoles; Thiophenes; Vasoconstriction

Topics: Acrylates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Diuretics; Dizziness; Drug Combinations; Drug Interactions; Heart Failure; Humans; Hypertension; Imidazoles; Irbesartan; Kidney Diseases; Losartan; Olmesartan Medoxomil; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

Topics: Acrylates; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Clinical Trials as Topic; Germany; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Olmesartan Medoxomil; Placebos; Telmisartan; Tetrazoles; Therapeutic Equivalency; Thiophenes; Time Factors; Valine; Valsartan

Effects of angiotensin II type 1 (AT1) receptor antagonists eprosartan and candesartan and AT2 receptor antagonist PD123319 on Ang II-induced facilitation of noradrenergic neurotransmission were investigated in isolated rabbit mesenteric artery under isometric conditions. Sympathoinhibitory potency of AT1 blockers was compared with their potency concerning inhibition of direct vasoconstrictor effect of Ang II. To investigate blockade of presynaptic AT1 and AT2 receptors, effects of Ang II on electrical field stimulation (EFS)-induced contractions in presence or absence of eprosartan, candesartan, or PD123319 were studied. To investigate blockade of postsynaptic AT1 receptors, effects of either eprosartan or candesartan on concentration-response curves of Ang II were studied. In addition, effect of Ang II on postsynaptic alpha-adrenoceptor-mediated responses was studied using noradrenaline. EFS (1, 2, and 4 Hz) caused an increase of contractile force. At stimulation frequencies of 1, 2, and 4 Hz, a subpressor concentration of Ang II (0.5 nM) increased stimulation-induced vasoconstrictor responses by 2.8 +/- 0.5, 2.4 +/- 0.4, and 1.6 +/- 0.1 of control values, respectively (p < 0.05 compared with control for all frequencies). The enhancement could be antagonized by eprosartan (1 nM-0.1 microM) and candesartan (1 nM-0.1 microM). The AT2 antagonist PD123319 (10 nM) did not influence Ang II-induced facilitation of stimulation-induced contractions. Contractile responses to exogenous noradrenaline were unaltered in presence of Ang II 0.5 nM. Ang II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force, which could be antagonized by eprosartan (pD2; 8.8 +/- 0.19) and candesartan (pD2; 11.3 +/- 0.23). Thus, the facilitating effect of Ang II on noradrenergic neurotransmission is mediated by presynaptically located AT1 receptors and not by AT2 receptors. For eprosartan, sympathoinhibition was achieved at concentrations that also block AT1 receptors on vascular smooth muscle. In contrast, for candesartan, presynaptic inhibitory concentrations were considerably higher than those required for postsynaptic inhibition.

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Dose-Response Relationship, Drug; Female; Imidazoles; In Vitro Techniques; Male; Mesenteric Arteries; Rabbits; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Presynaptic; Tetrazoles; Thiophenes

In the present study, we analyzed the effects of two angiotensin II type 1 receptor antagonists, candesartan (0.1 microM) and eprosartan (1 microM), on hKv1.5, HERG, KvLQT1+minK, and Kv4.3 channels expressed on Ltk(-) or Chinese hamster ovary cells using the patch-clamp technique. Candesartan and eprosartan produced a voltage-dependent block of hKv1.5 channels decreasing the current at +60 mV by 20.9 +/- 2.3% and 14.3 +/- 1.5%, respectively. The blockade was frequency-dependent, suggesting an open-channel interaction. Eprosartan inhibited the tail amplitude of HERG currents elicited on repolarization after pulses to +60 mV from 239 +/- 78 to 179 +/- 72 pA. Candesartan shifted the activation curve of HERG channels in the hyperpolarizing direction, thus increasing the current amplitude elicited by depolarizations to potentials between -50 and 0 mV. Candesartan reduced the KvLQT1+minK currents elicited by 2-s pulses to +60 mV (38.7 +/- 6.3%). In contrast, eprosartan transiently increased (8.8 +/- 2.7%) and thereafter reduced the KvLQT1+minK current amplitude by 17.7 +/- 3.0%. Eprosartan, but not candesartan, blocked Kv4.3 channels in a voltage-dependent manner (22.2 +/- 3.5% at +50 mV) without modifying the voltage-dependence of Kv4.3 channel inactivation. Candesartan slightly prolonged the action potential duration recorded in guinea pig papillary muscles at all driving rates. Eprosartan prolonged the action potential duration in muscles driven at 0.1 to 1 Hz, but it shortened this parameter at faster rates (2--3 Hz). All these results demonstrated that candesartan and eprosartan exert direct effects on Kv1.5, HERG, KvLQT1+minK, and Kv4.3 currents involved in human cardiac repolarization.

Topics: Acrylates; Action Potentials; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Cation Transport Proteins; Cell Line; CHO Cells; Cricetinae; DNA-Binding Proteins; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Heart Conduction System; Heart Ventricles; Humans; Imidazoles; In Vitro Techniques; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Kv1.5 Potassium Channel; Mice; Papillary Muscles; Patch-Clamp Techniques; Potassium Channels; Potassium Channels, Voltage-Gated; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Shal Potassium Channels; Tetrazoles; Thiophenes; Trans-Activators; Transcriptional Regulator ERG

Topics: Acrylates; Angioedema; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Black or African American; Clinical Trials as Topic; Cough; Female; Humans; Imidazoles; Irbesartan; Losartan; Male; Randomized Controlled Trials as Topic; Sex Factors; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

In the pithed rat model, endogenously generated angiotensin (Ang) II can enhance sympathetic neurotransmission by acting on Ang II type 1 (AT1) receptors that are located on sympathetic nerve terminals.. To compare the inhibitory potency of candesartan, valsartan, eprosartan and embusartan in blocking presynaptically and postsynaptically located AT1 receptors.. To investigate blockade of presynaptic AT1 receptors, we studied the effect of AT1 receptor blockade on the sequelae of electrical stimulation of the thoracolumbar sympathetic outflow (0.25-8 Hz). To investigate the interaction between postsynaptic AT1 blockers and alpha-adrenoceptors, the effects of these compounds on pressor responses to exogenous noradrenaline were determined. To investigate blockade of postsynaptic AT1 receptors, we studied the effect of the AT1 antagonists on dose-response curves elicited by exogenous Ang II.. The stimulation-induced increase in diastolic blood pressure (DBP) and the Ang II-elicited DBP response were dose-dependently reduced by all AT1 receptor blockers. Interestingly, the greatest doses of the AT1 antagonists caused less than maximal reduction in the stimulation-induced increase in DBP, resulting in a U-shaped dose-response relationship. To compare sympathoinhibitory potencies, the doses that, at 2 Hz, reduced the change in DBP by 20 mmHg (ED20 values, expressed as -log mol/kg) were calculated; they were 5.50 +/- 0.12, 5.77 +/- 0.10, 6.32 +/- 0.12 and 5.62 +/- 0.13 for valsartan, candesartan, eprosartan and embusartan, respectively. The order of potency, therefore, was eprosartan> valsartan = candesartan = embusartan (where > signifies P < 0.05). To compare the order of potency for inhibition of the Ang II-induced increase in DBP, we calculated pA2 values (the X intercept in Schild regression). They were 7.20 +/- 0.17, 8.01 +/- 0.01, 7.20 +/- 0.03 and 7.25 +/- 0.16, for valsartan, candesartan, eprosartan and embusartan, respectively. Accordingly, the order of potency for inhibition of the direct pressor effects of Ang II was candesartan> valsartan = eprosartan = embusartan (where > signifies P < 0.05).. In the pithed rat, the effects on DBP of stimulation of the thoracolumbar spinal cord are partly dependent on endogenously formed Ang II. These effects can be counteracted by blockade of presynaptically located AT1 receptors. No interaction was found between postsynaptically located AT1 receptors and alpha-adrenoceptors. The order of potency of the agents tested for sympathoinhibition clearly differed from that for inhibition of the direct pressor effects of Ang II. These findings suggest considerable differences in affinity of the various AT1 blockers for pre- and postsynaptic AT1 receptors.

Topics: Acrylates; Adrenergic alpha-Agonists; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Decerebrate State; Dihydropyridines; Dose-Response Relationship, Drug; Imidazoles; Male; Norepinephrine; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Sympathetic Nervous System; Synaptic Transmission; Tetrazoles; Thiophenes; Valine; Valsartan

Metabolic interactions at the level of drug-metabolising enzymes are important for drug therapy. We investigated potential interactions of losartan, irbesartan, valsartan, eprosartan and candesartan with cytochrome P450 (CYP) enzymes in human liver microsomes.. In incubations with human liver microsomes in vitro, the inhibitory potency of angiotensin-II receptor antagonists (sartans) on CYP-specific model activities were compared by measuring the IC50 and, with respect to more potent inhibition, Ki values.. None of the five sartans inhibited CYP2A6-, CYP2D6- or CYP2E1-associated activities (coumarin 7-hydroxylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation, respectively) to any significant extent. Losartan and irbesartan inhibited the CYP2C9-associated tolbutamide methylhydroxylation more potently (Ki values 4.1 microM and 24.5 microM), than valsartan, candesartan or eprosartan (Ki values 135 microM, 155 microM and > 1000 microM, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4-associated activities (ethoxyresorufin O-deethylation and testosterone 6beta-hydroxylation) with relatively weak affinities (IC50 values between 200 microM and 500 microM). CYP2C1OFF S-mephenytoin 4'-hydroxylation activity was inhibited by losartan (IC50 value 138 microM) and much less or not at all by the other sartans tested.. All sartans except eprosartan have at least some affinity for CYP2C9, but only losartan has an affinity for CYP2C19. Losartan and irbesartan have modest affinity for CYP1A2 and CYP3A4. This would suggest that the theoretical potential for drug interactions is likely to be quite low, with the possible exceptions of losartan and irbesartan for CYP2C9. Based on these findings, further studies on the interaction potential of losartan and irbesartan are warranted.

Topics: Acrylates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Inhibitors; Humans; Imidazoles; In Vitro Techniques; Inhibitory Concentration 50; Irbesartan; Losartan; Microsomes, Liver; Protein Isoforms; Tetrazoles; Thiophenes; Valine; Valsartan