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Article ; Online: Factors influencing hepatic metabolism of antihypertensive drugs: impact on clinical response.

Höcht, Christian / Bertera, Facundo M / Santander Plantamura, Yanina / Parola, Luciano / Del Mauro, Julieta S / Polizio, Ariel H

Expert opinion on drug metabolism & toxicology

2018 Volume 15, Issue 1, Page(s) 1–13

Abstract: Introduction: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral ... ...

Abstract	Introduction: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including β-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific β-blockers, calcium channel blockers, and angiotensin receptor blockers.
MeSH term(s)	Adrenergic beta-Antagonists/administration & dosage ; Adrenergic beta-Antagonists/pharmacokinetics ; Angiotensin Receptor Antagonists/administration & dosage ; Angiotensin Receptor Antagonists/pharmacokinetics ; Antihypertensive Agents/administration & dosage ; Antihypertensive Agents/pharmacokinetics ; Antihypertensive Agents/pharmacology ; Blood Pressure/drug effects ; Calcium Channel Blockers/administration & dosage ; Calcium Channel Blockers/pharmacokinetics ; Dose-Response Relationship, Drug ; Genotype ; Humans ; Hypertension/drug therapy
Chemical Substances	Adrenergic beta-Antagonists ; Angiotensin Receptor Antagonists ; Antihypertensive Agents ; Calcium Channel Blockers
Language	English
Publishing date	2018-12-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2214462-6
ISSN	1744-7607 ; 1742-5255
ISSN (online)	1744-7607
ISSN	1742-5255
DOI	10.1080/17425255.2019.1558204
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Article ; Online: What is the Real Efficacy of Beta-Blockers for the Treatment of Essential Hypertension?

Hocht, Christian / Bertera, Facundo M / Del Mauro, Julieta S / Santander Plantamura, Yanina / Taira, Carlos A / Polizio, Ariel H

Current pharmaceutical design

2017 Volume 23, Issue 31, Page(s) 4658–4677

Abstract: Objective: This review covers the pharmacokinetics and pharmacodynamic of β-blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third-generation β-blockers ... ...

Abstract	Objective: This review covers the pharmacokinetics and pharmacodynamic of β-blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third-generation β-blockers beyond hypertension. Background: The efficacy and safety of β-blockers in the treatment of hypertension and other cardiovascular diseases have been established during more than 50 years of clinical experience. Recent updates of clinical guidelines have downgraded the use of β-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that β-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating β-blockers (atenolol and metoprolol) are inferior to first-line antihypertensive agents in terms of cardioprotection due to lower ability to reduce central blood pressure and its variability and the adverse effects on glycemic and lipid metabolism. Conclusion: New vasodilating β-blockers, mainly carvedilol and nebivolol, show enhanced hemodynamic and metabolic properties, which probably result in a higher prevention of major cardiovascular events in hypertensive patients. Despite head-to-head clinical trials comparing the effects of vasodilating vs nonvasodilating β-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation β-blockers are superior to conventional β-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation β-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a "promissory new era" of this newly group.
MeSH term(s)	Adrenergic beta-Antagonists/adverse effects ; Adrenergic beta-Antagonists/therapeutic use ; Antihypertensive Agents/adverse effects ; Antihypertensive Agents/therapeutic use ; Blood Pressure/drug effects ; Essential Hypertension/drug therapy ; Glycemic Index/drug effects ; Humans ; Lipid Metabolism/drug effects
Chemical Substances	Adrenergic beta-Antagonists ; Antihypertensive Agents
Language	English
Publishing date	2017
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	1304236-1
ISSN	1873-4286 ; 1381-6128
ISSN (online)	1873-4286
ISSN	1381-6128
DOI	10.2174/1381612823666170608085109
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Article ; Online: Effects of third-generation β-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats.

Del Mauro, Julieta S / Prince, Paula D / Allo, Miguel A / Santander Plantamura, Yanina / Morettón, Marcela A / González, Germán E / Bertera, Facundo M / Carranza, Andrea / Gorzalczany, Susana B / Chiappetta, Diego A / Morales, Celina / Gelpi, Ricardo J / Taira, Carlos A / Polizio, Ariel H / Donato, Martín / Höcht, Christian

Journal of hypertension

2020 Volume 38, Issue 3, Page(s) 536–545

Abstract: Background: β-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection.: Method: Considering the differences in the pharmacological properties of β-blockers, the present work compared the effects of ... ...

Abstract	Background: β-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. Method: Considering the differences in the pharmacological properties of β-blockers, the present work compared the effects of third-generation β-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor β (TGF-β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Results: Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-β, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine. Conclusion: Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating β-blockers, as atenolol, in hypertension must not be translated to third-generation β-blockers.
MeSH term(s)	Adrenergic beta-Antagonists/adverse effects ; Adrenergic beta-Antagonists/pharmacology ; Amlodipine/adverse effects ; Amlodipine/pharmacology ; Animals ; Antihypertensive Agents/pharmacology ; Aorta/drug effects ; Atenolol/adverse effects ; Atenolol/pharmacology ; Blood Pressure/drug effects ; Cytokines/metabolism ; Heart Ventricles/drug effects ; Rats ; Rats, Inbred SHR
Chemical Substances	Adrenergic beta-Antagonists ; Antihypertensive Agents ; Cytokines ; Amlodipine (1J444QC288) ; Atenolol (50VV3VW0TI)
Language	English
Publishing date	2020-02-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605532-1
ISSN	1473-5598 ; 0263-6352 ; 0952-1178
ISSN (online)	1473-5598
ISSN	0263-6352 ; 0952-1178
DOI	10.1097/HJH.0000000000002284
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Article ; Online: Nebivolol is more effective than atenolol for blood pressure variability attenuation and target organ damage prevention in L-NAME hypertensive rats.

Del Mauro, Julieta S / Prince, Paula D / Santander Plantamura, Yanina / Allo, Miguel A / Parola, Luciano / Fernandez Machulsky, Nahuel / Morettón, Marcela A / Bin, Eliana P / González, Germán E / Bertera, Facundo M / Carranza, Andrea / Berg, Gabriela / Taira, Carlos A / Donato, Martín / Chiappetta, Diego A / Polizio, Ariel H / Höcht, Christian

Hypertension research : official journal of the Japanese Society of Hypertension

2021 Volume 44, Issue 7, Page(s) 791–802

Abstract: β-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional β-blockers compared with other antihypertensive drugs. It is unknown whether third-generation β-blockers share the limitations of ... ...

Abstract	β-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional β-blockers compared with other antihypertensive drugs. It is unknown whether third-generation β-blockers share the limitations of traditional β-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor β (TGF-β), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional β-blockers must not be carried forward to third-generation β-blockers.
MeSH term(s)	Animals ; Antihypertensive Agents/pharmacology ; Atenolol/pharmacology ; Blood Pressure/drug effects ; Blood Pressure/physiology ; Hypertension/drug therapy ; Male ; Nebivolol/pharmacology ; Rats ; Rats, Wistar ; Treatment Outcome
Chemical Substances	Antihypertensive Agents ; Nebivolol (030Y90569U) ; Atenolol (50VV3VW0TI)
Language	English
Publishing date	2021-02-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1175297-x
ISSN	1348-4214 ; 0916-9636
ISSN (online)	1348-4214
ISSN	0916-9636
DOI	10.1038/s41440-021-00630-4
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Article ; Online: Novel carvedilol paediatric nanomicelle formulation: in-vitro characterization and in-vivo evaluation.

Wegmann, Marcel / Parola, Luciano / Bertera, Facundo M / Taira, Carlos A / Cagel, Maximiliano / Buontempo, Fabian / Bernabeu, Ezequiel / Höcht, Christian / Chiappetta, Diego A / Moretton, Marcela A

The Journal of pharmacy and pharmacology

2017 Volume 69, Issue 5, Page(s) 544–553

Abstract: Objectives: Carvedilol (CAR) is a poorly water-soluble beta-blocker. Its encapsulation within nanomicelles (NMs) could improve drug solubility and its oral bioavailability, allowing the development of a paediatric liquid CAR formulation with ... ...

Abstract	Objectives: Carvedilol (CAR) is a poorly water-soluble beta-blocker. Its encapsulation within nanomicelles (NMs) could improve drug solubility and its oral bioavailability, allowing the development of a paediatric liquid CAR formulation with commercially available copolymers: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(vinyl caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) (Soluplus Methods: Drug-loaded NMs were prepared by copolymer and CAR dispersion in distilled water. Micellar size and morphology were characterized by dynamic light scattering and transmission electron microscopy, respectively. In-vitro drug permeation studies were evaluated by conventional gut sac method. In-vivo CAR oral bioavailability from NMs dispersions and drug control solution was evaluated in Wistar rats. Key findings: Carvedilol apparent aqueous solubility was increased (up to 60.4-folds) after its encapsulation within NMs. The micellar size was ranged between 10.9 and 81.9 nm with a monomodal size distribution. There was a significant enhancement of CAR relative oral bioavailability for both copolymers vs a micelle-free drug solution (P < 0.05). This improvement was higher for TPGS-based micelles (4.95-fold) in accordance with the in-vitro CAR permeation results. Conclusions: The present investigation demonstrates the development of highly concentrated CAR liquid micellar formulation. The improvement on drug oral bioavailability contributes to the potential of this NMs formulation to enhance CAR paediatric treatment.
MeSH term(s)	Administration, Oral ; Animals ; Biological Availability ; Carbazoles/chemistry ; Carbazoles/metabolism ; Chemistry, Pharmaceutical/methods ; Drug Carriers/chemistry ; Male ; Micelles ; Microscopy, Electron, Transmission/methods ; Nanoparticles/chemistry ; Particle Size ; Polyethylene Glycols/chemistry ; Polymers/chemistry ; Polyvinyls/chemistry ; Propanolamines/chemistry ; Propanolamines/metabolism ; Rats ; Rats, Wistar ; Solubility ; Vitamin E/chemistry
Chemical Substances	Carbazoles ; Drug Carriers ; Micelles ; Polymers ; Polyvinyls ; Propanolamines ; polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer ; carvedilol (0K47UL67F2) ; Vitamin E (1406-18-4) ; Polyethylene Glycols (30IQX730WE) ; tocophersolan (O03S90U1F2)
Language	English
Publishing date	2017-05
Publishing country	England
Document type	Journal Article
ZDB-ID	3107-0
ISSN	2042-7158 ; 0022-3573 ; 0373-1022
ISSN (online)	2042-7158
ISSN	0022-3573 ; 0373-1022
DOI	10.1111/jphp.12605
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Article: Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension.

Bertera, Facundo M / Mayer, Marcos A / Opezzo, Javier A W / Taira, Carlos A / Höcht, Christian

The Journal of pharmacy and pharmacology

2009 Volume 61, Issue 1, Page(s) 79–87

Abstract: Objectives: The aim of this work was to evaluate the pharmacokinetic-pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this ...

Abstract	Objectives: The aim of this work was to evaluate the pharmacokinetic-pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers. Methods: A 'shunt' microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham-operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified Emax model. Key findings: Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effect was greater in ACo rats than in SO rats. Conclusions: ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high-renin levels.
MeSH term(s)	Algorithms ; Animals ; Antihypertensive Agents/blood ; Antihypertensive Agents/pharmacokinetics ; Antihypertensive Agents/therapeutic use ; Area Under Curve ; Blood Pressure/drug effects ; Calcium Channel Blockers/administration & dosage ; Calcium Channel Blockers/pharmacokinetics ; Calcium Channel Blockers/therapeutic use ; Chromatography, High Pressure Liquid ; Diltiazem/blood ; Diltiazem/pharmacokinetics ; Diltiazem/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Heart Rate/drug effects ; Hypertension/blood ; Hypertension/drug therapy ; Hypertension/physiopathology ; Injections, Intravenous ; Male ; Microdialysis ; Rats ; Rats, Sprague-Dawley ; Renin/blood ; Treatment Outcome
Chemical Substances	Antihypertensive Agents ; Calcium Channel Blockers ; Renin (EC 3.4.23.15) ; Diltiazem (EE92BBP03H)
Language	English
Publishing date	2009-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3107-0
ISSN	2042-7158 ; 0022-3573 ; 0373-1022
ISSN (online)	2042-7158
ISSN	0022-3573 ; 0373-1022
DOI	10.1211/jpp/61.01.0011
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Article ; Online: Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability.

Del Mauro, Julieta S / Prince, Paula D / Donato, Martín / Fernandez Machulsky, Nahuel / Morettón, Marcela A / González, Germán E / Bertera, Facundo M / Carranza, Andrea / Gorzalczany, Susana B / Chiappetta, Diego A / Berg, Gabriela / Morales, Celina / Gelpi, Ricardo J / Taira, Carlos A / Höcht, Christian

Journal of the American Society of Hypertension : JASH

2017 Volume 11, Issue 4, Page(s) 227–240

Abstract: The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were ... ...

Abstract	The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor β, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor β, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats.
Language	English
Publishing date	2017-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2276144-5
ISSN	1878-7436 ; 1933-1711
ISSN (online)	1878-7436
ISSN	1933-1711
DOI	10.1016/j.jash.2017.02.007
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Article: Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension.

Bertera, Facundo M / Mayer, Marcos A / Opezzo, Javier A W / Taira, Carlos A / Höcht, Christian

Journal of pharmacological and toxicological methods

2008 Volume 57, Issue 3, Page(s) 212–219

Abstract: Introduction: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension.: Methods: A "shunt" ... ...

Abstract	Introduction: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg(-1)). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified E(max) model. Results: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and E(max) model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified E(max) model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. Discussion: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical E(max) model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified E(max) model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified E(max) pharmacodynamic model is the most suitable for verapamil PK-PD modeling.
MeSH term(s)	Animals ; Aorta/surgery ; Aortic Coarctation/complications ; Aortic Coarctation/surgery ; Blood Pressure/drug effects ; Calcium Channel Blockers/pharmacokinetics ; Dose-Response Relationship, Drug ; Heart Rate/drug effects ; Hypertension, Renovascular/etiology ; Hypertension, Renovascular/metabolism ; Hypertension, Renovascular/physiopathology ; Injections, Intravenous ; Male ; Models, Biological ; Rats ; Rats, Wistar ; Reproducibility of Results ; Verapamil/pharmacokinetics
Chemical Substances	Calcium Channel Blockers ; Verapamil (CJ0O37KU29)
Language	English
Publishing date	2008-05
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2008.03.002
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Article: Involvement of angiotensin-(1-7) in the hypothalamic hypotensive effect of captopril in sinoaortic denervated rats.

Höcht, Christian / Gironacci, Mariela M / Mayer, Marcos A / Schuman, Mariano / Bertera, Facundo M / Taira, Carlos A

Regulatory peptides

2008 Volume 146, Issue 1-3, Page(s) 58–66

Abstract: The role of anterior hypothalamic angiotensin-(1-7) (Ang-(1-7)) on blood pressure regulation was studied in sinoaortic denervated (SAD) rats. Since angiotensin-converting enzyme inhibitors increase endogenous levels of Ang-(1-7), we addressed the ... ...

Abstract	The role of anterior hypothalamic angiotensin-(1-7) (Ang-(1-7)) on blood pressure regulation was studied in sinoaortic denervated (SAD) rats. Since angiotensin-converting enzyme inhibitors increase endogenous levels of Ang-(1-7), we addressed the involvement of Ang-(1-7) in the hypotensive effect induced by captopril in SAD rats. Wistar rats 7 days after SAD or sham operation (SO) were anaesthetized and the carotid artery was cannulated for monitoring mean arterial pressure (MAP). A needle was inserted into the anterior hypothalamus for drug administration. Intrahypothalamic administration of Ang-(1-7) (5 pmol) was without effect in SO rats but reduced MAP in SAD rats by 15.5+/-3.2 mm Hg and this effect was blocked by 250 pmol [D-Ala(7)]-Ang-(1-7), a Mas receptor antagonist. Angiotensin II (Ang II) induced an increase in MAP in both groups being the effect greater in SAD rats (DeltaMAP=15.8+/-1.4 mm Hg) than in SO rats (DeltaMAP=9.6+/-1.0 mm Hg). Ang-(1-7) partially abolished the pressor response caused by Ang II in SAD rats. Whilst the captopril intrahypothalamic injection did not affect MAP in SO animals, it significantly reduced MAP in SAD rats (DeltaMAP=-13.3+/-1.9 mm Hg). Either [D-Ala(7)]-Ang-(1-7) or an anti-Ang-(1-7) polyclonal antibody partially blocked the MAP reduction caused by captopril. In conclusion, whilst Ang-(1-7) does not contribute to hypothalamic blood pressure regulation in SO normotensive animals, in SAD rats the heptapeptide induces a reduction of blood pressure mediated by Mas receptor activation. Although Ang-(1-7) is not formed in enough amount in the AHA of SAD animals to exert cardiovascular effects in normal conditions, our results suggest that enhancement of hypothalamic Ang-(1-7) levels by administration of captopril is partially involved in the hypotensive effect of the ACE inhibitor.
MeSH term(s)	Angiotensin I/administration & dosage ; Angiotensin I/pharmacology ; Animals ; Antihypertensive Agents/pharmacology ; Aorta, Thoracic ; Captopril/pharmacology ; Denervation ; Drug Synergism ; Hypotension/chemically induced ; Hypotension/drug therapy ; Hypotension/physiopathology ; Hypothalamus/drug effects ; Hypothalamus/metabolism ; Male ; Peptide Fragments/administration & dosage ; Peptide Fragments/pharmacology ; Rats ; Rats, Wistar
Chemical Substances	Antihypertensive Agents ; Peptide Fragments ; Angiotensin I (9041-90-1) ; Captopril (9G64RSX1XD) ; angiotensin I (1-7) (IJ3FUK8MOF)
Language	English
Publishing date	2008-02-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	225685-x
ISSN	1873-1686 ; 0167-0115
ISSN (online)	1873-1686
ISSN	0167-0115
DOI	10.1016/j.regpep.2007.08.001
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Article: Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: a microdialysis study.

Bertera, Facundo M / Mayer, Marcos A / Opezzo, Javier A W / Taira, Carlos A / Bramuglia, Guillermo F / Höcht, Christian

Journal of pharmacological and toxicological methods

2007 Volume 56, Issue 3, Page(s) 290–299

Abstract: Introduction: The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar ... ...

Abstract	Introduction: The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. Methods: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized SHR and WKY rats for simultaneous determination of unbound plasma concentrations of diltiazem and their effects on mean arterial pressure (MAP) and heart rate (HR) after the intravenous application of 1 and 3 mg kg(-1) of the drug. Correlation between diltiazem plasma levels and their cardiovascular effects was established by fitting the data to a conventional and modified E(max) model. Results: Volume of distribution and clearance of diltiazem was greater in SHR than in WKY animals. A proportional increase of area under curve with dose increment was observed in WKY animals but not in SHR. A good correlation between plasma unbound concentrations of diltiazem and their hypotensive and chronotropic effects was found in both experimental groups using both PK-PD models. The application of the modified E(max) model for PK-PD modeling of diltiazem allowed a more accurate and precise estimation of PK-PD parameters than the E(max) equation do. Chronotropic effect of 3 mg kg(-1) diltiazem was lower in SHR compared to WKY animals. Initial sensitivity (S(0)) to diltiazem chronotropic effect was greater in SHR with regards to WKY animals after administration of 1 mg kg(-1). S(0) to diltiazem hypotensive effect was greater in SHR with regards to WKY animals after administration of both doses of diltiazem. Discussion: Microdialysis sampling is a useful technique for the pharmacokinetic study and pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem. The modified E(max) model allows an accurate estimation of drug sensitivity in conditions when maximal pharmacological response can not be attained. Genetic hypertension induced changes in the pharmacokinetic and PK-PD behavior of diltiazem suggesting that SHR is an interesting animal model for pre-clinical evaluation of calcium channel blockers.
MeSH term(s)	Algorithms ; Animals ; Antihypertensive Agents/administration & dosage ; Antihypertensive Agents/pharmacokinetics ; Area Under Curve ; Blood Pressure/drug effects ; Chromatography, High Pressure Liquid/methods ; Dialysis Solutions/analysis ; Diltiazem/administration & dosage ; Diltiazem/pharmacokinetics ; Dose-Response Relationship, Drug ; Heart Rate/drug effects ; Injections, Intravenous ; Male ; Metabolic Clearance Rate ; Microdialysis/methods ; Models, Biological ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Species Specificity
Chemical Substances	Antihypertensive Agents ; Dialysis Solutions ; Diltiazem (EE92BBP03H)
Language	English
Publishing date	2007-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2007.04.001
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