Drugs affecting blood pressure variability: an update.

Blood pressure variability (BPV) is considered nowadays a novel risk factor for cardiovascular disease. Clinical evidences support that short-term and long-term BPV independently contribute to target organ damage, cardiovascular events and mortality in patients with hypertension or diabetes. Attenuation of excessive fluctuations of systolic and diastolic BPV has been suggested as an additional therapeutic target in cardiovascular prevention. A growing number of preclinical and clinical studies have focused in the assessment of drug effects or other interventions on the different types of BPV and their contribution in the prevention of cardiovascular events. Prospective clinical trials have shown that antihypertensive classes differ in their ability to control excessive BP fluctuations with an impact in clinical outcomes. Current evidences suggest that calcium channel blockers are more effective than other blood pressure lowering drugs for the reduction of short-term, mid-term and long-term BPV. In order to increase actual knowledge regarding the therapeutic significance of BPV in cardiovascular disease, there is a need for additional clinical studies specifically designed for the study of the relevance of short-term and long-term BPV control by antihypertensive drugs.

Models for evaluating the pharmacokinetics and pharmacodynamics for ß-blockers.

INTRODUCTION: ß-blocker therapy plays an important role in the treatment of various diseases, including hypertension, myocardial infarction and heart failure. Although all ß-blockers shared their ability to competitively block ß1-adrenoceptor, this therapeutic class showed great heterogeneity in their pharmacokinetic (PK) and pharmacodynamic (PD) properties. AREAS COVERED: The present review describes the models used for PK and PK/PD evaluation of ß-blockers and their applicability in preclinical and clinical studies. PK behavior of different ß-blockers has been studied by means of individual compartmental and population PKs, allowing the estimation of relevant PK parameters and factors involved in intersubject variability. Different PK/PD models have been developed for the in vivo estimation of PD parameters of different cardiovascular effects of ß-blockers. EXPERT OPINION: PK models and PK/PD modeling have clearly contributed to characterization of the PK and PD properties of ß-blockers. Differences in cardiovascular actions between classical ß-blockers and vasodilatory ß-blockers need to be further studied in order to confirm the clinical benefits of the new-generation of ß-blockers. PK/PD modeling may contribute to clarify the importance of heterogeneity of PK and PD properties of ß-blockers potentially improving the selection of the adequate agent and dose regimen in the treatment of cardiovascular diseases.

Enantioselective pharmacokinetics and cardiovascular effects of nebivolol in L-NAME hypertensive rats.

The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg(-1) i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): -16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: -1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that ß-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.

Acute effects of third generation ß-blockers on short-term and beat-to-beat blood pressure variability in sinoaortic-denervated rats.

An increase in blood pressure variability (BPV) contributes to the development of target organ damage associated with hypertension. Treatment with conventional ß-blockers, such as atenolol, has been associated with an increase in BPV; however, the extrapolation of these results to third generation ß-blockers with pleiotropic effects seems to be inappropriate. The cardiovascular effects of third generation ß-blockers, carvedilol and nebivolol, were assessed in sinoaortic-denervated rats (SAD) and compared with the second generation ß-blocker atenolol and the calcium channel blocker verapamil, with a special focus on short-term BPV. Male SAD rats were acutely treated with carvedilol, nebivolol, atenolol or verapamil at two different doses, and the effects on blood pressure and BPV were recorded. Short-term BPV was assessed by the s.d. of BP recordings. Beat-to-beat BPV was studied using spectral analysis to assess the vascular sympatholytic activity of carvedilol and nebivolol by estimating the effects of these drugs on the ratio of low frequency (LF) to high frequency (HF) BPV (LF/HF ratio). Nebivolol, carvedilol and the calcium channel blocker verapamil significantly attenuated short-term BPV at both doses in SAD animals, and there were no differences between the drugs. Conversely, atenolol did not modify baseline s.d. values at either dose. Carvedilol and nebivolol significantly reduced the LF/HF ratio in SAD rats compared with the effects of atenolol and verapamil, suggesting the ability of the third generation ß-blockers to reduce vascular sympathetic activity. In conclusion, third generation ß-blockers induce a marked reduction in short-term BPV in SAD rats compared to atenolol. Moreover, the ability of carvedilol and nebivolol to reduce short-term BPV in SAD rats is equivalent to that of verapamil, suggesting that these ß-blockers may have an additional beneficial effect through their control of short-term variability to a similar extent to calcium channel blockers.

Effect of nebivolol on beat-to-beat and short-term blood pressure variability in spontaneously hypertensive rats.

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability.

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg(-1) (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic-pharmacodynamic (PK-PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg(-1) compared with WKY rats. PK-PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats.

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic-pharmacodynamic (PK-PD) modeling. Male Sprague-Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Enantioselective pharmacokinetic-pharmacodynamic modelling of carvedilol in a N-nitro-l-arginine methyl ester rat model of secondary hypertension.

OBJECTIVES: The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic-pharmacodynamic (PK-PD) modelling. METHODS: Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L-NAME rats received L-NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK-PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. KEY FINDINGS: A dose-dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S-carvedilol as compared with the R-enantiomer was found in both experimental groups. Although the PK-PD properties of the S-carvedilol chronotropic effect were not altered in L-NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L-NAME rats. CONCLUSIONS: Carvedilol showed enantioselective non-linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L-NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.

Issues in drug metabolism of major antihypertensive drugs: beta-blockers, calcium channel antagonists and angiotensin receptor blockers.

Several first-line antihypertensive drugs, including calcium channel blockers, beta-adrenergic blockers and angiotensin receptor blockers, undergo metabolism through different CYP isoforms. As a consequence of CYP-dependent metabolism, wide interindividual variability of plasma concentrations of antihypertensive drugs has been found in clinical practice compromising blood pressure lowering response and clinical outcomes. Several factors, including aging, hepatic impairment, drug interactions, conditions affecting hepatic blood supply and polymorphisms, contribute to changes in oral and systemic clearance affecting drug exposure during antihypertensive therapy and cardiovascular response. Considering that the degree of blood pressure reduction is related to antihypertensive drug plasma concentrations, a greater knowledge of the sources of pharmacokinetic variability of hepatically eliminated antihypertensive drugs and the applicability of an individualized approach in hypertension management by means of pharmacokinetic/pharmacodynamic modeling and pharmacogenetic testing could enhance blood pressure lowering response to pharmacological therapy. The aim of the present review is to discuss the relevance of drug metabolism in the treatment of hypertension.

Importance of blood pressure variability in the assessment of cardiovascular risk and benefits of antihypertensive therapy.

Although there is no doubt regarding the relationship between short-term blood pressure variability (BPV) and cardiovascular events in the hypertensive population, to date, the association between long-term BPV and target organ damage is unknown. Rothwell et al. recently published a post-hoc analysis of two large randomized trials, Anglo Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BLPA) and the Medical Research Council (MRC), aimed at demonstrating whether drug effects on short-term and long-term BPV explain the differences of antihypertensive treatment in stroke prevention. Analysis found that short-term and long-term BPV was lower in hypertensive patients treated with amlodipine with regards to atenolol. The amlodipine group showed a lower risk of stroke and coronary events with respect to subjects assigned to atenolol. Interestingly, the lower stroke risk detected in hypertensive patients treated with amlodipine was abolished after adjusting by within-individual BPV. Taking into account these findings, the authors concluded that the opposite effect of calcium channel blockers and ß-blockers on BPV explains the disparity in the risk of stroke of patients under antihypertensive treatment. Therefore, to effectively prevent cerebrovascular events, blood pressure-lowering agents need both to reduce mean blood pressure and its short-term and long-term variability.

Is urethane-chloralose anaesthesia appropriate for pharmacokinetic-pharmacodynamic assessment? Studies with carvedilol.

INTRODUCTION: The aim of the work was to establish the impact of urethane-chloralose anaesthesia on pharmacokinetic-pharmacodynamic (PK-PD) properties of carvedilol in control rats and L-NAME hypertensive animals. METHODS: Male Wistar Rats were randomly divided into: control (n=12) with tap water to drink and L-NAME rats (n=12) with L-NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of carvedilol (1 mg kg(-1), i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg(-1), i.p.) - chloralose (50 mg kg(-1), i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK-PD modeling of carvedilol was made by means of an effect compartment model. RESULTS: Neither urethane-chloralose nor L-NAME modified estimation of pharmacokinetic parameters of carvedilol. Although urethane-chloralose did not modify potency of carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L-NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to carvedilol in control rats. Whilst no differences were found in the estimated potency of carvedilol hypotensive response comparing control and L-NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of carvedilol was significantly greater in anaesthetized control and L-NAME animals in comparison to conscious rats. L-NAME rats showed a greater maximal hypotensive response comparing to control group. DISCUSSION: Urethane-chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK-PD properties of carvedilol, considering that it does not affect the potency of carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane-chloralose anaesthetized animals, regarding the impact of l-NAME treatment on PK-PD properties of carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of carvedilol in both normotensive and L-NAME hypertensive rats.

In vitro and in vivo pharmacodynamic properties of metoprolol in fructose-fed hypertensive rats.

BACKGROUND: This study of metoprolol pharmacokinetic and pharmacodynamic properties investigates cardiac beta1-adrenoceptors activity and its involvement in the hypertensive stage in 6-week-old fructose-fed male Sprague-Dawley rats. METHODS: A microdialysis probe was inserted in the carotid artery to monitor metoprolol levels, blood pressure, and heart rate after drug administration (3-10 mg/kg intravenously). The relationship between levels and cardiovascular effects was studied using a pharmacokinetic-pharmacodynamic model with effect compartment. Dissociation constant and inverse agonism were evaluated in isolated atria. RESULTS: Metoprolol pharmacokinetics were similar in both groups. Metoprolol induced a greater hypotensive effect in fructose-fed animals (Emax: -24 +/- 1 mm Hg, n = 6, P < 0.05 vs. control) than in control rats (Emax: -14 +/- 1 mm Hg, n = 6). Bradycardic response was similar in both groups; metoprolol chronotropic potency was greater in fructose-fed rats (IC50: 123 +/- 15 ng/mL, P < 0.05 vs. control) compared to control animals (IC50: 216 +/- 36 ng/mL) after administration of 3 mg/kg. Metoprolol constants of dissociation for beta1-adrenoceptors and inverse agonism were similar in both groups. CONCLUSION: Results demonstrate the beta1-adrenoceptors involvement in the fructose hypertension. A greater potency to metoprolol in vivo chronotropic effect was found in fructose-fed rats. This greater potency was not caused by alteration in the activity of beta1-adrenoceptors.

Effects of clonidine on the experimental hypertension by abdominal aortic coarctation in rats.

Cardiovascular baroreflex mechanisms and sympathetic tone could be involved in the arterial hypertension by coarctation of abdominal aorta artery (CoA). The present work analyzes the effect on the arterial pressure and heart rate (HR) of the clonidine, an alpha(2)-adrenergic central acting antihypertensive agent, after intravenous (i.v.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration in rats anesthetized with pentobarbital (40 mg/kg i.p.).Wistar rats of both sexes (240-270 g) were used to the 7 days of the CoA or a sham operation (SO). Values of mean arterial pressure (MAP) and of HR were calculated from intraarterial recordings of blood pressure. The MAP of the CoA rats (161.5+/-5.3 mmHg, n=20) was significantly higher (P<0.01) than that of the SO rats (101.6+/-3.3 mmHg, n=20). The i.v. injection of clonidine (3-30 microg/kg) produced an increase of blood pressure in the rats SO and in the CoA animals, followed by a fall of arterial pressure in both groups of rats. Clonidine showed a small pressor effect but also a great depressor action in the hypertensive rats. Except for with the dose of 10 microg/kg, differences in cardiac response to clonidine were not seen in both groups of rats. Injection of clonidine by the i.c.v. via (10 microg) like by the i.t. (3 microg) also produced a greater fallen of the MAP in the hypertensive rats than in the controls SO animals. In conclusion, these hypertensive animals would be sensitive to the antihypertensive action of central acting alpha(2)-adrenoceptor agonist clonidine administered by different ways, suggesting a great sensitivity of the post-synaptic alpha(2)-adrenoceptor of central nervous system.

La estimulación colinérgica central en la desnervación sinoaórtica. Efecto de la administración i.c.v. de agentes colinomiméticos / The central cholinergic stimulation in the sinoaortic denervation. Effect of the intracerebroventricular administration of cholinomimetic agents

Se decidió encarar el estudio farmacológico de la participación colinérgica en el modelo de desnervación sinoaórtica analizando los efectos cardiovasculares de agonistas muscarínicos diversos y del anticolinesterásico neostigmina administrados por vía endovenosa o por la vía intracerebroventricular. También se evaluó la actividad de la enzima acetilcolinesterasa en diversas estructras del sistema nervioso central luego de la a inhibición por administración intracerebral de neostigmina pero disminuye el efecto bradicardizante. Sin embargo no alteraría las respuestas cardiovasculares correspondientes a la inyección i.v. del agonista oxotremorina y a la i.c.v. del agonista McNeil-A-343. Luego de la administración i.c.v. de neostigmina, la actividad enzimática remanente osciló entre 24 por ciento a 30 por ciento en las estructuras hipotalámicas y entre 42 por ciento a 52 por ciento en los restantes tejidos, sin diferencias entre las ratas con operación simulada y aquellas con desnervación sinoaórtica. Los resultados sugieren que en los efectos cardiovasculares de la estimulación colinérgica central posiblemente no estarían involucrados receptores muscarínicos del subtipo M1. Por otra parte, no estaría afectada la degradación de la acetilcolina en el sistema nervioso central, lo que apoyaría la idea de un compromiso de receptores muscarínicos en los cambios observados. Por la ruta de administración utilizada de neostigmina, se observa un mayor grado de inhibición de la acetilcolinesterasa hipotalámica, sugiriendo entonces que las estructuras hipotalámicas podrían estar comprometidas en los efectos cardiovasculares inducidos por la administración intracerebral del anticolinesterásico.

La estimulación colinérgica central en la desnervación sinoaórtica. Efecto de la administración i.c.v. de agentes colinomiméticos / The central cholinergic stimulation in the sinoaortic denervation. Effect of the intracerebroventricular administration of cholinomimetic agents

Se decidió encarar el estudio farmacológico de la participación colinérgica en el modelo de desnervación sinoaórtica analizando los efectos cardiovasculares de agonistas muscarínicos diversos y del anticolinesterásico neostigmina administrados por vía endovenosa o por la vía intracerebroventricular. También se evaluó la actividad de la enzima acetilcolinesterasa en diversas estructras del sistema nervioso central luego de la a inhibición por administración intracerebral de neostigmina pero disminuye el efecto bradicardizante. Sin embargo no alteraría las respuestas cardiovasculares correspondientes a la inyección i.v. del agonista oxotremorina y a la i.c.v. del agonista McNeil-A-343. Luego de la administración i.c.v. de neostigmina, la actividad enzimática remanente osciló entre 24 por ciento a 30 por ciento en las estructuras hipotalámicas y entre 42 por ciento a 52 por ciento en los restantes tejidos, sin diferencias entre las ratas con operación simulada y aquellas con desnervación sinoaórtica. Los resultados sugieren que en los efectos cardiovasculares de la estimulación colinérgica central posiblemente no estarían involucrados receptores muscarínicos del subtipo M1. Por otra parte, no estaría afectada la degradación de la acetilcolina en el sistema nervioso central, lo que apoyaría la idea de un compromiso de receptores muscarínicos en los cambios observados. Por la ruta de administración utilizada de neostigmina, se observa un mayor grado de inhibición de la acetilcolinesterasa hipotalámica, sugiriendo entonces que las estructuras hipotalámicas podrían estar comprometidas en los efectos cardiovasculares inducidos por la administración intracerebral del anticolinesterásico. (AU)

Acción anticolinérgica de clonidina sobre los efectos cardiovasculares de la estimulación colinérgica central / Anticholinergic action of clonidine on cardiovascular effects of the central cholinergic estimulation

Fue realizado un estudio acerca de la acción anticolinérgica del agonista adrenérgico alfa2 clonidina sobre las respuestas cardiovasculares a la inyección i.c.v. del agente anticolinesterásico cuaternario neostigmina a ratas conscientes. E1 agente colinérgico neostigmina (0,1-1 mug i.c.v.) indujo en las ratas una respuesta presora y bradicardia en forma dependiente de la dosis. Clonidina, a la dosis de 10 mug. Kg(-1) (i.v.) y administrado 30 min antes del anticolinesterásico, no modificó el efecto presor de neostigmina (0,1-1 mug i.c.v.) pero previno la bradicardia. Por otra parte, la administración i.c.v. de clonidina (3 mug), inyctada 15 min. antes de neostigmina, sólo previno el efecto bradicardizante del anticolinesterásico (0,3 mug i.c.v.) pero la acción presora central de la droga. Estos resultados sostienen la idea de que la clonidina tiene una acción anticolinérgica en la rata. Sin embargo, la prevención por clonidina de la bradicardia inducida por estimulación central sugiere una interacción diferente colinérgica-adrenérgica según la respuesta cardiovascular originada por la administración central de agentes colinérgicos. .

Acción anticolinérgica de clonidina sobre los efectos cardiovasculares de la estimulación colinérgica central / Anticholinergic action of clonidine on cardiovascular effects of the central cholinergic estimulation

Fue realizado un estudio acerca de la acción anticolinérgica del agonista adrenérgico alfa2 clonidina sobre las respuestas cardiovasculares a la inyección i.c.v. del agente anticolinesterásico cuaternario neostigmina a ratas conscientes. E1 agente colinérgico neostigmina (0,1-1 mug i.c.v.) indujo en las ratas una respuesta presora y bradicardia en forma dependiente de la dosis. Clonidina, a la dosis de 10 mug. Kg(-1) (i.v.) y administrado 30 min antes del anticolinesterásico, no modificó el efecto presor de neostigmina (0,1-1 mug i.c.v.) pero previno la bradicardia. Por otra parte, la administración i.c.v. de clonidina (3 mug), inyctada 15 min. antes de neostigmina, sólo previno el efecto bradicardizante del anticolinesterásico (0,3 mug i.c.v.) pero la acción presora central de la droga. Estos resultados sostienen la idea de que la clonidina tiene una acción anticolinérgica en la rata. Sin embargo, la prevención por clonidina de la bradicardia inducida por estimulación central sugiere una interacción diferente colinérgica-adrenérgica según la respuesta cardiovascular originada por la administración central de agentes colinérgicos. (AU).