In silico design and pharmacological evaluation of conjugates of atenolol with modified saccharide for cardiovascular targeting.

Amongst a wide range of biological macromolecules, saccharides exhibit the potential to be specifically recognized by cell-surface receptors and hence can be utilized as ligands in targeted drug delivery. The current study aims to use saccharides viz. Galactose, Pectin and Chitosan to improve targeting of Atenolol by oxalyl chloride mediated grafting. Conjugates were engineered by grafting Atenolol, a cardiovascular agent with the modified saccharide units. The conjugates were characterized by FTIR, DSC and 1H NMR study. Drug release analysis and cellular uptake study was carried out using H9c2 cell lines which represent that concentration of drug in cells treated with all atenolol-saccharide conjugates is enhanced by almost two-folds in comparison with cells treated with atenolol solution. Thus cell line study confers the evidence of selective cardiac delivery. No significant cytotoxicity was observed in case of all synthesized conjugates in the Brine shrimp lethality bioassay. Possible binding of the developed conjugates with the GLUT-4 receptors was assessed by in silico analysis using homology model developed by Swiss Model server. Hence it was concluded that the application of these conjugates with saccharides in selective cardiovascular drug delivery can be a promising approach to increase bioavailability, minimize drug loss by degradation and prevent harmful side effects by increasing specific cell targeting.

Comparative effect of Beta blocker-Atenolol and Murraya koenigii (L.) spreng (Curry leaves) on cardiac enzyme (CK-MB) level in male albino rats.

Murraya koenigii (L.) spreng (curry leaves) have traditionally been used for its various medicinal properties. The current study was conducted to assess the comparative effect of Murraya koenigii (L.) spreng (curry leaves) and market available beta blocker drug Atenolol on cardiac enzyme (CK-MB) level in male albino rats. Out of total 26 locally bred male Albino Wistar rats (180 to 200gm weight) two rats were treated with only voltral for dose adjustment. Remaining 24 rats were randomly categorized into following 1 control (C) group and 3 experimental groups Model (M), Test 1 (T1) and Test 2 (T2) containing 6 rats in each group. Rats in C group were orally fed by 0.9% saline solution while rats of M and both test groups T1 and T2 were orally treated with voltral tablet (30mg /kg body weight) for three weeks to increase the level of CK-MB heart enzyme. After voltral treatment rats in test group T1 were treated orally with Atenolol (30 mg/kg body weight) and T2 with Murraya koenigii (L.) spreng (curry leaves) extract (180 mg/kg body weight) for last three weeks. Results show that rats treated with Atenolol showed a decrease in level of heart enzyme as compare to M group, while Murraya koenigii (L.) spreng treated rats group T2 showed more significant decrease of heart enzyme (CK-MB) level as compared to M and T1 groups with significantly improved behavioral activity including increased locomotor activity, short-term memory and reduction in depression. These results demonstrate that natural herbal treatment by curry leaves extract play an effective role in lowering the cardiac enzyme (CK-MB) level to its normal range which helps reducing the risk of CVD and CHD.

Taurine Ameliorates Thyroid Hypofunction and Renal Injury in L-NAME-Induced Hypertensive Rats.

There is a growing global interest in hypertension due to its associated complications including renal dysfunction in patients. The thyroid system reportedly regulates renal function in both animal and human. The present study investigated the therapeutic efficacy of taurine on renal and thyroid dysfunctions in hypertensive rats. Hypertension was induced by oral administration of nitric oxide synthase inhibitor, N-nitro L-arginine-methyl-ester (L-NAME), at 40 mg/kg body weight to the male Wistar rats for 14 consecutive days. The hypertensive rats were subsequently treated with either taurine (100 and 200 mg/kg) or reference drug atenolol (10 mg/kg) for another 14 consecutive days. Hypertensive rats showed renal damage evidenced by elevated plasma creatinine and urea levels when compared with normotensive control rats. Furthermore, L-NAME-induced hypertensive rats showed decreased circulatory concentrations of thyroid stimulating hormone, thyroxine, triiodothyronine and the ratio of triiodothyronine to thyroxine. The marked decrease in the renal antioxidant enzyme activities and nitric oxide level was accompanied by significant increase in myeloperoxidase activity and biomarkers of oxidative stress in hypertensive rats. Histological examination of kidneys from hypertensive rats revealed congestion of blood vessels, hemorrhagic lesion and disorganized glomerular structure. However, treatment with taurine or atenolol significantly reversed the suppression of thyroid function, ameliorated renal oxidative stress and histopathological lesions in L-NAME-induced hypertensive rats. Taurine may be a useful chemotherapeutic supplement in enhancing renal and thyroid functions in hypertensive patients.

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance.

At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.

Evaluation of cardiac function in unrestrained dogs and monkeys using left ventricular dP/dt.

INTRODUCTION: Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. METHODS: From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. RESULTS: Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. DISCUSSION: Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes.

Effects of hippadine on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Hippadine is an alkaloid isolated from Crinum macowanii. Crinum macowanii is used in South Africa to treat oedema, 'heart disease', rheumatic fever, cancer and skin diseases, and belongs to the plant family Amaryllidaceae, assumed to have originated in the South African region. The aim of this study was to evaluate the effect of hippadine, an alkaloid extracted from Crinum macowanii, on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive Wistar rats (SHR); and to find out if α1 and⧸or ß1 adrenoceptors contribute to its effects. MATERIALS AND METHODS: Hippadine (2.5-12.5mg/kg), adrenaline (0.05-0.20mg/kg), atenolol (0.5-40mg/kg) and prazosin hydrochloride (100-500µg/kg) were infused intravenously, and the BP and HR measured via a pressure transducer connecting the femoral artery and the PowerLab. Adrenaline increased the systolic, diastolic and mean arterial BP, while hippadine, atenolol and prazosin respectively decreased the systolic, diastolic and mean arterial BP. Increases in HR were observed with both adrenaline and prazosin, while reductions in HR were observed with atenolol and hippadine. Infusion of adrenaline in rats pre-treated with atenolol (30mg/kg), prazosin (400µg/kg), and hippadine (10mg/kg) led to similar increases in BP and HR in all groups. All changes in HR or BP were significant (p<0.05) and dose dependent. CONCLUSION: Hippadine decreases the BP and HR in SHR, and these effects may be due to α1 and ß1 adrenoceptor inhibition.

Effect of aged garlic extract and s-allyl cysteine and their interaction with atenolol during isoproterenol induced myocardial toxicity in rats.

OBJECTIVES: The study evaluates the cardioprotective effect of aged garlic extract (AGE) and its constituent; S-allylcysteine (SAC) and their interaction with atenolol during isoproterenol induced cardiac toxicity in rats. MATERIALS AND METHODS: Rats were administered AGE at two different doses of 2 ml/kg or 5 ml/kg orally whereas SAC was administered either at a dose 13.1 mg/kg or 32.76 mg/kg. The AGE or SAC was given alone or in combination with atenolol (6 mg/kg, p.o), every alternate day for three weeks. At the end of treatment, two doses of isoproterenol (150 mg/kg, s.c) were administered to rats. The electrocardiogram (ECG) was recorded followed by withdrawal of blood to estimate serum lactate dehydrogenase (LDH) and creatinine kinase-MB (CK-MB) activities. The activities of LDH, CK-MB as well as superoxide dismutase (SOD), catalase and thiobarbituric acid reactive substances (TBARS) were also determined in the heart tissue homogenate (HTH). RESULTS: The isoproterenol induced ECG changes were restored to normal in all treated groups. The AGE and SAC administration caused a decrease in serum LDH and CK-MB activities and an elevation of LDH and CK-MB activities in HTH. Atenolol alone or in combination with AGE and S-allylcsyteine demonstrated similar changes in biomarker activities. CONCLUSION: AGE showed dose-dependent cardioprotection. However, concurrent administration of SAC with atenolol (6 mg/kg, p.o) combated more effectively the myocardial dysfunction during isoproterenol induced cardiotoxicity in rats.

ß-adrenergic blockade attenuates cardiac dysfunction and myofibrillar remodelling in congestive heart failure.

Although ß-adrenoceptor (ß-AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective ß(1) -AR antagonist, or propranolol, a non-selective ß-AR antagonist, for 5 weeks. Sham operated rats served as controls. All animals were assessed haemodynamically and echocardiographically and the left ventricle (LV) was processed for the determination of myofibrillar ATPase activity, α- and ß-myosin heavy chain (MHC) isoforms and gene expression as well as cardiac troponin I (cTnI) phosphorylation. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated cardiac hypertrophy and lung congestion in addition to increasing LV ejection fraction and LV systolic pressure as well as decreasing heart rate, LV end-diastolic pressure and LV diameters in the infarcted animals. Treatment of infarcted animals with these agents also attenuated the MI-induced depression in myofibrillar Ca(2+) -stimulated ATPase activity and phosphorylated cTnI protein content. The MI-induced decrease in α-MHC and increase in ß-MHC protein content were attenuated by both atenolol and propranolol at low and high doses; however, only high dose of propranolol was effective in mitigating changes in the gene expression for α-MHC and ß-MHC. Our results suggest that improvement of cardiac function by ß-AR blockade in CHF may be associated with attenuation of myofibrillar remodelling.

Cardiovascular autonomic dysfunction in a novel rodent model of polycystic kidney disease.

Autonomic dysfunction, hypertension and cardiovascular morbidity in end stage renal disease are critically linked, however there are limited models available to investigate this relationship and develop clinical interventions. This study aimed to define the relationship between hypertension and autonomic function in a new rodent model of polycystic kidney disease (PKD). Using measures of heart rate and systolic blood pressure variability (HRV, SBPV), and time domain analysis of cardiac and sympathetic baroreflex function, we compared the Lewis PKD model (LPK) to a Lewis control. Systolic BP and SBPV were significantly higher in LPK vs. Lewis (168+/-7 vs. 131+/-8mm Hg, P

Assessment of the pharmacological effects of inotropic drugs on left ventricular pressure and contractility: an evaluation of the QA interval as an indirect indicator of cardiac inotropism.

INTRODUCTION: The ICH S7A and S7B guidelines require that effects of test substances on the cardiovascular system be assessed with respect to blood pressure, heart rate and electrocardiogram intervals. Where adverse effects are identified additional supplemental studies, including ventricular contractility, should be conducted as deemed appropriate. However, there is an absence of definitive guidance regarding when to pursue supplementary studies, in part due to ill-defined criteria of what constitutes an adverse effect and to surgical/technical monitoring limitations of study designs. However with advances in technology it is now feasible to develop models for assessing LVP and contractility in conjunction with standard assessments. The objectives of this study were to 1) develop a model for chronic evaluation of LVP and contractility, 2) illustrate changes in LV contractility without concurrent proportional changes in heart rate and/or systemic blood pressure and 3) determine if the QA interval, the time between the Q on the ECG and the beginning of the upstroke on the arterial blood pressure, can be used as a indicator of altered LV contractility. METHODS: Dogs (N=4) were implanted with a telemetry transmitter. LVP, contractility, ECG and BP were assessed prior to and up to 24 h following administration of Atenolol (10 mg/kg) and Pimobendan (0.45 mg/kg). RESULTS: Atenolol caused an approximately 30% decrease in HR, followed by a sustained decrease in maximum left ventricular contractility (+dP/dt mmHg/s). No effects were noted on blood pressure. Pimobendan caused a 100% increase in contractility (+dP/dt mmHg/s) which remained elevated for approximately 4 h. No effects were noted on blood pressure. Heart rate was highly variable initial decreasing, followed by a highly variable increase until 4 h postdose. Following administration of both compounds changes in maximum left ventricular contractility correlated with reverse changes in QA interval duration. DISCUSSION: This model demonstrates that evaluation of LV contractility complements measurements of heart rate and blood pressure as part of a more complete cardiovascular safety assessment strategy. Furthermore, we demonstrate an apparent correlation between dP/dt and QA interval and concluded that QA interval can be utilized as an indicator of a potential inotropic effect. However further confirmation should be assessed through additional in-vivo measurements of LVP and contractility.

Comparison of hypotensive and hypolipidemic effects of Catharanthus roseus leaves extract with atenolol on adrenaline induced hypertensive rats.

The leaves extract of Catharanthus roseus was investigated for hypotensive and hypolipidemic effects in adrenaline-induced hypertensive rats (AIHR) and compared with those of Atenolol in a crossover design. The pharmacologically Active components responsible for hypotensive activities were isolated from plant using bioassay guided purification approach and the structure of the compounds was proposed by spectroscopic methods. Catharanthus roseus leaves extract and commercial drug Atenolol were administered through intraperitoneal (i.p) route for one week. Different biochemical parameters such as heart weight, blood glucose level, serum cholesterol level, serum triglyceride level, body weight and the relationships between them were measured. Catharanthus roseus leaves extract at a dose of 30 mg/155+/-15 gm of body weight was injected in rat at every morning during the treatment period. The dose of Atenolol was determined according to its pharmacokinetic parameters. Clinically effective plasma concentration as a hypotensive drug was obtained after the injection of 0.1 mg/155+/-15 gm of body weight of the drug. The Catharanthus roseus leaves extract made significant changes in each cardiovascular parameter after investigation. Catharanthus roseus leaves extract treated animals have shown the hypotensive effects. Hypotensive effects were also shown by Atenolol.

Effect of atropine, propranolol, and atenolol on wave structure of heart rate oscillations in rats.

Were studied the effects of atropine and beta-adrenoblockers on the power of very low (<0.25 Hz), low (0.25-0.70 Hz), and high frequency (0.7-1.8 Hz) waves of the heart rhythm in wakeful rats. Atropine reduced the power of all waves in 100% cases. Propranolol on average decreased the power of very low frequency waves and increased the power of low and high frequency waves, although opposite effects were observed in many cases. Atenolol produced similar effects. Some animals demonstrated spontaneous moderation of respiratory rate to a level corresponding to low-frequency oscillations of the heart rhythm accompanied by elevation of the relative power of low frequency waves. Inconsistency of the effects of beta-adrenoblockers in rats can be related to variability of sympathetic tone and spontaneous deceleration of respiration with the corresponding changes of low frequency waves. Augmentation of the high frequency waves during application of beta-adrenoblockers is not related to their action on CNS.

Sex differences in blood pressure response to antihypertensive therapy in Chinese patients with hypertension.

BACKGROUND: Sex-specific responses to antihypertensive drugs are not very well understood. OBJECTIVE: To investigate sex-related differences in blood pressure response to antihypertensive drugs in a community-based prospective clinical trial. METHODS: We recruited 3535 untreated hypertensive patients (2326 women), aged 40-75 years, from 7 rural communities in China. Subjects were randomized to 1 of 4 drug groups: atenolol, hydrochlorothiazide (HCTZ), captopril, or sustained-released nifedipine; duration of the study was 8 weeks. Mean blood pressure reduction, blood pressure control rates, and frequency of adverse events were compared between men and women. RESULTS: Women had a better response to HCTZ in relation to diastolic blood pressure (1.8 mm Hg lower) than did men (p < 0.05) and were 57% more likely to reach the control goal of diastolic blood pressure than were men (p < 0.05). In the atenolol group, mean systolic blood pressure decreased 3.9 mm Hg more in women than in men (p < 0.05), and women were 65% more likely to reach the control goal of systolic blood pressure and 57% more likely to reach the control goal of diastolic blood pressure than were men (p < 0.05). Significant sex-related differences were also found in drug-related adverse events in the nifedipine group (15.8% in women vs 9.8% in men; p = 0.017) and in the captopril group (14.3% in women vs 8.4% in men; p = 0.005), but no differences were seen with HCTZ or atenolol. CONCLUSIONS: Women have better blood pressure responses to HCTZ and atenolol and experience more adverse effects with sustained-release nifedipine and captopril than do men, indicating that sex should be taken into account when selecting antihypertensive drugs.

Antihypertensive effects of crude extracts from leaves of Echinodorus grandiflorus.

The antihypertensive action of a crude ethanolic extract (EEEG) from leaves of Echinodorus grandiflorus (Alismataceae) was investigated in spontaneously hypertensive rats. The intraperitoneal injection of increasing doses of EEEG (300-1000 mg/kg) elicited dose-dependent reductions in mean arterial pressure (MAP) that were paralleled by reductions of cardiac output and systemic vascular resistance, reaching the maximum of 23 +/- 5%, 13 +/- 3% and 18 +/- 4%, respectively (n = 5, P < 0.05). Comparable reductions of MAP were obtained upon i.v. administration of EEEG (3-100 mg/kg), reaching the maximum decrease of 51 +/- 6% (n = 7; P < 0.001). The blockade of nitric oxide synthesis significantly reduced the hypotension induced by i.v. administration of EEEG. Moreover, the pre-treatment of the animals with a selective antagonist of cholinergic muscarinic receptors or of platelet-activating factor (PAF) receptors partially blunted the cardiovascular effects of EEEG. The i.v. pre-treatment with the selective B(2) bradykinin receptor antagonist HOE 140 or with indomethacin, an inhibitor of the enzyme cyclooxygenase, did not prevent the hypotensive effects induced by EEEG. Finally, the chronic oral treatment with EEEG presented a significant antihypertensive effect that was comparable to that of reference antihypertensive drugs currently used to treat arterial hypertension. It is concluded that EEEG elicits significant acute antihypertensive effects through the release of nitric oxide and the stimulation of cholinergic muscarinic and PAF receptors. Moreover, our results suggest that EEEG may be appropriate to chronic oral treatment of arterial hypertension.

Comparative efficacy of two different beta-blockers on 24-hour blood pressure control.

Atenolol and metoprolol succinate, dosed once daily, have different pharmacokinetic profiles. This study tests the hypothesis that differences that are especially noted in the early morning period, when cardiovascular risk is highest, in 24-hour blood pressure (BP) control exist between these 2 beta-blockers. This was a small, randomized open-label study with blinded end point evaluation in 36 hypertensive patients. All participants received hydrochlorothiazide 12.5 mg for 2 weeks before randomization to either 50 mg atenolol or metoprolol succinate given every morning; both treatments were force-titrated to 100 mg/d at 4 weeks. The primary end point was the change in early morning ambulatory systolic BP. Early morning (12 AM-6 AM) systolic BP differences were 3+/-14 mm Hg with atenolol vs -7+/-8 mm Hg with metoprolol succinate (P=.03). The overall 24-hour changes in systolic BP were 1+/-15 mm Hg with atenolol vs -9+/-11 mm Hg with metoprolol (P=.03). In conclusion, metoprolol succinate was more effective in sustaining 24-hour and early morning BP reductions compared with atenolol in a small group of hypertensive patients also treated with once-daily low-dose hydrochlorothiazide. It is possible that differences in outcome between atenolol-based and other therapies may be the result of inadequate dosing of atenolol, a medication that may not be effective for the entire 24-hour period.

Blood pressure variability, baroreflex sensitivity and organ damage in spontaneously hypertensive rats treated with various antihypertensive drugs.

Besides blood pressure, blood pressure variability and baroreflex sensitivity maybe important factors determining organ damage in hypertension. This study was designed to investigate the effects of various antihypertensive drugs on blood pressure and blood pressure variability reductions, baroreflex sensitivity, and target organ damage in spontaneously hypertensive rats (SHR). The dose is 20 mg/kg/day for atenolol, and 10 mg/kg/day for nifedipine, irbesartan and hydrochlorothiazide. We used relatively low doses of drugs to avoid a very remarkable normalization of blood pressure in the treatment, which would make it much difficult to distinguish the contribution of blood pressure variability and baroreflex sensitivity to organ protection from that of blood pressure. Drugs at the aforementioned doses were mixed into rat chow. SHR were treated for 4 months. Blood pressure was then continuously recorded for 24 h. After the determination of baroreflex sensitivity, rats were killed for organ-damage evaluation. It was found that long-term treatment with atenolol, nifedipine, irbesartan or hydrochlorothiazide all markedly reduced blood pressure variability, enhanced baroreflex sensitivity, and produced significant organ protection. Compared with blood pressure level, blood pressure variability and baroreflex sensitivity values showed a much closer or similar relationship with organ-damage parameters in every treatment group of rats. Multiple-regression analysis showed that the decrease in left ventricular hypertrophy, the decrease in aortic hypertrophy and the amelioration in renal lesion were all most closely correlated with the increase in baroreflex sensitivity and the decrease in systolic blood pressure variability. In conclusion, long-term treatment with atenolol, nifedipine, irbesartan or hydrochlorothiazide produced organ protection in SHR. Besides the blood pressure reduction, the decrease in blood pressure variability and the restoration of baroreflex sensitivity may contribute to this organ protection.

Sympathetic and parasympathetic component of bradycardia triggered by stimulation of NTS P2X receptors.

We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist alpha,beta-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg i.v.), a beta1-selective antagonist, and after atropine methyl bromide (2 mg/kg i.v.), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After beta1-adrenergic blockade, the bradycardia was reduced to just -5.1 +/- 0.5 versus -28.8 +/- 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both beta1-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, -37.4 +/- 6.4 and -40.6 +/- 3.7 beats/min, respectively, compared with -88.0 +/- 11 beats/min in control animals. Double blockade of both beta1-adrenergic and muscarinic receptors virtually abolished the response (-2.5 +/- 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation.

[Research on the effect of atenolol on lidocaine pharmacokinetics in rats]. / Studiul influentei atenololului asupra unor parametri farmacocinetici ai lidocainei la sobolani.

UNLABELLED: The aim was to determine the influence of atenolol on lidocaine pharmacokinetics in rats for one hour interval of time (average of a dental intervention). The study was carried out on 2 groups of Wistar rats treated with saline solution (0.5 ml/kg), respectively with atenolol (1.5 mg/kg), administered orally 24 hours and 3 hours before intraperitoneal administration of lidocaine (1.5 mg/kg). Blood samples were collected before and 5, 10, 20, 30, 60 minutes after lidocaine administration. Lidocaine plasma concentrations were determined by HPLC. Some pharmacokinetic parameters of lidocaine were statistically significant higher (p < 0.05, ANOVA) for the rats treated with atenolol compared with control group: Cmax (196.97 +/- 2.15 ng/ml vs. 125.29 +/- 2.90 ng/ml), AUD (7734.07 +/- 129.06 ng/ ml x min vs. 4478.57 +/- 296.61 ng/ml x min), AUC1 after 5 minutes (314.23 +/- 6.59 ng/ml x min vs. 190.71 +/- 19.75 ng/ml x min). Tmax was 20 minutes, similar for both groups. CONCLUSION: local anesthesia with lidocaine might be enhanced in the presence of atenolol compared to controls.

Synergistic effects of atenolol and amlodipine for lowering and stabilizing blood pressure in 2K1C renovascular hypertensive rats.

AIM: To test the synergistic effects of atenolol and amlodipine on lowering blood pressure (BP) and reducing blood pressure variability (BPV) in 2-kidney, one-clip (2K1C) renovascular hypertensive rats. METHODS: Forty-eight 2K1C renovascular hypertensive rats were randomly divided into 6 groups. They were respectively given 0.8% carboxymethylcellulose sodium (control), atenolol (10.0 mg/kg), amlodipine (1.0 mg/kg), and combined atenolol and amlodipine (low dose: 5.0+0.5 mg/kg; intermediate dose: 10.0+1.0 mg/kg; high dose: 20.0+2.0 mg/kg). The drugs were given via a catheter in a gastric fistula. BP was recorded for 25 h from 1 h before drug administration to 24 h after administration. RESULTS: Compared with BP before medication, all 3 doses of combined atenolol and amlodipine significantly decreased the BP at 24 h after administration, except for the low dose on diastolic BP. Compared with the control group, all 3 doses of combined atenolol and amlodipine significantly reduced the average BP levels for the 24 h period after administration; furthermore, the high and intermediate doses also significantly decreased the BPV levels for the same period. The q values calculated by probability sum analysis for systolic and diastolic BP for the 24 h period after administration were 2.29 and 1.45, respectively, and for systolic and diastolic BPV for the same period they were 1.41 and 1.60, respectively. CONCLUSION: There is significant synergism between atenolol and amlodipine in lowering and stabilizing BP in 2K1C renovascular hypertensive rats.