Antihypertensive Drugs Aliskiren, Nebivolol, and Olmesartan Reduce Hypertension by Reducing Endothelial Microparticles and Regulating Angiogenesis.

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

The anti-epileptic drugs valproate, carbamazepine and levetiracetam cause bone loss and modulate Wnt inhibitors in normal and ovariectomised rats.

Secondary osteoporosis is the major concern associated with long term intake of antiepileptic drugs (AEDs). Women are the vulnerable targets owing to post-menopausal bone loss. In the present work, we evaluated the effect of 10 weeks of treatment with AED therapy (carbamazepine, CBZ, 75 mg/kg; sodium valproate, SVP, 300 mg/kg; levetiracetam, LTM, 150 mg/kg) on bone mineral density and microarchitecture at femoral epiphysis, lumbar vertebrae and proximal tibia of normal and ovariectomised Wistar rats. In addition, we measured serum levels of vitamin D, receptor activator of nuclear factor kappa ß-ligand (RANKL), procollagen type 1 amino-terminal propeptide (P1NP) and wnt inhibitors (sclerostin and DKK-1) following AED therapy. Micro-computed tomography analysis of bones revealed significant reduction in BMD at femur epiphysis and lumbar vertebrae with all the three AEDs evaluated. At proximal tibia, only CBZ showed a significant decline. The reduction in BMD was more pronounced in ovariectomised rats. AEDs also resulted in alteration of micro-CT parameters. These changes were accompanied by an increased serum RANKL with all AEDs while vitamin D levels were reduced only with CBZ treatment and P1NP levels were reduced with SVP and CBZ. Serum sclerostin levels were elevated following all AEDs in normal and ovariectomised rats except with CBZ in normal rats. However, increase in DKK-1 levels was observed with only LTM. Ovariectomy itself resulted in increased RANKL, sclerostin and DKK-1 and reduced vitamin D and P1NP levels. Significant differences were discernible between normal and ovariectomised rats treated with AEDs in all the parameters. However, while sclerostin increased further upon AEDs treatment, P1NP decreased with SVP and CBZ and serum DKK-1 levels showed a declining trend with all the three AEDs studied. We confirm adverse effects on bone following AEDs in female rats. Further, our results demonstrate for the first time that these effects are more pronounced in ovariectomised rats as compared to normal rats and that this could be related to estrogen deficiency which in turn enhances bone resorption via increased RANKL and reduces bone formation via increased sclerostin and reduced P1NP. Finally, our study demonstrated for the first time that AED treatment displayed changes in the serum levels of wnt inhibitors and hence modulation of wnt inhibitors might be partly involved in their adverse effects on bone.

Pharmacokinetic-pharmacodynamic modeling of the antihypertensive interaction between azilsartan medoxomil and chlorthalidone in spontaneously hypertensive rats.

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of blood pressure following oral administration of azilsartan medoxomil (AZM) and/or chlorthalidone (CLT) in spontaneously hypertensive (SH) rats. The drug concentration and pharmacological effects, including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tail-cuff manometry, respectively. Sequential PK-PD analysis was performed, wherein the plasma concentration-time data was modeled by one compartmental analysis. Subsequently PD parameters were calculated to describe the time-concentration-response relationship using indirect response (IDR) PK-PD model. The combination of AZ and CLT had greater BP lowering effect compared to AZ or CLT alone, despite of no pharmacokinetic interaction between two drugs. These findings suggest synergistic antihypertensive pharmacodynamic interaction between AZ and CLT noncompetitively, which was simulated by inhibitory function of AZ and stimulatory function of CLT after concomitant administration of the two drugs. The present model was able to capture the turnover of blood pressure adequately at different time points at two different dose levels. The current PK-PD model was successfully utilized in the simulation of PD effect at a dose combination of 0.5 and 2.5 mg/kg for AZ and CLT, respectively. The developed preclinical PK-PD model may provide guidance in the optimization of dose ratio of individual drugs in the combined pharmacotherapy of AZ and CLT at clinical situations.

Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension.

Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg-1 multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using Emax model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC50. The EC50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC50, Ke and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.