Acute Effects of Two Angiotensin Receptor Blockers on Vascular Hemodynamics , Arterial Stiffness , and Oxidative Stress in Patients withMild toModerate Hypertension : An Open Label Parallel Group Study

Introduction. We studied the acute effects of Olmesartan and Telmisartan at baseline and at the end of four weeks on indices of hemodynamics (heart rate HR, blood pressure BP), vascular (carotid femoral pulse wave velocity cf PWV, digital arterial tone expressed as Re�ection index RI, and endothelial dependent vasodilator response EDVR), and oxidative stress (serum Malondialdehyde MDA) in hypertensive patients. Materials and Methods. e eligible patients were randomly allocated to either 20mgOlmesartan or 40mg Telmisartan. Results. 40 subjects received Olmesartan, and 29 received Telmisartan. Aer four weeks of treatment themean changes from baseline in theOlmesartan group versus Telmisartan group are SBP−9.8±10 versus−6.3±12mm Hg,PP P 0.2P; DBP −6.1±11 versus −P.2±12.5mmHg,PP P 0.55; cf PWV −1.6±1.2 versus −0.9±1.Pm/s,PP P 0.0P; EDVR −8.2±5.2 versus −5.2 ± 5.7%, PP P 0.0P; and MDA −1.9 ± 1.1 versus −1.2 ± 1.2 ηηMol/mL, PP P 0.03. Conclusion. Olmesartan showed a better improvement in cf PWV, EDVR, and MDA than Telmisartan with an identical reduction in blood pressure.


Introduction
In hypertension, whole arterial system undergoes both structural and functional alterations.e alteration in function occurs early and manifests as decreased endothelial dependent vasodilator response and increased arterial stiffness.It can be understood that one or every possible mechanism such as an imbalance between L-arginine-nitric oxide system, mechanical stretch due to high blood pressure, oxidative stress, and endothelial dysfunction may be liable for increased resting arterial tone [1][2][3][4][5][6].Angiotensin receptor blockers (ARB) may offer potential therapeutic bene�ts on cardiovascular system through multiple mechanisms, in addition to blood pressure lowering effect.However, selective inhibition of the AT-II type 1 depends on the affinity of the ARB to the receptor.Olmesartan and Telmisartan have high binding affinities to type-1 receptors than other ARBs.To this purpose, we studied the acute effects of Olmesartan and Telmisartan on indices of hemodynamics, (Heart rate HR, Blood pressure BP), vascular (carotid femoral pulse wave velocity cf PWV, digital arterial tone expressed as Re�ection index RI, and endothelial dependent vasodilator response EDVR), and oxidative stress (serum Malondialdehyde MDA) in hypertensive patients.

Materials and Methods
e Institutional Ethical Committee approved this open label randomized parallel group study protocol.Informed consent was obtained from study participants.All the treatment naive patients in the age group between 20 to 60 years with sitting systolic blood pressure between 140-160 mmHg and diastolic blood pressure between 90-99 Hg were included in the study.Patients were excluded if the hypertension was secondary to hepatic, renal, cardiac, or endocrine disorders; pregnant or lactating; receiving Olmesartan or Telmisartan; or hypersensitive to Salbutamol, Olmesartan, or Telmisartan.e eligible patients randomly received either 20 mg of Olmesartan or 40 mg of Telmisartan.e treatments were given for duration of four weeks.BP, HR, cf PWV, RI, EDVR, and MDA were measured at baseline and at the end of four weeks.Demographic, clinical, and laboratory records of the enrolled patients were also recorded.Aer the completion of the study, the patients were instructed to consult their physician for further management.
2.1.Pulse Wave Velocity.e cf PWV was measured using a volume-plethysmographic apparatus (Periscope, M/S Geneisis Medical Systems, Hyderabad).is instrument also records blood pressure and electrocardiogram.e subjects were examined in the spine position aer a 10-minute rest, with electrodes connected to all the four limbs and cuffs wrapped on both the brachia and ankles.e plethysmographic sensor and the oscillometric pressure sensors were positioned in these cuffs records volume waveforms and blood pressure, respectively.Initially the brachial ankle pulse wave velocities baPWV of the right and le were obtained from the stored wave forms.Subsequently, cf PWV was calculated automatically from the mathematical equation cf PWV = 0.833 * average baPWV-233.3[7].

Endothelial Dependent Vasodilatory
Function.RI was measured from the waveforms recorded from the index �nger of the right hand by digital volume plethysmography (Dicrowin, M/S Genesis Medical Systems, Hyderabad) as per the procedure described in detail by Naidu et al. [8].At each visit RI was measured at base line, then 400 micrograms of Salbutamol was administered through spacer, and at the end of 15 minutes aer inhalation RI was measured again.At each time, three such recordings were collected.e mean of these three measurements was used for �nal analysis.e percentage decrease in RI at the end of the test compared to baseline was used to assess EDVR [9].

Serum MDA (Malondialdehyde).
Measurement of MDA provides a sensitive index of the lipid peroxidation.e lipid peroxidation products react with thiobarbituric acid forming a pink coloured adduct on boiling.At each visit, 6 mL of blood was collected in clean dry test tubes.e test tubes were then centrifuged at 2000 rpm for 10 minutes; serum was separated and collected in aliquots labeled with patient code and date of collection and they were stored at 20 ∘ centigrade in a refrigerator for the analysis of serum MDA.To 0.5 mL of serum, 0.5 mL of 20% TCA (trichloroacetic acid) and 250 microliters of TBA reagent (0.33%, Sigma Chemical Co., USA) were added in plastic tubes.ese tubes were �rst kept in water bath for 60 minutes at 95 degrees centigrade then cooled and vortexed.e absorbance of the supernatant was read at 532 nm at room temperature against blank.e concentration of MDA was read from standard calibration

Discussion
In this study, treatment with ARB Olmesartan and Telmisartan resulted in signi�cant decrease in RI and PWV from baseline in hypertensive patients.is reduction in aortic PWV and arterial wave re�ections was in parallel to the decrease of blood pressure.It is possible that such an improvement in arterial compliance in our study may involve acute functional changes such as vascular smooth muscle relaxation and blood pressure reduction.Beuge and Aust [11] reported that treatment with Losartan for 4 weeks signi�cantly reduced PWV with BP reduction.Mahmud and Feely [12] reported that in mild to moderate essential hypertensive patients, treatment with Telmisartan has the potential to improve PWV greater than effects due to lowering of BP alone.However, Uchida et al. [13] has shown that in essential hypertensive patients aer 16 weeks of treatment with 10-40 mg of Olmesartan cf PWV was reduced independently of the decrease in systolic BP. e mechanisms for such an independent improvement of arterial stiffness may possibly be improved by endothelial function and/or decreased oxidative stress.It is unlikely that structural changes would occur aer 4 weeks of therapy.
We also observed an improvement in endothelial dependent vasodilator response to Salbutamol aer with treatment both Olmesartan and Telmisartan.However the magnitude of improvement was more or less similar in both the treatments as compared to baseline.Our study results were in procession with the available literature; for example, change in postischemic reactive hyperemia as shown by Mediavilla and colleagues [14] was found to be greater aer treatment with Telmisartan than Valsartan treatment, regardless of a similar reduction in BP exerted by both compounds.Tomiyama et al. [15] also demonstrated an improvement in endothelium-dependent coronary dilation in hypertensive patients aer treatment with Olmesartan.Another possible bene�t observed in our study population was reductions in serum MDA aer treatment with both Olmesartan and Telmisartan.Such a �nding was also observed in other studies such as Losartan, [16] Valsartan, [17] Irbesartan, [18] Olmesartan [19], and Telmisartan [20].On comparison, Olmesartan showed a better improvement in cf PWV, EDVR, and MDA than Telmisartan.e magnitude of drop in supine either systolic or diastolic blood pressures was not signi�cant statistically between the two groups.When we evaluated baseline demographic, biochemical, hemodynamic, vascular, and lipid peroxidation parameters, we found that they were similar in both Olmesartan and Telmisartan groups.One of the possible explanations for such an improvement with Olmesartan is that Olmesartan may have long lasting blood pressure lowering effects and vasculoprotective properties in patients with hypertension due to its strongest AT-II type 1 receptor antagonistic ability.In vitro studies have shown that the rank order of binding affinity to AT-II type 1 receptor varies between different ARBs and appears to be as follows: Valsartan > Olmesartan > Candesartan > Irbesartan > Telmisartan > Losartan > Eprosartan [21].

Study Limitations
In the present study, Olmesartan showed a better improvement in cf PWV, EDVR, and MDA than Telmisartan without much difference in BP reduction.However, such an interpretation needs carefulness because fewer numbers of patients received Telmisartan.e time at which they took the medication before each study day, concomitant medications and intrapatient variability can be confounding factors.Although, to con�rm the role of free radicals in essential hypertension, we have estimated free radical marker MDA, we could not estimate concentration of serum nitric oxide or its end-product nitrites in the present study.

Conclusion
Both Olmesartan and Telmisartan, which are known to decrease blood pressures, have demonstrated their efficacy in reducing arterial stiffness.is was associated with an improvement in EDVR and a signi�cant reduction of serum MDA levels in patients with essential hypertension.Olmesartan showed a better improvement in cf PWV, EDVR, and MDA than Telmisartan with an identical reduction in blood pressure.us, it can be concluded that, in patients with essential hypertension both the ARBs Olmesartan and Telmisartan offered their bene�cial effects on cardiovascular system through multiple mechanisms.

Con�ic� of �n�eres�s
e authors declare that they have no con�ict of interests.

F 1 :F 2 :
Effect of Olmesartan versus Telmisartan on carotid femoral pulse wave velocity (cf PWV) in patients with Hypertension.Effect of Olmesartan versus Telmisartan on Endothelial Dependent Vascular Response (EDVR %) in Patents with Hypertension.

F 3 :
Effect of Olmesartan versus Telmisartan on index of digital artery tone Re�ection index (RI) in Patents with Hypertension.

T 1 :
Base line clinical, hemodynamic, and vascular characteristics of mild-moderate essential hypertensive patients according to treatment group.USA.Continuous data was presented as mean, median, range, and standard deviation.Categorical data was presented as actual numbers and percentages.For normally distributed data, within group analysis was performed by using paired  test and between group analyses by unpaired  test.Nonnormally distributed data was analyzed by using nonparametric Mann-Whitney  test.Categorical variables were analyzed with Fischer's exact test.All the efficacy parameters were presented as absolute change from base T 2: Comparison of hemodynamic, vascular, and oxidative stress parameters before and aer Olmesartan and Telmisartan in patients with hypertension.: heart rate, SBP: systolic blood pressure, MBP: mean blood pressure, DBP: diastolic blood pressure, PP: pulse pressure, cf PWV: carotid femoral pulse wave velocity, RI: Re�ection index, EDVR: endothelial dependent vascular response to salbutamol challenge, MDA: serum malondialdehyde.
8DL cholesterol, mg/dL 55.8± 14.7 51.9 ± 19.9 0.31 LDL cholesterol, mg/dL 127.1 ± 28.1 135.9 ± 42.9 0.34 MDA,  mol/mL 5.8 ± 2.8 6.4 ± 3.HRline.Negative sign indicates decrease and vice versa.For statistical signi�cance, a two-tailed probability value of less than 0.05 was considered.A sample of 25 patients per group was required to demonstrate an estimated change in primary efficacy variable cf PWV of 1 m/s from baseline in both groups, with 80% power to detect the difference and twosided alpha error of 0.05.Additionally 30 percent of subjects were added to each group in view of dropouts and missing data.A total of 40 subjects have been planned to allocate to each treatment.