12 Perintopril

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Manikandan et al. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 7.421
Volume 7, Issue 6, 1272-1282 Research Article ISSN 2278 – 4357
THE EFFECT OF PERINDOPRIL IN HYPERTENSIVE AND

TYPE II DIABETES MELLITUS PATIENTS
Manikandan S.*1,2, Ramanathan M.2 and Vivek R.1
1
KM College of Pharmacy, Madurai- 625 107, Tamil Nadu, India.
2
Sankaralingam Bhuvaneswari College of Pharmacy, Anaikuttam, Sivakasi. – 626130.
OBJECTIVES
Article Received on
13 April 2018, Today’s big challenge in the medical fraternity is control and
Revised on 03 May 2018,
Accepted on 23 May 2018
management of non-communicable disease. In India the diabetes and
DOI: 10.20959/wjpps20186-11807 hypertension incidence is increasing day by day, to optimize the
therapy would be beneficial for patients. The aim of the Study was to
evaluate the effect of Perindopril in improving endothelial dysfunction
*Corresponding Author
Manikandan S. in patient with hypertension and type II diabetes mellitus. This clinical
Associate Professor, study focus was to assess diameter of brachial artery by flow mediated
Sankaralingam dilatation (FMD) and endothelial function by microalbuminuria (It is
Bhuvaneswari College of
one of the biomarker for endothelial dysfunction). For this study 50
Pharmacy, Sivakasi - 626
subjects (40 patients and 10 healthy volunteers) were selected based on
130.
the inclusion and exclusion criteria (Group B) and (Group A) are
enrolled. The patient’s age ranged from 20 to 80 years. Majority of the patients fall between
the age group of 41-50 years. The observation ensures Perindopril reduces microalbuminuria
and blood pressure to a greater extent in hypertensive and Type II diabetes mellititus patients
and thus reduces cardiovascular risk and mortality. Perindopril is found to have no effect on
flow mediated dilatation.
KEYWORDS: Perindopril, Endothelial dysfunction, Flow mediated dilatation,

Microalbuminuria, cardiovascular risk and mortality.
INTRODUCTION
Diabetes mellitus is an increasing public health problem and is rapidly increasing in India due
to changes in dietary habits. In last two decades it has become evident that the endothelium is
not an inert, which plays a crucial role in regulating vascular tone and structure. The healthy
endothelium inhibits platelet and leukocyte adhesion to the vascular surface and maintains a
www.wjpps.com Vol 7, Issue 6, 2018. 1272

balance of profibrinolytic and prothrombotic activity. Endothelial dysfunction is a potential

contributor to the pathogenesis of vascular disease in diabetes mellitus. Under physiological
conditions, there is a balanced release of endothelial-derived relaxing and contracting factors,
but this balance is altered in diabetes and atherosclerosis, thereby leads to progression of
vascular and end-organ damage.[1] Hyperglycemia is the major causal factor in the
development of endothelial dysfunction in diabetes mellitus. Insulin resistance has been
described in several diseases that increase cardiovascular risk and mortality, such as diabetes,
obesity, hypertension, metabolic syndrome, and heart failure.
The progression of insulin resistance to type 2 diabetes parallels the progression of

endothelial dysfunction to atherosclerosis. Insulin resistance is closely linked with visceral
adiposity and early data suggested that free fatty acids were responsible for this association.[2]
There are plasma biomarkers produced by adipose tissue, including TNF and resistin, have
been shown to have elevated levels during obesity and to mediate insulin resistance.
Numerous studies have established that nitric oxide (NO)-mediated vasodilation is abnormal
in patients with type 2 diabetes.[3] Brachial artery responses were found to be abnormal to
both endogenous and exogenous NO donors, due to increased inactivation of NO, possibly
caused by enhanced metabolism of NO or abnormal vascular smooth muscle cell (VSMC)
responses to NO because of alterations in signal transduction in the guanylate cyclase
pathway. Obese patients without type 2 diabetes have been shown also to have abnormal
endothelial function.
Normal endothelial function and nitric oxide

The endothelium keeps vascular homeostasis through multiple regulatory functions involving
the release of several vasoactive factors that maintain vessel wall tone and blood fluidity
while limiting smooth muscle cell proliferation and inflammation.[4,5] The important of the
endothelium-derived molecules is nitric oxide (NO), although maintenance of endothelial
function also involves endothelin-1 (ET-1), angiotensin II, prostacyclin and endothelial-
derived hyperpolarising factor (EDHF).
In reaction to stress or activation of muscarinic receptors by the G-protein signalling

pathway, endothelial NO synthase (eNOS) is activated. This generates, NO and citrulline
from L-arginine, molecular oxygen and reduced nicotinamide adenine dinucleotide phosphate
(NADPH). NO released by this process stimulates soluble guanylate cyclase. The production

of cyclic guanosine 3’,5’-monophosphate (cGMP) results in vasodilatation and inhibits

chemotaxis and platelet aggregation.
Endothelial dysfunction
Endothelial dysfunction is the preliminary step in inflammatory and prothrombotic vascular
diseases. These take in risk factors of atherosclerosis, chronic infections and
Hypercholesterolemia. A weakened function or structure of the vascular endothelium
consequences in a disturbed balance between vasoconstriction and vasodilation and triggers a
number of processes (increased endothelial permeability, leukocyte adhesion, platelet
aggregation, synthesis and release of cytokines) which play crucial roles in development,
progression, and exacerbation of atherosclerotic vascular disease.[6]
Hypertension
Hypertension alters endothelial morphology and function. Platelets and monocytes interact
with endothelial cells to a greater degree than in normotensive control vessels[7], and
endothelium-dependent vascular relaxation is reduced. In a number of earlier studies,
antihypertensive therapy was unable to restore normal endothelium-dependent vascular
relaxation in resistance vessels in patients with essential hypertension when blood pressure
was normalized. The vasodilator response to acetylcholine was blunted even in patients who
had received appropriate medical therapy. The endothelial vasodilator dysfunction observed
in subjects with essential hypertension appears to be due to a defect in the NO synthase
pathway that is not reversible by administration of the NO precursor, L-arginine.[8]
Flow mediated dilatation

Flow mediated dilatation of large arteries has been confirmed in many vessels in vitro and in
vivo in animals and in humans, and it appears to be an endothelium-dependent phenomenon.
In 1992, Celermajer and colleagues described a simple, but elegant method to study
endothelial function in humans.[9] They postulated that increasing blood flow through a
superficial conduit artery would induce flow-dependent dilatation that could be measured
non-invasively using high-resolution ultrasound, the degree of dilatation indicating the
functional integrity of the endothelium. Blood flow was increased in the brachial artery by
releasing a forearm cuff that had been inflated for five minutes. Sublingual glyceryl trinitrate
was used as a control endothelium-independent stimulus. Brachial artery diameter may be
measured during diastole by ‘onscreen’ calipers applied to a B-mode (2 dimensional imaging)
ultrasound image.

Clinical study observation of perindopril

The effect of perindopril endothelial improvement function was evaluated by this study. A
total of 50 patients were selected based on the inclusion and exclusion criteria (Group B).
Also 10 healthy individuals (Group A) are enrolled (age group: 20 to 30 years, sex: 6 male
and 4 females). All the patient receives Perindopril 2mg OD. Study was conducted at Arthur
Asirvatham Hospital, Madurai, following grid of patients under our study. The patient’s age
ranged from 20 to 80 years. Majority of cases of the study patients fall between the age group
of 40-50 years. Age group of 30-40 includes 24% of patients. Age group of 50-60 includes
20% of patients.
The patient age group distribution was shown in table no.3, sex distribution, patient medical
history, social habits and family history were shown in table 2 to 5.
Table 1: Patient age group distribution.

Age group Number of % of
Sl.No
(years) patients patients
1 21-30 2 4%
2 31-40 12 24%
3 41-50 14 28%
4 51-60 10 20%
5 61-70 8 16%
6 71-80 4 8%
Table 2: Patient sex distribution.

Sl.No Sex Number of patients
1 Male 32
2 Female 18
Table 3: Medical history of DM and Hypertension.

Sl.No Medical history Number of patients
1 Diabetes 17
2 Hypertensive 9
3 Diabetes and Hypertension 24
Table 4: Social habits of patient.

Sl.No Social habits Number of patients
1 Smoker 4
2 Smoker & Alcoholic 3
3 Non Smoker & alcoholic 43

Table 5: Family history of DM or hypertension.

Sl.No Family history Number of patients
1 Presence 38
2 Absence 12
RESULTS
Microalbuminuria
Microalbuminuria is one of the biomarker for endothelial dysfunction. The baseline readings
of Microalbuminuria has been taken in all patients while enrolling them into the study.
Obtain the data after 8th and 16th week. The table 6 shown the data of microalbuminuria.
Table 6: Microalbuminuria of healthy vs. patients.

Microalbuminuria Mean SD SEM
Healthy individuals 13.98 1.404 0.628
Pt. Before Treatment 32.456 40.291 8.058
Percentage of change between healthy and patients = 43.07%
P value is < 0.0001, extremely significant.
Table 7: Microalbuminuria of patients at visit I and visit II.

After Treatment (I VISIT) 20.56 15.387 3.077
After Treatment (II VISIT) 17.64 8.173 1.635
st nd
Percentage of change between I Visit and II Visit = 14.20%
P value is < 0.0001, extremely significant.
Table 8: Microalbuminuria of patients before treatment Vs visit II.

Before Treatment 32.456 40.291 8.058
After Treatment (IInd visit) 17.64 8.173 1.635
Percentage of change between patients before and after treatment = 45.63%
P value is 0.0005, extremely significant.
Blood pressure
The mean Systolic and Diastolic blood pressure before therapy was 147.12 and 89.36
respectively. After 8 weeks therapy, the mean Systolic and Diastolic blood pressure was
140.24 and 86.4 respectively. After 16 weeks therapy, the mean Systolic and Diastolic blood
pressure was 130.16 and 83.36 respectively.

Table 9: Blood pressure of healthy Vs patients.

Blood pressure Mean SD SEM
Healthy Systolic 117 9.96 4.454
individuals Diastolic 78 4.472 2.00
Patients (Before Systolic 147.12 19.009 3.802
Treatment) Diastolic 89.36 11.33 2.268
Percentage of change in Systolic Blood Pressure between healthy and patients = 20.47%
Percentage of change in Diastolic Blood Pressure between healthy and patients = 12.71%
P value for blood pressure is < 0.0001, extremely significant.
Table 10: Blood pressure of patients at visit I Vs visit II.

After Treatment Systolic 140.24 13.333 2.667
(I Visit) Diastolic 86.4 8.185 1.637
(II Visit) Diastolic 83.36 5.345 1.069
Percentage of change in Systolic Blood Pressure between I Visit and II Visit = 7.18%
Percentage of change in Diastolic Blood Pressure between I Visit and II Visit = 3.51
P value is for Systolic and Diastolic BP is 0.0032 and 0.1266 respectively. Change in Systolic
BP is very significant.
Table 11: Blood pressure of patients before treatment Vs visit II.

Before Systolic 147.12 19.009 3.802
Treatment Diastolic 89.36 11.33 2.268
(II Visit) Diastolic 83.36 5.345 1.069
Percentage of change in Systolic Blood Pressure between patients before treatment and II
Visit = 11.52%
Percentage of change in Diastolic Blood Pressure between patients before treatment and II
Visit = 6.37%
P value is for Systolic and Diastolic BP is 0.0002 and 0.0207. Systolic BP is extremely
significant, Diastolic BP is considered significant.
Flow Mediated Dilatation (FMD)

It is one of the method for the assessment of endothelial function. The diameter of the
endothelium is measured in brachial artery before and after inflating BP cuff.

Before inflating BP cuff

Table 12: FMD of healthy Vs patients during systole.
Flow mediated dilatation Mean SD SEM
Healthy individuals During Systole 3.64 0.3647 0.1631
Before Treatment During Systole 3.424 0.7120 0.1424
Percentage of change in Flow mediated dilatation during Systole = 5.9%
P value of FMD during Systole is 0.1758, not significant.
Table 13: FMD of patients at visit I Vs visit II during systole.

After Treatment (Visit I) During Systole 3.536 0.6951 0.139
After Treatment (Visit II) During Systole 3.56 0.7042 0.1408
Table 14: FMD of patients before treatment Vs visit II during systole.

% of change in Flow mediated dilatation during Systole = 3.82%
Table 15: FMD of healthy Vs patients during diastole.

Healthy individuals During Diastole 4.62 0.4868 0.2177
Before Treatment During Diastole 3.98 0.7106 0.1421
Percentage of change in Flow mediated dilatation during Diastole = 13.85%
P value for Flow mediated dilatation during Diastole is 0.0004, extremely significant.
Table 16: FMD of patients at visit I Vs visit II during diastole.

After Treatment (Visit I) During Diastole 4.044 0.7072 0.1414
After Treatment (Visit II) During Diastole 4.072 0.7185 0.1437
P value for Flow mediated dilatation during Diastole is 0.8901, not significant.
Table 17: FMD of patients before treatment Vs visit II during diastole.


After inflating BP cuff for 5 minutes

Table no 18: FMD of healthy Vs patients during systole.
Healthy individuals During Systole 4.14 0.6427 0.2874
P value for Flow mediated dilatation during Systole is 0.0914, not quite significant.
Table 19: FMD of patients at visit I Vs visit II during systole.

Flow mediated dilatation MEAN SD SEM
After Treatment (Visit I) During Systole 3.89 0.7729 0.1546
P value for Flow mediated dilatation during Systole is 0.8680, not significant.
Table 20: FMD of patients before treatment Vs visit ii during systole.

P value for Flow mediated dilatation during Systole is 0.5608, not significant.
After inflating BP cuff for 5 minutes

Table 21: FMD of healthy Vs patients during diastole.
Healthy individuals During Diastole 5.08 0.5404 0.2417
P value for Flow mediated dilatation during Diastole is 0.0006, extremely significant.
Table 22: FMD of patients at visit I Vs visit II during diastole.

After Treatment (Visit I) During Diastole 4.44 0.7709 0.1542

Table 23: FMD of patients before treatment Vs visit II during diastole.

DISCUSSION
Endothelial dysfunction is supposed to be a key event in the development of atherosclerosis.
This is because endothelial dysfunction is associated with reduced anticoagulant properties as
well as increased adhesion molecule expression, cytokine release and reactive oxygen species
production. All of this plays an important role in the development of atherosclerosis. The
initiation and progression of atherosclerosis may have its origin in endothelial function that
can be detected at the earliest stages of development of the metabolic syndrome.
In diabetes, hyperglycaemia and components of the metabolic syndrome cause endothelial

dysfunction directly or indirectly. A common mechanism underlying endothelial dysfunction
relates to an increase in oxidative stress.
Endothelial dysfunction and Microalbuminuria

Microalbuminuria is defined as a urinary albumin excretion rate of 30-300 mg in 24hrs urine
collection. Microalbuminuria is an independent risk factor for the development of
cardiovascular diseases and cardiovascular mortality in the diabetic population.
Flow Mediated Dilatation is considered as an effective means to evaluate endothelial

dysfunction non-invasively. Also useful for early detection of atherosclerosis and
determining the efficacy of treatment.
ACE inhibition and endothelial dysfunction

Angiotensin II is thought to play a key role in the development of endothelial dysfunction in a
variety of disease states. ACE inhibitors have been suggested as having favourable effects on
the vascular wall beyond those of blood pressure reduction.
Effect on Microalbuminuria
The mean microalbuminuria of healthy volunteers and patients are 13.98 and 32.456
respectively (43% change). Treatment with Perindopril shows significant reduction in

Microalbuminuria. After 8 weeks therapy, microalbuminuria is 20.56 (% change is 36.65%)

and it further decreases to 17.64 on 16 weeks treatment. The percentage of change between
1st and 2nd visit is 14.20%.
Effect on Blood Pressure

The mean systolic and diastolic blood pressure of patients before initiation of therapy was
147.12 and 89.36 respectively. On treating with Perindopril for 8 weeks, mean systolic and
diastolic blood pressure reduces to 140.24 (4.6% reduction) and 86.4 (3.31% reduction)
respectively. Further treatment up to 16 weeks reduces systolic and diastolic blood pressure
to 130.16 (7.18% reduction) and 83.36 (3.51% reduction) respectively.
Flow Mediated Dilatation of control Vs. patients

Before inflating BP cuff, the mean diameter of brachial artery in healthy volunteers and
patients during systole is 3.64 and 3.424 respectively. (Change is 5.9%). Whereas, during
diastole the diameter of brachial artery between control and patients are 4.62 and 3.98
respectively. (Change is 13.85%).
After inflating BP cuff, the diameter of artery during systole in healthy volunteers and
patients is 4.14 and 3.8 respectively (Change is 8.21%). Whereas diameter of artery during
diastole between the groups is 5.08 and 4.38 respectively (Change is 13.77%).
Flow Mediated Dilatation after treatment

On treating with Perindopril for 8 weeks, the mean diameter of brachial artery during systole
and diastole before inflating BP cuff is 3.536 and 4.044 respectively. After inflating BP cuff,
the mean diameter during systole and diastole is 3.89 and 4.44 respectively.
On further treatment up to 16 weeks, mean diameter of artery during systole and diastole
before inflating BP cuff is 3.56 and 4.072 respectively. After inflating BP cuff, the mean
diameter during systole and diastole 3.928 and 4.46 respectively.
CONCLUSION
In this study Perindopril reduces microalbuminuria and blood pressure in hypertensive and
Type II DM patients in a great extent and thus reduces cardiovascular risk and mortality rate.
Perindopril is found to have no effect on Flow Mediated Dilatation. Further long term studies
are needed to confirm the effect of drug on Flow mediated Dilatation.

ACKNOWLEDGEMENT
The authors are thankful to Arthur Asirvatham Hospital, Madurai for clinical study support.
The authors are very grateful to the management and Principal of KM College of Pharmacy,
Madurai and Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi, for providing
laboratory, library, internet facilities and constant encouragement.
REFERENCE
1. Tan KC, Chow WS, Ai VH, et al. 2002. Effects of angiotensin II receptor antagonist on
endothelial vasomotor function and urinary albumin excretion in type 2 diabetic patients
with microalbuminuria. Diabetes Metab Res Rev, 18: 71–6.
2. Boden G, Shulman GI. 2002. Free fatty acids in obesity and type 2 diabetes: defining
their role in the development of insulin resistance and beta cell dysfunction. Eur J Clin
Invest, 32(Suppl 3): 14–23.
3. Williams SB, Cusco JA, Roddy MA, et al. 1996. Impaired nitric oxide mediated
vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol,
27: 567–74.
4. Widlansky ME, Gokce N, Keaney J, Vita JA. The clinical implications of endothelial
dysfunction. J Am Coll Cardiol, 2003; 42: 1149-60.
5. Esper R, Nordaby R, Vilarino J, Paragano A, Cacharron J, Machado R. Endothelial
dysfunction: a comprehensive appraisal. Cardiovasc Diabetol, 2006; 5: 4-21.
6. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation,
2004; 109(suppl 1): III27- III32.
7. Luscher TF, Tanner FC, Tschudi MR, Noll G: Endothelial dysfunction in coronary artery
disease. Ann Rev Med, 1993; 44: 395–418.
8. Cooke JP, Dzau VJ: Nitric oxide synthase: Role in the genesis of vascular disease. Ann
Rev Med, 1997; 48: 489–509.
9. Celermajer DS, Sorensen KE, Gooch VM et al. Non-invasive detection of endothelial
dysfunction in children and adults at risk of atherosclerosis. Lancet, 1992; 340: 1111-15.

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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Manikandan et al. World Journal of Pharmacy and Pharmaceutical Sciences

Volume 7, Issue 6, 1272-1282 Research Article ISSN 2278 – 4357

THE EFFECT OF PERINDOPRIL IN HYPERTENSIVE AND

Manikandan S.*1,2, Ramanathan M.2 and Vivek R.1

KEYWORDS: Perindopril, Endothelial dysfunction, Flow mediated dilatation,

www.wjpps.com Vol 7, Issue 6, 2018. 1272

balance of profibrinolytic and prothrombotic activity. Endothelial dysfunction is a potential

The progression of insulin resistance to type 2 diabetes parallels the progression of

Normal endothelial function and nitric oxide

In reaction to stress or activation of muscarinic receptors by the G-protein signalling

www.wjpps.com Vol 7, Issue 6, 2018. 1273

of cyclic guanosine 3’,5’-monophosphate (cGMP) results in vasodilatation and inhibits

Flow mediated dilatation

www.wjpps.com Vol 7, Issue 6, 2018. 1274

Clinical study observation of perindopril

Table 1: Patient age group distribution.

Table 2: Patient sex distribution.

Table 3: Medical history of DM and Hypertension.

Table 4: Social habits of patient.

www.wjpps.com Vol 7, Issue 6, 2018. 1275

Table 5: Family history of DM or hypertension.

Table 6: Microalbuminuria of healthy vs. patients.

Table 7: Microalbuminuria of patients at visit I and visit II.

Table 8: Microalbuminuria of patients before treatment Vs visit II.

www.wjpps.com Vol 7, Issue 6, 2018. 1276

Table 9: Blood pressure of healthy Vs patients.

Table 10: Blood pressure of patients at visit I Vs visit II.

Table 11: Blood pressure of patients before treatment Vs visit II.

Flow Mediated Dilatation (FMD)

www.wjpps.com Vol 7, Issue 6, 2018. 1277

Before inflating BP cuff

Table 13: FMD of patients at visit I Vs visit II during systole.

Table 14: FMD of patients before treatment Vs visit II during systole.

Table 15: FMD of healthy Vs patients during diastole.

Table 16: FMD of patients at visit I Vs visit II during diastole.

Table 17: FMD of patients before treatment Vs visit II during diastole.

www.wjpps.com Vol 7, Issue 6, 2018. 1278

After inflating BP cuff for 5 minutes

Table 19: FMD of patients at visit I Vs visit II during systole.

Table 20: FMD of patients before treatment Vs visit ii during systole.

After inflating BP cuff for 5 minutes

Table 22: FMD of patients at visit I Vs visit II during diastole.

www.wjpps.com Vol 7, Issue 6, 2018. 1279

Table 23: FMD of patients before treatment Vs visit II during diastole.

In diabetes, hyperglycaemia and components of the metabolic syndrome cause endothelial

Endothelial dysfunction and Microalbuminuria

Flow Mediated Dilatation is considered as an effective means to evaluate endothelial

ACE inhibition and endothelial dysfunction

www.wjpps.com Vol 7, Issue 6, 2018. 1280

Microalbuminuria. After 8 weeks therapy, microalbuminuria is 20.56 (% change is 36.65%)

Effect on Blood Pressure

Flow Mediated Dilatation of control Vs. patients

Flow Mediated Dilatation after treatment

www.wjpps.com Vol 7, Issue 6, 2018. 1281

www.wjpps.com Vol 7, Issue 6, 2018. 1282

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