Dobutamine and Isoprenaline Effects on Heart Rate after Drug and Exercise-Induced Cardiac Stress Test

Abstract
K. S. Chah. Purpose: To investigate the potency of Dobutamine and Isoprenaline as an agonist at the presence/absence of antagonist, Carvedilol and Terazosin. Methods:
15 males subject with coronary insufficiency are recruited and two series of stress test is carried out. Drug-induced stress test and Exercise-induced stress test. For
the exercise-induced cardiac stress test, same number of controls (person without and cardiovascular disease) is recruited as control. Results: Dobutamine is a more
stable drugs that Isoprenaline as agonist. When prescribed at higher dose, the effectiveness of Isoprenaline decrease and Dobutamine shows a stable increase.
Carvedilol is a strong antagonist comparing to Terazosin. A higher dose of Dobutamine is required to overcome the effect of Carvedilol. Terazosin on the other hand
doesn’t show, or its antagonist effect is not strong to inhibit the activity of Dobutamine. Exercise-induced cardiac stress test shows that Carvedilol is a stronger
antagonist compare to Terazosin. Carvedilol significantly lowered the patient’s heart rates where Terazosin shows neither increase of decrease in heart rate and match
the pattern like normal control patients. Conclusions: Isoprenaline is an appropriate inotropic agent when prescribed at low dose. Dobutamine is a better inotropic
agent than Isoprenaline at higher dosage. Carvedilol is a strong antagonist that is capable of inhibits the activity of Dobutamine at low-moderate dose. Terazosin
effect as a cardiac antagonist is vague.
KEY WORD: GRAPHPAD PRISMTM, AGONIST, ANTAGONIST, DRUGS, CARVEDILOL, TERAZOSIN
Introduction
I
n patients with cardiovascular disease, inotropes have been given out to increase cardiac contractility. It is known as an agent that alters the force or energy of
muscular contractions. Microvascular blood flow alterations are often seen in patients with cardiovascular disease. This alteration results in a decrease in
perfusion of blood vessel, leading to the development of multiple organ failure or death due to lack of blood supply. With the use of inotropic agents such as
Dobutamine and Isoprenaline, these alterations can be revert (3).
Dobutamine and Isoprenaline is primarily ß-adrenergic agonist. ß-adrenergic agent is agent that works on smooth muscle relaxation, striated muscle contraction
and blood vessel dilations (6). It is capable of stimulating sympathetic nervous system, increasing cardiac contractibility in person. Experimental studies have
evaluated it use in improving microcirculatory blood flow (3).
Dobutamine is one the commonly used ß-adrenergic agent. It has been reported to maintained blood flow in intestine and liver (3). It can be administered
parenteral, and have lower risk of to induce hypertension in patients. It does not increase the peripheral vascular resistance. Although Dobutamine contains beta for
extra stimulatory effects, it do not increase heart rate significantly (5). Dobutamine is used in patients to increase cardiac output.
Isoprenaline is a non-selective synthetic catecholamine ß-adrenoceptor agonist. Isoprenaline is capable of producing an increase myocardial contractibility and
heart rate. It is also used as therapy in treatment of hypovolaemic states, septic and cardiogenic shock, and heart failure. Since it also stimulate the release of
insulin, it had to be used with caution especially in persons with diabetes mellitus (2).
For every cardiac agonist used, there are antagonists to revert its effect. ß-adrenoreceptor antagonist (ß-blocker) competitively block ß-adrenoreceptor located
on the heart, smooth muscle, blood vessels, kidney, pancreas, uterus, brain and liver (2). Carvedilol are a-adrenoceptor blockade and non-selective ß-adrenoreceptor
blockade. It causes a decrease in intrinsic sympathetic activity (4). Carvedilol is a potent antihypertensive and causes reduction in blood pressure. Carvedilol has
an oral bioavailability of about 25% (2), but it is completely absorbed into the patient and peaked within one or two hours. Studies show that Carvedilol has a
beneficial effect in patients with chronic mild or moderate heart failure (2, 4). Carvedilol is particularly effective in lowering blood pressure (7).
Terazosin is another effective a1-adrenoceptor blocker. It is often used in management of hypertension and prostate hyperplasia (1). Terazosin absorption is
not affected by food. It almost completely absorbed after oral administration. Terazosin are able to affect the endothelial cell adhesion reducing prostatic tissue
vascularity (8).
The effectiveness of Dobutamine and Isoprenaline as an agonist remains unclear. In this study the effects of Dobutamine and Isoprenaline as an agonist, and its
effectiveness with the presence of antagonist is investigated.

Methods
Study population. 15 male subjects with coronary insufficiency were recruited. Two series of ‘stress test’ were carried out.
Drug-induced Cardiac Stress Test. The first was a ‘drug-induced’ stress test that consisted of determining the effect of infusing increasing doses of two
agonists on heart rate, Dobutamine and Isoprenaline. The same doses were infused again after infusion of two antagonists, Terazosin (10mg) and Carvedilol (25mg).
Exercise-induced Cardiac Stress Test. The second test was a graded cardiovascular exercise stress test conducted on a treadmill where subjects were subjected to
increasing workloads and heart rate measured at different ‘exercise doses’. The subjects were then undertook the same test 1 week later, 4 hours after 25 mg (oral) of
Carvedilol and again a week later, 4 hours after 10mg of Terazosin (oral).
Statistical analysis. Appropriate dose-response curve for each agonist, antagonist, presence and absence of antagonists is constructed using GraphPad PRISMTM.
The EC50 value is analyzed and the estimated best fit value is used to interpretation.

Results
The clinical data of the 16 male patients are presented by three different graphs. All patients were treated with Dobutamine, Isoprenaline, Carvedilol and
Terazosin.
Figure 1 below shows the dose response curves for two types of agonists, Dobutamine and Isoprenaline.

Figure 1 Dose response curves for two types of agonists, Dobutamine and Isoprenaline. Increasing dose of Dobutamine and Isoprenaline has shown increase in heart rate
at lower dose. Dobutamine had shown a significant increase in heart rate when prescribed at a higher dose. EC50 of Dobutamine 1.875 x 10-5 µg/kg/min, EC50 of
Isoprenaline 4.395 x 10-8µg/kg/min.
Based on figure 1, Isoprenaline shows an increase in heart rate at lower dose. Dobutamine shows an increase in heart rate at higher dose (-6 to -4 g/kg/min). The
trend of the line suggests that Dobutamine effect is more stable in increasing heart rate. Isoprenaline effect is more unstable when it is prescribed at higher dose.
The activity of Isoprenaline decreased at higher dose (-7 to -6 g/kg/min). Using the GraphPad PRISMTM, EC50 of Dobutamine and Isoprenaline is determined. Dobutamine
has EC50 of 1.870 x 10-5 µg/kg/min. Isoprenaline has EC50 of 4.395x 10-8 µg/kg/min.
Figure 2 below shows the dose response curves for Dobutamine at the presence or absence of antagonist, Carvedilol and Terazosin.
Figure 2 Dose Response Curves for Dobutamine (DOB) alone, Dobutamine in the presence and absence of two antagonist, Terazosin (10mg) and Carvedilol (25 mg). Terazosin
antagonist effect is overrid by Dobutamine dose when increased from -6 to -5 g/kg/min. With the presence of Carvedilol as antagonists, a higher dose of Dobutamine
have to be prescribed to overrid the antagonist effect. EC50 of Dobutamine (DOB) 4.732 x 10-5µg/kg/min, EC50 of Carvedilol + DOB 3.635 x 10-4µg/kg/min, EC50 of
Terazosin + DOB 3.751 x 10-5µg/kg/min.
Terazosin have a lower potency as an antagonist when compared to Carvedilol. When Dobutamine doses increased from -6 to -4 g/kg/min, Terazosin antagonist effect
is not seen. It shows a same trend of results comparing it to figure 1. When Dobutamine doses increased from -4 to -3 g/kg/min, the heart rate of the patient
gradually increased. Carvedilol demonstrated it antagonist effect, a higher dose of dobutamine is required to overcome the antagonist effect. Dobutamine alone has
EC50 of 4.732 x 10-5 µg/kg/min. When Carvedilol is present, the EC50 of dobutamine increase to 3.635 x 10-4 µg/kg/min. When Terazosin is present, the EC50 of
dobutamine increase to 3.751 x10-5 µg/kg/min.
Figure 3 below shows the dose response curve of exercise-induced cardiac stress test in patients and controls with the presence of antagonist, Carvedilol and
Terazosin.

Figure 3 Exercise Dose-Response curves in the presence and absence of the two antagonists, Terazosin (10mg) and Carvedilol (25mg). Presence of Terazosin cause no
changes in heart rate compare to normal control group. Presence of Carvedilol as an antagonist lowered the patient’s heart rate. EC50 of Control and Exercise +
Carvedilol 90 watts, EC50 value of 130 watts for Terazosin.

In patients prescribed with Terazosin, the heart rate appears to be in the same trend of pattern like the controls. Patients prescribed with Carvedilol shows a
significant lowering in heart rate as the exercise intensity increases. Controls and patient group with Terazosin as prescription have EC50 of 90 watts. For patient
group with Carvedilol as prescription, it has a EC50 value of 130 watts.
Discussion
In this study, the effects of Dobutamine and Isoprenaline as an agonist, and its effectiveness with the presence of antagonist are interested.
Isoprenaline have higher potency than Dobutamine. It has a significant effect in increasing heart rate even at a lower dose. EC50 of Isoprenaline indicates the
potency of the drugs is effective at lower dose. Isoprenaline induced a higher degree of coronary perfusion.
On the other hand, Dobutamine demonstrate a lower EC value. It is less effective than Isoprenaline. However, when it is use in conjunction with Carverdilol and
Terazosin, dobutamine agonist effect is able to overcome the effect of Terazosin. The EC50 value of dobutamine dropped significantly. Interestingly, when Carvedilol
is present, dobutamine has decrease potency. In exercised patient with Carvedilol prescribed, the heart rate of the patients is significantly lowered. Studies
suggest that Carvedilol reduces the occurrence of cardiac muscle apoptosis, reducing the heart rate. It have a cardio protective effect (6). This explains the trends
of the results seen on figure 3.
Terazosin effect as antagonist seems to be vague. When Dobutamine is used in conjunction with Terazosin, no antagonist effects can be seen. It displays the same
trend of pattern like when there’s only Dobutamine used. It is observed in exercise-induced cardiac stress test patient who is prescribed with Terazosin. The dose of
Terazosin given is only 10mg. This may explains the low/no-activity of the antagonist. Since the mechanism of terazosin is not well studied, there are many
possibilities about why this happen. More studies have to be carried to evaluate the performance of cardiac agonist, Dobutamine and Isoprenaline, and cardiac
antagonist, Carvedilol and Terazosin.
Conclusion
Isoprenaline is an appropriate inotropic agent when prescribed at low dose. Dobutamine is a better inotropic agent than Isoprenaline at higher dosage.
Carvedilol is a strong antagonist that is capable of inhibits the activity of Dobutamine at low-moderate dose. Terazosin effect as a cardiac antagonist is vague.
Conflict of Interest
There are no known conflicts of interest.
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