Dopamine D2R Agonist-Induced Cardiovascular Effects in Healthy Male Subjects: Potential Implications in Clinical Settings

Abstract

Dopamine D2 receptor agonists represent a first line treatment option in young patients with signs and symptoms of idiopathic Parkinson's disease. An association between the use of D2 receptor agonists in Parkinson's disease patients and heart failure has been reported. The identification of the underlying mechanism is needed to minimize the resultant cardiovascular morbidity. In a phase I clinical trial, a D2 receptor agonist (pramipexole) was administered to 52 healthy male subjects following a dose escalation scheme. Serial measurements of resting blood pressure, heart rate, and derived parameters including pulse pressure, pulsatile stress, and rate pressure product were analysed. Statistically significant and clinically relevant increases in most of the assessed parameters were found. Ten subjects were removed prematurely from the trial because of clinically significant increases in blood pressure and/or heart rate requiring immediate intervention with IV rescue medications including a selective β -1 blocker. The observed drug-related changes in vital signs were of clinical relevance and might explain some of the cardiovascular morbidity reported in patients receiving D2 receptor agonist in clinical settings. We suggest that the additional use of a β -1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.

Figure 1

Means of resting supine systolic blood pressure (S) and diastolic blood pressure (D). Significance tests: (1) SBP-UPT versus BL, P < 0.0001; STS versus BL, P < 0.0001. (2) DBP-UPT versus BL, P = 0.0310; STS versus BL, P = 0.1171.

Figure 2

Means of resting standing systolic and diastolic blood pressure. S: systolic blood pressure, D: diastolic blood pressure; Significance tests: (1) SBP-UPT versus BL,  P < 0.0001; STS versus BL, P < 0.0001. (2) DBP-UPT versus BL, P = 0.09; STS versus BL, P = 0.02.

Figure 3

Mean resting supine heart rate. BPM: beat per minute; significance tests: UPT versus BL, P < 0.0001; STS versus BL, P < 0.0001.

Figure 4

Mean resting standing heart rate. BPM: beat per minute; significance tests: UPT versus BL, P < 0.0001; STS versus BL, P < 0.0001.

Figure 5

Trends in supine systolic blood pressure and heart rate over 13 uptitration days. SBP: systolic blood pressure, HR: heart rate, BPM: beat per minute.

Figure 6

Trends in standing systolic blood presure and heart rate over 13 uptitration days. SBP: systolic blood pressure, HR: heart rate, BPM: beat per minute.

Figure 7

Trends in supine pulsatile stress (PS) and rate pressure product (RPP) over 13 uptitration days.

Figure 8

Trends in standing pulsatile stress (PS) and rate pressure product (RPP) over 13 uptitration days.