Arterial hypertension is associated with alterations in myocardial perfusion and vascular resistance. However, it is unknown how long-term antihypertensive treatment influences myocardial vascular regulation. Thirty patients (age 50±6 (SD) years) with uncomplicated and previously untreated essential hypertension were randomized in a double blind fashion to treatment with either the ACE-inhibitor perindopril (4-8 mg, n=15) or the beta-blocker atenolol (50-100 mg, n=15) with the possible addition of 5 mg bendroflumethiazide to reach a diastolic blood pressure (BP) <90 mmHg. Myocardial perfusion (MP) was measured at rest and during dipyridamole-induced (0.56 mg/kg) hyperemia before and after 12 months treatment (on medication) using positron emission tomography (PET) with 13N-ammonia. BP reduction was similar in the two treatment groups with ambulatory BP decreasing from 160/105 to 138/88 mmHg (P<0.01) in the perindopril group and from 158/105 to 131/86 mmHg (P<0.01) in the atenolol group (P=NS for comparison). Resting MP decreased significantly more in the atenolol group (from 0.91±0.22 to 0.67±0.15 ml/g/min) than in the perindopril group (from 0.95±0.16 to 0.84±0.18 ml/g/min). However, when corrected for changes in myocardial workload (expressed as the rate-pressure product) there was no difference. Resting myocardial vascular resistance (defined as mean arterial BP divided by MP) was not significantly affected by either of the treatments. Dipyridamole-induced hyperemia was unaltered in the perindopril group (from 2.27±0.71 to 2.12±0.40 ml/g/min, p=NS), but was reduced by 34% in the atenolol group (from 2.06 to 1.35±0.42 ml/g/min, p<0.01). This resulted in an unchanged hyperemic vascular resistance in the perindopril group (from 54±14 to 47±11 mmHg/ml/g/min, P=NS), but a 34% increase in the atenolol group (from 61±22 to 77±33 mmHg/ml/g/min, p<0.05). The study demonstrates that despite similar BP reduction, ACE-inhibition and beta-blockade affect myocardial circulation differently. Both drugs reduce resting MP according to changes in myocardial workload, whereas hyperemic MP is reduced by atenolol but not affected by perindopril. Thus, myocardial vasodilatory capacity during beta-blockade is markedly attenuated.