Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog.

2. Doses in the range 0.1–3 μmin⁻¹ kg⁻¹ caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min⁻¹kg⁻¹), and a dose of 10 μgmin⁻¹ kg⁻¹ had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 μmin⁻¹ kg⁻¹ for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 ± 11.2 to 95.0 ± 12.8 mmHg) and a rise in heart rate (from 84.6 ± 15.1 to 103 ± 15.2 beats/min). Baseline plasma angiotensin II (42.5 ± 11.8 pg/ml) and renin (64.5 ± 92.7 μ-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 ± 11.6 mmHg) was reduced at 15 min (11.8 ± 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 ± 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ngmin⁻¹kg⁻¹, +19.9 ± 8 mmHg; 2000ngmin⁻¹ kg⁻¹, +52.8 ± 13.9 mmHg) with a fall in heart rate (1000 ng min⁻¹ kg⁻¹, −27.9 ± 11.5 beats/min; 2000 ng min⁻¹ kg⁻¹, −31.2 ± 17.3 beats/min). During Losartan infusion the 1000 but not the 2000 ng min⁻¹ kg⁻¹ noradrenaline infusion caused a greater rise in mean arterial blood pressure and a greater fall in heart rate. The fall in heart rate tended to decrease with continued infusion of Losartan. Plasma catecholamine concentrations were unaffected by Losartan. In a further study, higher doses of Losartan (100, 300 and 1000 μg min⁻¹ kg⁻¹; 30 min) produced greater falls in mean arterial blood pressure also with a rise in heart rate and complete blockade of the pressor effect of infused angiotensin II. Some animals became disturbed at the highest dose. 3. Losartan produces rapid dose-related falls in blood pressure and a rise in heart rate and renin release with elevation of plasma angiotensin II. Pressor responses to angiotensin II are reduced at intermediate doses and are eliminated at high doses. Losartan does not appear to inhibit angiotensin II clearance from the plasma and may in some way increase it.