Haemodynamic and Hormonal Responses to Losartan (DuP753/MK954) Infusion during Cardiac Catheterization in Conscious Salt-Deplete Dogs

1. Haemodynamic and hormonal responses to infused angiotensin II were studied in conscious salt-deplete dogs during infusion of D-glucose or losartan (DuP753/MK954).

2. Mean arterial pressure (118±13mmHg) fell rapidly after losartan (60 min 106±18 mmHg) with a rise in heart rate (107±16 beats/min) from baseline (98±17 beats/min). Pressor responses to angiotensin II during D-glucose infusion (6 ng min⁻¹ kg⁻¹, 99±10 mmHg; 18 ng min⁻¹ kg⁻¹, 140±15 mmHg; 54 ng min⁻¹ kg⁻¹, 157±12 mmHg; 162 ng min⁻¹ kg⁻¹, 178±14 mmHg) showed a parallel shift during losartan infusion with very similar pressures in response to higher rates of angiotensin II infusion (54 ng min⁻¹ kg⁻¹,108 ± 17 mmHg;162 ng min⁻¹ kg⁻¹ 138±14 mmHg; 486 ng min⁻¹ kg⁻¹, 155±14 mmHg; 1458 ng min⁻¹ kg⁻¹, 177 ± 12 mmHg). Losartan caused a fall in baseline systemic vascular resistance. Despite the similar mean arterial pressure, the rise in systemic vascular resistance after angiotensin II during D-glucose infusion (162 ng min⁻¹ kg⁻¹, 8065± 1967 dyn s cm⁻⁵) was reduced during losartan infusion (1458 ng min⁻¹ kg⁻¹, 6645 ±1720 dyn s cm⁻⁵. Losartan caused a small rise in cardiac output related to a rise in heart rate and increased stroke volume. Pressure infusions of angiotensin II caused a fall in cardiac output during D-glucose infusion, which was blocked during losartan infusion. The rise in heart rate in response to angiotensin II was similar during both D-glucose and losartan infusion, but with higher absolute values during losartan alone. There was a linear relationship between heart rate and the plasma concentration of angiotensin II, which was unaffected by losartan. Pulmonary pressure was marginally elevated by losartan, related to the rise in cardiac output, and was much less sensitive to angiotensin II infusion, rising only at the highest rate of infusion during both D-glucose and losartan infusion.

3. Losartan infusion alone caused a rise in plasma angiotensin II concentration with a fall in aldosterone concentration. During pressor infusions the measured angiotensin II concentrations suggested that losartan increased the clearance of angiotensin II. 4. Losartan has complex effects on cardiovascular function. The pressor response of mean arterial pressure to angiotensin II shows competitive inhibition, but this marks subtle effects on cardiac output and heart rate, in addition to systemic vascular resistance. In addition to elevating endogenous angiotensin II and suppressing aldosterone, losartan may enhance clearance of infused angiotensin II.