Interpretation of nitrate plasma concentrations. Effect of cardiac output on nitroglycerin pharmacokinetics in experimental animals

We tested the hypothesis that the pharmacokinetics of nitroglycerin might be governed by haemodynamics, viz: cardiac output. The steady state pharmacokinetics of nitroglycerin, both in arterial and in venous plasma, were investigated in 11 rats after sequential infusions either of nitroglycerin alone (10 μgkg^-1 min^-1) or of nitroglycerin plus vasopressin (the latter at 5.5 mU kg^-1 min^-1). Cardiac output was estimated twice in each animal using ⁸⁵Sr and ¹⁴¹Ce microspheres. Nitroglycerin systemic clearance in arterial plasma was found to be correlated strongly with cardiac output (r = 0.784, N = 22, P < 0.001). Using the distribution ratio of nitroglycerin between red blood cells and plasma, we determined the systemic clearance of nitroglycerin in arterial blood to be about 3/4 of cardiac output. Vasopressin co-infusion decreased both the cardiac output and the arterial nitroglycerin clearance, but it also increased the arteriovenous extraction of nitroglycerin. Thus, vasopressin had no net effect on the venous plasma clearance of nitroglycerin. In animals infused with nitroglycerin alone, cardiac output also significantly correlated with nitroglycerin venous plasma clearance (P < 0.01) and arteriovenous extraction (P < 0.05). These data indicate that haemodynamic alterations may have profound effects on the observed plasma concentrations of nitroglycerin. These parameters need to be standardized and controlled if meaningful plasma concentrations of organic nitrates are to be obtained and interpreted.