Cardiovascular profile of 5 novel nitrate‐esters: a comparative study with nitroglycerin in pigs with and without left ventricular dysfunction
Authors: van Woerkens L.J. , van der Giessen W.J. , Verdouw P.D. 
Published: July 2012

Four cumulative 10 min intravenous infusions of 0.05, 0.2, 0.5 and 2.0 mg min−1 were used to compare the cardiovascular profile of 5 novel nitrate‐esters dissolved in Intralipid 10% to that of nitroglycerin (GTN) in conscious pigs.

Infusion of Intralipid 10% alone had no effect on any of the systemic haemodynamic parameters. GTN infusions decreased mean arterial blood pressure dose‐dependently from 94 ± 2 mmHg to 79 ± 3 mmHg (P < 0.05) and raised cardiac output from 2.74 ± 0.09 l min−1 to 3.40 ± 0.18 l min−1 (P < 0.05) due to an increase in heart rate (by up to 43 ± 3%), as stroke volume decreased slightly. Systemic vascular resistance decreased (by 32 ± 3%) and left ventricular end‐diastolic pressure fell from 5.2 ± 0.4 mmHg to 2.2 ± 0.5 mmHg (both P < 0.05).

The novel compounds CEDO 8811, CEDO 8834 and CEDO 8901 increased cardiac output only at the highest dose (7%, 8% and 9%, respectively). There was no change in mean arterial blood pressure as the increase in cardiac output was counterbalanced by arterial vasodilatation. All three compounds reduced left ventricular end‐diastolic pressure slightly.

CEDO 8816 was a more potent arterial and venodilator than the aforementioned CEDO compounds, as the decreases in systemic vascular resistance and left ventricular end‐diastolic pressure were already significant at lower doses. The fall in stroke volume was fully compensated by the increase in heart rate and as a result cardiac output increased by 11 ± 3% (P < 0.05) at the highest dose.

CEDO 8956 was the most potent vasodilator of the novel compounds and exhibited a cardiovascular profile similar to that of GTN. Left ventricular end‐diastolic pressure decreased significantly during infusion of 0.2 mg min−1. Mean arterial blood pressure decreased by 11 ± 2% (P < 0.05) in spite of an increase in cardiac output by up to 20 ± 2% (P < 0.05), due to a decrease (by 27 ± 1%, P < 0.05) in systemic vascular resistance. The increases in heart rate (20 ± 5%, P < 0.05) and LVdP/dtmax (38 ± 4%, P < 0.05) were, however, considerably less after CEDO 8956 than after GTN.

The potential of CEDO 8956 in the treatment of chronic left ventricular dysfunction was evaluated during administration to conscious pigs (21–23 kg), in which the left circumflex coronary artery was ligated 4 weeks earlier. In these animals, baseline values for cardiac output and LVdP/dtmax were lower and those of systemic vascular resistance and left ventricular end‐diastolic pressure were higher than in the first group of experiments.

Both GTN and CEDO 8956 in doses of 0.05 to 2.0 mg min−1 increased cardiac output dose‐dependently (by up to 34% and 19%, respectively). The decrease in systemic vascular resistance was larger with GTN (35%) than with CEDO 8956 (17%), which resulted in a 13% decrease in mean arterial pressure during infusion of GTN, whereas there was no change in mean arterial pressure during infusion of CEDO 8956. Both compounds increased LVdP/dtmax (by 48% and 30%, respectively) and lowered left ventricular end‐diastolic pressure to normal levels.

At a dose of 1.0 mg min−1, both GTN and CEDO 8956 increased left ventricular blood flow parallel to the increase in myocardial oxygen demand. At this dose, GTN also caused vasodilatation in the vascular beds of the brain, kidneys and adrenals. With CEDO 8956 no significant changes were achieved.

We conclude that the cardiovascular profile of CEDO 8956 in both normal animals and in animals with chronic left ventricular dysfunction warrants further study on its usefulness in the treatment of a number of cardiovascular disorders.