Cardiovascular profile of 5 novel nitrate‐esters: a comparative study with nitroglycerin in pigs with and without left ventricular dysfunction

Abstract

1 Four cumulative 10 min intravenous infusions of 0.05, 0.2, 0.5 and 2.0mg min I were used to compare the cardiovascular profile of 5 novel nitrate-esters dissolved in Intralipid 10% to that of nitroglycerin (GTN) in conscious pigs. 2 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 + 0.091 min' to 3.40 + 0.18 1 min' (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). 3 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. 4 CEDO 8816 was a more potent arterial and venodilator than the aforementioned CEDO cbmpounds, 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. 5 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 0.2mgmin-'. 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. 6 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/dtx were lower and those of systemic vascular resistance and left ventricular end-diastolic pressure were higher than in the first group of experiments.7 Both GTN and CEDO 8956 in doses of 0.05 to 2.0 mg inm increased cardiac output dosedependently (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/dt,,,,X (by 48% and 30%, respectively) and lowered left ventricular end-diastolic pressure to normal levels...

Cardiovascular effects of the novel potassium channel opener bimakalim in conscious pigs after myocardial infarction: A comparative study with nicorandil

“…These results are similar to those reported earlier [11,12,14]. (I) 14-+ 1 a 14-+ 1 14-+ 1 14-+2 14+-1 HR = heart rate (beats/min); CO = cardiac output (1/min); MAP = mean arterial blood pressure (mmHg); SVR = systemic vascular resistance (mmHg.min/1); LVdP/dtr~x = maximum rate of rise of left ventricular pressure (mmHg/s); LVEDP = left ventricular end-diastolic pressure (mmHg).…”

“…The increases in heart rate and LVdP/dtm~ x were, however, attenuated in the last group of animals. This observation is similar to what we have observed earlier with the calcium antagonists nisoldipine and elgodipine, the phosphodiesterase inhibitor pimobendan, and nitroglycerine, and were attributed to an attenuated adrenergic response [11,12,14]. However, the latter does not explain why heart rate still increased up to 40% in the normal animals and less than 15% in the animals with the infarctions when bimakalim was infused after beta-adrenoceptor blockade.…”

“…Subsequently the animals were intubated and mechanically ventilated with a mixture of oxygen and nitrous oxide (1:2) to which 1-4% (v/v) enflurane was added. Un-d-e~rile conditions the animals were instrumented for the measurement of left ventricular pressure (Konigsberg pressure transducer), left atrial and aortic pressures, and ascending aortic blood flow (electromagnetic flow probe) as described earlier [11,12].…”

Synthesis and pharmacology of a series of new organic nitrate esters

“…Only the experimentally established in vitro and in vivo activities of several nitrate esters have allowed us to proceed with the evaluation of the haemodynamic profiles of the compounds in mini-pigs. The results of these experiments and the selection of compound 21 (CEDO 8956) for further development have been described elsewhere [14].…”