The Effect of vasoactive substances on the st segment

M. de Chantal^1,2, C. Pharand², J. G. Diodati²
¹Université de Montréal, 2960, Chemin de la tour
Montréal, Québec, CANADA H3T 1J4
²Hôpital du Sacré-Coeur de Montréal, Université de Montréal, 5400 Gouin west boulevard, Montreal, Quebec, CANADA, H3A 2B4

Abstract: Neuropeptide Y (NPY) is a peptide with vasoconstrictor effect. We inject NPY (1 pmol/kg and 10 pmol/kg) in the proximal left anterior descending coronary artery of 4 pigs. NPY caused ST segment in the antero-posterior Z lead. This change was observe with or without proximal stenosis and with two doses of NPY. No consistent changes were seen in the X and Y leads.

INTRODUCTION

NPY is a major neuropeptide in the heart. It was discovered in 1982 from the porcine brain. There are three major sources: the sympathetic system, the platelet and the adrenal medulla[1]. It has influences on blood pressure, blood volume, cardiac function and vasomotion[2]. It has many effects on the coronary arterial system, in vivo and in vitro. In healthy dog heart, concentration of NPY is more important around the coronary vessel[3]. NPY has a potent vasoconstrictor effect. It acts preferentially on the microvascular level through four different pathways. First, it has a direct vasoconstrictor effects on many organs. Second, it potentiates the vasoconstrictor effect of the alpha adrenergic receptors. Thirds, it diminishes the postsynaptic release of norepinephrine. Fourth, it inhibits the cholinergic transmission.

The coronary injection of NPY in patients with typical angina without critical epicardial vessel stenosis causes vasoconstriction of the microcirculation. This injection causes ischemia with typical chest pain[4]. This peptide induces some pathological condition like hypertension[5]. When patients with angina exercise ST segment depression is observed on the ECG caused by a myocardial ischemia[6]. This ischemia correlates with the liberation of NPY.

The objective of the present protocol was to study the ischemic response caused by intracoronary injection of NPY. We verify this response in a pig model with the displacement of the ST segment. These results are preliminary on only four pigs.

METHODS

Domestic pigs (30-40 kg) were chosen as experimentals animals. They were anaesthetized with intramuscular ketamine/xylazine (20 mg/kg; 2 mg/kg; Wyeth-Ayerst, Montreal, Canada; Bayer, Toronto, Canada) intubated and ventilated with a positive pressure ventilator. Anaesthesia was maintained with isoflurane (Abbott Laboratory, Canada) 1.5% in O₂:N₂O (2:1). Muscular relaxation was obtained prior to thoracotomy with (vecuronium 0.1 mg/kg IV). Systemic anticoagulation was achieved with sodium heparin (Leo Pharma, Canada), with an initial intravenous bolus of 200 U/kg, followed by additional boluses of 200 U/kg to maintain ACT > 250 sec.

The right carotid artery was cannulated and a catheter introduced in the left ventricle for microsphere injections. The left carotid artery was cannulated and a catheter advanced into the left coronary artery ostium. A catheter was then inserted into the proximal left anterior descending (LAD) coronary artery for drug injection and coronary pressure monitoring. Finally, a left thoracotomy at the fifth intercostal space was performed to allow placement of a perivascular flowmeter (Transonic T106/T206 systems, NY, USA) and a perivascular balloon constrictor (IVM, USA) around the proximal LAD. Seven electrodes were positioned on the chest and back of the animal for continuous recording of a pseudoorthogonal ECG which corresponds approximately to Cm₅, III and an anteroposterior lead.

After the stabilization period, normal saline was infused over 5 minutes, followed by the study agent assigned. A 15-30 min rest period was allowed between normal saline and study drug administration and between each dose of study drug. All medications were infused intracoronarily. Animals receive NPY (Sigma-Aldrich Co., St-Louis, USA), under two conditions, normal and reduced coronary blood flow. The reduced flow corresponds to 50% of baseline coronary blood flow. Administration of NPY occured after a ³ 15-minutes period of stable coronary blood flow.

RESULTS

Figure 1. Changes of ST deviation in the Z lead in response to NPY (1 pmol/kg) without occlusion.

Figure 2. Changes of ST deviation in the Z lead in response to NPY (1 pmol/kg) with occlusion.

Figure 3. Changes of ST deviation in the Z lead in response to NPY (10 pmol/kg) without occlusion.

Figure 4. Changes of ST deviation in the Z lead in response to NPY (10 pmol/kg) with occlusion.

A bolus dose of NPY was administered to 4 pigs. Neuropeptide Y had no effect on the heart rate and LAD coronary blood flow (results are not shown). The injection NPY caused ST segment depression in the Z derivation (antero-posterior in the LAD territory)(figure 1,2,3 and 4). After beginning the infusion of NPY we observed maximum of effect (diminution of ST segment) around 5 minutes and the ST segment returned to baseline five minutes after the end of the infusion. We saw these changes with both concentrations and without or with proximal stenosis. No consistent changes were seen in the X and Y derivations (results are not shown).

DISCUSSION

The platelet is a source of neuropeptide Y. NPY is a potent vasoconstrictor[1]. In acute coronary syndromes, when an atherosclerotic plaque ruptures, platelets are activated. This activation of platelets leads to, among others, NPY secretion. The release of NPY affects the coronary microcirculation. It has minimal effect on epicardial vessel and epicardial blood flow remains unchanged. Because of the wall tension in the left ventricle, the endocardial microcirculation is more susceptible to a vasoconstrictive stimulus like the effect of NPY. Diminution of blood flow in the endocardium leads to ischemia and modification in tissue property with resultant ST depression. Our results respect findings by Gullestad et al. who recently demonstrated that exercise produces an increase in the release of NPY. The concentration of NPY correlated with myocardial ischemia and depression of ST segment in patients with coronary artery disease[6].

REFERENCES

[1] Z. Zukowska-Grojec, C. Wahlestedt, The Biology of Neuropeptide Y and Related Peptides, New Jersey, Humana Press, 1993.

[2] T. Komaru, K. Ashikawa, N. Sekiguchi, et al. Circulation Research, 1990; 67: 1142-1151.

[3] J.M. Allen, P. Gjöstrup, J.A. Björkman, et al., Acta Physiol. Scand., 1986; 405-411.

[4] J.G. Clarke, R. Kerwin, S. Larkin, et al. The Lancet, 1987; 1057-1059.

[5] A. Franco-Cereda, J.M. Lundberg, C. Dahlöf, Acta Physiol. Scand., 1985; 361-369.

[6] L. Gullestad, B. Jørgensen, T. Bjurø, et al, Circulation, 2000; 987-993.