Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide

Abstract

Increased circulating levels of adrenomedullin (ADM) cause peripheral vasodilatation and hypotension, accompanied by cardiac actions including tachycardia and increases in cardiac contractility, cardiac output, coronary conductance (CC) and coronary blood flow (CBF). It is unclear to what extent these cardiac effects are direct actions of ADM or secondary to the hypotension and altered cardiac loading. The direct cardiac actions of ADM were examined in conscious sheep previously implanted with aortic and coronary flow probes, and an indwelling left coronary artery cannula. Responses to infusion of ADM (0.5 microg kg(-1) h(-1) for 1 h) into the left coronary artery or jugular vein were compared (n=6). The effect of blockade of nitric oxide (NO) synthase with intracoronary (i.c.) N(omega)-nitro-l-arginine (l-NNA; 1.5 mg kg(-1) h(-1), infused for 2 h before and during ADM infusion, was assessed to determine whether the responses to ADM were mediated by NO (n=5). I.c. ADM caused large and sustained increases in CC (0.35+/-0.07-0.55+/-0.13 ml min(-1) mmHg-1, P<0.05) and CBF (28+/-6-42+/-9 ml min(-1), P<0.05), but had no effect on arterial pressure or indices of cardiac contractility (first differential of the upstroke of systole and peak aortic flow rate). Intravenous infusion of ADM had no effects. I.c. l-NNA, at a dose that abolished the coronary vasodilator action of acetylcholine, blocked ADM-induced coronary vasodilatation. In conclusion, ADM had a direct coronary vasodilator action that was mediated by release of endogenous NO and resulted in increased CBF. There was no evidence for a direct inotropic action of ADM.

Figure 1

Effect of i.c. ADM (0.5 μg kg⁻¹ h⁻¹), i.v. ADM (0.5 μg kg⁻¹ h⁻¹) and i.c. saline (12 ml h⁻¹) on MAP, HR, CO, stroke volume (SV), TPC, change in central venous pressure (ΔCVP), CBF, CC, Fmax and dF/dt in conscious sheep (n=6). A multifactor repeated ANOVA was used to determine the effect of drug treatment (i.c. ADM vs i.c. vehicle) and route of administration (i.c. ADM vs i.v. ADM) during the infusion period (0 to +1 h). *Represents a significant effect of ADM (P<0.05). †Represents a significant effect of the route of administration of ADM (P<0.05).

Figure 2

Effect of i.c. infusions of ADM (0.5 μg kg⁻¹ h⁻¹), L-NNA (1.5 mg kg⁻¹ h⁻¹), ADM+L-NNA or vehicle on MAP, HR, CO, SV, TPC, ÄCVP, CBF, CC, Fmax and dF/dt in conscious sheep (n=5). The interaction between L-NNA and ADM was collectively compared using repeated-measures ANOVA for the infusion period 0 to +1 h. *Represents a significant effect of ADM (P<0.05). ‡ Represents a significant interaction between L-NNA and ADM (P<0.05). The effect of L-NNA infusion was tested using a two-way repeated-measures ANOVA for the infusion period from –2 to +1 h. †Represents significant effect of L-NNA.