212 Heart 2001;86:212–216 Magnesium causes nitric oxide independent coronary artery vasodilation in humans Heart: first published as 10.1136/hrt.86.2.212 on 1 August 2001. Downloaded from H Teragawa, M Kato, T Yamagata, H Matsuura, G Kajiyama Abstract Objective—To determine how magnesium aVects human coronary arteries and whether endothe- lium derived nitric oxide (EDNO) is involved in the coronary arterial response to magnesium. Design—Quantitative coronary angiography and Doppler flow velocity measurements were used to determine the eVects of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on magnesium induced dilation of the epicardial and resistance coronary arteries. Setting—Hiroshima University Hospital a tertiary cardiology centre. Patients—17 patients with angiographically normal coronary arteries. Interventions—Magnesium sulfate (MgSO4) (0.02 mmol/min and 0.2 mmol/min) was infused for two minutes into the left coronary ostium before and after intracoronary infusion of L-NMMA. Main outcome measures—Diameter of the proximal and distal segments of the epicardial cor- onary arteries and coronary blood flow. Results—At a dose of 0.02 mmol/min, MgSO4 did not aVect the coronary arteries. At a dose of 0.2 mmol/min, MgSO4 caused coronary artery dilation (mean (SEM) proximal diameter 3.00 (0.09) to 3.11 (0.09) mm; distal 1.64 (0.06) to 1.77 (0.07) mm) and increased coronary blood flow (79.3 (7.5) to 101.4 (9.9) ml/min, p < 0.001 v baseline for all). MgSO4 increased the changes in these parameters after the infusion of L-NMMA (p < 0.001 v baseline). Conclusions—Magnesium dilates both the epicardial and resistance coronary arteries in humans. Furthermore, the coronary arterial response to magnesium is dose dependent and inde- pendent of EDNO. (Heart 2001;86:212–216) Keywords: coronary artery; coronary blood flow; magnesium sulfate; nitric oxide Much interest has been focused on the relation women) undergoing coronary angiography for http://heart.bmj.com/ between magnesium and cardiovascular the evaluation of chest pain. Chest pain was disease.1–3 Furthermore, the benefits of magne- atypical for eVort angina in all of the patients. sium administration have been shown in a vari- All patients had angiographically normal epi- ety of cardiovascular diseases.4–7 In the setting of cardial coronary arteries, normal left ventricu- coronary artery disease, several studies have lar function (contrast ventriculographic ejec- shown the eYcacy of magnesium infusion in tion fraction > 50%) and a normal coronary patients with acute myocardial infarction,4 va- flow reserve. Patients with angiographically 5 8 sospastic angina, and unstable angina. While documented coronary spasm (> 50% luminal on September 26, 2021 by guest. Protected copyright. several mechanisms are probably responsible for narrowing) after intracoronary injection of the favourable eVects of magnesium, the coron- acetylcholine were excluded from the study. ary vasodilatory eVect seems to be the primary No patients had a history of prior myocardial mechanism responsible for the beneficial eVects infarction, heart failure, or other serious of magnesium.9–11 However, only a few studies diseases. Written informed consent was ob- have investigated human coronary responses to tained from all patients before the study. The magnesium infusion in vivo.12 13 protocol was approved by the human investiga- One potential mechanism responsible for tion ethics committee of Hiroshima University. magnesium induced coronary dilation involves activation of the endothelium derived nitric The First Department oxide (EDNO) pathway.14–17 However, it is STUDY DESIGN of Internal Medicine, The study design has been previously de- unclear whether EDNO is involved in the Hiroshima University scribed in detail.18 In brief, all drugs including human coronary responses to magnesium. School of Medicine, antianginal agents were discontinued 48 hours 1-2-3 Kasumi, Therefore, in the present study we investigated before catheterisation, except for the unre- Minamiku, Hiroshima, the coronary vascular responses to intracoronary stricted use of sublingual glyceryl trinitrate, Japan 734-8851 infusion of magnesium. In addition, we deter- H Teragawa which was withheld 1 hour before catheterisa- mined whether EDNO contributes to the MKato tion. A 6 French guide catheter was introduced coronary vascular response to magnesium by T Yamagata into the left main coronary artery. A using NG-monomethyl-L-arginine (L-NMMA), H Matsuura 0.0014 inch Doppler flow guide wire (FloWire, G Kajiyama a nitric oxide synthase inhibitor. Cardiometrics, Mountain View, USA) was Correspondence to: advanced through the guide catheter into the Dr Teragawa Methods proximal segment of the left anterior descend- teragawa@ STUDY POPULATION ing coronary artery. The wire tip was carefully mcai.med.hiroshima-u.ac.jp We studied 17 Japanese patients (mean age 62 positioned in a straight segment of the vessel to Accepted 23 January 2001 years, range 44–69 years; seven men, 10 obtain an adequate flow velocity signal. www.heartjnl.com Magnesium and coronary dilation 213 <th;2> Table 1 Systemic haemodynamic and coronary diameter and blood flow variables Coronary diameter (mm) Heart: first published as 10.1136/hrt.86.2.212 on 1 August 2001. Downloaded from HR MAP (mm Coronary blood flow (beats/min) Hg) Proximal segments Distal segments (ml/min) Baseline before L-NMMA 68 (2) 108 (4) 3.00 (0.09) 1.64 (0.06) 79.3 (7.5) Low MgSO4 69 (2) 105 (4) 3.03 (0.09) 1.67 (0.06) 82.8 (7.3) High MgSO4 68 (3) 105 (4) 3.11 (0.09)*† 1.77 (0.07)*† 101.4 (9.9)*† Baseline after L-NMMA 67 (2) 108 (4) 2.89 (0.09)** 1.58 (0.06)** 68.3 (6.1)** Low MgSO4 68 (2) 106 (4) 2.93 (0.08) 1.62 (0.06) 71.7 (7.4) High MgSO4 67 (3) 106 (3) 3.01 (0.09)*† 1.67 (0.06)*‡ 86.2 (8.3)*† Glyceryl trinitrate 75 (3)§ 98 (4)¶ 3.26 (0.09)§ 1.95 (0.06)§ 98.4 (12.0)†† Values are mean (SEM). Low MgSO4 was at a dose of 0.02 mmol/min; high MgSO4 wasatadoseof0.2mmol/min. HR, heart rate; L-NMMA, NG-monomethy-L-arginine; MAP, mean arterial pressure. *p<0.001vbaseline; †p < 0.01 v low MgSO4;‡p<0.05vlow MgSO4; **p < 0.05 v baseline before L-NMMA;††p < 0.05 v oth- ers except high MgSO4;§p<0.001vothers; ¶p < 0.01 v others. STUDY PROTOCOL measured without knowledge of the clinical After baseline control conditions were estab- characteristics of the patients. An end diastolic lished, magnesium sulfate (MgSO4) was in- frame was selected and analysed by a computer fused at rates of 0.02 and 0.2 mmol/min for 2 assisted coronary angiographic analysis system minutes. These doses were determined based (CAAS II/QUANTCOR, Siemens AG, Berlin on preliminary studies performed in six other and Munich, Germany). The average values of patients who had undergone cardiac catheteri- triplicate measurements of luminal diameter sation. On the basis of these preliminary stud- were used for analysis. ies, intracoronary infusion of MgSO4 at the doses used in the present study had no eVects on either systemic haemodynamic variables or ESTIMATION OF CORONARY BLOOD FLOW systemic serum electrolyte concentrations and Coronary blood flow was calculated as the did not cause conduction disturbance. In con- product of coronary blood flow velocity and trast, these doses caused significant increases in vessel diameter using the following formula: × × × 2 the serum ionised magnesium concentration in ð average peak velocity 0.125 diameter . the coronary sinus (mean baseline concentra- For calculating coronary blood flow, the inter- tion (SEM): 0.50 (0.02) mmol/l; 0.02 mmol/ nal diameter of the vessel at the location of the flow measurements (2–3 mm distal to the wire min: 0.65 (0.04) mmol/l, p < 0.01 v baseline; 0.2 mmol/min: 1.65 (0.15) mmol/min, tip) was measured using the method described above. p < 0.001 v baseline). After 5 minutes, L-NMMA was infused into the left coronary http://heart.bmj.com/ artery at a rate of 40 µmol/min for five minutes. BIOCHEMICAL PARAMETERS After control conditions had been reestab- Venous blood was drawn from a femoral sheath lished, MgSO4 (0.02 and 0.2 mmol/min) was before the first and second administration of again infused serially. Finally, an intracoronary magnesium to measure serum ionised magne- infusion of glyceryl trinitrate was given at a rate sium and calcium concentrations using a selec- of 200 µg/min for one minute. All drugs were tive ion electrode (NOVA 8; NOVA Biomedi- infused directly into the left coronary ostium cal, Waltham, USA). All measurements were through a catheter using an infusion pump performed in duplicate. on September 26, 2021 by guest. Protected copyright. (TE-311, Terumo, Tokyo, Japan) set at a rate of 1 ml/min. Coronary angiography was performed under DRUG PREPARATIONS control conditions and at the end of each drug MgSO4 (Toa Pharmaceutical Co, Tokyo, administration. The coronary blood flow veloc- Japan) was dissolved in an isotonic glucose ity was monitored continuously by a 12 MHz solution. L-NMMA (Sigma) and glyceryl pulsed Doppler velocimeter (FloMap, Cardio- trinitrate (Nihonkayaku, Tokyo, Japan) were metrics). Arterial pressure, heart rate, and dissolved immediately before use in physiologi- ECG were monitored continuously and re- cal saline. L-NMMA was sterilised in the corded by a multichannel recorder (Ni- department of pharmacy of Hiroshima Univer- honkoden Polygraph System, Nihonkoden, sity Hospital. Tokyo, Japan). We waited at least five minutes after each drug infusion to obtain stable values STATISTICAL ANALYSIS for blood flow velocity and coronary diameter. All data are expressed as the mean (SEM). Serial changes in haemodynamic variables, QUANTITATIVE CORONARY ANGIOGRAPHY epicardial coronary diameter, and coronary The trunk of the left anterior descending and blood flow in response to MgSO4 were left circumflex coronary artery were divided compared by one way analysis of variance into the proximal and distal segments of equal (ANOVA).