Impact of Nitroglycerin and Verapamil on Coronary Arterial Distensibility as Assessed by Intravascular Ultrasound

From the Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California. The authors report no conflicts of interest regarding the content herein. Address for correspondence: Robert J. Siegel, MD, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048. E-mail: Robert.Siegel@cshs.org ______________________________ ABSTRACT: Objectives. To examine the effects of coronary artery vasodilators on coronary arterial distensibility using intravascular coronary ultrasound (IVUS). Background. There is limited information on the effect of coronary artery vasodilators on coronary arterial distensibility. Methods. We studied 20 patients using IVUS. Patients received 100 µg of nitroglycerin (10 patients) or 1 mg of verapamil (10 patients) intravenously. We measured coronary arterial elasticity, the distensibility index, compliance and stiffness index. There were no differences in patient characteristics, lesion characteristics or baseline coronary arterial distensibility between the two groups. Results. Systolic and diastolic blood pressure decreased in both groups (p Methods Study population. All 20 patients were undergoing coronary angiography and IVUS for the assessment of their proximal left ascending coronary artery or proximal left circumflex artery disease. Exclusion criteria for the study were as follows: 1) patients known to have contraindications to nitroglycerin or verapamil; 2) patients with significant stenosis in the proximal coronary arteries (> 70%); and 3) patients with low blood pressure (Results Reproducibility of IVUS image analysis. We measured all cross-sections every three cardiac cycle during the study (43 ± 1 image, 38–61 images). For the interobserver measurement reproducibility, the absolute measurement error was 0.22 ± 0.01 mm2 (2.9 %), the coefficient regression ratio was r2 = 0.98, p Discussion In the present study, we administered nitroglycerin and the calcium channel blocker verapamil intravenously during IVUS, and demonstrated differing acute hemodynamic effects as well as distinct changes in coronary vasomotion, which showed different pharmacological effects on coronary arterial distensibilities between the two groups. Our study is the first ever to illustrate that there is a differential effect on coronary vasomotion between verapamil and nitroglycerin. The patients who received nitroglycerin and verapamil had similar clinical characteristics, as well as similar coronary arterial vascular morphology, degree of atherosclerosis and luminal dimensions. Despite the fact that nitroglycerin and verapamil are both vasodilators, as shown in Figures 2 and 3, the acute coronary vascular responses to each drug were quite different. Nitroglycerin dilated the coronary artery throughout the cardiac cycle-dilating both the maximal LA (by 5%) and the minimal LA (by 8%), which resulted in a relative decrease in the change in dLA by 25%. Verapamil dilated the maximal LA by 4%; this value was statistically similar to the maximal LA dilation in the nitroglycerin group. However, the dilation of the minimal LA by verapamil was only 2%, which resulted in the relative increase of dLA by 40%. Thus nitroglycerin had a greater dilatory effect on the coronary artery during the phase of the artery’s smallest cross-sectional luminal area in the cardiac cycle. As a result of these effects on maximal LA and minimal LA, nitroglycerin reduced the indices of coronary arterial distensibility and verapamil increased the parameters of coronary arterial distensibility. The changes in arterial dimensions depend in part on aortic pressure. However, nitroglycerin and verapamil have intrinsic vasodilatory properties. That is, the different effects on pulse pressure would be caused by the different vasodilation properties between nitroglycerin and verapamil. Further study is needed to clarify this issue. Meanwhile, both nitroglycerin and calcium channel blockers reduce the contractile processes of vascular smooth muscle cells; however, their pharmacological pathways are quite different from one another.11–13 Nitroglycerin is converted into nitric oxide in the vascular smooth muscle cells, which activates guanylate cyclase and induces the concentration of cGMP. The increase in cGMP activates cGMP-dependent protein kinase, which leads to dephosphorylation of the myosin light-chain phosphatase. Thus, the nitroglycerin-induced dephosphorylation of the myosin light-chain signals the cells to release calcium, thereby relaxing the smooth muscle cells and producing vasodilation.12,13 Conversely, calcium channel blockers generally reduce the intake of calcium ions into vascular smooth muscle cells. The decrease in intracellular calcium inhibits the contractile processes of the smooth muscle cells, resulting in dilation of the coronary and systemic arteries.12 Furthermore, the changes in pulse pressure clearly correlated with the changes in dLA, and verapamil group and nitroglycerin group were clearly separate from one another (Figure 5). This finding might indicate that the present data are derived from the drug effects on the pulse pressure, which affects the pressure dependent coronary arterial cross- sectional luminal area dilation. In the present study, we found that nitroglycerin decreased pulse pressure, which resulted in both dilation of the maximal LA and the minimal LA to a similar extent. However, verapamil increased pulse pressure, which resulted in dilation of the maximal LA to a greater extent than the minimal LA. These findings suggest the following: 1) 100 µg of nitroglycerin might result in greater relaxation of vascular smooth muscle cells, both in the contractile process and in the resting process, resulting in the dilation of both maximal and minimal LA; and 2) a low dose of the calcium channel blocker verapamil simply inhibits the contractile process of the vascular smooth muscle cells. These findings on the differential effects of nitroglycerin and verapamil suggest very different vasodilatory responses. The clinical implication will require clinical trials comparing the efficacy of these agents in patients with standard exertional angina, microvascular disease angina, as well as those with epicardial coronary artery vasospasm. Our findings suggest that the administration of one or both agents may be useful in certain subsets of patients. The appropriate clinical application of these novel findings remains to be elucidated. Study limitations. This study has several limitations. First, we did not use a pressure wire, but rather monitored intracoronary artery pressure using the coronary artery guiding catheter. Consequently, we administered the drugs intravenously. Second, we performed this study in moderately diseased coronary arteries. Because of the lack of inclusion of normal vessels and severely disease vessels, the conclusions from this study are limited. We performed this study giving one drug to each patient and leaving the IVUS catheter in the left coronary artery during the entire study. The results would be more definitive if we had administered both drugs to each patient. However, this would have required waiting for the washout of the first drug. Conclusions We assessed the acute impact of nitroglycerin and verapamil on coronary artery distensibility by IVUS. While both drugs acutely dilate the coronary arteries, nitroglycerin reduced local coronary arterial distensibility. Verapamil, however, increased local coronary arterial distensibility. These findings indicate that even though both nitroglycerin and verapamil are vasodilators, they have substantially different effects on coronary arterial distensibility.

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