Isolated systolic hypertension(ISH) is defined as a systolic BP above 140 mmHg and a diastolic BP below 90 mmHg, and this is a common type of hypertension, especially in elderly patients. In America, about 2/3 of all hypertensive patients in their seventh decade have ISH and about 3/4 of all hypertensive patients over the age of 75 have ISH.1) Compared with hypertension in the young for whom the diastolic BP usually increases due to high peripheral vascular resistance, the main cause of hypertension in elderly patients is the increase in central arterial stiffness.2) It is known that the ISH is closely related to the increase in the pulse wave velocity (PWV), which reflects aortic stiffness,3) so ISH increases cardiovascular complications more than does the diastolic BP.4)5) However, it is difficult to control a systolic BP below 140 mmHg, and a sudden excessive drop in BP causes a decrease in the diastolic BP and coronary blood flow, which finally causes an increase in the risk of ischemic heart disease.6) All the calcium channel blockers,7)8) angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers(ARBs)9) and diuretics,10) which are broadly used in clinics, not only decrease the systolic BP, but they also decrease the diastolic BP. So it is important to choose drugs that act selectively on the systolic BP. Nevertheless, there are no guidelines similar to the JNC-7 that recommend the drugs to control ISH.11) It has been known that nitrates are very useful for selective control of the systolic BP,12)13) but the use of nitrates is limited by the diurnal variation of BP due to nitrates' short half-life, drug tolerance and side effects, and there is no evidence that a decrease in the BP via nitrates is accompanied by a decrease in the PWV.

In our study, we planned to validate the amount of decrease of the BP and the onset time and whether or not a decrease in PWV is observed after intravenous injection of isosorbide dinitrate. We also intended to understand the effect of nitrate when this is given to patients in combination with already prescribed antihypertensive drugs.

ISH is a risk factor for developing coronary artery disease,14) heart failure15) and cerebrovascular disease,16) and it is closely related to an increase in aortic stiffness. According to a survey performed in 2001, 4.3% of adult Koreans have ISH, and this is related to the increase in their age and BMI.17) There is much evidence that cardiovascular complications could be decreased if the systolic BP were effectively controlled. On a meta analysis that specifically combined data on individuals 80 years or older from the SHEP, SHEP-pilot, Syst-Eur, and STOP-Hypertension studies, active treatment was associated with a 39% reduction in congestive heart failure, a 34% reduction in stroke and a 22% reduction in cardiovascular disease.18) But it is difficult to control systolic BP without causing a drop in the diastolic BP, and usually more than two antihypertensive drugs in combination must be taken to reach the target systolic BP.11) It is rare that the systolic BP was effectively controlled by various antihypertensive drugs to less than 150 mmHg in many large-scaled clinical trials. The structure of the aorta changes with aging. Initially, the endothelial function and the production of intrinsic nitric oxide decreases, and this is accompanied by an increase in collagen production, decreases and destruction of elastin and proliferation of vascular smooth muscle cells, which all results in an increase in arterial stiffness and a decrease in the compliance of arteries.19)

It is difficult to control the systolic BP because many antihypertensive drugs can not decrease the arterial stiffness directly and effectively. PWV, which directly reflects the arterial stiffness, is very important as a marker of atherosclerosis and as a prognostic factor.20) So, it would be ideal if antihypertensive drugs could decrease not only the systolic BP, but also the PWV. In general, diuretics, calcium channel blockers, ACE inhibitors and ARBs are used in the treatment of the ISH, and they usually decrease the PWV, though the response is variable according to the individual drugs. The systolic BP lowering effects were evaluated in one clinical trial performed on patients with a systolic BP higher than 150 mmHg and the patients used diuretics, calcium channel blockers, ACE inhibitors and beta-blockers. Diuretics and calcium channel blockers were most effective, followed by the ACE inhibitors; the beta-blockers were least effective.21) Drugs having superior antihypertensive effects decrease the central BP more than the brachial BP. While they also decrease the diastolic BP to some degree, they don't decrease the systolic BP very much. For example, in one clinical study, when the subjects were given eprosartan 600 mg for 10 weeks, the systolic BP decreased by 17.5±14.5 mmHg and the diastolic BP also decreased by 5.0±7.9 mmHg.22) Nitrates decrease the systolic BP in an endothelial independent manner even though the endothelial function is impaired, but they have little effect on the diastolic BP. It is expected that nitrates can reduce arterial stiffness because it was observed that nitrates can decrease the augmentation index.23) However, when nitroglycerin was injected intravenously in normotensive subjects, the acute changes in BP produced the expected changes in PWV, yet in hypertensive subjects, although the BP was reduced, there was no detectable reduction in the PWV.24)

In our study, the finding that the systolic BP dropped by more than 20 mmHg was similar to the results of a previous study that used oral nitrates. In addition, the response was observed within 1 minute after injection, so can be used preferentially when a prompt drop in BP is needed. Isosorbide dinitrate is recommended as the drug of choice, especially for surgical patients. When the patient is under general anesthesia, the coronary perfusion can be impaired due to a decrease in the diastolic BP.25) It was also proved that this drug relieves aortic stiffness, according to the observation that the PWV was also decreased. It has been known that the decrease in elasticity and increase in stiffness in the arteries in diabetic patients was caused by advanced glycation end products.26) In our study, the results of the diabetic subgroup were similar to the results of the total subjects. The results for the subgroup of subjects who had a PWV greater than 13 m/s were also similar, which implies that isosorbide dinitrate is useful in patients who have shown a poor response to antihypertensive drugs due to their far advanced atherosclerosis. The systolic BP often cannot reach the targeted BP, even when two or more drugs are used. The results of the subgroup of subjects who were already taking antihypertensive drugs verified that isosorbide dinitrate has an additional BP-lowering effect. Unfortunately, because most of them were taking two or more antihypertensive drugs, we could not identify which drug showed synergistic effects when isosorbide dinitrate was injected. However, the fact that the systolic BP, which had not been controlled by any other drugs, decreased to the target BP when isosorbide dinitrate was used, suggests that this drug is superior to other drugs for controlling the systolic BP in ISH patients. The limitation of this study is that the subgroup analysis has limitations due to the small number of subjects. Yet it is estimated that because the p value is definite, the results will be similar when the number of subjects is sufficient. To discriminate between two antihypertensive drugs, a study comparing the effects on the central BP and PWV under the condition of the same brachial BP is needed.

In conclusion, a significant reduction of the central systolic BP was observed without any change of the diastolic BP by intravenous injection of isosorbide dinitrate in patients with ISH, which suggests that more active treatment with using this drug is necessary in clinics.