Different Hernodynamic (24-H Ambulatory Blood Pressure Monitoring) a d Renin-Inhibiting Effect of a 1-Week Treatment with Enalapril and Lisinopril

Summary: Ambulatory blood pressure and heart rate monitoring were used for comparing the antihypertensive effect of a 1 -week treatment with enalapril and lisinopril 10 mg once daily (double-blind crossover placebo-controlled d y ) . Welve outpatients with mild to moderate hypertension were treated. Both drugs had a significant and identical hypotensive effect. Neither drug affected the diurnal rhythm of blood pressure or heart rate. Therefore the two drugs are equipotent antihypertensive agents. Both drugs inhibited ACE activity to a highly significant extent, but in this regard lisinopril was more effective than enalapril. However, lisinopril's greater ACE inhibition was not accompanied by a greater hypotensive effect. The clinical value of this difference is not yet established.


Introduction
Enalapril, the prodrug of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat,' is used in the treatment of hypertension. Lisinopril is the lysine analog of enalaprilat* and is also an ACE inhibit~r.~ Unlike enalapril, lisinopril is directly active? There is also evidence to suggest that lisinopril produces more prolonged inhibition of plasma ACE5 and has a longer-lasting antihypertensive effect than enalapril.6 The antihypertensive effect of single doses of enalapril and lisinopril is known,7 but it is conceivable that the response might be different after several days of active therapy. To our knowledge, direct comparative data from treatment more than one day were unavailable. On the other hand, it was conceivable that, enalapril and lisinopril being long-acting ACE inhibitors, there could be a greater response as plasma and tissue concentrations rise over time. Our study was planned to clarify this question.

Material and Method
Twelve outpatients (5 males and 7 females) aged between 44 and 66 years were selected and treated. All had mild to moderate essential hypertension (duration 2 to 4 years). Their antihypertensive therapy was stopped because of insufficient effect or side effects: the patients were without treatment for 2 to 3 weeks. No other drugs were used and no contraindications to ACE inhibitors were present. The study was approved by the ethical committee and all patients gave informed consent. No patient was withdrawn before receiving the test medications because of normalization of blood pressure (BP). The test medications were placebo, enalapril, and lisinopril, 10 mg/day given as monotherapy once a day between 7:OO and 8:OO a.m. Treatment was given according to a randomized, doubleblind, crossover design. Each test medication was given for a double-blind period of 7 days, followed by a singleblind placebo period of 4 days before the next crossover. Fixed dose regimens are necessary for research purposes; on the other hand, they are not likely to be adequate for the long-term treatment of hypertension: therefore, the duration of the treatment with the individual test medications was limited to 7 days. Hypmtension was defined by a mean diastolic BP of between 95 and 115 mmHg, this being the mean value of a 24-h ambulatory blood pressure monitoring (ABPM). Routine prestudy clinical laboratory tests were either normal or the abnormalities were clinically irrelevant. Blood samples and laboratory plus renin estimations were taken 24 h after the last dose of the 1week treatment periods and 40 h before the ABPM. Baseline measurements of BP were obtained from the same ann throughout using simultaneously a mercury sphygmomanometer and a Disetronic CH-Druck@ equipment.8 Afterward, BP and heart rate (HR) were automatically measured with the CH-Druck equipment: two times per hour between 8:OO and 22: OO h (daily period) and once per hour between 22:OO and 8:OO h (night period). Again at the end of the ABPM, BF and HR were checked simultaneously. The mean difference between manual and CH-Druck BP was less than 3 mmHg (range: -2 to +2 mmHg for systolic B P 0 + 3 mmHg for diastolic BP). ABPM was obtained 24 to 26 h after the last dose and during the last 24-h period of the 1 -week treatment periods. Adverse events were recorded in response to the question: "Have you had any symptoms or problems since your last visit?' All data were analyzed by means of a paired f-test and by calculation of the area under the curve (AUC) of the ABPM. Both methods gave identical statistical values. The presentation of the clinical data (figures) was better with the paired t-test analysis and therefore this method was used for presentation of the results.

Results
The portable automatic CH-Druck equipment was well accepted by the patients and functioned optimally. All patients ended the study with complete ABPM profiles.
The circadian rhythm was not affected.

Heart Rate
Neither placebo nor the test dwgs affected HR to ar significant extent (Fig. 3).

Side Effects
Few side effects were observed. One patient complaine of mild nausea at Day 2 with both drugs. Another patier complained of mild headache with enalapril on Day : Drug-related effects on the laboratory results were nc detectable.

Discussion
Oftice blood pressures have been the primary basis fc the physician's decisions in the diagnosis and treatment c hypertension. In some patients, however, the office pre! Our study confirms the optimal function of the CH-Druck equipment and ABPM was important in assessing the antihypertensive effects of the tested drugs. Our data confirm the results of the single dose study by Dews er ~z f . :~ while both drugs were equally effective and potent for the treatment of hypertension, the greater renin-inhibiting effect of lisinopril was not reflected by a greater antihypertensive effect. The antihypertensive effect of enalapril and lisinopril was similar (duration and magnitude) and persisted for 24 h. The diurnal profile of BP and HR were not affected by treatment. On the other hand, our data do not confirm the results of the single dose study by Millar er aL,6 where the antihypertensive effect of lisinopril was longer than that of enalapril. Obviously, the response of the drugs is different on repeated treatment. We used a fixed dose, and therefore our data are not sufficient for judging the effect of different doses.
In spite of a similar antihypertensive effect, the renin inhibiting effect of lisinopril was superior. Clearly, the physiologic effects of enalapril and lisinopril (and all known ACE inhibitors) are not clearly related to plasma renin alone. Indeed it has been known for some time that responses of patients with hypertension to ACE inhibitors cannot be predicted by renin profiling alone.')-l6 Bradykinin, prostacyclin, and other humoral factors may play an important role in the pharmacologic effect of renin Renin inhibitors seem to be effective in preventing progression of ventricular dysfunction and may delay or prevent the appearance of heart failure:l7, I* the full effect of these drugs, however, develops slowly and it may take more than 12 weeks to become maximal. Obviously our data from a 1-week treatment cannot be extrapolated for the long-term treatment of patients with heart failure and, as Sir Arthur Conan Doyle said, "It is a capital mistake to theorize before one has data." However, since the greater renin-inhibiting effect of lisinopril is not accompanied by a greater antihypertensive effect, it would be interesting to compare their long-term effect in the matment of heart failure.