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Acute hemodynamic effects of terazosin in hypertensive and normotensive patients
Acute hemodynamic effects of terazosin hypertensive and normotensive patients
in
Terazosin, a selective aI-adrenergic antagonist, was administered intravenously to 10 patients undergoing cardiac catheterization to determine its short-term hemodynamic effects. Hemodynamic measurements were performed before and 30 minutes after three doses of the drug: 1, 1, and 3 mg. One milligram of terazosin reduced the blood pressure (systolic/diastolic, mean) from a mean of 152.0/86.3, 110.7 mm Hg by -24.31-9.4, -15.3 mm Hg (p < 0.05). In the flve patients who received 5 mg of the drug, blood pressure declined in a dose-dependent manner by -21.81-3.8, -11.6 mm Hg after 1 mg, and by -35.81-14.8, -22.8 mm Hg (p < 0.05) after all 5 mg of the drug. The changes in blood pressure paralleled the terazosin-induced decrease in systemic resistance. Similar changes were recorded for pulmonary artery and capillary wedge pressures and pulmonary vascular resistance. The greatest hemodynamic response was noted with the first drug dose; succeeding doses had a progressively diminished incremental effect. Cardiac output, heart rate, and maximum left ventricular dp/dt demonstrated little change, whereas left ventricular end-diastolic pressure decreased after all three doses, reaching significance after 2 mg (-3.4 2 0.9 mm Hg, p < 0.05), and left ventricular ejection fraction tended to increase (+ 5.6% ?I 2.4%, p < 0.05 after 1 mg) and showed a dose dependence analogous to that of systemic resistance. Although not generally reaching statistical significance, indexes of aortic stiffness and compliance displayed a favorable effect. These data are consistent with terarosin’s specific al-antagonism. Left ventricular performance is improved by afterload reduction, since terazosin demonstrated no direct effect on cardiac contractility. The reduction of systemic vascular resistance, coupled with reduction in blood pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, and improved left ventricular performance without myocardial depression after intravenous terazosin, makes this agent a useful adjunct in antihypertensive therapy. (AM HEART J 1991;122:892-900.)
Joel A. Strom, MD, Benjamin Zola, MD, William Frishman, MD, Atul Laddu, MD, John P. Wexler, MD, PhD, Kenneth Carlson, BS, and Alphonzo Jordan, MD Bronx, N.Y., and Abbott Park, Ill.
Terazosin (2.[4-{(tetrahydro-2.furanyl) carbonylj1 - piperazinyl] - 6,7 - dimethoxy - 4 - quinazolinamine) HCl, a quinazoline compound similar to prazosin, is a highly specific, competitive, postsynaptic cri-adrenergic antagonist with little cuz-antagonism.1-4 It has a saturated furan ring that increases its water solubility, thereby allowing for intravenous administration.5 Both the oral and intravenous preparations of terazosin have a more gradual onset of action and longer pharmacologic duration of action than does prazosin,6y 7 which allows for once-a-day administration of terazosin.5p s The vasodilating properties and absence of significant reflex &stimulation make terazosin an attracFrom Croup.
the Albert Einstein College of Medicine Pharmaceutical Products Division, Abbott
and the Cardiovascular Laboratories.
Reprint requests: Joel A. Strom, MD, Cardiac Noninvasive vision of Cardiology, Jack D. Weiler Hospital of the Albert of Medicine, 1825 Eastchester Rd., Bronx. NY 10461.
4/O/30198
892
Laboratory, DiEinstein College
tive agent for the treatment of hypertension,7, x which is frequently caused by an inappropriate elevation in the peripheral vascular resistance.g Oral terazosin has been found to be both safe and effective once monotherapy 7, 8 that can be administered daily8, lo because of its long half-life.6 Sustained antihypertensive efficacy has been demonstrated for at least 2 years of therapy.” Despite extensive clinical experience in the treatment of hypertension, few human data are available on the effects of terazosin on left ventricular performance. Animal data demonstrate that terazosin is a vasodilator that is hemodynamically similar to prazosin.4 Like prazosin, terazosin dilates both the arterial and venous systems by blocking al-mediated smooth muscle contracti0n.l These actions are not inhibited by P-b1ockade.l In contrast to nonspecific vasodilators, with terazosin vasodilation is accompanied less often by significant reflex tachycardia’, lo-l’ or renin secretion13 as a result of its high degree of
Volume Number
122 3, Part
Acute hemodynamics
2
specificity for the al-receptor.7 The effects of oral terazosin on cardiac performance have been reported in patients with congestive heart failure.14y l5 However, no data are available on the short-term hemodynamic response to this drug when administered intravenously to patients with or without hypertension who are not in heart failure. The purpose of this article is to report the results of a trial to evaluate the short-term hemodynamic effects of intravenous terazosin in 10 patients undergoing diagnostic cardiac catheterization for suspected coronary artery disease. Both normotensive and hypertensive patients were studied. METHODS Patient population.
a93
terazosin
of
I. Baseline hemodynamic measurementsand effect of 1 mg of intravenous terazosin
Table
Change after Baseline Variable
N
Mean
dose
Mean
SE
4.4
0.8
10
23.8
3.3
-4.4
1.6*
10
10.5
2.0
-3.0
0.9t
10
15.2
2.4
-3.6
1.1*
10
7.0
1.6
-2.6
0.9*
10 10 10
155.4 11.9 1502.9
12.1 1.9 140.3
-20.4 -2.1 38.5
4.0$ 1.3 46.9
10 10 10 10 10 10 10
76.1 152.0 86.3 110.7 4.6 2.6 64.4
6.5 12.2 5.4 7.4 0.5 0.3 8.4
2.6 -24.3 -9.4 -15.3 0.3 0.2 -0.4
3.1 5.8t 3.2* 2.91 0.1 0.1s 5.6
10 10 9 10 10 10 10 10
35.4 166.6 1994.3 2148.1 63.1 1.15 1.18 0.014
3.7 34.5 307.3 291.3 5.4 0.22 0.21 0.002
0.3 -39.4 -448.0 -484.3 5.6 0.15 -0.35 -0.003
2.7 17.1* 138.3* 127.1t 2.4* 0.15 0.18s 0.002
RAmeanpressure 9 (mm Hd PAS pressure (mm Hd PAd pressure (mm Hg) PAmean pressure (mm I-W PCW pressure (mm Hd LVSP (mm Hg) LVEDP (mm Hg) LV dpldt max
first
0.2
SE
0.9
The study group consistedof 10patients who underwent cardiac catheterization and coronary angiography for suspectedcoronary artery disease.Four patients were men and six were women. Eight were white, 1 was black, and 1 wasHispanic. Their meanagewas 58.1 years (range, 43 to 74 years). Four patients had coronary artery disease,one had cardiomyopathy with normal coronary arteries, and five had no coronary artery diseaseand normal left ventricular systolic function. Patients with the following characteristicswereexcluded from the study: (1) the ability to bear children in female patients of childbearing years; (2) ECG evidence of other than sinusrhythm or a PR interval of 2 0.28 seconds;(3) a myocardial infarction within 14 days of the date of catheterization; (4) a cerebrovascularaccident within 3 months of the date of catheterization; (5) evidence of a significant left main or other coronary lesionthat would preclude drug administration; (6) systolic blood pressure(BPS)
Study design. After completion of the diagnosticcardiac catheterization and coronary angiogram, an 8F pigtail Millar micromanometer catheter was placed in the left ventricle by way of the femoral artery. A 7F Swan-Ganz double-lumen thermodilution catheter had been previously positioned in the pulmonary artery by way of a femoral vein. Baseline hemodynamic measurementswere obtained at least 30 minutes after the last doseof x-ray contrast agent (Renografin-76). These measurementswere repeated 25 to 30 minutes after each of the three intravenousdosesof terazosin. All measurementswere completed before the administration of the next drug dose. The following pressureswere measured: mean right atria1 (RAmean); pulmonary artery systolic (PAS), diastolic (PAd), and mean (PAmean); mean pulmonary capillary wedge (PCWmean); and left ventricular systolic (LVSP) and end-diastolic (LVEDP). BPS and BPd were obtained by cuff measurement,with the disappearanceof the sounds
try
taken
into
the
study.
(mmHg/sec) HR (beats/min) BPS (mm Hg) BPd (mm Hg) BPmean (mm Hg) CO (L/min) CI (L/min/m2) Stroke volume (ml) SVI (ml/m2) PVR (cg units) SVR (cg units) TVR(cg units) LVEF (“;m ) AC (ml/mm Hg) AS (mm Hg/ml) ASn (ml-‘) p Values determined
by Student
t test for paired values
sp < 0.1. *p < 0.05.
tp < 0.01. $p < 0.001.
as the
diastolic
pressure.
Heart
rate
(HR),
cardiac
Strom et al.
894
American
September 1991 Heart Journal
II. Baseline hemodynamic measurementsand changesfrom baselineafter the first and seconddosesin patients who received the first two terazosin doses Table
Change after first dose
Baseline Variable
N
RAmeanpressure(mmHg) PASpressure(mmHg) PAd pressure(mmHg) PAmeanpressure(mmHg) PCW pressure(mmHg) LVSP (mmHg) LVEDP (mmHg) LV dp/dt max (mmHg/sec) Heart rate (beats/min) BPS(mmHg) BPd (mmHg) BPmean(mmHg) CO(L/min) CI (L/min/m2) Strokevolume(ml) SVI (ml/m2) PVR (cgunits) SVR (cgunits) TVR (cgunits) LVEF (0; ) AC (ml/mmHg) AS (mmHg/ml) ASn (ml-‘) p Values determined *p < 0.1. tp < 0.05. tp < 0.01.
by the Student
Change second
after dose
Mean
SE
Mean
SE
Mean
SE
4.6 24.3 10.4 15.6 6.9 161.1 11.6 1557.3 69.7 160.3 88.0 115.1 4.8 2.6 71.1 38.5 168.0 2066.4 2150.0 67.8 1.18 1.15 0.012
0.9 4.2 2.4 3.0 1.7 17.1 1.6 168.5 7.6 16.8 7.0 10.2 0.5 0.3 9.6 3.6 45.8 385.6 394.7 4.8 0.29 0.27 0.002
0.9 -3.6 -2.6 -3.4 -2.1 -18.9 -1.6 61.1 4.0 -25.0 -6.7 -14.1 0.2 0.1 -2.6 -0.7 -42.4 -450.8 -440.4 4.9 0.16 -0.34 -0.003
1.1 1.8* 0.91 1.3$ 1.1* 5.44 1.3 59.6 3.9 7.61 x4* 3.91 0.2 0.1 7.9 3.8 23.1 177.11 172.3$ 2.6 0.16 0.21 0.002
0.4 -6.0 -4.9 -5.7 -3.1 -30.1 -3.4 39.7 4.0 -34.1 -9.6 -19.5 0.3 0.2 1.4 1.1 -67.5 -601.0 -601.6 5.3 0.45 -0.46 -0.004
0.8 1.6f 1.41 1.3t 0.91 9.2$ 0.9t 79.8 t.‘i* 1.7t
5.5 4.5t 0.3 0.2 7.0 :x7 32.4* 209.8$ 212.53 4.2 0.21* 0.22* 0.002
t test for paired values.
output (CO), and left ventricular ejection fraction (LVEF) were obtained; the methodology for the last two measurements is describedin the following sections.Maximal left ventricular dpldt (LV dpldt max) wasobtained by an electronic differentiating circuit contained in the cardiac catheterization laboratory computer (model No. 8890B/5600, M Hewlett-Packard, Waltham, Mass.). These data were used to calculate the following with standard formulas: pulmonary vascular resistance (PVR), systemic vascular resistance(SVR), total vascular resistance(TVR), cardiac index (CI), and stroke volume index (SVI). Mean blood pressure(BPmean) wascalculatedas(1/3)BPs + (2/3)BPd. Three indexesof aortic complianceand stiffness were calculated from the following formulas: (1) aortic compliance (AC) = stroke volume/(BPs - BPd); (2) aortic stiffness (AS) = (BPS - BPd)/stroke volume; and (3) normalized aortic stiffness (ASn) = AS/BPd. CO measurements. CO wasmeasuredby the thermodilution technique. Injections of 10 ml of iced salinesolution were used.CO wascalculated by a commercially available COcomputer (American EdwardsmodelNo. 9520A, American Edwards, Santa Ana, Calif.). The mean of three determinations that differed by lessthan 10% wasusedas the CO.
LVEF measurements. Radioisotope measurementsof the LVEF were performed by the multiple-gated acquisition technique. The patient’s red blood cells were labeled in vivo with technetium 99m, and the heart wasscannedin the left anterior oblique view. A semiautomated edge detection program run on a commercially available computer was used. The LVEF was taken as the ratio of the difference between the end-diastolic and end-systolic counts divided by the end-diastolic counts after these valueswerecorrected for background activity. The LVEF was determined at baselineand 30 minutes after each doseof terazosin. Drug administration. After baselinemeasurements,patients received three intravenous dosesof terazosin (1, 1, and 3 mg), eachof which wasdiluted in 10 ml of saline solution and administered 30minutes apart. This time interval waschosenbecausethe major proportion of terazosin’s hypotensive effect occurs by that time5 and so that the study would not be unnecessarilylong. Becauseof the long half-life of the drug and the relatively flat hypotensive responsebetween 30 minutes and 5 hours,’ the effective total doseswere 1,2, and 5 mg. The patient’s blood pressure was measured immediately before each drug dose. For normotensive patients, a fall in BPd of >15 mm Hg or to
Volume Number
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Acute hemodynumics
of
terazosin
895
Table III. Baseline hemodynamic measurementsand changesfrom baselineafter the first, second,and third dosesin patients receiving all three dosesof terazosin Change after first dose
Baseline
-
Change second
after dose
Change after third dose
Variable
N
Mean
SE
Mean
SE
Mean
SE
Mean
SE
RAmean pressure (mm Hg) PAS pressure (mmHg) PAd pressure (mm Hg) PAmean pressure (mm Hg) PCW pressure (mm Hg) LVSP (mm Hg) LVEDP (mm Hg) LV dp/dt max (mm Hg/sec) Heart rate (beats/min) BPS (mm Hg) BPd (mm Hg) BP mean (mm Hg) CO (L/min) CI (L/min/m2) Stroke volume (ml) SVI (mI/m2) PVR (cg units) SVR (cg units) TVR (cg units) LVEF (TO)
5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
3.4 22.6 9.4 14.0 5.8 159.0 11.8 1532.6 69.0 155.2 85.2 112.7 4.9 2.6 74.5 39.0 157.7 2058.9 2119.6 65.2 1.32 1.13 0.012
0.8 5.5 3.4 4.0 2.3 24.5 2.3 200.0 9.5 23.7 9.7 14.6 0.7 0.4 13.7 5.1 59.9 534.4 542.9 4.9 0.39 0.39 0.003
1.2 -3.8 -2.2 -3.0 -1.6 -16.2 -0.8 28.6 1.2 -21.8 -3.8 -11.6 0.1 0.1 -3.7 -1.0 -39.2 -392.4 -369.9 4.6 0.13 -0.37 -0.003
1.6 2.2 1.2 1.8 1.4 6.0* 1.2 76.2 4.4 10.3 3.7 5.1* 0.2 0.1 10.6 4.9 25.9 228.7 214.3 3.6 0.19 0.27 0.003
0.6 -6.0 -5.2 -5.6 -3.2 -21.2 -3.2 135.6 5.8 -26.2 -5.0 -14.5 0.3 0.2 --1.6 -0.4 -62.5 -536.8 -530.3 7.6 0.30 -0.43 -0.004
1.0 2.2* 2.0* 1.9t 1.2* 4.61 0.9-f 32.3t 1.at 8.37 5.7 4.2t 0.3 0.2 7.4 3.8 37.9 265.0 255.2 4.4 0.18 0.28 0.003
-1.6 -8.0 -5.2 -6.2 -4.0 -38.8 -3.6 72.6 2.8 -35.8 -14.8 -22.8 0.2 0.1 -3.6 -1.3 -49.3 -520.4 -542.8 7.2 0.46 -0.36 -0.002
1.1 3.1* 2.5 2.5* 1.7* 10.7t 2.3 113.6 3.7 10.3t 3.6t 5.q 0.2 0.1 7.3 3.5 26.6 224.7* 208.5* 4.0 0.13t 0.19 0.002
AC (ml/mmHg) AS (mm Hg/ml) ASn (ml-‘)) p Values determined ‘p < 0.1.
by the Student
t test for paired values.
tp < 0.05. tp < 0.01.
<65 mm Hg precluded administration of the next doseof the drug. For hypertensive patients (BPd 290 mm Hg), a fall in BPd of ~20 mm Hg or to <75 mm Hg terminated the study. Postcatheterization follow-up. Blood pressureand HR were recorded hourly for at least 12 hours after cardiac catheterization. A postcatheterization ECG was recorded, and blood samplesfor complete blood count and SMA 18 were obtained the next day. Statistical analysis. The meaneffects of terazosin compared with baselinevalues are presented as the mean difference + 1 SE of the mean. Statistical comparisonswith pretreatment measurementsare made with the Student t test for paired values. Ap value of <0.05 is taken to be significant. RESULTS
Ten patients were studied. Their BPmeans
before
hemodynamic evaluation were 152.0 2 12.2/86.3 + 5.4 mm Hg. Five of the 10 patients had baseline BPds
of 290 mm Hg before entry into the study. Baseline hemodynamic measurements are presented in Table I. All 10 patients received 1 mg; their results are
summarized in Table I. Table II summarizes the results in the seven patients who received 2 mg; Table III shows the results in the five patients who received a total of 5 mg of terazosin. Effects on blood pressure and systemic resistance. A 1 mg dose of terazosin (Table I) caused mean decreases of 24.3 + 5.8 mm Hg (16.0%) in BPS (p < O.Ol), 9.4 + 3.2 mm Hg (10.9% ) in BPd (p < 0.05), and 15.3 + 2.9 mm Hg (13.8% ) in BPmean (p < 0.001). Both SVR (-448 + 138.3, p < 0.05) and TVR (-484.3 + 127.1, p < 0.01) showed significant reductions, whereas CI and HR did not change. The decrease in TVR correlated with its level before treatment (r = 0.938, p < 0.001). The decrease in BPmean correlated with the pretreatment blood pressure (r = 0.732, p < 0.01) as well as with the decline in TVR (r = 0.644, p< 0.004, Fig. 1). An additional 1 mg dose of terazosin augmented the changes noted with the first 1 mg dose of terazosin (Table II). BPmean fell with both doses by a mean of 12.3% (-14.1 +- 3.9 mm Hg,p < 0.05) after 1 mg and by 16.9% (-19.5 + 4.5 mm Hg, p < 0.01) after a to-
896
September 1991 American Heart Journal
Strom et cd.
in BP
(mm W 0
i.,L -25 -30 -1200
-1000
-800
-600 -400 -200 Change in TVR (CGS Units) y=-8.290620+0.0148557*x, r=0.644, PcO.004
I 0
200
Fig. 1. Effect of a change in TVR on blood pressure after 1 mg of intravenous terazosin (abbreviations explained in the text).
tal of 2 mg in the seven patients who received at least 2 mg of terazosin. The second milligram of terazosin caused an incremental response of only 37% of the hypotensive response of the first dose. These changes were paralleled by similar falls in SVR: -450.8 r 177.1(21.8%) after 1 mgand -601.0 + 209.8 (29.1%) after 2 mg (both p < 0.05). Blood pressure and resistance data of the five patients who received all three doses of the drug are tabulated in Table III and presented graphically in Figs. 2 and 3. Dose-dependent declines in BPmean, which were noted with all three doses, reached statistical significance for this small group of patients for the 2 and 5 mg cumulative doses. The mean incremental decrease in BPmean compared with the preceding dose is 11.6 mm Hg/mg for the first dose, 2.9 mm Hg/mg for the second, and 2.8 mm Hg/mg for the last (3 mg) dose. Similar changes were recorded for both SVR and TVR for the first two doses, but the last drug dose caused essentially no change in either value. Finally, all five patients with a screening BPd ?90 mm Hg maintained a BPd < 90 mm Hg during the 13- to 24-hour period after the study. HR and Cl. There was no significant change in HR either in the total group or the subset receiving 2 mg of terazosin. However, HR increased significantly after a total of 2 mg by 5.8 t- 1.8 beats/min (p < 0.05) in the subset receiving the full 5 mg of terazosin. After 5 mg of the drug, HR returned toward baseline values (Table III). The mean CI was in the low normal range (2.6 +- 0.3 L/min/m2) before terazosin administration. It was reduced (<2.5 L/min/m2) in 6 of
10 patients at baseline. The mean value for CI did not significantly change after any dose of terazosin. However, five of six patients with a reduced pretreatment CI experienced an increase after 1 mg of terazosin, but the mean increase did not reach statistical significance. Similarly, terazosin induced no significant change in the mean value for SVI. LVEDP and LV dp/dt max. A 1 mg dose of terazosin did not significantly change either LVEDP or LV dp/dt max, although there was a tendency for the former to fall (-2.1 k 1.3 mm Hg) and the latter to rise (38.5 f 46.9). After 2 mg of terazosin, mean LVEDP declined significantly by a mean of 29.3% (-3.4 + 0.9 mm Hg, p
Volume
122
Number
3. Part
Acute hemodynamics of terazosin 897
2
yF;d
Pressure
(mm Hg)
I--
-
160
BPS BPmean BPd
140
80 60 0
1
2 Cumulative
3 Teratosin
Dose
4
5
(mg IV)
2. Dose-responsecurves for blood pressurein five patients receiving all three terazosin doses(abbreviations explained in the text).
Fig.
PVR (CGS Units) 300
SVR, TVR (CGS Units)
TVR e=1 SVR
1
2 Cumulative
Terazosin
3 Dose
4
250
5
(mg IV)
3. Dose-response curves for PVR, TVR, and SVR in patients receiving a11terazosin doses(abbreviations explained in the text).
Fig.
and was accompanied by no significant change in LV dpldt max. As noted in the two previous groups, there was a trend for the LVEF to increase in the subset receiving a total of 5 mg of terazosin. The maximal increase of 7.6% +- 4.4% (p = NS) was recorded after 2 mg had been administered. Right heart pressures and PVR. The mean right atria1 pressure did not significantly change. There was an insignificant decrease in RAmean after 5 mg of ter-
azosin. A 1 mg dose of terazosin caused the PAmean and PCWmean pressures to decrease significantly (p < 0.05), as did PVR @ < 0.05). Similar changes were noted after 2 and 5 mg. Calculated indexes of AC and AS. AC did not significantly change after either 1 mg or 2 mg of terazosin. In the subset receiving a total of 5 mg, AC increased with each dose compared with baseline, but the difference reached statistical significance only after 5
898
Strom et al.
mg of the drug was given (a change of 0.46 ml/mm Hg from a baseline of 1.32 ml/mm Hg, p < 0.05). Similarly, AS and ASn tended to fall after all three doses of terazosin, but none of the changes reached statistical significance for this small patient group. Side effects. In general, except for the development of hypotension, intravenous terazosin was well tolerated. Six patients developed hypotension; five were given a saline solution infusion for precautionary correction, whereas the sixth patient required no intervention. Chest pain that responded to sublingual nitroglycerin was observed in one patient. Two patients developed nausea and vomiting; one case was clearly related to the x-ray contrast agent. The other patient may have had drug-induced nausea. Laboratory evaluation. The mean hemoglobin (-1.4 -+ 0.3 gm/dl, p < 0.002) and hematocrit (-4.5% + 1.2%) p < 0.006) values decreased after catheterization. A minor increase in the white blood cell count and a decrease in the platelet count were observed. Although these changes were statistically significant, they were of no clinical importance. No change was recorded in either the mean blood urea nitrogen or creatinine levels. Although there were statistically significant decreases in the mean alkaline phosphatase, total protein, albumin, and potassium levels and increases in the mean glucose and bilirubin concentrations, none of the changes was clinically important. DISCUSSION
This study demonstrates that the hemodynamic profile of intravenous terazosin in humans is similar to that observed in animals.‘~ 4 It is also qualitatively similar to the actions of oral terazosin,14> l5 prazosin,ls and doxazosin.r7 Like other al-antagonists, terazosin is an arteriolar dilator. Prazosin is known to reduce the calculated systemic and forearm vascular resistances while simultaneously increasing forearm blood flow.16+la Intravenous terazosin reduced both blood pressure and systemic resistance, and a significant correlation occurred between the change in both measurements (Fig. 1). The magnitude of the fall in blood pressure also correlated with the initial blood pressure level. These relationships, which are consistent with terazosin’s cul-antagonism,‘-4 are typical for a vasodilator1g-21 but have also been observed with sodium restriction.22 These observations suggest that terazosin would be expected to be most useful in the treatment of patients whose hypertension is from a catecholamine-induced elevation of systemic resistance. The dose-response curve for blood pressure and systemic resistance demonstrates a characteristic
September 199 1 American Heart Journal
pattern. The first dose of terazosin induced the greatest relative decline in blood pressure, paralleled by a similar fall in the systemic resistance. The two subsequent doses induced a progressively diminished hemodynamic response per milligram of administered drug. As with the first dose, the dose-dependent changes in blood pressure after the second 1 mg dose paralleled those for the systemic resistance. However, despite no change in the mean calculated systemic resistance between the second and third dose in patients who received all 5 mg of terazosin, the blood pressure declined further after the third dose. The blood pressure decrease noted after the last dose can be attributed to the observed drop in CO compared with that of the preceding dose, which appears to be caused by a terazosin-induced reduction in preload, XI A dose-response pattern similar to that for systemic resistance is seen for LVEDP, PCWmean, the pulmonary artery pressures, and PVR. These observations are in contrast to those of Leier et a1,14 who failed to demonstrate a dose-response curve in patients given terazosin for congestive heart failure. The dose-response curve for terazosin can be explained in several ways. Selective al-blockade causes a greater decrease in blood pressure after the first dose than after subsequent doses of the same strength.7, ” This first-dose effect has been attributed to either increased a-activity or blunted renin reactivity in affected patients.25 The contribution of this potential mechanism to the dose-response curve cannot be determined in the present study. The cumulative subsequent doses of terazosin were higher than the first one, since additional doses were administered while the preceding ones were still active. Two other mechanisms could explain the observed dose-response curve. Saturation of the al-receptors by terazosin would lead to a loss of incremental efficacy. The similarity of the dose-response curve of peripheral resistance after terazosin to both the theoretic curve for a receptor blocker26 and to that observed for HR after @-blocker administratior?’ supports this explanation. Alternatively, efficacy could be blunted by counterregulatory neurohumoral compensatory mechanisms. These mechanisms are responsible for the loss of efficacy observed in some patients receiving long-term al-blocking therapy.28 However, the relative contribution of each of these two mechanisms to the observed hemodynamic doseresponse curve cannot be determined from this study design. Terazosin had a beneficial effect on left ventricular performance. LVEF increased in a dose-dependent manner and inversely to the systemic resistance
Volume Number
122 3, Part 2
dose-response curve despite a decline in the LVEDP. HR, CI, and SVI demonstrated little or no change.‘? 4 These effects are consistent with those previously reported with al-blockade in both hypertensive patients16-‘*, 2g and those with congestive heart failure.14p 3o Terazosin demonstrated no significant direct or reflex stimulation of myocardial contractility, as evidenced by the lack of an observed increase in LV dp/dt max, coupled with a lack of HR change. Reflex sympathetic stimulation can occur after the administration of an a-blocker drug by two mechanisms. Increased contractility can be induced by blood pressure reduction alone31 or by sustained reflex sympathetic stimulation, as has been reported with nonspecific a-blockers.32 The mean data are inconsistent with the aggregate operation of either mechanism. Therefore the observed increase in LVEF is the result of unloading of the left ventricle and not because of a change in contractility. The salutary effects of terazosin on left ventricular performance make it useful in the treatment of patients whose hypertension is complicated by left ventricular dysfunction.14a l5 Three components comprise impedance, the complete descriptor of left ventricular systolic loading.33s 34Vascular resistance, measured as either SVR or TVR assuming nonpulsatile flow, is the dominant factor. It mainly reflects the degree of arteriolar constriction. The other components of impedance are capacitance and inductance. Inductance reflects the inertial effect of accelerating blood out of the left ventricle. Inductance contributes less to the total impedance than does capacitance, which reflects the stiffness of peripheral vessels, particularly the large arteries. This component contributes approximately 5 % to 20 ‘3%of the left ventricular power required for ejection,34 and is important in the genesis of the arterial pressure waveform. 34t35Both hypertension and aging increase the stiffness of the large muscular arteries. In addition, the effects of tonic medial smooth muscle contraction and hypertrophy must be considered.2”, 21,36 Aortic stiffness37 and its reciprocal, aortic compliance, have been proposed as indexes to assess drug-induced changes in the capacitance or inversely the stiffness of the large arteries, A number of vasodilating drugs have been reported to have a beneficial effect on these and other indexes.38 However, both of these indexes are nonlinear functions of pressure, and the change induced by a drug is dependent on the initial state of the artery.39 Given the curvilinear shape of the arterial length-tension curve,3g a drug-induced reduction in blood pressure would be expected to improve arterial stiffness in the absence of any intrinsic effect of the drug on the aor-
‘4cute hemodynamics
of
terazosin
899
tic musculature. To overcome this problem, we chose to normalize the index of arterial stiffness to the BPd to correct for apparent changes in stiffness caused by blood pressure reduction alone. Although the number of patients is small, the index for AC increased significantly for the 5 mg dose, and the indexes for AS and ASn demonstrated a favorable trend. These results are consistent with the finding in animal experiments that although terazosin has no direct relaxing effect on aortic smooth muscle,40 it blocks norepinephrine-induced contractions of isolated aorta.l> 3 Both prazosin3”, 41 and oral terazosin14 dilate the venous and pulmonary vasculature. We observed that intravenous terazosin reduces pulmonary artery pressures and the calculated PVR in a dose-dependent manner, analogous to its effects on the systemic pressures and resistances. In contrast to others,14, 3o we did not note a significant drop in right atria1 pressure. However, there was a statistically insignificant decline in the right atria1 pressure after 5 mg of terazosin. The discrepancy between our results and those of others may be due to patient selection or the requirement for intravenous volume expansion during the study to correct hypotension in five patients. Finally, the x-ray contrast medium induces an osmotic diuresis that can also lower cardiac filling pressures. The intravenous administration of terazosin induced no unexpected side effects. Hypotension occurred in six patients and was easily corrected by a saline solution infusion. This finding is a well-recognized pharmacologic effect of ai-blockers.32 The decrease in the hemoglobin and hematocrit values is consistent with that experienced by patients undergoing cardiac catheterization. A clinically significant trend was not observed in any of the other laboratory values. In conclusion, intravenous terazosin is a vasodilator that lowers blood pressure by reducing SVR as a result of al-blockade-induced relaxation of arteriolar smooth muscle. Like other al-blockers, it improves left ventricular performance without augmenting myocardial contractility. These effects make it a useful drug for the short-term treatment of hypertensive patients with high peripheral resistance with or without concomitant left ventricular dysfunction. REFERENCES
1. Kyncl JJ. Pharmacology-_ of terazosin. Am J Med 1986:8O(suopl _ 5B):12-9. 2. Kyncl JJ, Hollinger RE, Oheim KW, Winn J. (ABBOTT459’75), 2-(4-tetrahvdro-2-furanvl) carbonvl-1-piperazinvl-6, 7-dimethoxy-4-quinazolinamide-HCl, a new ant’ihiperterkve agent of the quinazoline type [Abstract]. Pharmacologist 1980;22:272.
September
900
Strom et al.
3. Kyncl 4.
5.
6. 7.
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19.
20.
21.
JJ, Bush EN, Buckner SA. Alpha-adrenergic blocking properties of terazosin [Abstract]. Fed Proc 1982;41:1648. Kyncl JJ, Winn M, Stein HH, et al. Terazosin, a new quinazoline antihypertensive agent, I. General pharmacology. In: Rosenthal J, ed. Focus on alpha blockade and terazosin. Munich: Zuckschwerdt Verlag, 1986. Cohen A. Efficacy and safety of intravenous terazosin in hypertensive patients: a preliminary report. Am J Med 1986:80 (suppl 5B):86-93. Sonders RC. Pharmacokinetics of terazosin. Am J Med 1986; 8Ofsuppl 5B):20-4. Frishman WH, Eisen G, Lapsker J. Terazosin: a new long-acting alpha-adrenergic antagonist for hypertension. Med Clin North Am 1988;72:441-8. Deger G, Cutler RE, Diet.2 AJ Jr, Lewin HJ, Vlachakis N. Comparison of safety and efficacy of once-daily terazosin versus twice-daily prazosin for the treatment of mild to moderate hypertension. Am J Med 1986;8O(suppl 5B):62-7. Lund-Johansen P. Hemodynamic changes in late hypertension. In: Onesti G, Kim KE, eds. Hypertension in the young and old: the Sixth Hahnemann International Symposium on Hypertension. New York: Grune & Stratton, 1981:239-49. Dauer AD, Abraham PA, Cohen A, et al. Terazosin: an effective once-daily monotherapy for the treatment of hypertension. Am J Med 1986;8O(suppl 5B):29-34. Sperzel WD, Glassman HN, Jordan DC, Luther RR. Overall safety of terazosin as an antihypertensive agent. Am J Med 1986;8O(suppl 5B):77-81. Ruoff G, Cohen A, Hollifield JW, McCarron DA. Comparative trials of terazosin with other antihypertensive agents. Am .J Med 1986;BOisuppl 5B):42-8. Blair ML. Inhibition of renin secretion by intrarenal alphaadrenoceptor blockade. Am J Physiol 1981;240:E682-8. Leier CV, Patterson SE, Huss P, Parrish D, Unverferth DV. The hemodynamic and clinical responses to terazosin, a new LYblocking agent, in congestive heart failure. Am J Med Sci 1986;292:128-35. Magorien RD, Sinnathamby S, Leier CV, Boudoulas H, Unverferth DV. Rest and exercise cardiovascular effects of terazosin in congestive heart failure. Am J Cardiol1990;65:63843. Lund-Johansen P. Hemodynamic changes at rest and during exercise in long-term prazosin therapy for essential hypertension. Postgrad Med J 1975;58(suppl 1):45-52. Lund-Johansen P. Omvik P. Haueland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Pharmacol 1986;21:458-548. Mulvihill-Wilson J, Gaffney FA, Pettinger WA, Blomqvist CG, Anderson S, Graham RM. Hemodynamic and neuroendocrine responses to acute and chronic alpha-adrenergic blockade with prazosin and phenoxybenzamine. Circulation 1983;67:383-93. Strom JA, Vidt DG, Bugni W, et al. Mechanism of antihypertensive action of dilevalol compared with that of “cardioselective” beta-blocking agents. Am J Cardiol 1989;63: 251-331. Terazi RC. Pathophysiology of essential hypertension: role of the autonomic nervous system. Am J Med 1983; Ott 17 (suppl):2-8. Folkow B, Grimby G, Thulesius 0. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the oeriuheral resistance. Acta Phvsiol Stand 1958;44:255-‘72. I _
American
Heart
1991 Journal
22. MacGregor GA. Sodium is more important than calcium in essential hypertension. Hypertension 1985;7:633-7, 23. Smith TW, Braunwald E, Kelly RA. The management of heart failure. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 3rd ed. Philadelphia: WB Saunders Co. 1988516-7. 24. Graham RM. Thornell IR, Gain JM, Bagnoli C, Oates HF, Stokes GS. Prazosin: the first dose phenomenon Br Med J 1976;2:1293-4. 25. Nicholson ,JP, Resnick LM, Pickering TG, Marion R, Sullivan P, Laragh JH. Relationship of blood pressure response and the renin-angiotensin system to first-dose prazosin. Am .J Med 1985;78:241-4. 26. Lefkowitz RJ. Direct binding studies of adrenergic receptors: biochemical, physiologic, and clinical implications. Ann Intern Med 1979;91:450-8. 27. Strom ,J, Josephson M, Frishman WH, et al. Hemodynamic effects of flestolol, a titratable short-acting intravenous betaadrenergic receptor blocker. J Clin Pharmacol1988;28:276-82. 28. Izzo JL, Horwitz D, Keiser HR. Physiologic mechanisms opposing the hemodynamic efl’ects of prazosin. Clin Pharmacol Ther 1981;29:7-11. 29. Scharf SC. Hyo-bok L, Wexler JP, Blaufox MD. Cardiovascular consequences of primary antihypertensive therapy with prazosin hydrochloride. Am J Cardiol 1984;53:32A-6k. 30. Awan NA. Miller RR. Mason DT. Comaarison of effects of nitroprusside and prazosin on left ventricular function and the peripheral circulation in chronic refractory congestive heart failure. Circulation 1978;57:152-9. 31. Quinones M.4. Gaasch W, Alexander JK. Influence of acute changes in preload, afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in man. Circulation 1976;53:293-302. 32. Frishman WH, Charlap S. a-Adrenergic blockers. Med Clin North Am 1988;72:427-40. 33. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortie input impedance in normal man: relationship to pressure wave forms. Circulation 1980;62:105-16. WR. Arterial impedance as ventricular afterload. Circ 34. Milnor Res 1975;36:565-70. 35. O’Rourke MF, Kelly RP, Avolio AP, Hayward C. Effects of arterial dilator agents on central aortic systolic pressure and on left ventricular hydraulic load. Am J Cardiol 1989;63:381441. 36. Folkow B. Hallback M, Lundgren Y, Sivertsson R, Weiss L. Importance of adaptive changes in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats. Circ Res 1973;32(suppl l):l-13. 37. Messerli FH. Frolich ED. Ventura HO. Arterial comoliance in essential hypertension. d’cardiovasc Pharmacol 1985;7:S33-5. JA, Bouthier JE, Benetos A. 38. Simon AC. Safar ME, Levenson Action of vasodilating drugs on small and large arteries of hypertensive patients. J Cardiovasc Pharmacol 1983;5:626-31. 39. McDonald DA. Blood flow in arteries. 2nd ed. Baltimore: Williams and Wilkins Co, 1974:238-82. 40. Mizogami S; Hanazuka M. Antihypertensive effect of 2[4 - ((tetrahydro-2-furanyl) carbonyl) 1 - piperazinyl] 6,7-dimethoxy-4-quinazolinamine hydrochloride dihydrate [terazosin]. Jpn J Pharmacol 1982;32(suppl):174P. K, Mason DT. Effects of pra41. Awan NA, Miller RR, Maxwell zosin on forearm resistance and capacitance vessels. Clin Pharmacol Ther 1977:22:79-84.
in
Terazosin, a selective aI-adrenergic antagonist, was administered intravenously to 10 patients undergoing cardiac catheterization to determine its short-term hemodynamic effects. Hemodynamic measurements were performed before and 30 minutes after three doses of the drug: 1, 1, and 3 mg. One milligram of terazosin reduced the blood pressure (systolic/diastolic, mean) from a mean of 152.0/86.3, 110.7 mm Hg by -24.31-9.4, -15.3 mm Hg (p < 0.05). In the flve patients who received 5 mg of the drug, blood pressure declined in a dose-dependent manner by -21.81-3.8, -11.6 mm Hg after 1 mg, and by -35.81-14.8, -22.8 mm Hg (p < 0.05) after all 5 mg of the drug. The changes in blood pressure paralleled the terazosin-induced decrease in systemic resistance. Similar changes were recorded for pulmonary artery and capillary wedge pressures and pulmonary vascular resistance. The greatest hemodynamic response was noted with the first drug dose; succeeding doses had a progressively diminished incremental effect. Cardiac output, heart rate, and maximum left ventricular dp/dt demonstrated little change, whereas left ventricular end-diastolic pressure decreased after all three doses, reaching significance after 2 mg (-3.4 2 0.9 mm Hg, p < 0.05), and left ventricular ejection fraction tended to increase (+ 5.6% ?I 2.4%, p < 0.05 after 1 mg) and showed a dose dependence analogous to that of systemic resistance. Although not generally reaching statistical significance, indexes of aortic stiffness and compliance displayed a favorable effect. These data are consistent with terarosin’s specific al-antagonism. Left ventricular performance is improved by afterload reduction, since terazosin demonstrated no direct effect on cardiac contractility. The reduction of systemic vascular resistance, coupled with reduction in blood pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, and improved left ventricular performance without myocardial depression after intravenous terazosin, makes this agent a useful adjunct in antihypertensive therapy. (AM HEART J 1991;122:892-900.)
Joel A. Strom, MD, Benjamin Zola, MD, William Frishman, MD, Atul Laddu, MD, John P. Wexler, MD, PhD, Kenneth Carlson, BS, and Alphonzo Jordan, MD Bronx, N.Y., and Abbott Park, Ill.
Terazosin (2.[4-{(tetrahydro-2.furanyl) carbonylj1 - piperazinyl] - 6,7 - dimethoxy - 4 - quinazolinamine) HCl, a quinazoline compound similar to prazosin, is a highly specific, competitive, postsynaptic cri-adrenergic antagonist with little cuz-antagonism.1-4 It has a saturated furan ring that increases its water solubility, thereby allowing for intravenous administration.5 Both the oral and intravenous preparations of terazosin have a more gradual onset of action and longer pharmacologic duration of action than does prazosin,6y 7 which allows for once-a-day administration of terazosin.5p s The vasodilating properties and absence of significant reflex &stimulation make terazosin an attracFrom Croup.
the Albert Einstein College of Medicine Pharmaceutical Products Division, Abbott
and the Cardiovascular Laboratories.
Reprint requests: Joel A. Strom, MD, Cardiac Noninvasive vision of Cardiology, Jack D. Weiler Hospital of the Albert of Medicine, 1825 Eastchester Rd., Bronx. NY 10461.
4/O/30198
892
Laboratory, DiEinstein College
tive agent for the treatment of hypertension,7, x which is frequently caused by an inappropriate elevation in the peripheral vascular resistance.g Oral terazosin has been found to be both safe and effective once monotherapy 7, 8 that can be administered daily8, lo because of its long half-life.6 Sustained antihypertensive efficacy has been demonstrated for at least 2 years of therapy.” Despite extensive clinical experience in the treatment of hypertension, few human data are available on the effects of terazosin on left ventricular performance. Animal data demonstrate that terazosin is a vasodilator that is hemodynamically similar to prazosin.4 Like prazosin, terazosin dilates both the arterial and venous systems by blocking al-mediated smooth muscle contracti0n.l These actions are not inhibited by P-b1ockade.l In contrast to nonspecific vasodilators, with terazosin vasodilation is accompanied less often by significant reflex tachycardia’, lo-l’ or renin secretion13 as a result of its high degree of
Volume Number
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Acute hemodynamics
2
specificity for the al-receptor.7 The effects of oral terazosin on cardiac performance have been reported in patients with congestive heart failure.14y l5 However, no data are available on the short-term hemodynamic response to this drug when administered intravenously to patients with or without hypertension who are not in heart failure. The purpose of this article is to report the results of a trial to evaluate the short-term hemodynamic effects of intravenous terazosin in 10 patients undergoing diagnostic cardiac catheterization for suspected coronary artery disease. Both normotensive and hypertensive patients were studied. METHODS Patient population.
a93
terazosin
of
I. Baseline hemodynamic measurementsand effect of 1 mg of intravenous terazosin
Table
Change after Baseline Variable
N
Mean
dose
Mean
SE
4.4
0.8
10
23.8
3.3
-4.4
1.6*
10
10.5
2.0
-3.0
0.9t
10
15.2
2.4
-3.6
1.1*
10
7.0
1.6
-2.6
0.9*
10 10 10
155.4 11.9 1502.9
12.1 1.9 140.3
-20.4 -2.1 38.5
4.0$ 1.3 46.9
10 10 10 10 10 10 10
76.1 152.0 86.3 110.7 4.6 2.6 64.4
6.5 12.2 5.4 7.4 0.5 0.3 8.4
2.6 -24.3 -9.4 -15.3 0.3 0.2 -0.4
3.1 5.8t 3.2* 2.91 0.1 0.1s 5.6
10 10 9 10 10 10 10 10
35.4 166.6 1994.3 2148.1 63.1 1.15 1.18 0.014
3.7 34.5 307.3 291.3 5.4 0.22 0.21 0.002
0.3 -39.4 -448.0 -484.3 5.6 0.15 -0.35 -0.003
2.7 17.1* 138.3* 127.1t 2.4* 0.15 0.18s 0.002
RAmeanpressure 9 (mm Hd PAS pressure (mm Hd PAd pressure (mm Hg) PAmean pressure (mm I-W PCW pressure (mm Hd LVSP (mm Hg) LVEDP (mm Hg) LV dpldt max
first
0.2
SE
0.9
The study group consistedof 10patients who underwent cardiac catheterization and coronary angiography for suspectedcoronary artery disease.Four patients were men and six were women. Eight were white, 1 was black, and 1 wasHispanic. Their meanagewas 58.1 years (range, 43 to 74 years). Four patients had coronary artery disease,one had cardiomyopathy with normal coronary arteries, and five had no coronary artery diseaseand normal left ventricular systolic function. Patients with the following characteristicswereexcluded from the study: (1) the ability to bear children in female patients of childbearing years; (2) ECG evidence of other than sinusrhythm or a PR interval of 2 0.28 seconds;(3) a myocardial infarction within 14 days of the date of catheterization; (4) a cerebrovascularaccident within 3 months of the date of catheterization; (5) evidence of a significant left main or other coronary lesionthat would preclude drug administration; (6) systolic blood pressure(BPS)
Study design. After completion of the diagnosticcardiac catheterization and coronary angiogram, an 8F pigtail Millar micromanometer catheter was placed in the left ventricle by way of the femoral artery. A 7F Swan-Ganz double-lumen thermodilution catheter had been previously positioned in the pulmonary artery by way of a femoral vein. Baseline hemodynamic measurementswere obtained at least 30 minutes after the last doseof x-ray contrast agent (Renografin-76). These measurementswere repeated 25 to 30 minutes after each of the three intravenousdosesof terazosin. All measurementswere completed before the administration of the next drug dose. The following pressureswere measured: mean right atria1 (RAmean); pulmonary artery systolic (PAS), diastolic (PAd), and mean (PAmean); mean pulmonary capillary wedge (PCWmean); and left ventricular systolic (LVSP) and end-diastolic (LVEDP). BPS and BPd were obtained by cuff measurement,with the disappearanceof the sounds
try
taken
into
the
study.
(mmHg/sec) HR (beats/min) BPS (mm Hg) BPd (mm Hg) BPmean (mm Hg) CO (L/min) CI (L/min/m2) Stroke volume (ml) SVI (ml/m2) PVR (cg units) SVR (cg units) TVR(cg units) LVEF (“;m ) AC (ml/mm Hg) AS (mm Hg/ml) ASn (ml-‘) p Values determined
by Student
t test for paired values
sp < 0.1. *p < 0.05.
tp < 0.01. $p < 0.001.
as the
diastolic
pressure.
Heart
rate
(HR),
cardiac
Strom et al.
894
American
September 1991 Heart Journal
II. Baseline hemodynamic measurementsand changesfrom baselineafter the first and seconddosesin patients who received the first two terazosin doses Table
Change after first dose
Baseline Variable
N
RAmeanpressure(mmHg) PASpressure(mmHg) PAd pressure(mmHg) PAmeanpressure(mmHg) PCW pressure(mmHg) LVSP (mmHg) LVEDP (mmHg) LV dp/dt max (mmHg/sec) Heart rate (beats/min) BPS(mmHg) BPd (mmHg) BPmean(mmHg) CO(L/min) CI (L/min/m2) Strokevolume(ml) SVI (ml/m2) PVR (cgunits) SVR (cgunits) TVR (cgunits) LVEF (0; ) AC (ml/mmHg) AS (mmHg/ml) ASn (ml-‘) p Values determined *p < 0.1. tp < 0.05. tp < 0.01.
by the Student
Change second
after dose
Mean
SE
Mean
SE
Mean
SE
4.6 24.3 10.4 15.6 6.9 161.1 11.6 1557.3 69.7 160.3 88.0 115.1 4.8 2.6 71.1 38.5 168.0 2066.4 2150.0 67.8 1.18 1.15 0.012
0.9 4.2 2.4 3.0 1.7 17.1 1.6 168.5 7.6 16.8 7.0 10.2 0.5 0.3 9.6 3.6 45.8 385.6 394.7 4.8 0.29 0.27 0.002
0.9 -3.6 -2.6 -3.4 -2.1 -18.9 -1.6 61.1 4.0 -25.0 -6.7 -14.1 0.2 0.1 -2.6 -0.7 -42.4 -450.8 -440.4 4.9 0.16 -0.34 -0.003
1.1 1.8* 0.91 1.3$ 1.1* 5.44 1.3 59.6 3.9 7.61 x4* 3.91 0.2 0.1 7.9 3.8 23.1 177.11 172.3$ 2.6 0.16 0.21 0.002
0.4 -6.0 -4.9 -5.7 -3.1 -30.1 -3.4 39.7 4.0 -34.1 -9.6 -19.5 0.3 0.2 1.4 1.1 -67.5 -601.0 -601.6 5.3 0.45 -0.46 -0.004
0.8 1.6f 1.41 1.3t 0.91 9.2$ 0.9t 79.8 t.‘i* 1.7t
5.5 4.5t 0.3 0.2 7.0 :x7 32.4* 209.8$ 212.53 4.2 0.21* 0.22* 0.002
t test for paired values.
output (CO), and left ventricular ejection fraction (LVEF) were obtained; the methodology for the last two measurements is describedin the following sections.Maximal left ventricular dpldt (LV dpldt max) wasobtained by an electronic differentiating circuit contained in the cardiac catheterization laboratory computer (model No. 8890B/5600, M Hewlett-Packard, Waltham, Mass.). These data were used to calculate the following with standard formulas: pulmonary vascular resistance (PVR), systemic vascular resistance(SVR), total vascular resistance(TVR), cardiac index (CI), and stroke volume index (SVI). Mean blood pressure(BPmean) wascalculatedas(1/3)BPs + (2/3)BPd. Three indexesof aortic complianceand stiffness were calculated from the following formulas: (1) aortic compliance (AC) = stroke volume/(BPs - BPd); (2) aortic stiffness (AS) = (BPS - BPd)/stroke volume; and (3) normalized aortic stiffness (ASn) = AS/BPd. CO measurements. CO wasmeasuredby the thermodilution technique. Injections of 10 ml of iced salinesolution were used.CO wascalculated by a commercially available COcomputer (American EdwardsmodelNo. 9520A, American Edwards, Santa Ana, Calif.). The mean of three determinations that differed by lessthan 10% wasusedas the CO.
LVEF measurements. Radioisotope measurementsof the LVEF were performed by the multiple-gated acquisition technique. The patient’s red blood cells were labeled in vivo with technetium 99m, and the heart wasscannedin the left anterior oblique view. A semiautomated edge detection program run on a commercially available computer was used. The LVEF was taken as the ratio of the difference between the end-diastolic and end-systolic counts divided by the end-diastolic counts after these valueswerecorrected for background activity. The LVEF was determined at baselineand 30 minutes after each doseof terazosin. Drug administration. After baselinemeasurements,patients received three intravenous dosesof terazosin (1, 1, and 3 mg), eachof which wasdiluted in 10 ml of saline solution and administered 30minutes apart. This time interval waschosenbecausethe major proportion of terazosin’s hypotensive effect occurs by that time5 and so that the study would not be unnecessarilylong. Becauseof the long half-life of the drug and the relatively flat hypotensive responsebetween 30 minutes and 5 hours,’ the effective total doseswere 1,2, and 5 mg. The patient’s blood pressure was measured immediately before each drug dose. For normotensive patients, a fall in BPd of >15 mm Hg or to
Volume Number
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895
Table III. Baseline hemodynamic measurementsand changesfrom baselineafter the first, second,and third dosesin patients receiving all three dosesof terazosin Change after first dose
Baseline
-
Change second
after dose
Change after third dose
Variable
N
Mean
SE
Mean
SE
Mean
SE
Mean
SE
RAmean pressure (mm Hg) PAS pressure (mmHg) PAd pressure (mm Hg) PAmean pressure (mm Hg) PCW pressure (mm Hg) LVSP (mm Hg) LVEDP (mm Hg) LV dp/dt max (mm Hg/sec) Heart rate (beats/min) BPS (mm Hg) BPd (mm Hg) BP mean (mm Hg) CO (L/min) CI (L/min/m2) Stroke volume (ml) SVI (mI/m2) PVR (cg units) SVR (cg units) TVR (cg units) LVEF (TO)
5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
3.4 22.6 9.4 14.0 5.8 159.0 11.8 1532.6 69.0 155.2 85.2 112.7 4.9 2.6 74.5 39.0 157.7 2058.9 2119.6 65.2 1.32 1.13 0.012
0.8 5.5 3.4 4.0 2.3 24.5 2.3 200.0 9.5 23.7 9.7 14.6 0.7 0.4 13.7 5.1 59.9 534.4 542.9 4.9 0.39 0.39 0.003
1.2 -3.8 -2.2 -3.0 -1.6 -16.2 -0.8 28.6 1.2 -21.8 -3.8 -11.6 0.1 0.1 -3.7 -1.0 -39.2 -392.4 -369.9 4.6 0.13 -0.37 -0.003
1.6 2.2 1.2 1.8 1.4 6.0* 1.2 76.2 4.4 10.3 3.7 5.1* 0.2 0.1 10.6 4.9 25.9 228.7 214.3 3.6 0.19 0.27 0.003
0.6 -6.0 -5.2 -5.6 -3.2 -21.2 -3.2 135.6 5.8 -26.2 -5.0 -14.5 0.3 0.2 --1.6 -0.4 -62.5 -536.8 -530.3 7.6 0.30 -0.43 -0.004
1.0 2.2* 2.0* 1.9t 1.2* 4.61 0.9-f 32.3t 1.at 8.37 5.7 4.2t 0.3 0.2 7.4 3.8 37.9 265.0 255.2 4.4 0.18 0.28 0.003
-1.6 -8.0 -5.2 -6.2 -4.0 -38.8 -3.6 72.6 2.8 -35.8 -14.8 -22.8 0.2 0.1 -3.6 -1.3 -49.3 -520.4 -542.8 7.2 0.46 -0.36 -0.002
1.1 3.1* 2.5 2.5* 1.7* 10.7t 2.3 113.6 3.7 10.3t 3.6t 5.q 0.2 0.1 7.3 3.5 26.6 224.7* 208.5* 4.0 0.13t 0.19 0.002
AC (ml/mmHg) AS (mm Hg/ml) ASn (ml-‘)) p Values determined ‘p < 0.1.
by the Student
t test for paired values.
tp < 0.05. tp < 0.01.
<65 mm Hg precluded administration of the next doseof the drug. For hypertensive patients (BPd 290 mm Hg), a fall in BPd of ~20 mm Hg or to <75 mm Hg terminated the study. Postcatheterization follow-up. Blood pressureand HR were recorded hourly for at least 12 hours after cardiac catheterization. A postcatheterization ECG was recorded, and blood samplesfor complete blood count and SMA 18 were obtained the next day. Statistical analysis. The meaneffects of terazosin compared with baselinevalues are presented as the mean difference + 1 SE of the mean. Statistical comparisonswith pretreatment measurementsare made with the Student t test for paired values. Ap value of <0.05 is taken to be significant. RESULTS
Ten patients were studied. Their BPmeans
before
hemodynamic evaluation were 152.0 2 12.2/86.3 + 5.4 mm Hg. Five of the 10 patients had baseline BPds
of 290 mm Hg before entry into the study. Baseline hemodynamic measurements are presented in Table I. All 10 patients received 1 mg; their results are
summarized in Table I. Table II summarizes the results in the seven patients who received 2 mg; Table III shows the results in the five patients who received a total of 5 mg of terazosin. Effects on blood pressure and systemic resistance. A 1 mg dose of terazosin (Table I) caused mean decreases of 24.3 + 5.8 mm Hg (16.0%) in BPS (p < O.Ol), 9.4 + 3.2 mm Hg (10.9% ) in BPd (p < 0.05), and 15.3 + 2.9 mm Hg (13.8% ) in BPmean (p < 0.001). Both SVR (-448 + 138.3, p < 0.05) and TVR (-484.3 + 127.1, p < 0.01) showed significant reductions, whereas CI and HR did not change. The decrease in TVR correlated with its level before treatment (r = 0.938, p < 0.001). The decrease in BPmean correlated with the pretreatment blood pressure (r = 0.732, p < 0.01) as well as with the decline in TVR (r = 0.644, p< 0.004, Fig. 1). An additional 1 mg dose of terazosin augmented the changes noted with the first 1 mg dose of terazosin (Table II). BPmean fell with both doses by a mean of 12.3% (-14.1 +- 3.9 mm Hg,p < 0.05) after 1 mg and by 16.9% (-19.5 + 4.5 mm Hg, p < 0.01) after a to-
896
September 1991 American Heart Journal
Strom et cd.
in BP
(mm W 0
i.,L -25 -30 -1200
-1000
-800
-600 -400 -200 Change in TVR (CGS Units) y=-8.290620+0.0148557*x, r=0.644, PcO.004
I 0
200
Fig. 1. Effect of a change in TVR on blood pressure after 1 mg of intravenous terazosin (abbreviations explained in the text).
tal of 2 mg in the seven patients who received at least 2 mg of terazosin. The second milligram of terazosin caused an incremental response of only 37% of the hypotensive response of the first dose. These changes were paralleled by similar falls in SVR: -450.8 r 177.1(21.8%) after 1 mgand -601.0 + 209.8 (29.1%) after 2 mg (both p < 0.05). Blood pressure and resistance data of the five patients who received all three doses of the drug are tabulated in Table III and presented graphically in Figs. 2 and 3. Dose-dependent declines in BPmean, which were noted with all three doses, reached statistical significance for this small group of patients for the 2 and 5 mg cumulative doses. The mean incremental decrease in BPmean compared with the preceding dose is 11.6 mm Hg/mg for the first dose, 2.9 mm Hg/mg for the second, and 2.8 mm Hg/mg for the last (3 mg) dose. Similar changes were recorded for both SVR and TVR for the first two doses, but the last drug dose caused essentially no change in either value. Finally, all five patients with a screening BPd ?90 mm Hg maintained a BPd < 90 mm Hg during the 13- to 24-hour period after the study. HR and Cl. There was no significant change in HR either in the total group or the subset receiving 2 mg of terazosin. However, HR increased significantly after a total of 2 mg by 5.8 t- 1.8 beats/min (p < 0.05) in the subset receiving the full 5 mg of terazosin. After 5 mg of the drug, HR returned toward baseline values (Table III). The mean CI was in the low normal range (2.6 +- 0.3 L/min/m2) before terazosin administration. It was reduced (<2.5 L/min/m2) in 6 of
10 patients at baseline. The mean value for CI did not significantly change after any dose of terazosin. However, five of six patients with a reduced pretreatment CI experienced an increase after 1 mg of terazosin, but the mean increase did not reach statistical significance. Similarly, terazosin induced no significant change in the mean value for SVI. LVEDP and LV dp/dt max. A 1 mg dose of terazosin did not significantly change either LVEDP or LV dp/dt max, although there was a tendency for the former to fall (-2.1 k 1.3 mm Hg) and the latter to rise (38.5 f 46.9). After 2 mg of terazosin, mean LVEDP declined significantly by a mean of 29.3% (-3.4 + 0.9 mm Hg, p
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Acute hemodynamics of terazosin 897
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1
2 Cumulative
3 Teratosin
Dose
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2. Dose-responsecurves for blood pressurein five patients receiving all three terazosin doses(abbreviations explained in the text).
Fig.
PVR (CGS Units) 300
SVR, TVR (CGS Units)
TVR e=1 SVR
1
2 Cumulative
Terazosin
3 Dose
4
250
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3. Dose-response curves for PVR, TVR, and SVR in patients receiving a11terazosin doses(abbreviations explained in the text).
Fig.
and was accompanied by no significant change in LV dpldt max. As noted in the two previous groups, there was a trend for the LVEF to increase in the subset receiving a total of 5 mg of terazosin. The maximal increase of 7.6% +- 4.4% (p = NS) was recorded after 2 mg had been administered. Right heart pressures and PVR. The mean right atria1 pressure did not significantly change. There was an insignificant decrease in RAmean after 5 mg of ter-
azosin. A 1 mg dose of terazosin caused the PAmean and PCWmean pressures to decrease significantly (p < 0.05), as did PVR @ < 0.05). Similar changes were noted after 2 and 5 mg. Calculated indexes of AC and AS. AC did not significantly change after either 1 mg or 2 mg of terazosin. In the subset receiving a total of 5 mg, AC increased with each dose compared with baseline, but the difference reached statistical significance only after 5
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mg of the drug was given (a change of 0.46 ml/mm Hg from a baseline of 1.32 ml/mm Hg, p < 0.05). Similarly, AS and ASn tended to fall after all three doses of terazosin, but none of the changes reached statistical significance for this small patient group. Side effects. In general, except for the development of hypotension, intravenous terazosin was well tolerated. Six patients developed hypotension; five were given a saline solution infusion for precautionary correction, whereas the sixth patient required no intervention. Chest pain that responded to sublingual nitroglycerin was observed in one patient. Two patients developed nausea and vomiting; one case was clearly related to the x-ray contrast agent. The other patient may have had drug-induced nausea. Laboratory evaluation. The mean hemoglobin (-1.4 -+ 0.3 gm/dl, p < 0.002) and hematocrit (-4.5% + 1.2%) p < 0.006) values decreased after catheterization. A minor increase in the white blood cell count and a decrease in the platelet count were observed. Although these changes were statistically significant, they were of no clinical importance. No change was recorded in either the mean blood urea nitrogen or creatinine levels. Although there were statistically significant decreases in the mean alkaline phosphatase, total protein, albumin, and potassium levels and increases in the mean glucose and bilirubin concentrations, none of the changes was clinically important. DISCUSSION
This study demonstrates that the hemodynamic profile of intravenous terazosin in humans is similar to that observed in animals.‘~ 4 It is also qualitatively similar to the actions of oral terazosin,14> l5 prazosin,ls and doxazosin.r7 Like other al-antagonists, terazosin is an arteriolar dilator. Prazosin is known to reduce the calculated systemic and forearm vascular resistances while simultaneously increasing forearm blood flow.16+la Intravenous terazosin reduced both blood pressure and systemic resistance, and a significant correlation occurred between the change in both measurements (Fig. 1). The magnitude of the fall in blood pressure also correlated with the initial blood pressure level. These relationships, which are consistent with terazosin’s cul-antagonism,‘-4 are typical for a vasodilator1g-21 but have also been observed with sodium restriction.22 These observations suggest that terazosin would be expected to be most useful in the treatment of patients whose hypertension is from a catecholamine-induced elevation of systemic resistance. The dose-response curve for blood pressure and systemic resistance demonstrates a characteristic
September 199 1 American Heart Journal
pattern. The first dose of terazosin induced the greatest relative decline in blood pressure, paralleled by a similar fall in the systemic resistance. The two subsequent doses induced a progressively diminished hemodynamic response per milligram of administered drug. As with the first dose, the dose-dependent changes in blood pressure after the second 1 mg dose paralleled those for the systemic resistance. However, despite no change in the mean calculated systemic resistance between the second and third dose in patients who received all 5 mg of terazosin, the blood pressure declined further after the third dose. The blood pressure decrease noted after the last dose can be attributed to the observed drop in CO compared with that of the preceding dose, which appears to be caused by a terazosin-induced reduction in preload, XI A dose-response pattern similar to that for systemic resistance is seen for LVEDP, PCWmean, the pulmonary artery pressures, and PVR. These observations are in contrast to those of Leier et a1,14 who failed to demonstrate a dose-response curve in patients given terazosin for congestive heart failure. The dose-response curve for terazosin can be explained in several ways. Selective al-blockade causes a greater decrease in blood pressure after the first dose than after subsequent doses of the same strength.7, ” This first-dose effect has been attributed to either increased a-activity or blunted renin reactivity in affected patients.25 The contribution of this potential mechanism to the dose-response curve cannot be determined in the present study. The cumulative subsequent doses of terazosin were higher than the first one, since additional doses were administered while the preceding ones were still active. Two other mechanisms could explain the observed dose-response curve. Saturation of the al-receptors by terazosin would lead to a loss of incremental efficacy. The similarity of the dose-response curve of peripheral resistance after terazosin to both the theoretic curve for a receptor blocker26 and to that observed for HR after @-blocker administratior?’ supports this explanation. Alternatively, efficacy could be blunted by counterregulatory neurohumoral compensatory mechanisms. These mechanisms are responsible for the loss of efficacy observed in some patients receiving long-term al-blocking therapy.28 However, the relative contribution of each of these two mechanisms to the observed hemodynamic doseresponse curve cannot be determined from this study design. Terazosin had a beneficial effect on left ventricular performance. LVEF increased in a dose-dependent manner and inversely to the systemic resistance
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dose-response curve despite a decline in the LVEDP. HR, CI, and SVI demonstrated little or no change.‘? 4 These effects are consistent with those previously reported with al-blockade in both hypertensive patients16-‘*, 2g and those with congestive heart failure.14p 3o Terazosin demonstrated no significant direct or reflex stimulation of myocardial contractility, as evidenced by the lack of an observed increase in LV dp/dt max, coupled with a lack of HR change. Reflex sympathetic stimulation can occur after the administration of an a-blocker drug by two mechanisms. Increased contractility can be induced by blood pressure reduction alone31 or by sustained reflex sympathetic stimulation, as has been reported with nonspecific a-blockers.32 The mean data are inconsistent with the aggregate operation of either mechanism. Therefore the observed increase in LVEF is the result of unloading of the left ventricle and not because of a change in contractility. The salutary effects of terazosin on left ventricular performance make it useful in the treatment of patients whose hypertension is complicated by left ventricular dysfunction.14a l5 Three components comprise impedance, the complete descriptor of left ventricular systolic loading.33s 34Vascular resistance, measured as either SVR or TVR assuming nonpulsatile flow, is the dominant factor. It mainly reflects the degree of arteriolar constriction. The other components of impedance are capacitance and inductance. Inductance reflects the inertial effect of accelerating blood out of the left ventricle. Inductance contributes less to the total impedance than does capacitance, which reflects the stiffness of peripheral vessels, particularly the large arteries. This component contributes approximately 5 % to 20 ‘3%of the left ventricular power required for ejection,34 and is important in the genesis of the arterial pressure waveform. 34t35Both hypertension and aging increase the stiffness of the large muscular arteries. In addition, the effects of tonic medial smooth muscle contraction and hypertrophy must be considered.2”, 21,36 Aortic stiffness37 and its reciprocal, aortic compliance, have been proposed as indexes to assess drug-induced changes in the capacitance or inversely the stiffness of the large arteries, A number of vasodilating drugs have been reported to have a beneficial effect on these and other indexes.38 However, both of these indexes are nonlinear functions of pressure, and the change induced by a drug is dependent on the initial state of the artery.39 Given the curvilinear shape of the arterial length-tension curve,3g a drug-induced reduction in blood pressure would be expected to improve arterial stiffness in the absence of any intrinsic effect of the drug on the aor-
‘4cute hemodynamics
of
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899
tic musculature. To overcome this problem, we chose to normalize the index of arterial stiffness to the BPd to correct for apparent changes in stiffness caused by blood pressure reduction alone. Although the number of patients is small, the index for AC increased significantly for the 5 mg dose, and the indexes for AS and ASn demonstrated a favorable trend. These results are consistent with the finding in animal experiments that although terazosin has no direct relaxing effect on aortic smooth muscle,40 it blocks norepinephrine-induced contractions of isolated aorta.l> 3 Both prazosin3”, 41 and oral terazosin14 dilate the venous and pulmonary vasculature. We observed that intravenous terazosin reduces pulmonary artery pressures and the calculated PVR in a dose-dependent manner, analogous to its effects on the systemic pressures and resistances. In contrast to others,14, 3o we did not note a significant drop in right atria1 pressure. However, there was a statistically insignificant decline in the right atria1 pressure after 5 mg of terazosin. The discrepancy between our results and those of others may be due to patient selection or the requirement for intravenous volume expansion during the study to correct hypotension in five patients. Finally, the x-ray contrast medium induces an osmotic diuresis that can also lower cardiac filling pressures. The intravenous administration of terazosin induced no unexpected side effects. Hypotension occurred in six patients and was easily corrected by a saline solution infusion. This finding is a well-recognized pharmacologic effect of ai-blockers.32 The decrease in the hemoglobin and hematocrit values is consistent with that experienced by patients undergoing cardiac catheterization. A clinically significant trend was not observed in any of the other laboratory values. In conclusion, intravenous terazosin is a vasodilator that lowers blood pressure by reducing SVR as a result of al-blockade-induced relaxation of arteriolar smooth muscle. Like other al-blockers, it improves left ventricular performance without augmenting myocardial contractility. These effects make it a useful drug for the short-term treatment of hypertensive patients with high peripheral resistance with or without concomitant left ventricular dysfunction. REFERENCES
1. Kyncl JJ. Pharmacology-_ of terazosin. Am J Med 1986:8O(suopl _ 5B):12-9. 2. Kyncl JJ, Hollinger RE, Oheim KW, Winn J. (ABBOTT459’75), 2-(4-tetrahvdro-2-furanvl) carbonvl-1-piperazinvl-6, 7-dimethoxy-4-quinazolinamide-HCl, a new ant’ihiperterkve agent of the quinazoline type [Abstract]. Pharmacologist 1980;22:272.
September
900
Strom et al.
3. Kyncl 4.
5.
6. 7.
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19.
20.
21.
JJ, Bush EN, Buckner SA. Alpha-adrenergic blocking properties of terazosin [Abstract]. Fed Proc 1982;41:1648. Kyncl JJ, Winn M, Stein HH, et al. Terazosin, a new quinazoline antihypertensive agent, I. General pharmacology. In: Rosenthal J, ed. Focus on alpha blockade and terazosin. Munich: Zuckschwerdt Verlag, 1986. Cohen A. Efficacy and safety of intravenous terazosin in hypertensive patients: a preliminary report. Am J Med 1986:80 (suppl 5B):86-93. Sonders RC. Pharmacokinetics of terazosin. Am J Med 1986; 8Ofsuppl 5B):20-4. Frishman WH, Eisen G, Lapsker J. Terazosin: a new long-acting alpha-adrenergic antagonist for hypertension. Med Clin North Am 1988;72:441-8. Deger G, Cutler RE, Diet.2 AJ Jr, Lewin HJ, Vlachakis N. Comparison of safety and efficacy of once-daily terazosin versus twice-daily prazosin for the treatment of mild to moderate hypertension. Am J Med 1986;8O(suppl 5B):62-7. Lund-Johansen P. Hemodynamic changes in late hypertension. In: Onesti G, Kim KE, eds. Hypertension in the young and old: the Sixth Hahnemann International Symposium on Hypertension. New York: Grune & Stratton, 1981:239-49. Dauer AD, Abraham PA, Cohen A, et al. Terazosin: an effective once-daily monotherapy for the treatment of hypertension. Am J Med 1986;8O(suppl 5B):29-34. Sperzel WD, Glassman HN, Jordan DC, Luther RR. Overall safety of terazosin as an antihypertensive agent. Am J Med 1986;8O(suppl 5B):77-81. Ruoff G, Cohen A, Hollifield JW, McCarron DA. Comparative trials of terazosin with other antihypertensive agents. Am .J Med 1986;BOisuppl 5B):42-8. Blair ML. Inhibition of renin secretion by intrarenal alphaadrenoceptor blockade. Am J Physiol 1981;240:E682-8. Leier CV, Patterson SE, Huss P, Parrish D, Unverferth DV. The hemodynamic and clinical responses to terazosin, a new LYblocking agent, in congestive heart failure. Am J Med Sci 1986;292:128-35. Magorien RD, Sinnathamby S, Leier CV, Boudoulas H, Unverferth DV. Rest and exercise cardiovascular effects of terazosin in congestive heart failure. Am J Cardiol1990;65:63843. Lund-Johansen P. Hemodynamic changes at rest and during exercise in long-term prazosin therapy for essential hypertension. Postgrad Med J 1975;58(suppl 1):45-52. Lund-Johansen P. Omvik P. Haueland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Pharmacol 1986;21:458-548. Mulvihill-Wilson J, Gaffney FA, Pettinger WA, Blomqvist CG, Anderson S, Graham RM. Hemodynamic and neuroendocrine responses to acute and chronic alpha-adrenergic blockade with prazosin and phenoxybenzamine. Circulation 1983;67:383-93. Strom JA, Vidt DG, Bugni W, et al. Mechanism of antihypertensive action of dilevalol compared with that of “cardioselective” beta-blocking agents. Am J Cardiol 1989;63: 251-331. Terazi RC. Pathophysiology of essential hypertension: role of the autonomic nervous system. Am J Med 1983; Ott 17 (suppl):2-8. Folkow B, Grimby G, Thulesius 0. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the oeriuheral resistance. Acta Phvsiol Stand 1958;44:255-‘72. I _
American
Heart
1991 Journal
22. MacGregor GA. Sodium is more important than calcium in essential hypertension. Hypertension 1985;7:633-7, 23. Smith TW, Braunwald E, Kelly RA. The management of heart failure. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 3rd ed. Philadelphia: WB Saunders Co. 1988516-7. 24. Graham RM. Thornell IR, Gain JM, Bagnoli C, Oates HF, Stokes GS. Prazosin: the first dose phenomenon Br Med J 1976;2:1293-4. 25. Nicholson ,JP, Resnick LM, Pickering TG, Marion R, Sullivan P, Laragh JH. Relationship of blood pressure response and the renin-angiotensin system to first-dose prazosin. Am .J Med 1985;78:241-4. 26. Lefkowitz RJ. Direct binding studies of adrenergic receptors: biochemical, physiologic, and clinical implications. Ann Intern Med 1979;91:450-8. 27. Strom ,J, Josephson M, Frishman WH, et al. Hemodynamic effects of flestolol, a titratable short-acting intravenous betaadrenergic receptor blocker. J Clin Pharmacol1988;28:276-82. 28. Izzo JL, Horwitz D, Keiser HR. Physiologic mechanisms opposing the hemodynamic efl’ects of prazosin. Clin Pharmacol Ther 1981;29:7-11. 29. Scharf SC. Hyo-bok L, Wexler JP, Blaufox MD. Cardiovascular consequences of primary antihypertensive therapy with prazosin hydrochloride. Am J Cardiol 1984;53:32A-6k. 30. Awan NA. Miller RR. Mason DT. Comaarison of effects of nitroprusside and prazosin on left ventricular function and the peripheral circulation in chronic refractory congestive heart failure. Circulation 1978;57:152-9. 31. Quinones M.4. Gaasch W, Alexander JK. Influence of acute changes in preload, afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in man. Circulation 1976;53:293-302. 32. Frishman WH, Charlap S. a-Adrenergic blockers. Med Clin North Am 1988;72:427-40. 33. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortie input impedance in normal man: relationship to pressure wave forms. Circulation 1980;62:105-16. WR. Arterial impedance as ventricular afterload. Circ 34. Milnor Res 1975;36:565-70. 35. O’Rourke MF, Kelly RP, Avolio AP, Hayward C. Effects of arterial dilator agents on central aortic systolic pressure and on left ventricular hydraulic load. Am J Cardiol 1989;63:381441. 36. Folkow B. Hallback M, Lundgren Y, Sivertsson R, Weiss L. Importance of adaptive changes in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats. Circ Res 1973;32(suppl l):l-13. 37. Messerli FH. Frolich ED. Ventura HO. Arterial comoliance in essential hypertension. d’cardiovasc Pharmacol 1985;7:S33-5. JA, Bouthier JE, Benetos A. 38. Simon AC. Safar ME, Levenson Action of vasodilating drugs on small and large arteries of hypertensive patients. J Cardiovasc Pharmacol 1983;5:626-31. 39. McDonald DA. Blood flow in arteries. 2nd ed. Baltimore: Williams and Wilkins Co, 1974:238-82. 40. Mizogami S; Hanazuka M. Antihypertensive effect of 2[4 - ((tetrahydro-2-furanyl) carbonyl) 1 - piperazinyl] 6,7-dimethoxy-4-quinazolinamine hydrochloride dihydrate [terazosin]. Jpn J Pharmacol 1982;32(suppl):174P. K, Mason DT. Effects of pra41. Awan NA, Miller RR, Maxwell zosin on forearm resistance and capacitance vessels. Clin Pharmacol Ther 1977:22:79-84.