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Clin Investig (1992) 70:S 58-S 64 Glinical Investigator © Springer-Verlag 1992 Long-term hemodynamic effects of antihypertensive treatment P. Lund-Johansen, P. Omvik, and J.E. Nordrehaug Section of Cardiology, Medical Department, University of Bergen, School of Medicine, Haukeland Hospital Summary. The cardinal hemodynamic disorder in established essential hypertension is increased total peripheral resistance. During exercise, the increase in stroke volume of the heart is abnormal. A 20- year follow-up study of the hemodynamics in es- sential hypertension demonstrated a progressive increase in total peripheral resistance and deterio- ration of the heart pump function. Long-term treatment with antihypertensive agents modifies the circulatory system in different ways. Vasodila- tors (angiotensin converting enzyme inhibitors, cq- blockers, and calcium antagonists) all reduce total peripheral resistance, and in general, cardiac out- put, heart rate, and stroke volume remain un- changed. Calcium antagonists like verapamil and diltiazem reduce the heart rate approximately 10% during exercise, but since stroke volume increases, cardiac output is unchanged. Chronic treatment with conventional/?-blockers induces a permanent reduction in cardiac output and heart rate during exercise. In contrast, carvedilol - a/?1,/?2-blocker with ~j-blocking activity - prevents the immediate increase in total peripheral resistance during acute /?-blockade. In 19 patients followed by hemody- namic measurements over 6-9 months, blood pres- sure was well controlled by carvedilol. During ex- ercise, total peripheral resistance decreased 6% (P<0.05), and the reductions in heart rate and cardiac index were less than on conventional /?- blockade. Echo-Doppler studies showed a signifi- cant reduction in the intraventricular septum of 13%. Abbreviations: ACE = angiotensin converting enzyme; CI = car- diac index; CO = cardiac output; DAP = diastolic blood pres- sure; HR=heart rate; ISVD =intraventricular septal thickness during systole; MAP=mean arterial pressure; SAP=systolic blood pressure; SV = stroke volume; TPR = total peripheral re- sistance; VO2 = oxygen consumption Key words: Hypertension - Hemodynamics - Car- diac output - Exercise -/?-Blockers - Carvedilol Hemodynamic changes in untreatedhypertension Even in the 1990s, hypertension remains a very common disorder, and no real breakthrough has been made in the clarification of why about 10% of the population in most societies develops high blood pressure, while 90% does not. However, whatever the cause might be, in nearly all forms of hypertension it is still agreed that the cardinal hemodynamic disorder in the established phase is an increased vascular resistance found in most vas- cular beds [1, 4, 18]. Although young subjects with mild hyperten- sion undoubtedly often have a high cardiac output (CO), heart rate (HR), and oxygen consumption (go2) during the rest situation, exercise studies reveal insufficient reduction in total peripheral re- sistance (TPR) and a restricted increase in stroke volume (SV) [13]. It seems likely that these func- tional disorders are at least partially due to the so-called remodelling of the high pressure com- partments of the circulatory system - the arteries, the arterioles, and the left ventricle [4, 18]. Echo- Doppler studies have shown that disturbances in left ventricular diastolic function (caused by in- creased stiffness in the left ventricle) appear at an early stage in essential hypertension [5]. The 20-year follow-up studies from our labora- tory have shown that when young subjects with permanent but mild hypertension are left untreated over 10-20 years, there is clearly a shift in the hemodynamics from the "high cardiac output- low resistance" pattern in the early phase towards the "low cardiac output - high resistance" pattern

Long-term hemodynamic effects of antihypertensive treatment

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Page 1: Long-term hemodynamic effects of antihypertensive treatment

Clin Investig (1992) 70:S 58-S 64 Glinical Investigator

© Springer-Verlag 1992

Long-term hemodynamic effects of antihypertensive treatment P. Lund-Johansen, P. Omvik, and J.E. Nordrehaug Section of Cardiology, Medical Department, University of Bergen, School of Medicine, Haukeland Hospital

Summary. The cardinal hemodynamic disorder in established essential hypertension is increased total peripheral resistance. During exercise, the increase in stroke volume of the heart is abnormal. A 20- year follow-up study of the hemodynamics in es- sential hypertension demonstrated a progressive increase in total peripheral resistance and deterio- ration of the heart pump function. Long-term treatment with antihypertensive agents modifies the circulatory system in different ways. Vasodila- tors (angiotensin converting enzyme inhibitors, cq- blockers, and calcium antagonists) all reduce total peripheral resistance, and in general, cardiac out- put, heart rate, and stroke volume remain un- changed. Calcium antagonists like verapamil and diltiazem reduce the heart rate approximately 10% during exercise, but since stroke volume increases, cardiac output is unchanged. Chronic treatment with conventional/?-blockers induces a permanent reduction in cardiac output and heart rate during exercise. In contrast, carvedilol - a/?1,/?2-blocker with ~j-blocking activity - prevents the immediate increase in total peripheral resistance during acute /?-blockade. In 19 patients followed by hemody- namic measurements over 6-9 months, blood pres- sure was well controlled by carvedilol. During ex- ercise, total peripheral resistance decreased 6% (P<0.05), and the reductions in heart rate and cardiac index were less than on conventional /?- blockade. Echo-Doppler studies showed a signifi- cant reduction in the intraventricular septum of 13%.

Abbreviations: ACE = angiotensin converting enzyme; CI = car- diac index; CO = cardiac output; DAP = diastolic blood pres- sure; H R = h e a r t rate; ISVD =intraventr icular septal thickness during systole; M A P = m e a n arterial pressure; SAP=systol ic blood pressure; SV = stroke volume; TPR = total peripheral re- sistance; VO2 = oxygen consumption

Key words: Hypertension - Hemodynamics - Car- diac output - Exercise -/?-Blockers - Carvedilol

Hemodynamic changes in untreated hypertension

Even in the 1990s, hypertension remains a very common disorder, and no real breakthrough has been made in the clarification of why about 10% of the population in most societies develops high blood pressure, while 90% does not. However, whatever the cause might be, in nearly all forms of hypertension it is still agreed that the cardinal hemodynamic disorder in the established phase is an increased vascular resistance found in most vas- cular beds [1, 4, 18].

Although young subjects with mild hyperten- sion undoubtedly often have a high cardiac output (CO), heart rate (HR), and oxygen consumption (go2) during the rest situation, exercise studies reveal insufficient reduction in total peripheral re- sistance (TPR) and a restricted increase in stroke volume (SV) [13]. It seems likely that these func- tional disorders are at least partially due to the so-called remodelling of the high pressure com- partments of the circulatory system - the arteries, the arterioles, and the left ventricle [4, 18]. Echo- Doppler studies have shown that disturbances in left ventricular diastolic function (caused by in- creased stiffness in the left ventricle) appear at an early stage in essential hypertension [5].

The 20-year follow-up studies from our labora- tory have shown that when young subjects with permanent but mild hypertension are left untreated over 10-20 years, there is clearly a shift in the hemodynamics from the "high cardiac o u t p u t - low resistance" pattern in the early phase towards the "low cardiac output - high resistance" pattern

Page 2: Long-term hemodynamic effects of antihypertensive treatment

later [12]. In two groups of hypertensive patients with the same mean arterial pressure (MAP) of 114 mmHg during rest - one group in their 20s, the other in their 60s - the hemodynamics pattern was very different. In the oldest group TPR during rest was 69% higher and cardiac output 42% lower than in the younger group. During exercise, the expected fall in TPR was less pronounced. In the older group, stroke volume fell in parallel from moderate to severe exercise, probably an early indi- cation of latent heart failure [12].

In brief, these are some of the most important changes in central hemodynamics in essential hy- pertension, changes we would like to prevent or counteract with modern antihypertensive treat- ment.

Long-term effects of antihypertensive agents

Over the years we have studied the hemodynamic long-term effects in approximately 500 patients with essential hypertension treated with the most commonly used antihypertensive agents [11]. Inva- sive studies have been performed at rest and during graded exercise on an ergometer bicycle. During exercise, the measurements were taken after 7- 9 rain exercise during the steady state condition at 50, 100, and 150 W. The methodology has been kept unchanged over many years in order to com- pare the different agents [7]. References to most of our drug studies are found in [11].

Vasodilators (ACE inhibitors, ~l-blockers, and calcium antagonists)

Our results show clearly that so-called vasodilating drugs like angiotensin converting enzyme (ACE) inhibitors, cq-blockers, and calcium antagonists largely induce the same type of changes in our model (chronic, l-year studies in mild and moder- ately severe hypertension) [10, 15].

Thus, blood pressure during rest is usually re- duced (about 13%-17%), associated with a reduc- tion in total peripheral resistance of the same order, while there are no significant changes in CO, HR or SV. During exercise, blood pressure is re- duced (usually 13%-17%), also associated with a reduction in total peripheral resistance and no changes in HR, SV, or CO.

The "unloading" of the heart via reduction in blood pressure and total peripheral resistance should perhaps be expected to result in an increase in SV and CO after I year of treatment. However, this has not been the case in patients with mild to moderately severe essential hypertension. Only

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in our studies in which the heart rate during exer- cise was reduced (with calcium antagonists like ver- apamil and diltiazem) was there an increase in SV which compensated for the reduction in HR, and as a consequence CO remained unchanged (com- pared with pretreatment values). The reason for the lack of increase in SV with the other drugs could be that the left ventricular filling pressure was reduced as welt, but it could also be related to therapy resistant fibrosis of the heart preventing the expected increase in SV [23]. However, as we have not measured the filling pressure or the stiff- ness in the left ventricle by the refined echo- Doppler technique, this explanation remains hypo- thetical.

fl-Blockers

The typical hemodynamic changes induced by 1 year of treatment with conventional /~-blockers (without intrinsic sympathicomimetic activity) is a reduction in HR and CO during rest of approxi- mately 25%, a fall of blood pressure of 17% and an increase in calculated TPR of approximately 20% [16]. During exercise, the reduction in blood pressure is relatively similar to that achieved dur- ing rest, but the reduction in HR is often of the order of 30%. There is a marked reduction in the pressure-HR product. Since oxygen consumption is not changed by/?-blockade either at rest or dur- ing exercise, there is a reduction in the amount of oxygen in the venous blood and an increase in the arteriovenous oxygen difference. Thus, the reduction in blood pressure achieved through /~- blockade has to be "paid for" by a reduction in the reserve mechanisms serving oxygen transport [8].

fl-Blockers with vasodilating activity

Over the years several /~-blockers with so-called vasodilating activity have been produced, the first being labetalol, later prizidilol (withdrawn), and more recently dilevalol (withdrawn) and carvedilol. The hemodynamic effects of these drugs differ from what is seen with pure /%blockers [9, 14]. Carvedilol combines nonselective /~l,/~2-blockade with el-blockade [3, 17, 20, 22]. Theoretically, this combination should reduce blood pressure in a more physiologic way than "pure"/%blockade.

Hemodynamic effects of carvedilol

Our study involved 20 males with essential hyper- tension in WHO stage I. All were actively working

Page 3: Long-term hemodynamic effects of antihypertensive treatment

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Table 1. Central hemodynamics at initial predrug study (B) and changes 2 h after carvedilol dose during the chronic study (n = 19)

Supine Sitting 100-W Exercise

B Percentage B Percentage B Percentage

SAP (mmHg) Mean 158.9 - 17% SD 16.0 P <0.001

DAP (mmHg) Mean 96.1 - 17% SD 6.2 P <0.001

MAP (mmHg) Mean 120.4 - 17% SD 8.8 P < 0.001

TPRI (dyn/s- cm s" m 2) Mean 3409 - 6% SD 588 P NS

HR (beats/rain) Mean 64.6 - 12% SD 10.4 <0.001 P

CI (min/m 2) Mean 2.90 - 12% SD 0.53 P < 0.05

SI (ml/stroke- m 2) Mean 45.6 0% SD 8.9 P NS

174.0 - 2 0 % 208.9 - 17% 17.8 19.0

<0.001 <0.001

109.3 - 1 7 % 115.0 - 1 8 % 7.8 9.6

<0.001 <0.001

133.6 - 1 8 % 155.2 - 1 7 % 9.7 12.1

<0.001 <0.001

4401 + 3% 1897 -- 5% 669 325

NS NS

70.3 - 12% 129.5 - 17% 9.7 17.1

<0.001 <0.001

2.46 - 17% 6.62 - 12% 0.27 0.94

<0.001 <0.01

35.3 - 7% 51.6 + 5% 3.5 6.9

NS NS

through the entire study and had no other diseases. Age ranged from 33 to 59 years (mean 44 years); mean body surface area was 2.07 m 2. Patients who had been previously treated underwent a washout period of at least 8 weeks before they were included in the study. All patients were known to be hyper- tensive for at least 6 months before inclusion in the study; the majority had been hypertensive for more than 2 years. Patients were included in the study if diastolic blood pressure was above 100 mmHg but below 130 mmHg after a 2-week placebo run-in period.

As in our previous studies, the hemodynamics was studied by invasive methods. Blood pressure was recorded intraarterially via a thin catheter placed in the brachial artery. SAP, DAP, and MAP were recorded continuously. MAP was obtained by electrical damping of the curve. HR was re- corded by electrocardiograph, cardiac output was measured in duplicate by the dye-dilution method (Cardio-green). VO2 was recorded by the Douglas bag technique and Beckman instruments for deter- mination of 02 and CO2.

Acute study

In the acute study the hemodynamics was recorded at rest (supine and sitting) and then during a work- load of 100 W exercise for 6-8 min. Following these evaluations, patients were given 25 mg ofcar- vedilol orally. The patients then rested supine, and their hemodynamics was recorded after 1 and 2 h. After 2 h recordings were obtained also sitting at rest and during exercise [19].

The acute response to carvedilol clearly differed from the hemodynamic response to "pu re" /?- blockers. One hour after tablet intake, there was a significant reduction in TPR and also a fall in blood pressure of 11%. After 2 h the /?-blocking effect was more predominant and a reduction in HR of 12% and in CO of 12% was seen [19].

Two hours after tablet intake, the exercise hemodynamics was studied. There was a reduction in SAP, MAP, and DAP ranging from 11% to 14%, associated with a reduction in total peripher- al resistance during exercise of 6% (p <0.05). The /?-blocking effect was demonstrated as a reduction

Page 4: Long-term hemodynamic effects of antihypertensive treatment

BP mmHg

220-

200-

180,

160

lZ~0.

120

100

80

TPRI dyn s cm s m 2 5000-

z, ooo-

~ ~ - 1 7 % 3000"

~O- . . . . . . 2000"

o~ a; ,0~WATr

A A + ] %

/ \ d z~-6%

' ~ ~0~ATT o - ~

$61

Fig. 1. Changes in blood pressure (BP) during chronic treatment with carvedilol. SAP, systolic pressure; MAP, mean arterial pressure; DAP, diastolic pressure; TPRI, total peripheral resistance index; ~ = supine; ~ = sitting. Chmages expressed as percentage of predrug value. All changes in SAP, MAP, and DAP, supine, sitting, and during 100 W exercise were statistically significant (not marked on the figure), e - - e Before; o---o after

HR beats rain -~ Sl rn[ stroke 1 m 2

I30

110-

90~

70-

50"

60 ~

50~ L

~o- %

30- ZX-7 O/o A-12% zo-

,,' f ........... j ~ 101) WATT ~ ~ IooWATT

"* zx-12 %

CI min I m "2

/

ZX-12% ! A-17%

,

o---a lO() WATT

Fig. 2. Changes in heart rate (HR), stroke index (SI), and cardiac index (CI) during chronic treatment with carvedilol. Legend as in Fig- 1. * P<0.05; ** P < 0.01 ; *** P<0.001

in exercise HR of 12%, but because of the increase in SV during exercise, the reduction in CI was only 6% (P < 0.05).

Chronic study

After the acute study on the following day, the patients started taking 25 mg carvedilol and re- turned for clinical follow-ups at monthly or bi- monthly intervals. The goal of treatment was a casual blood pressure in the sitting position of <140/90 mmHg without side effects. The daily dose of carvedilol was 25 mg for 8 patients and was increased to 50 mg for 7 patients, to 75 mg (50 mg morning plus 25 mg evening) for 3, and to 100 mg (50 mg morning and evening) for 2. The mean dose was 52 rag. After 6-9 months, a second hemodynamic study was performed.

The patients reported to the laboratory in the morning from 24 to 12 h after the last dose. The central hemodynamics was recorded at rest in the supine and sitting positions and then during 100 W

bicycle exercise. After the recordings had been ob- tained, the patients took 25 mg of carvedilol, and after 1 and 2 h the hemodynamics was recorded.

One patient had to be excluded because he de- veloped diabetes; 19 patients completed the chron- ic study. The differences between means were tested statistically by Student's t-test for paired samples.

Casual blood pressure dropped during the fol- low-up period from 171/108 mmHg at the end of the placebo period to 156/87mmHg, 144/ 95mmHg, and 144/94mmHg after 1, 2, and 3 months on carvedilol, respectively. The hemody- namic results are shown in Table 1 and Figs. 1 and 2.

After 1 year of carvedilol treatment, the study was redone 12-24 h after the last tablet intake. The mean arterial pressure was reduced 11%. This was associated with a reduction in HR of 10%, partly compensated for by an increase in SV of 5%, and the reduction in CI was only 5% (NS). TPR was reduced 5% (NS).

Page 5: Long-term hemodynamic effects of antihypertensive treatment

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Table 2. Left ventricular end-diastolic diameter (LVED), left ventricular end-systolic diameter (LVES), intraventricular sep- turn thickness in diastole (IVSD), and posterior wall thickness during diastole (PWD) before drug treatment and after 6- 9 months on carvedilol

Before On drug A %

LVED 5 .06_+0 .58 5.17_+0.61 + 2 NS L V E S 3 . 1 0 _ + 0 . 7 4 3.40_+0.60 +10"** I V S D 1 . 3 3 - + 0 . 1 1 1.18_+0.13 -13"** PWD 1 . 2 2 _ + 0 . 1 3 1.18_+0.13 - 3 NS

values (in cm) and SD; NS=not significant; *** P<0.001

Table 3. Fractional shortening (FS), ejection fraction (EF), maximal aortic (AO) flow, early mitral flow (E), atrial mitral flow (A), and E/A ratio before and after 6--9 months of carvedi- lol therapy

Before On drug A%

FS 0.39___0.1t 0.34_+0.08 -13" EF 0.75___0.12 0.70_+0.10 - 7(*) Max AO flow (m/s) 1.IM+0.14 0.93 ±0.12 -11 *** Mitral flow (E) (m/s) 0.65_+0.17 0.58_+0.10 -11 NS Mitral flow (A) (m/s) 0.61 -+0.15 0.50_+0.10 - 18"** E/A ratio 1.03_+0.35 1,21 _+0.30 +17"

* P<0.05; ** P<0.01; *** P<0.001

When the addit ional dose of 25 nag carvedilol was given, there was a fur ther fall in b lood pres- sure. This was associated with a reduct ion in T P R I o f 10% ( P < 0 . 0 5 ) , while there were only modes t changes in CI and H R dur ing the first hour . Two hours after the addit ional dose, M A P was reduced by 17% and H R by 12% during rest; dur ing exer- cise M A P as well as H R was reduced by 17%. The reduct ion in H R was par t ly compensa ted for by an increase in exercise SI of 5%. Dur ing exer- cise, the T P R was increased compared with pre- t rea tment level, but when the addit ional dose was given, it fell 5% below the pre t rea tment level (NS).

Echo-Doppler results

In 14pa t ien ts sat isfactory echo-Dopple r signals were obta ined a few days before the first and sec- ond hemodynamic investigations. A Vingmed echo-Doppler appara tus was employed. Studies were per formed at the same time of the day in the first and the second study. The results are shown in Tables 2 and 3.

Intraventr icular septal thickness (during dias- tole) (ISVD) was significantly reduced 13% ( P < 0.001), while there was no significant change in the poster ior wall. Lef t ventr icular mass index was

IVSd cm

1.5

1.4

1.3

1,2 o

1,1

1. 0 ~//,

8O

o o

o o

o

O o

o

9'

90 I00

o

• •

o o

• • mr,

o •

o

Ii0 1½0 >

IL0 MAP mrnHg

Fig. 3. Intraventricular septum thickness in diastole (IVSD) ver- sus mean arterial pressure (MAP) in the supine position before and after 6-9 months on carvedilol treatment. • Before; o on drug

-,MAP mmHg-GO -30

I ....... I

0 0

0

-20 -10 i .... i

o o 0

0 0 o 0

0 0 0

0

-0.10

- 0.20

-0.30

- 0,/,0 zdVSd cm

Fig. 4. Changes in mean arterial pressure (MAP) and IVSD after 6-9 months on carvedilol treatment (rest supine)

slightly reduced ( f rom 161 to 155 g/m2), but the reduct ion was not statistically significant. The ear- ly to atrial filling rat io (E/A ratio) increased by 17% (P<0.05).

Figure 3 shows the relat ion between ISVD and b lood pressure and Fig. 4, between the changes in ISVD and the fall in MAP.

D i s c u s s i o n

Our observat ions during chronic t rea tment with ant ihypertensive agents at rest and during exercise have shown that with most classes of drugs, it is possible to reduce b lood pressure at rest as well as dur ing exercise on the order o f 1 2 % M 8 % . With vasodilat ing drugs like A C E inhibitors, a-blockers, and calcium antagonists , the reduct ion in b lood

Page 6: Long-term hemodynamic effects of antihypertensive treatment

BP mmHg TPRI dyn s cm s m 2

200

150

100-

NAP

__43 .o-

4000-

3000.

2000

/~\\ A * 2 1 %

I II \\\

iI /~ \\\

\ ' ,

\\\\\ zx+15%

70~ o-

~ I;0 WATT ~ ~ I()0 WATT

Fig. 5. Changes in central hemodynamics after 1 year's treat- ment with the nonselective E-blocker timolol. Legend as in Fig. 1. All changes in blood pressure were significant (not marked on the figure)

pressure is associated with a fall in TPR [11]. How- ever, a pure normalization of CO and SV (com- pared with values seen in normotensive subjects) is difficult to achieve. Chronic treatment with con- ventional/%blockers does not reduce total periph- eral resistance below the pretreatment level, and CO is permanently depressed, particularly during exercise, when the HR is reduced approximately 25%. There is, however, a marked reduction in the pressure-heart rate product on chronic/%block- ade, a greater reduction than that achieved with drugs not reducing the HR [8, 16].

Several studies in spontaneously hypertensive rats and also in humans indicate that it is not just the increased blood pressure which is responsible for the derangement of the heart and vessels in hypertension. Likewise, regression of functional and structural changes in the high pressure com- partment are difficult to achieve, in spite of blood pressure control. Our own 20-year follow-up study

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supports this: In patients well treated for 20 years, the SV during exercise fell, and the values were rather similar in patients with and without left ven- tricular hypertrophy [13]. It is possible that the development of fibrosis in the left ventricle could be partially responsible for these functional changes [23].

No long-term studies covering several years are available for carvedilol. Our acute and 6- 9 months' results on carvedilol support this com- pound being a/~l,/~2-blocker with c~l-blocking ac- tivity [3, 17, 20, 22]. When given acutely, no in- crease in TPR was seen in contrast to conventional /~,#2-blockers. The e-blockade was present earlier than the /?-blockade. Thus, during the first hour after tablet intake in the initial study and during the chronic study after the additional dose, the re- duction in TPR was most prominent during the first hour.

When the long-term hemodynamic responses to carvedilol are compared with those to a conven- tional /%blocker like timolol, the differences are quite marked. Both drugs reduce blood pressure approximately 14%-17%. With carvedilol there was a reduction in TPR of 5% during exercise; In contrast, with timolol there was an increase in TPR of 15%. The reduction in CO on timolol was 32%-25% and on carvedilol, only 17% and 12% (Figs. 5, 6). Since oxygen consumption did not change significantly with any of these compounds, the increase in AVO= difference was less marked on carvedilol than on timolol. This might be a po- tential advantage.

Our echo-Doppler results showed that carvedi- lol reduced IVSD, but since there was a slight in- crease in left ventricular end-diastolic diameter (LVED), there was no reduction in left ventricular mass index (LVMI). There was a reduction in max- imal aortic flow of 11%, similar to the reduction

HR beats rain-1

150-

125-

100-

75-

S0-

70-

60"

7% 50-

30- ,I o__~o I

zx-28%

o~ ~ 100WATT

SI m[ s t roke -1 i11-2

C[ [ min -1 m -2

5%

o,. /

A - 3 2 %

IO;WATT o5 ~ 10~Wm

Fig. 6. Chronic changes in heart rate (HR), stroke index (SI), and cardiac index (CI) during 1 year of treatment with timolol. Legend as in Fig. 2. o - - e Before; o---o on drug

Page 7: Long-term hemodynamic effects of antihypertensive treatment

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in CI in the supine position. There was also a re- duction in mitral flow of 18% (P<0.001) in the atrial component. The ratio of early to atrial filling was increased. Fractional shortening (FS) was re- duced 13% (P<0.05).

In our study carvedilol was well tolerated. However, during the acute experiment 4 patients had excessive blood pressure drops when they changed from the supine position to the sitting po- sition 2 h after 25 mg orally. Outside the laborato- ry, however, no patients had any orthostatic prob- lems, and during the follow-up, no orthostatic re- actions were seen after 25 mg orally in the labora- tory setting. Nevertheless, the initial dose should probably be only 12.5 mg.

We did not study the regional circulation, but others have shown that carvedilol reduces blood pressure without any reduction in renal blood flow [2] or cerebral [6] blood flow. It has no adverse effects on blood lipids [21].

Although a new antihypertensive agent like carvedilol appears to have a favorable effect on central and regional hemodynamics and has been well tolerated in our patients now treated for more than 1 year, only long-term clinical studies can tell whether this will be associated with a reduction in myocardial infarction, strokes, and total mortal- ity.

References

1. Conway J (1984) Hemodynamic aspects of essential hyper- tension in humans. Physiol Rev 64:617-659

2. Dupont AG (1990) Effects of carvedilol on renal function. Eur J Clin Pharmacol [Suppl 2] 38:96-100

3. Eggertsen R, Sivertsson R, Andren L, Hansson L (1984) Haemodynamic effects of carvedilol, a new beta-adrenocep- tor blocker and precapillary vasodilator in essential hyper- tension. J Hypertens 2:529 534

4. Folkow B (1982) Physiological aspects of primary hyperten- sion. Physiol Rev 62:347-504

5. Friberg P, Nordlander M (1990) Influence of left ventricular and coronary vascular hypertrophy on cardiac perfor- mance. J Hypertens 8:879-889

6. Kuriyama Y, Nakamura M, Kyougoku I, Sawada T (1990) Effects of carvedilol on cerebral blood flow and its autore- gulation in previous stroke patients with hypertension. Eur J Clin Pharmacol [Suppl 2] 38 : 120-121

7. Lund-Johansen P (1967) Hemodynamics in early essential hypertension. Acta Med Scand [Suppl 482] 181 : 1-101

8. Lund-Johansen P (1983) Central hemodynamic effects of beta-blockers in hypertension. A comparison between aten-

olol, metoprolol, timolol, penbutolol, alprenolol, pindolol and bunitrolol. Eur Heart J [Suppl D] 4:1-12

9. Lund-Johansen P (1984) Pharmacology of combined alpha- beta-blockade II. Haemodynamic effects of labetalol. Drugs [Suppl 2] 29:35-50

10. Lund-Johansen P (1987) Treatment of hypertension: the role of betablockers, calcium antagonists and ACE-inhibi- tors. Med Clin North Am 71:947-957

11. Lund-Johansen P (1988) Hemodynamic effects of antihyper- tensive agents. In: Doyle AE (ed) Handbook of hyperten- sion, vol 11. Clinical pharmacology of antihypertensive drugs. Elsevier, Amsterdam, pp 41-72

12. Lund-Johansen P (1989) Central hemodynamics in essential hypertension at rest and during exercise: a 20 year follow-up study. J Hypertens [Suppl 6] 7:52-55

13. Lund-Johansen P, Omvik P (1990) Hemodynamic patterns of untreated hypertensive disease. In: Laragh JH, Brenner BM (eds) Hypertension: pathophysiology, diagnosis and management. Raven Press, New York, pp 305-327

14. Lund-Johansen P, Omvik P (1990) The role of multiple ac- tion agents in hypertension. Eur J Clin Pharmacol 38:89-95

15. Lund-Johansen P, Omvik P, Haugland H (1986) Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 2 i:45 S-54 S

16. Man In't Veld A, Meiracker AH (1990) Effects of antihyper- tensive drugs on cardiovascular hemodynamics. In: Laragh JH, Brenner BN (eds) Hypertension: pathophysiology, di- agnosis and management. Raven Press, New York, pp 2117-2130

17. Morgan TO, Anderson A, Cripps J, Adam W (1990) The use of carvedilot in elderly hypertensive patients. Eur J Clin Pharmacol [Suppl 2] 38 : 129-133

18. Mulvany MJ (1987) The structure of the resistance vascula- tory in essential hypertension. J Hypertens 5:129-136

19. Omvik P, Lund-Johansen P (1991) Acute hemodynamic ef- fects of carvedilol in essential hypertension at rest and dur- ing exercise. Eur Heart J 12:736-740

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P. Lund-Johansen, M.D., Section of Cardiology, Medical Department, Haukeland Hospital, N-5021 Bergen, Norway