Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Hemodynamic Response: Decrease in Cardiac Output vs Reduction in Vascular Resistance PER LUND-JOHANSEN, M.D. Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 SUMMARY From a hemodynamic point of view, an adequate response to antihypertensive therapy would be restoration of a normal circulatory system. In most patients with mild to moderate essential hypertension considered to need drug therapy, the cardinal hemodynamic disturbance is an increased total peripheral resistance (TPR) and a normal or reduced cardiac output (CO). During a 10- to 17year follow-up of untreated hypertensives, a gradual increase in TPR, increase in MAP, and a decrease in CO and stroke volume (SV) were seen. Hemodynamic responses to chronic drug therapy were studied at rest and during exercise in 250 men with mild to moderate essential hypertension in WHO Stage I. A significant reduction in TPR was seen on thiazide diuretics, nifedipine and verapamil, but there was no increase of subnormal CO or SV. A greater normalization of central hemodynamics was achieved by prazosin, which induced a reduction in TPR and an increase in CO and SV, particularly during exercise. In contrast, beta-blocker therapy was associated with a chronic reduction in CO and heart rate (HR) and usually no reduction in TPRI below pretreatment values. The chronic CO reduction was associated with an increase in arteriovenous oxygen difference. In 14 patients with therapy-resistant hypertension, a marked increase in TPR was found. Captopril induced a reduction in TPR with rest and exercise, and also a reduction in cardiac output. Prolonged therapy for 5 years with beta-blockers did maintain blood pressure control, but with no further decrease in TPR. In contrast, 5 years of therapy with labetalol induced a gradualfall in TPR below pretreatment levels, and a gradual increase in CO. (Hypertension 5 (supp til): 111-49—Hf-57, 1983) KEY WORDS * hypertension • hemodynamics • diuretics • beta-blockers • labetalol • vefapamil • nifedipine • captopril F ROM a hemodynamic point of view, an adequate response to antihypertensive therapy could be defined as a restoration of a normal circulatory system — at rest as well as during exercise. An inadequate response would mean lack of this effect even if the blood pressure is reduced. The central hemodynamic disturbance in most hypertensive patients considered to need drug treatment is an increased total peripheral resistance (TPR).1-3 Increased vascular resistance is generally found in most vascular beds, such as in the kidneys, splanchnic organs, and skin, and in advanced hypertension, also in the skeletal muscles.2 4 The cardiac output (CO) during rest is usually normal or reduced, and the stroke volume (SV) is subnormal. During muscular exercise, subnormal CO and SV are usually found even in mild hypertension in young persons.1 * prazosin When hypertension is left untreated, the spontaneously occurring changes are characterized by a gradual fall in CO and SV and an increase in TPR - at rest as well as during muscular exercise.1 The changes in blood pressure (BP) may vary, but in most patients with mild or moderate established hypertension (not borderline hypertension), BP will increase over a 10to 17-year period. Ina 10-year follow-up of 29 patients with mild hypertension, CO fell by 20% and TPR increased by 30% during rest.1 Eight of these subjects have had a third hemodynamic study after 17 years. The changes seen at the 10-year follow-up had progressed, as shown in figure 1. This review will first discuss how the most commonly used antihypertensive agents affect central hemodynamics during chronic treatment in typical patients with mild to moderate essential hypertension. It will also discuss whether inadequate blood pressure reduction could be due to extreme degrees of hemodynamic disturbances and/or to improper drug selection. The review will be limited to diuretics, alpha- and beta-blockers (alone or in combination), calcium antagonists, and to the converting-enzyme inhibitor, captopril. From the Cardiology Section, Medical Department, University of Bergen, Bergen, Norway. Address: Prof. P. Lund-Johansen, Cardiology Section, Medical Department, 5016 Haukeland Hospital, Bergen, Norway. 111-49 111-50 RESPONSE TO HYPERTENSION THERAPY SUPP III HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983 TPRI dyn s*c c m - ' m'c MAP mmHg \ 140 • ••" 130 4000 r * ••• • I > no R5 SOW 100W 150 W ° . !•- 2000 I R5 75 3000 / 120 1965(17-39yrs) o \"5 -82 (34-56yrs) «•« 1000 50W 100 W 150 W RS 50W 100W 150 W HR b«ati mm- 1 SI ml stroke ' m ' 160 Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 70 140 60 120 50 100 40 80 RS sow 100 W 150W RS 50 W 100 W 150 W FIGURE 1. Systemic hemodynamics in eight men with untreated essential hypertension first studied in 1965 (17-39 years of age), then in 1975, and in 1982 (aged 34-56 years). RS = rest sitting.W = wat;Cl = cardiac index; MAP = mean arterial pressure; TPRI = total peripheral resistance index; SI = stroke index; HR = heart rate. Stars show statistical significance of differences between the first and last study. * = p < 0.05; • • = p < 0.01; *•* = p < 0.001. Hemodynamic Changes Induced by 1-Year Therapy Over the years, we have studied the hemodynamic responses to chronic drug therapy in 250 men with mild to moderate essential hypertension (diastolic pressure 100-120 mm Hg) in WHO Stage I. Before treatment, practically all the subjects demonstrated an increased TPRI* ( > 2800 d y n s e c c m " 5 -m2) at rest and also increased values during exercise. CO was normal or moderately decreased; SV was usually normal during rest and subnormal during exercise (reduced by about 20%). During exercise, the arteriovenous oxygen difference was generally increased by 10% to 15%.' Diuretics (Thiazide Diuretics and Tienilic Acid) About 20 years ago it was shown by Conway and Lauwers5 that BP reduction during the first days of thiazide treatment was associated with fall in CO and no change in TRP. However, prolonged use over sev- *TPRI = MAP x 80 -H CI. eral months caused a fall in TPR toward normal levels and a gradual increase in CO. About 10 years later, these results were confirmed in our laboratory and we also showed that the BP control during exercise was maintained by the same mechanisms — a fall in TRP without reduction in CO. The heart rate (HR) response to exercise was unaffected.6 A similar hemodynamic response was later demonstrated with tienilic acid.7 Thus, the thiazide diuretics and tienilic acid might be said to induce at least a partial correction of the hemodynamic disturbances: partial because the subnormal SV and CO during exercise is not corrected.^ Beta-Blockers There are well-documented differences among hemodynamic responses to the different types of betablockers during the rest situation, but the responses during muscular exercise are largely the same, especially during chronic treatment.9'13 We have studied seven different beta-blockers in 89 patients with mild to moderate essential hypertension, all previously untreated.14 The typical response to chronic treatment with beta-blockers without intrinsic sympathomimetic activity (ISA) was a BP reduction of about 15% to 111-51 HEMODYNAMIC RESPONSE/Lund-Johansen Cl l/min/m2 1O MAP mmHg 4000 150 TPRI dyn sec cm"5 m 2 3000 2OOO 100 90 300 1000 1000 500 1OO0 500 1000 VOj ml /mm / m 2 HR/beats / min •10 HRxMAP b e a t s / m m mm Hg 26 r 150 9 ml /strc+e/m 2 20 70 60 Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 100 50 10 40 3O 50 500 1000 500 1000 500 . 1000 \O 2 ml /min/rry? FIGURE 2. Hemodynamic changes induced by I-year therapy of atenolol in 13 men with essential hypertension. V02 = oxygen consumption. Legends are as in figure 1; = before therapy; = on therapy. Note the increase in SI during exercise after therapy, partly compensating the reduction in HR (see ref. 15). 20%, and a fall in HR and CO of about 20% to 25% during rest. During exercise, there was some compensatory increase in SV and a somewhat less reduction in CO (10% to 15%). TPR did usually not fall below pretreatment levels. Figure 2 shows the results in a group of hypertensives treated with atenolol for 1 year.15 Beta-blockers with strong ISA, such as pindolol, usually maintained BP reduction during rest, with less decrease in HR and CO than from beta-blockers without ISA. TPR stayed at pretreatment levels or was slightly reduced. During exercise (when sympathetic tone is increased), the reduction in HR was significant but usually less than on beta-blockers without ISA. SV increased (compared to pretreatment level) and TPR during exercise fell slightly below pretreatment level. Most investigators have agreed upon these hemodynamic changes,10"13 but some reports have differed and patients responding to chronic beta-blocker therapy with increase in CO and marked fall in TPR have been described.16'17 In patients with mild to moderate essential hypertension, however, this reaction pattern is rare. Figure 3 shows the individual changes in cardiac index (CI) in our series. It is seen that CI fell in most patients and the fall was greatest in those with the highest CI values. However, also in patients with rather low CI substantial reductions in CI were seen. Figure 4 shows that in this type of patient relatively few responded with reduction in TPRI. Table 1 shows that the number of patients who demonstrated at least a 10% reduction in TPRI at rest and during two exercise loads was relatively small. Most studies have shown that chronic beta-blocker treatment causes little change in oxygen consumption (V0 2 ) at rest as well as during exercise.14 Since Cl is reduced (usually 20% to 25%), this means that the arteriovenous oxygen difference is increased accordingly. The significance of this is not known. However, although many patients react to initiation of betablocker therapy with muscular fatigue and cold hands and feet, these complaints often disappear during chronic treatment, at least in patients with mild to moderate hypertension. Cold extremities, however, which are most likely due to reduced peripheral blood flow, are an important problem in cold climate. However, from a hemodynamic point of view, patients on chronic beta-blocker therapy have replaced their normokinetic hypertensive circulatory system by a nor- 111-52 RESPONSE TO HYPERTENSION THERAPY FIGURE 3. Changes in cardiac index (Cl) related to pretreatment cardiac index sitting at rest in 89 men with mild to moderate essential hypertension treated with different betablockers (see ref. 14). SUPP III HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983 g.55 Cl I mlrr'nr 2 0 • -/A- -#-oA • -0.5 ?<£ a -1.0 a oa • -1.5 • Atenolol • Metoprolol A Timolol o Penbutolol • Alprenolol * Pindolol + Bunitrolol -2.0- -25 Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 ACI I mirr1 rrr2 motensive but hypokinetic system. It is of course important that the blood pressure x heart rate product is markedly reduced on beta-blocker therapy, especially during muscular exercise when a 40% reduction or more might be seen. This reaction is of course most adequate in patients with a compromised coronary circulation. A TPRI dyn sec cm"5m2 Alpha-Blockers (Prazosin) Studies of prazosin have generally agreed that acutely as well as chronically BP is reduced entirely through reduction in TPR.18"20 HR as well as CO is unchanged during rest. During exercise, CO is increased due to an increase in SV and a slight, insignificant increase in HR. Fall in TPR is a very consistent finding. The 2107 1 2000- 1000- &a O A o-yy *». • •< «• • + o + -1000 TPRI dyn sec cm"5m2-1O3 5 A • o A o • * • Atenolol Metoprolol Timolol Penbutolol Alprenolol Pindolol Bunitrolol FIGURE 4. Changes in total peripheral resistance index (TPRI) related to pretreatment TPRI during chronic beta-blockade in 89 men (see ref. 14). ffl-53 HEMODYNAMIC RESPONSEJLund-Johansen TABLE 1. sponses Individual Total Peripheral Resistance (TPR) Re- A TPR > - 10% (Rest sitting — 2 workloads) no. Drug 1/13 1/12 0/16 4/13 1/10 0/11 3/14 10/89 (11%) Atenolol Metoprolol Timolol Penbutolol Alprenolol Bunitrolol Pindolol Total Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 results from our 1-year study are shown in figure 5. In conclusion, prazosin might be said to restore normal circulation in the majority of patients with mild to moderate essential hypertension. No reduction in renal or peripheral blood flow is seen.20 However, in patients with compromised coronary circulation it should be noted that the workload on the heart is reduced far less than by the use of beta-blockers, since HR is not decreased, only the BP. Combination of Alpha- and Beta-Blockade (Labetalol) When alpha- and beta-blockade is properly balanced, a marked reduction in BP is often achieved, the BP reduction being partly due to reduction in TPR and partly due to fall in CO. 21 An increase in SV might be expected, and the decrease in CO during exercise is less than when beta-blockers are used alone. Labetalol induced similar changes, as might be expected since this drug blocks alpha- as well as beta,and betaj-receptors.22"23 A substantial BP reduction might then be achieved by one single drug. In our series, the mean reduction was 23%. During exercise, CO was reduced much less than on conventional betablockers.24 Calcium Antagonists (Verapamil and Nifedipine) In recent years, the calcium antagonists have been introduced for therapy of hypertension.26"30 These drugs reduce BP through reduction in TPR. During long-term therapy, nifedipine,30 given in long-acting form, reduced BP 17% during rest without any significant changes in CO, SV, or HR (fig. 6). Verapamil induced similar reduction in TPR, but also about 10% CI l / m i n / m 2 10 TPRITdyn sec c m " 5 MAP mm Hg 4000 r 150 100 500 1000 500 1000 VO2 m l / m i n / m 2 500 1000 HR x MAP b«als / m i n mm Hg HR 500 1000 28000 beats/min 150 20000 100 10000 70 4000 500 1000 5000 1000 VO2 m l / m i n / m 2 FIGURE 5. Hemodynamic changes induced by I-year therapy with prazosin in 10 men with essential hypertension. Note the substantial fall in total peripheral resistance (TPRl). and the significant increase in cardiac index (CI) during exercise. Also note the small reduction in HR X MAP. Abbreviations are as in figures I and 2 (see ref. 19). m-54 RESPONSE TO HYPERTENSION THERAPY SUPP 111 HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983 • o Cl I min"'m'2 before afttr TPRl dyn sec crrr'm2 40001 MAP mmHg 3000- 1505- 1000 500 500 1000 500 HRMAP beats min'1mmHg 28 103! HR beats min'1 1000 150- SI ml stroke"'m"2 701 20- Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 60- r^---9 50- -? 10010- 40 50 10k -rr'/r500 1000 500 1000 500 1000 VO2 ml min' l m" 2 FIOURE 6. Hemodynamic changes during chronic treatment with long-acting nifedipine in 14 men with essential hypertension. Note the reduction in total peripheral resistance (TPRl), and no significant changes in cardiac index (Cl), stroke index (SI), and heart rate (HR) (see ref. 30). C I min" ni 1 m' 2 5O ?560 MAP mm Hg TPRl dyn sec cm" 5 m~2 140 4000 4.0 120 3000 3.0 100 2000 2.0 B 1year 5years B 1year 5years B 1year 5 years FIGURE 7. Individual changes in cardiac index (Cl), mean blood pressure (MAP), and total peripheral resistance (TPRl) in 10 men on chronic atenolol therapy studied before therapy, after 1 year, and after 5 years. shows mean values (see ref. 31). CI-55 HEMODYNAMIC RESPONSEJLund-Johansen decrease in HR. However, this was compensated by increase in SV and CO was unchanged. Thus, the calcium antagonists (like the diuretics) maintain BP control by partial correction of the hemodynamic disturbances: only partial because the subnormal CO during exercise is not corrected. Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 Hemodynamic Responses to Prolonged Drug Treatment (5-6 Years) Since at least some of the hemodynamic abnormalities in established hypertension are thought to be due to structural changes in the heart and in the resistance vessels, it could be hoped that permanent blood pressure control could induce regression of these changes and also further normalization of central hemodynamics during prolonged treatment. We have studied groups of patients treated with different beta-blockers (alprenolol, atenolol, or metoprolol) and with labetalol who have had a third hemodynamic study after 3-5 years. The results from the atenolol study (fig. 7) show that the systemic hemodynamics were practically unchanged from 1 year until 5 years after the start of therapy. Somewhat disappointingly there was no tendency for an increase in CO and SV or a decrease in TPRI. On the other hand, no obvious deterioration had taken place.31 Similar changes were seen with alprenolol and with metoprolol. The reduction of the workload on the heart was maintained. We have recently completed a 6-year follow-up on 15 patients with moderate hypertension treated with labetalol for 6 years. The responses were somewhat different from those seen on prolonged beta-blocker therapy. BP was controlled over these 6 years and did not change significantly. However, TPR had fallen at rest as well as during exercise, and after 6 years TPR was less than after 1 year on therapy (fig. 8). CI after 6 years was slightly higher than after 1 year, but the differences between the 1 -year and 6-year results were CI I 10 150 100500 1000 500 500 1000 VO2 ml min"1rri2 HR beats mirr,-1 1000 HRx MAP beats min"1mm Hg •103 28 150 1 SI ml stroke" rri 2 20 60 100 50 10 40 30 50 >• 500 XXX) 500 1000 VO2 ml min~1rn2 ,_ 500 XXX) FIGURE 8. Hemodynamic changes induced by 6-year therapy on labetalol in 15 men. Solid line = studied before therapy; dashed line = studied after I year; and dotted line = studied after 6 years. Mean values and SEM. Stars show differences between thefirstand the second study. Note the gradualfall in total peripheral resistance (TPRI) and a slight increase in stroke index (SI) and cardiac index (CI) during the 5 years between the second and the third study. 111-56 RESPONSE TO HYPERTENSION THERAPY SUPP III HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983 not statistically significant. However, the results point to a greater normalization of central hemodynamics on prolonged labetalol therapy than with prolonged betablocker treatment. Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 Hemodynamic Characteristics and Responses in Patients with Severe Therapy-Resistant Hypertension Anderson et al.32 studied a group of patients who had shown resistance to treatment with conventional antihypertensive agents (triple therapy with diuretics, beta-blockers, and vasodilators). When therapy was stopped and blood pressure increased, the characteristic hemodynamic disturbance was a marked increase in TPR associated with a subnormal SV and CO. The BP was very high (about 230/140 mm Hg during rest). In a similar group of patients, we have confirmed these hemodynamic characteristics at rest and during mild exercise (Omvik and Lund-Johansen, 1983, unpublished results). Since, apart from structural changes in the resistance vessels, the high resistance could also theoretically be due to an overactivity in the reninangiotensin system (not measured), the patients were treated with captopril and a diuretic. Most of the patients responded with a substantial drop in BP, with a few practically reaching normotensive levels. During rest, the BP was reduced through a drop in TPR, with little change in CO. During exercise, a decrease in CO was also seen. Similar responses during rest have been reported by others.33"34 Discussion and Conclusion This review has shown that most of the commonly used antihypertensive agents may control BP, but often only by partially correcting the hemodynamic disturbances. Particularly the beta-blockers will usually maintain a subnormal cardiac output at rest and during exercise, and of course a subnormal HR. The arteriovenous oxygen difference is increased at rest as well as during exercise. A greater degree of normalization of central hemodynamics is achieved by diuretics and calcium antagonists, but complete normalization of CO is usually not achieved. In our experience, the greatest normalization of central hemodynamics was achieved by the alpha-blocker, prazosin. During prolonged treatment for 5-6 years, the betablockers prevented a further decrease in SV and a further increase in TPR, and thus seem to arrest or stop the changes that could have been expected in untreated subjects. Prolonged therapy with combined alpha- and beta-blockade (by the use of labetalol) induced a gradual decrease in TPR and a slight increase in CO at rest as well as during exercise. Thus, combined alpha- and beta-blockade might induce more adequate responses than beta-blockers alone. This short review discusses only the typical response in patients with mild to moderate essential hypertension. Most of these patients generally seemed to tolerate the chronic reduction in CO induced by the beta-blockers surprisingly well, generally with little restriction in their physical activity. However, in spe- cial subgroups of patients, the use of a wrong antihypertensive agent may induce inadequate responses: i.e., a decrease in CI in patients with hypertension and peripheral vascular disorders. In patients with very severe therapy-resistant hypertension, converting-enzyme inhibitors are sometimes particularly useful, at least partly normalizing central hemodynamics through reduction in TPR. Finally, it should be emphasized that, although the responses to antihypertensive agents vary greatly from a hemodynamic point of view, other effects of the antihypertensive agents might of course have greater significance for the clinical outcome. However, at least when dealing with relatively young patients with mild to moderate essential hypertension where many years (perhaps life-long) therapy might be necessary, restoration of a normal circulatory system would seem to be the most logical way of treating this condition. References 1. Lund-Johansen P: State of the art review. Haemodynamics in essential hypertension. Clin Sci 59: 343, 1980 2. Birkenhager WH, de Leeuw PW, Schalekamp MADH: Control Mechanisms in Essential Hypertension. Amsterdam, New York, Oxford: Elsevier Biomedical Press, 1982 3. Bflhler FR: Pathophysiology of primary hypertension: role of adrenoceptors in the transformation from an early high cardiac output into a later high arteriolar resistance phase. In Hypertensive Cardiovascular Disease: Pathophysiology and Treatment, edited by Amery A. The Hague, Boston, London: Martinus Nijhoff Publishers, 1982, p 164 4. Folkow B: Physiological aspects of primary hypertension. Physiol Rev 62: 347, 1982 5. Conway J, Lauwers P: Hemodynamic and hypotensive effects of long-term therapy with chlorothiazide. Circulation 21: 21, 1960 6. Lund-Johansen P: Hemodynamic changes in long-term diuretic therapy of essential hypertension. Acta Med Scand 187: 509, 1970 7. Lund-Johansen P: Hemodynamic and metabolic long-term effects of tienilic acid in essential hypertension. Acta Med Scand 646 (suppl): 106, 1980 8. Van Brummelen P, Man in 't Veld AJ, Schalekamp MADH: Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders. Clin Pharmacol Ther 27: 328, 1980 9. Clark BJ, Beta-adrenoceptor-blocking agents: Are pharmacologic differences relevant? Am Heart J 104: 2334, 1982 10. Man in 't Veld AJ. Schalekamp MADH: How intrinsic sympathomimetic activity modulates the haemodynamic responses to beta-adrenoceptor antagonists. A clue to the nature of their antihypertensive mechanism. Br J Clin Pharmacol 13: 245, 1982 11. Tarazi RC, Dustan HP: Beta-adrenergic blockade in hypertension. Am J Cardiol 29: 633, 1972 12. Tarazi RC, Fouad FM, Bravo EL: Total peripheral resistance and beta-adrenergic blockade. In Frontiers in Hypertension Research, edited by Laragh JH, Biihler FR, Seldin DW. Berlin, Heidelberg, New York; Springer Verlag 1981, p 454 13. SvendsenTL, Carlsen JE, HartlingO, McNair A, Trap-Jensen J: A comparison of the acute haemodynamic effects of propranolol and pindolol atrestand during supine exercise in man. Cln Sci 59: 465, 1980 14. Lund-Johansen P: Central hemodynamic effects of betablockers in hypertension. A comparison between atenolol, metoprolol, timolol, penbutolol, alprenolol, pindolol and bunitrolol. Eur Heart J 4 (suppl): In press, 1983 15. Lund-Johansen P: Hemodynamic long-term effects of a new beta-adrenoceptor blocking drug atenolol (ICI66082) in essen- HEMODYNAMIC RESPONSE/Lund-Johansen Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 tial hypertension. Br J Clin Pharmacol 3: 445, 1976 16. Atterh0g JH, Duner H, Pemow B: Hemodynamic effects of pindolol in hypertensive patients. Acta Med Scand 606 (suppl): 55, 1977 17. Guazzi M, Polese A, Fiorentini C, Olivari MT, Magrini F: Cardiac performance and beta-adrenergic blockade in arterial hypertension. Am J Med Sci 273: 63, 1977 18. Smith IS, Femandes M, Kim KE, Swartz C, Onesti G: A threephase clinical evaluation of prazosin. In Prazosin — Clinical Symposium Proceedings, edited by McGraw-Hill. Post-grad Med: 53, 1975 19. Lund-Johansen P: Haemodynamic changes at rest and during exercise in long-term prazosin therapy of essential hypertension. In Prazosin — Evaluation of a New Antihypertensive Agent, edited by Cotton DWK. Amsterdam: Excerpta Medica, 1974, p 43 20. de Leeuw PW, Wester A, Stienstra R, Falke HE, Birkenhager WH: Hemodynamic and endocrinological studies with prazosin in essential hypertension. In Recent Advances in Hypertension and Congestive Heart Failure — Prazosin, edited by Lund-Johansen P, Mason DT. Amsterdam; Excerpta Medica, 1978, p II 21. Lund-Johansen P: Haemodynamic long-term effects of prazosin plus tolamolol in essential hypertension. Br J Clin Pharmacol 4: 141, 1977 22. Koch G: Haemodynamic effects of combined alpha- and betaadrenoceptor blockade after intravenous labetalol in hypertensive patients at rest and during exercise. Br J Clin Pharmacol 3 (suppl): 725, 1976 23. Omvik P, Lund-Johansen P: Acute hemodynamic effects of labetalol in severe hypertension. J Cardiovasc Pharmacol 4: 915, 1982 24. Lund-Johansen P, Bakke OM: Haemodynamic effects and plasma concentration of labetalol during long-term treatment of essential hypertension. Br J Clin Pharmacol 7: 169, 1979 111-57 25. Fagard R, Lijnen P, Amery A: Response of the systemic pulmonary circulation to labetalol at rest and during exercise. System Pulm Circ (suppl): 13S, 1982 26. Doyle AE, Anavekar SN, Oliver LE: A clinical trial of verapamil in treatment of hypertension. In Calcium Antagonism in Cardiovascular Therapy: Experience with verapamil, edited by Zanchetti A, Krikler DM. Amsterdam: Excerpta Medica, 1981, p 2 5 2 27. de Leeuw PW, Smout AJPM, Willemse PJ, Birkenhager WH: Effects of verapamil in hypertensive patients. In Calcium Antagonism in Cardiovascular Therapy: Experience with verapamil, edited by Zanchetti A, Krikler DM. Amsterdam: Excerpta Medica, 1981, p 233 28. Lund-Johansen P: Hemodynamic long-term effects of verapamil in essential hypertension at rest and during exercise. Acta Med Scand (suppl). In press, 1983 29. Olivari MT, Bartorelli C, Polese A, Fiorentini C, Moruzzi P, Guazzi MD: Treatment of hypertension with nifedipine, a calcium antagonistic agent. Circulation 59: 1056, 1979 30. Lund-Johansen P, Omvik P: Haemodynamic effects of nifedipine in essential hypertension at rest and during exercise. Hypertension In press, 1983 31. Lund-Johansen P: Hemodynamic consequences of long-term beta-blocker therapy: A 5-year follow-up study of atenolol. J Cardiovasc Pharmacol 1: 487-495, 1979 32. Anderson O, Hansson L, Sivertsson R: Primary hypertension refractory to triple drug treatment: a study on central and peripheral hemodynamics. Circulation 58: 615, 1978 33. Tarazi RC, Bravo EL, Fouad FM, Omvik P, Cody RJ Jr: Hemodynamic and volume changes associated with captopril. Hypertension 2: 576, 1980 34. Fagard R, Bulpitt C, Lijnen P, Amery A: Response of the systemic and pulmonary circulation to converting-enzyme inhibition (captopril) at rest and during exercise in hypertensive patients. Circulation 65: 33, 1982 Discussion DISCUSSANTS: S. JULIUS P. LUND-JOHANSEN MUIESAN P. SLEIGHT Are lowering the cardiac output and raising the vascular resistance necessarily bad? And is lowering the vascular resistance always good for the body? For example, if one pools all the blood to the skin the vascular resistance may be low but the renal blood flow may be decreased. Tarazi's study suggests that hydralazine causes cardiac hypertrophy in site of the fact that it lowers the vascular resistance. LUND-JOHANSEN: My philosophy is that the cardiac output should be tailored so that it gives a normal perfusionof the body. So in "healthy" patients with essential hypertension 1 aim at making things as normal as possible. Possibly this philosophy is wrong and it Could even be better to lower the cardiac output and heart rate at rest and during exercise by, say, 20%. But the pay-off is an increased arteriovenous oxygen difference. Patients with mild to moderate essential hypertension seem to tolerate both of these latter features surprisingly well. Finally, this type of treatment has now been in use for 20 JULIUS: years, but there haven't been any reports of a mysterious hypoperfusion syndrome. MUIESAN: Which doses of nifedepine and labetalol did you use? LUND-JOHANSEN: With nifedepine we started with 20 mg of the long acting form twice daily, raising this to a maximum total daily dose of 80 mg. With labetalol the initial dose was 100 mg twice daily increasing to 1200 mg maximum. Could you enlarge on your statement that patients with a reduced cardiac output and a raised resistance felt surprisingly well. LUND-JOHANSEN: Some of these subjects certainly felt dizzy and had "heavy legs" and muscular fatigue the first two to three weeks of therapy, but thereafter these sensations disappeared. Most of the subjects could participate in rather vigorous physical exercise (skiing, mountain hiking) without feeling any change in their physical working performance. SLEIGHT: Hemodynamic response: decrease in cardiac output vs reduction in vascular resistance. P Lund-Johansen Hypertension. 1983;5:III49 doi: 10.1161/01.HYP.5.5_Pt_2.III49 Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1983 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/5/5_Pt_2/III49 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/