Future directions in vasodilator therapy for heart failure

Future directions heart failure

in vasodilator

therapy

for

Vasodilator therapy has become a major pharmacologic approach for improving left ventricular function, and consequently, vasodilator drugs are being used increasingly in the treatment of heart failure. Ideally, vasodilator drugs used in the long-term management of heart failure should show clearly defined pharmacodynamic effects. These include reduced impedance to left ventricular ejection, increased venous capacitance, increased left ventricular ejection fraction and reduced heart size, absence of neurohormonal stimulation, and slowed progression of left ventricular dysfunction. The mechanisms of action and sites of activity of the various vasodilator drugs currently available vary considerably, and none as yet has proved ideal for the treatment of heart failure or hypertension. The complexity surrounding the multiple vasoconstrictor mechanisms involved in heart failure has led to a rationale for combined vasodilator therapy and certain combinations are discussed. From a therapeutic standpoint, the development of drugs with multiple mechanisms of action is particularly attractive. Flosequinan is a new vasodilator agent whose cellular mechanism of action remains uncertain. Flosequinan has the advantage of being able to relax both arterial and venous beds and as such may be particularly beneficial in the treatment of heart failure. (AM HEART J 1991;121:969.)

Jay N. Cohn, MD. Minneapolis,

Minn.

The clinical syndrome of heart failure is accompanied by impaired left ventricular function. Although the traditional management strategy to correct left ventricular dysfunction was the administration of a positive inotropic agent to increase myocardial contractility, during the past decade it has become apparent that left ventricular overload is a critical contributor to impaired left ventricular perf0rmance.r Consequently, vasodilator therapy to reduce impedance to left ventricular ejection has become an attractive pharmacologic management strategy.2 Indeed, the ineffectiveness of positive inotropic interventions to produce sustained improvement in left ventricular performance in many patients with heart failure3 and the potential toxicity of the newer oral agents being developed* have led to increased reliance on vasodilator therapy as the major approach for improving left ventricular function. The favorable effects of vasodilator drugs in patients with severe heart failure were first identified during hemodynamic measurements before and after the administration of sodium nitroprusside or From the Cardiovascular Division, Minnesota Medical School. Reprint 55455. 4lO126252

requests:

Jay

N. Cohn,

Department MD,

Box

of Medicine, 488 UMHC,

University

Minneapolis,

of MN

phentolamine. 5s6 These early short-term intervention trials demonstrated that these drugs produced a dramatic increase in cardiac output and a reduction in the elevated left ventricular filling pressure. The magnitude of this short-term hemodynamic effect was so dramatic in the setting of severe heart failure that it forced a major revision in the traditional concept that the terminally failing left ventricle was incapable of ejecting an adequate stroke volume. Furthermore, the magnitude of the increase in cardiac output in response to short-term vasodilator therapy was so effective in supporting forward flow that the vasodilator effect on the peripheral vasculature did not result in much reduction in mean systemic arterial pressure. Therefore even patients with low systemic pressures could be treated effectively with these agents, with restoration of more normal hemodynamics at a well-tolerated low blood pressure. Translation of these acute hemodynamic effects into long-term therapy for heart failure raised important experimental problems. The clinical syndrome of heart failure bears a poor correlation with resting systemic hemodynamics, and thus hemodynamic improvement could no longer be used as a guide to therapeutic efficacy in the management of chronic heart failure. Exercise tolerance, quality of life, and survival became the major endpoints in therapeutic trials. During the past 10 years, a num969

970

Cohn

American

ber of vasodilator drugs have been used in an attempt to demonstrate long-term efficacy in patients with heart failure. Some of these studies were carried out in very small patient populations within a single institution, and some were carried out in large scale multicenter trials. The latter design has been restricted to new agents in which the pharmaceutical company sponsor attempted to obtain regulatory body approval for the indication of heart failure. Although not all of these studies have proved efficacy of the vasodilator drugs, some trials have clearly demonstrated an improvement in exercise tolerance and quality of life or prolongation of survival.7-10 DESIRABLE

HEMODYNAMIC

EFFECTS

Because the vascular actions of individual vasodilater drugs vary considerably, it is important to address the desirable pharmacodynamic effects of a vasodilator drug aimed at producing a favorable longterm effect in the management of heart failure, a discussion of which follows. Reduced impedance to left ventricular ejection. The impedance to left ventricular ejection consists not only of arteriolar resistance but of arterial compliance, viscosity, and inertia. Although classic hemodynamic measurements lead to calculation of systemic vascular resistance, which is thought to serve as a guide to the load on the left ventricle during ejection, it is apparent that in a pulsatile system, the compliance of the arterial bed to distend in response to a pressure load is of considerable importance in defining the load that the left ventricle faces during ejection. The compliance of the large arteries provides storage of some of the stroke volume during systole, and the distensibility characteristics of the more distal vasculature contribute to reflected waves that may generate an increase in late systolic pressure in the root of the aorta that may further contribute to left ventricular afterload.ll Consequently, measurements of resistance provide only a partial quantitation of the vascular load placed on the left ventricle. Therefore ideally an effective vasodilator drug should reduce not only arteriolar resistance but also increase vascular compliance to minimize aortic impedance. increased venous capacitance. The filling pressure of the right and left ventricles is influenced not only by systolic ejection and the resultant end-systolic volume but more importantly by venous return. An inotropic stimulus that increases cardiac output will not of itself cause a reduction in ventricular filling pressure unless the increased volume ejected is stored in the capacitance of the vasculature rather than returning directly back to the heart. Vasodila-

March 1991 Heart .tournal

tor drugs that reduce left ventricular filling pressure usually exert this effect by an increase in the compliance of the venous reservoir vessels. This venous effect serves to redistribute volume from the heart to the peripheral venous capacitance bed. An alternative mechanism to account for the reduction in ventricular filling pressure in response to vasodilator drugs is an increase in compliance in the ventricle itself. Many vasodilator drugs have been found to increase compliance of the left ventricle. Increased duced heart

left ventricular ejection fraction and resize. A drug that reduces impedance to

left ventricular ejection would be assumedto improve systolic emptying and result in a fall in end-systolic volume and an increase in ejection fraction. Although vasodilator drugs may produce a profound increase in stroke volume, the magnitude of the increase in ejection fraction may be surprisingly small. Several explanations have been proposed to account for the inconsistent effect observed. First, it is possible that the increase in forward stroke volume may reflect at least in part a reduction in mitral regurgitation and not an increase in overall ejection fraction. Second, the imaging techniques used to measure ejection fraction are crude and particularly inaccurate in the setting of severe left ventricular dilatation. Therefore failure to demonstrate a striking improvement in ejection fraction may be related to technical deficiencies in the methodology. Third, the reduction in the filling pressure in the ventricle in response to these vasodilator drugs may not reflect a measurable fall in end-diastolic volume because of changes in compliance of the ventricle and the steep pressurevolume relationship that the failing ventricle exhibits.12 Therefore the fall in end-diastolic pressure may occur with little, if any, change in end-diastolic volume, and consequently the increases in ejection fraction would be minimized. Absence of neurohormonal stimulation. Reflex stimulation of the sympathetic nervous system and the renin-angiotensin system might be an adverse event in the setting of heart failure. Therefore vasodilator drugs that might be expected to lower systemic arterial pressure and unload carotid and aortic baroreceptors might be expected to stimulate further already activated neurohormonal mechanisms. Such reflex activation might further constrict the peripheral vasculature and lead to further maldistribution of peripheral blood flow and further myocardial stimulation that could adversely affect rhythm and performance. It is clear that some vasodilator drugs are more prone to reflex neurohormonal activation than others. In heart failure, however, reflex activation of these systems appears to be attenuated even

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3,

Part

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in response to drugs, which, in normal or hypertensive individuals, leads to considerable reflex tachycardia.“’ This attenuated neurohormonal response appears to be reversible, since restoration of normal responsiveness is demonstrated after successful heart transplantation. I4 Therefore even a lack of neurohormonal activation in response to the short-term administration of vasodilator drugs is not assurance that reflex activation will not occur at some subsequent time if the drug is continued and the patient demonstrates significant clinical improvement. Nonetheless, most of the drugs used to treat heart failure have not shown evidence of sustained stimulation of neurohormonal mechanisms. Slowed

progression

of left ventricular

dysfunction.

Growing evidence suggests that the syndrome of heart failure represents a gradual progression of left ventricular dilatation and impaired performance based not necessarily on continuation of the active process that initiated the left ventricular insult but rather on physiologic mechanisms that contribute to progressive functional deficiency.l” Some of this process may relate directly to left ventricular growth and remodelling of the ventricular chamber. Certain vasodilator drugs may exert some of their salutary effect by inhibiting this process of ventricular remodelling. l6 Although studies of these mechanisms are only in their infancy, it is possible that the ability of a vasodilator drug to accomplish this direct myocardial effect may influence its efficacy for longterm management. MECHANISMS

OF ACTION

The mechanism of action and sites of activity of various vasodilator drugs vary considerably. Drugs may act on arterial compliance, arteriolar resistance, and venous capacitance vessels. Furthermore, selective effects on regional vascular beds may result in redistribution of peripheral blood flow. Because reflex responses in individual vascular beds contribute to redistribution of blood flow during upright posture and exercise as well as in states of low cardiac output, inhibition of the reflex response can further alter peripheral distribution of blood flow in response to physiologic stresses. In addition, the state of vasoconstrictor tone in an individual vascular bed may well influence the responsiveness to a specific drug intervention. Therefore the complexity of these multiple factors playing on the integration of pressure and flow in the systemic circulation makes it difficult to predict the response to an individual vasodilator agent in any specific clinical circumstances. Many vasodilator drugs act through a cyclic guanosine monophosphate mechanism that may involve

therapy for heart failure

97 1

the release of endothelial-derived-relaxing factor or nitric oxide that stimulates intracellular guanylate cyclase. The cyclic guanosine monophosphate-mediated vasodilatation in response to nitroglycerin and the nitrates is largely at the venous capacitance and arterial compliance levels. For some as yet unexplained reason, sodium nitroprusside, which also releases nitric oxide, appears to exert a prominent effect at the arteriolar level as well. The vascular actions of acetylcholine, bradykinin, and histamine involve endothelial release of nitric oxide, but the net vascular effects of these agents varies depending on the site of release and the state of tone of the individual vascular bed. Atria1 natriuretic peptide exerts its vasodilator effect by stimulating particulate guanylate cyclase. Atria1 peptide levels are chronically increased in patients with heart failure, and the levels may be further increased by the administration of an endopeptidase inhibitor that slows the breakdown of atria1 natriuretic peptide. cu-Adrenoreceptor blockers, such as prazosin and terazosin, would be expected to dilate vascular beds under heightened sympathetic tone. Because heart failure is a syndrome associated with increased plasma norepinephrine and heightened sympathetic nerve traffic,17s I8 such drugs would be expected to have a salutary effect on the maldistribution of blood flow in patients with heart failure. Despite this theoretic advantage of a-adrenoreceptor blockade, regional blood flow studies in both humans and experimental animals have indicated that the short-term administration of these drugs results in overperfusion of the skeletal and splanchnic circulation without necessarily restoring flow to other critical vascular beds.l” Furthermore, inhibition of a-receptor tone may prevent sympathetic-mediated vasoconstriction of nonessential vascular beds during exercise and thus not favorably influence economy of blood flow during stress. Hydralazine, minoxidol, pinacidil, and other potent smooth muscle relaxants act predominantly on the arterial circulation to reduce resistance by a vasodilator mechanism that is not entirely clear. Activation of potassium channels or stimulation of sodium-potassium adenosine triphosphatase’e or other mechanisms to reduce intracellular calcium concentration may be operative. The vascular effect of these agents appears to be sustained during long-term administration, but the absence of any prominent venous effect of these drugs minimizes their effect on ventricular filling pressure, and a lesser action on the large arteries may minimize an effect to increase arterial compliance. As in hypertension, these drugs appear to be most effective when used in combination

with other agents that have a more generalized effect on vascular smooth muscle. The converting enzyme inhibitors exert a shortterm vasodilator effect that appears to be directly related to the intensity of renin-angiotensin activity as reflected by plasma renin activity. Consequently, in states of low plasma renin activity, the acute vasodilator effect of a converting enzyme inhibitor is, at most, very modest.21 Since angiotensin II is a potent smooth muscle stimulator in specific vascular beds, it is not surprising that converting enzyme inhibition tends to increase renal blood flow and reduce splanchnic blood flow.“” During long-term administration of a converting enzyme inhibitor, the vascular effects may be different. Whether a long-term reduction in systemic vascular resistance in response to these drugs can be attributed to a vasodilator effect of the drug or an inhibition of sympathetic nervous system activity mediated by reduction of angiotensin II-mediated norepinephrine release or whether the effects relate to an inhibitory action of the converting enzyme inhibitor on vascular growth remains to be established. Nonetheless, these drugs may be viewed as relatively weak vasodilators whose effect might be enhanced by the simultaneous administration of vasodilator drugs with other mechanisms of action. Calcium channel inhibition is a clearcut mechanism for producing vasodilatation by reducing calcium transport into the vascular smooth muscle cell or its internal release. Although these agents may inhibit calcium transport in both the myocardium and vascular smooth muscle and then result in alterations in myocardial contractility and conductivity, newer agents appear to have a more selective action on vascular smooth muscle. However, even with these new agents, distribution of vascular effects in individual beds may be quite diverse. These drugs, as well as other vasodilator drugs, may activate reflex vasoconstriction through the sympathetic nervous system or the renin-angiotensin system, and thus their administration in combination with either renin-angiotensin inhibition or sympathetic inhibition is particularly attractive. ENDPOINTS

FOR

CLINICAL

TRIALS

Because of the complexity of the vascular effects of vasodilator drugs and the poor relationship between hemodynamic effects and clinical response to therapy, assessment of long-term efficacy of vasodilator therapy for heart failure depends on the demonstration of a favorable effect on a wide array of clinical

responses. Peak exercise capacity, the anaerot,ic threshold for exercise capacity, and comfort wit h which submaximal exercise can be sustained, irn provement in quality of life, long-term reduction rn heart size, improvement in renal sodium excretion reducing the need for diuretic therapy, reduction in the risk of ventricular tachyarrhythmias, and irnprovement of survival are appropriate endpoints for such long-term trials. Studies to date have generally been confined to the assessment of the response t,o a single vasodilator drug superimposed on existing background therapy. Such an approach is clearly understandable for industry-sponsored studies aimed at gaining regulatory approval for a specific drug for the indication of heart failure. RATIONALE

FOR

COMBINED

VASODILATOR

THERAPY

As we evolve in our concepts of vasoconstrictor mechanisms in heart failure and their complex role in altering ventricular function, ventricular and vascular growth, and the symptoms, morbidity, and mortality of heart failure, it may become important to begin to assess the effects of vasodilator drugs used in combination. Such a combination approach addresses the rational concept that multiple vasoconstrictor mechanisms play a role in heart failure and interference with only one mechanism without interfering with the compensatory activation of others provides a limited response. Certain combinations are particularly rational. Administration

of a large

artery

and

large

vein

relaxant

This concept has been particularly useful in the development of the combination of hydralazine and a nitrate, which combines the arteriolar-dilating action of hydralazine with the venous capacitance and arterial compliance effects of a long-acting nitrate preparation. The hemodynamic response of this combination is clearly better than with either agent alone.“:’ Long-term studies have revealed a reduction in heart size, a modest improvement in exercise tolerance, and a prolongation of life.g Although proof that each of the components of this combination have been critical to the long-term benefits of this therapy has not been rigidly demonstrated, the complementary vascular actions and the long-term benefits of these long-term generic drugs make this combination particularly attractive. Replacement of the hydralazine in this regimen with a better-tolerated arteriolar dilator would be worthy of consideration. with

an arteriolar

Combination verting enzyme

relaxant.

of a direct-acting vasodilator inhibitor. Hydralazine,

with

nitrates,

a con-

and

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1

other direct-acting vasodilator drugs often result in reflex stimulation of the sympathetic nervous system and the renin-angiotensin system. The administration of these drugs with a converting enzyme inhibitor should result in an enhanced vascular effect and prevention of the renin-angiotensin or sympathetic stimulation. Early studies with this combination suggest a highly favorable hemodynamic response.z4 A calcium

antagonist

with

a converting

enzyme

inhib-

Calcium antagonists are potent vasodilators particularly on the arterial side of the circulation. The converting enzyme inhibitors produce a striking fall in ventricular filling pressure that may be mediated by a change in compliance of the heart or vasculature or by a direct relaxing effect on venous capacitance vessels. Thus the combination of a converting enzyme inhibitor and a calcium antagonist would have a favorable short-term hemodynamic effect. Furthermore, because calcium antagonists may stimulate the renin-angiotensin system, concomitant inhibition of angiotensin II generation by the converting enzyme inhibitor may favorably affect the long-term response to these drugs. Because both classes of compounds may inhibit vascular and cardiac muscle growth, their dual effects could be particularly beneficial. On the other hand, if tissue growth represents an important compensatory mechanism in heart failure, adverse long-term effects could become apparent. itor.

FUTURE

VASODILATOR

THERAPY

None of the vasodilator drugs currently available for the treatment of heart failure or hypertension is ideal. Side effects, toxicity, tachyphylaxis, and associated undesirable pharmacodynamic effects are characteristic of most of these drugs. The development of new vasodilator agents with unique mechanisms of action would be a major advance in our therapeutic armamentarium. Flosequinan may be such a drug because it appears to relax arterial and venous beds and its cellular mechanism of action remains uncertain. As we move to combined administration of drugs, the availability of agents with multiple mechanisms of action is particularly attractive from a therapeutic standpoint. The mechanisms of constriction of vascular smooth muscle remain incompletely understood. Exploration of new mechanisms of vasoconstriction may well lead to the development of drugs with more specific sites of action and a more favorable profile of effects. Because the vasculature appears to play a critical role in the natural history of heart failure, early intervention with agents

therapy for heart failure

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that could inhibit unwanted vasoconstriction might have a remarkably favorable effect on premature mortality in this syndrome. REFERENCES

1. Cohn ,JN. Vasodilator therapy for heart failure: the influence of impedance on left ventricular nerformance. Circulation 1973;48:5-8. 2. Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure. N Engl J Med 1977;297:27-31 and 254-8. 3. CohnrJN. Inotropic therapy for heart failure: paradise postponed. N Engl J Med 1989;11:729-31. 4. Packer M. Do positive inotropic agents adversely affect t,he survival of patients with chronic congestive heart failure:’ Protagonist’s viewpoint. J Am Co11 Cardiol 1988;12:559-69. 5. Franciosa JA, Guiha NH, Limas CJ, Rodriguera E, Cohn JN. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lancet lS87;1:650-4. 6. Majid PA, Sharma 8, Taylor SH. Phentolamine for vasodilator treatment of severe heart failure. Lancet 1971;2:720. 7. Captopril-Digoxin Multicenter Research Group 1988. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988; 259:539-44. 8. Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. J Am Co11 Cardiol 1983;2:755-63. 9. Cohn JN, Archibald DG, Ziesche S. et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study (VHeFT). N Engl J Med 1986;314:1547-52. 10. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-35. 11. Kelly R, Hayward C, Avolio A, O’Rourke M. Noninvasive determination of age-related change in the human arterial pulse. Circulation 1989;80:1652-9. 12. Gaasch WH, Levine HJ, Quinones MA, Alexander JK. Left ventricular compliance: mechanisms and clinical implications. Am J Cardiol 1976;61:73-84. 13. Olivari MT, Levine TB, Cohn JN. Abnormal neurohormonal response to nitroprusside infusion in congestive heart failure. J Am Co11 Cardiol 1983;2:411-7. 14. Levine TB. Olivari MT, Cohn JN. Effects of orthotopic heart transplantation on sympathetic control mechanisms in congestive heart failure. Am J Cardiol 1986;58:1035-40. 15. Francis GS, Cohn JN. Heart failure: mechanisms of cardiac and vascular dysfunction and the rationale for pharmacologic intervention. FASEB 1990;4:3068-86. 16. McDonald K, Carlyle P, Hauer K, Elbers T, Hunter D, Cohn JN. Early ventricular remodeling after myocardial damage in the dog and its prevention by converting enzyme inhibition [Abstract]. Clin Res 1990;38:414A. 17. Levine TB, Francis GS, Goldsmith SR, Simon A, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensm system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Car&o1 1982;49:1659-66. 18. Leimback WN. Wallin G. Victor RC. Avlward PE. Sundlof G. Mark AL. Direct evidence from intraneuronal recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986:73:913-S. 19. Carlyle PF, Cohn JN. Systemic and regional hemodynamic effects of alpha adrenoceptor blockade in chronic left ventricular dysfunction in the conscious dog. AM HEAK’I. J 1990; 120:619-24. of vascular smooth muscle 20. Limas CJ, Cohn ,JN. Stimulation

Cohn

American

sodium, potassium-adenosinetriphosphatase by vasodilators. Circ Res 1974;35:601-7. 21. Curtiss C, Cohn JN, Vrobel T, Franciosa JA. Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978;59:763-70. 22. Levine TB, Olivari MT, Cohn JN. Hemodynamic and regional blood flow response to captopril in congestive heart failure. Am J Med 1984;76:38-42.

Pharmacology

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24.

March 1991 Heart Journal

Pierpont GL, Cohn JN, Franciosa JA. Combined oral hydralazine-nitrate therapy in left ventricular failure. Hemodynamic equivalency to sodium nitroprusside. Chest 1978;73:8-13. Massie B. Packer M. Kramer B. et al. Hemodvnamic and clinical responses to combined captopril-hydralazine therapy. Circulation 1982;66(suppl II):210.

of flosequinan

Flosequinan is a novel quinolone with cardiovascular activity that is likely to be of value in the treatment of both heart failure and hypertension. Data generated from animal studies indicate that flosequinan produces dilatation in both veins and arteries, with little associated reflex tachycardia. The compound shows some positive inotropic effects, but the potency is very species dependent. The mode of action of flosequinan seems to involve intracellular calcium handling. (AM HEART J 1991;121:974.)

David B. Yates, PhD. Nottingham,

England

Flosequinan is a novel agent (7-fluoro-l-methyl3-methyl sulfinyl-4-quinolone) (Fig. 1) with cardiovascular activity that should make it useful in the treatment of both hypertension and congestive heart failure. Both the parent compound and its single major metabolite, the sulfone BTS 53 554, have similar inherent pharmacologic activity, although the half-life of the latter is longer than the parent in all species examined, especially humans.’ HYPOTENSIVE

ACTIVITY

In spontaneously hypertensive rats (Aoki-Okamoto strain), oral flosequinan at doses of 10 to 30 mg/kg significantly reduces blood pressure measured indirectly from the tail artery. Blood pressure and heart rate were measured 1% and 5 hours after administration, and hypotensive effects were greatest at 5 hours after 30 and 90 mg/kg. Hypotension was accompanied by increases in heart rate. The effects of long-term administration of flosequinan were studied in spontaneously hypertensive rats that were given 90 mg/kg flosequinan twice daily for 14 days. The study also included hydralazine given twice daily at 10 mg/kg for the first day and subsequently at 5 From

the Research

Department,

Reprint requests: David maceuticals, Pennyfoot 4/O/26026

974

Boots

Pharmaceuticals.

B. Yates, PhD, Research Department, Boots Street, Nottingham NG2 3AA, England.

Phar-

mg/kg. Blood pressure and heart rate were measured 3 hours after the first dose and 16 hours after the second dose. Significant hypotension and increase in heart rate occurred each day 3 hours after the first dose of both hydralazine and flosequinan and 16 hours after the second dose of hydralazine but not flosequinan. There was no evidence of a significant development of tolerance to the effects of either flosequinan or hydralazine. The threshold oral hypotensive dose of flosequinan in conscious rabbits was 30 to 90 mg/kg; hydralazine was about nine times more potent in this species. At equihypotensive doses, flosequinan produced a greater increase in heart rate than hydralazine. In conscious renal hypertensive dogs, dose-related falls in mean blood pressure and rises in heart rate were produced by 5, 10, and 20 mg/kg of oral flosequinan.2 The peak hypotensive effects occurred between 1 ‘/z and 3 hours after administration, but by 4 hours there was evidence of a return toward baseline blood pressure (Fig. 2). Hydralazine, which was simultaneously examined at 0.3,1, and 3 mg/kg by a crossover design, caused greater increases in heart rate than flosequinan for similar hypotensive effects (Fig. 3). At 0.3 mg/kg, hydralazine led only to a tachycardia unaccompained by a fall in blood pressure. Flosequinan was about 10 times less potent (on a milligram per kilogram basis) than hydralazine as a hypotensive agent. Flosequinan has also been