Arterial mechanical properties in dilated cardiomyopathy. Aging and the response to nitroprusside.

The effects of aging on arterial mechanical properties and the response to nitroprusside were examined in 25 patients with dilated cardiomyopathy. High-fidelity pressures were recorded with a multisensor catheter. Pulse wave velocity was determined between two sensors in the thoracic aorta. Arterial compliance was determined by an analysis of the diastolic waveform and cardiac output. At baseline, despite a similar systemic vascular resistance, the pulsatile load (e.g., arterial compliance) and wave transmission characteristics (e.g., pulse wave velocity) were altered with aging. Arterial compliance was reduced in older (greater than 50 yr, n = 8) versus younger (less than 35 yr, n = 8) patients (0.51 +/- 0.17 vs. 1.33 +/- 0.63 ml/mmHg, P less than 0.01) and intermediate in those 35-50 yr of age (n = 9, 0.72 +/- 0.40 ml/mmHg). There was a positive correlation between age and pulse wave velocity (r = +0.90). Nitroprusside infusion decreased resistance, increased arterial compliance, and lowered pulse wave velocity in all groups. Yet, advancing age was associated with a greater fall in wave velocity for a given fall in aortic pressure. The slope (K) of the relation between pulse wave velocity and aortic diastolic pressure progressively increased with age (0.01 +/- 0.03, 0.06 +/- 0.02, and 0.09 +/- 0.03 m/s-mmHg). Multiple linear regression analysis revealed a significant relation between K and age. These data demonstrate that in older patients with dilated cardiomyopathy the left ventricle is coupled to an arterial circulation that has a greater pulsatile load, despite a similar steady load. Furthermore, these age-related changes in the arterial system affect the hemodynamic response to pharmacologically-induced vasodilatation.

Perspective of the pharmaceutical industry on the development of new drugs for heart failure.

Despite recent therapeutic advances, patients with heart failure have considerable morbidity and a markedly shortened life span. The prevalence of heart failure increases with age and is the most common cause of hospital admission in the elderly. In developing innovative remedies for this disorder, the scientific challenges, regulatory agencies' guidelines, physician behavior and marketing requirements must be considered.

Sustained hemodynamic improvement during long-term therapy with levodopa in heart failure: role of plasma catecholamines.

Long-term therapy with oral sympathomimetic amines in patients with heart failure has been limited by the eventual development of diminished pharmacologic efficacy. However, a previous investigation in five subjects with heart failure suggested that long-term ingestion of levodopa, which is decarboxylated endogenously to dopamine, produces a sustained improvement in cardiac function. In the present study, levodopa was administered orally (1.5 to 2.0 g) to 14 patients with heart failure while hemodynamic responses and plasma catecholamines were monitored. Initially, an increase in cardiac index and stroke volume index was accompanied by a decline in systemic vascular resistance, mean pulmonary capillary wedge pressure and mean right atrial pressure. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of dopamine rose substantially after drug ingestion and correlated significantly with changes in cardiac index (r = 0.73, p less than 0.05). After 12 weeks of treatment with levodopa, the changes in cardiac index, stroke volume index, systemic vascular resistance and plasma dopamine levels persisted (n = 12 patients). Moreover, a significant decrease occurred in the heart rate at rest. Although there was an initial tendency for plasma norepinephrine concentrations to increase, a return to control levels was documented after long-term treatment. Thus, tolerance to the hemodynamic actions of levodopa did not develop during long-term administration of the drug. The hemodynamic responses observed can be ascribed to the activation of beta 1-adrenoceptors and dopamine1 receptors by dopamine generated from levodopa. The dopamine2 activity of dopamine does not appear to be responsible for the improvement in cardiac performance produced by levodopa.

Effects of dopamine on left ventricular afterload and contractile state in heart failure: relation to the activation of beta 1-adrenoceptors and dopamine receptors.

Although long-term therapy with oral beta-adrenoceptor agonists in patients with heart failure is generally associated with the development of diminished pharmacologic efficacy, the ingestion of levodopa, which is decarboxylated endogenously to dopamine, is associated with a sustained improvement in cardiac function. The beneficial hemodynamic actions of dopamine in patients with heart failure have been attributed to a positive inotropic effect that is mediated through activation of beta 1-adrenoceptors. However, a reduction in left ventricular afterload resulting from the activation of dopamine receptors may also lead to an improvement in the performance of the failing heart. To ascertain the relative importance of the positive inotropic and afterload-reducing effects of dopamine in patients with heart failure, dopamine (2, 4, 6 micrograms/kg per min), dobutamine (2, 6, 10 micrograms/kg per min) and nitroprusside (0.125 to 2.0 micrograms/kg per min) were administered to 13 patients with dilated cardiomyopathy while monitoring left ventricular wall thickness and dimensions by echocardiography and left ventricular and aortic pressures with a micromanometer-tipped catheter. Altering left ventricular afterload, quantified as end-systolic circumferential wall stress, with nitroprusside allowed generation of the left ventricular end-systolic circumferential wall stress-velocity of fiber shortening relation that represented the baseline contractile state of the myocardium. Left ventricular velocity of fiber shortening was elevated during the administration of dobutamine and dopamine when compared with measurements obtained with nitroprusside at the same left ventricular end-systolic circumferential wall stress. Furthermore, left ventricular end-systolic wall stress decreased with dopamine but not with dobutamine. Thus, the beta 1-adrenoceptor activity of dopamine and dobutamine augmented the contractile state of the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained beneficial hemodynamic responses to large doses of transdermal nitroglycerin in congestive heart failure and comparison with intravenous nitroglycerin.

The hemodynamic effects of a new transdermal preparation of nitroglycerin were evaluated in 9 patients with chronic congestive heart failure (CHF). A graded infusion of nitroglycerin was administered initially to establish the dose-response relation for nitroglycerin and estimate the dose of topical nitroglycerin to be applied. Significant hemodynamic improvement was observed 0.5 to 1.0 hour after the cutaneous application of the nitroglycerin-impregnated polymer. The peak effect occurred at 6 hours, with the left ventricular filling pressure decreasing from 24 +/- 2 to 18 +/- 1 mm Hg (mean +/- standard error of the mean) (p less than 0.01) and the cardiac index increasing from 2.0 +/- 0.2 to 2.6 +/- 0.2 liters/min/m2 (p less than 0.01). The systemic vascular resistance decreased from 1,860 +/- 198 to 1,531 +/- 162 dynes s cm-5 (p less than 0.01). Heart rate and mean arterial pressure were unchanged. Significant hemodynamic benefit was observed for 24 hours, and no rebound deterioration occurred upon withdrawal of the drug. The average dose of transdermal nitroglycerin applied was 51 +/- 6 cm2 (1.7 +/- 0.2 mg/kg; 6 of the 9 patients received 64 cm2). Thus, topical application of a new nitroglycerin-impregnated polymer induces an improvement in cardiac performance that is sustained for 24 hours in patients with chronic CHF. However, substantial doses of the drug may be required to produce a satisfactory hemodynamic response in most patients with CHF.

Role of the beta 2 adrenoceptor in mediating positive inotropic activity in the failing heart and its relation to the hemodynamic actions of dopexamine hydrochloride.

In patients with severe congestive heart failure, it has been suggested that since myocardial beta 1 adrenoceptors are selectively down-regulated, activation of beta 2 receptors may be a preferable approach to augmenting contractility. Accordingly, dopexamine hydrochloride (1, 2 and 4 micrograms/kg/min) and dopamine (2 and 4 micrograms/kg/min) were administered to 8 patients with dilated cardiomyopathy. Left ventricular (LV) dimensions, thicknesses and pressures were obtained using simultaneous high-fidelity pressure measurements and echocardiographic recordings. LV contractility was assessed using the load-independent relation between LV end-systolic wall stress and rate-corrected velocity of fiber shortening. Cardiac index increased in a dose-related manner with both drugs, and was accompanied by a decline in systemic vascular resistance, a measure of peripheral arteriolar tone. LV end-diastolic pressure was unaltered except for a decrease from 29 +/- 6 to 19 +/- 5 mm Hg (p less than 0.017) at the highest dose of dopexamine hydrochloride. Heart rate was unchanged during the infusion of dopamine but increased significantly with dopexamine hydrochloride. LV end-systolic wall stress, a measure of LV internal load, decreased with both drugs. With dopamine, a dose-dependent positive inotropic effect was observed. Dopexamine hydrochloride, at the 4 micrograms/kg/min infusion dose, exerted a mild positive inotropic effect comparable to that noted with dopamine at 2 micrograms/kg/min. Thus, dopamine and dopexamine hydrochloride improved overall LV performance. With dopamine, a substantial positive inotropic effect occurred in association with a reduction in LV afterload. The increased cardiac index observed with dopexamine hydrochloride was due primarily to peripheral vasodilatation and a positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Thallium-201 scintigraphy after surgical repair of hemodynamically significant primary coronary artery anomalies.

Nine patients with hemodynamically significant congenital coronary artery anomalies underwent surgical repair at our institution during the period 1960 to 1979. Four received diagnoses of anomalous left coronary artery arising from the pulmonary artery, while five patients had coronary artery fistulae. Stress 201Tl scintigraphy was performed on these patients 0.5 to 18 years after surgical correction as a means of assessing the adequacy of myocardial perfusion. No perfusion defects were visualized on any of the thallium studies. The surgical procedure used did not appear to influence the results of 201Tl stress imaging. Thus, these nine patients with surgically corrected primary coronary artery anomalies had no evidence of ischemia as assessed by stress thallium scintigraphy. Serial preoperative and postoperative thallium studies are now indicated to determine the role of this procedure in the management of hemodynamically significant congenital coronary artery anomalies.

Pharmacological characterization of the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arteries and veins.

This investigation was undertaken to characterize the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arterial and venous preparations. Contractile responses to cumulative additions of phenylephrine (selective alpha 1-adrenoceptor agonist), UK-14,304 (selective alpha 2-adrenoceptor agonist), noradrenaline (non-selective alpha-adrenoceptor agonist), and dopamine (non-selective alpha-adrenoceptor agonist) were measured in the presence and absence of rauwolscine, a selective alpha 2-antagonist, and terazosin, a selective alpha 1-antagonist. Phenylephrine was a more potent agonist in the mesenteric artery than in the mesenteric vein; UK-14,304 exhibited the opposite profile of activity. Terazosin was a more potent antagonist than rauwolscine against each of the agonists, except dopamine, in the mesenteric artery but rauwolscine was more potent than terazosin in the vein. Terazosin and rauwolscine were equipotent in inhibiting the contractile responses to dopamine in the artery while rauwolscine was more potent than terazosin in the vein. The pA2 values measured in both vessels failed, however, to demonstrate a high selectivity for either alpha-adrenoceptor antagonist. These results suggest that the alpha-adrenoceptors in the canine mesenteric artery and vein exhibit pharmacological characteristic typical of both alpha 1- and alpha 2-adrenoceptor subtypes.

Alpha-adrenoceptor blocking activity of fenoldopam (SK&F 82526), a selective DA1 agonist.

The alpha-adrenoceptor blocking activity of fenoldopam (SK&F 82526), a selective dopamine vascular receptor (DA1) agonist, was evaluated in isolated segmental preparations of rabbit aorta, dog mesenteric and rabbit splenic arteries. Fenoldopam, in concentrations ranging from 10(-6) to 10(-4) M, produced parallel, dextral shifts of concentration-contractile response curves to noradrenaline. Slopes of the Schild regression lines were not significantly different from unity in the three vessels. pA2 values for fenoldopam in the rabbit aorta, dog mesenteric and rabbit splenic arteries were 5.48 +/- 0.08, 5.78 +/- 0.05, and 5.20 +/- 0.05, respectively. In experiments where the drug was added to the bathing medium before exposing the vascular segments to the irreversible alpha-adrenoceptor antagonist, phenoxybenzamine, fenoldopam provided nearly complete protection against alpha-adrenoceptor blockade. These results demonstrate that fenoldopam possesses alpha-adrenoceptor antagonist activity and competes with alpha-phenoxybenzamine, for occupancy at the same receptor site.

Theoretical basis for the use of angiotensin II antagonists in the treatment of heart failure.

THERAPEUTIC USE OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: ACE inhibitors are now accepted as valuable therapeutic agents in the management of heart failure. The benefits include symptomatic relief, improvement in left ventricular function, prevention of progressive ventricular dilation, improved survival and decreased incidence of myocardial infarction and unstable angina. POTENTIAL OF ANGIOTENSIN (ANG) II ANTAGONISTS: Ang II antagonists are expected to produce similar beneficial effects to those of ACE inhibitors, through blockade of vascular, adrenal, renal and prejunctional neuronal Ang II type 1 receptors. DIFFERENCES BETWEEN ANG II ANTAGONISTS AND ACE INHIBITORS: Despite similarities between ACE inhibitors and Ang II inhibitors with respect to the mechanism of action, there are theoretical differences which may be of clinical importance. Adverse effects seen with ACE inhibitors that are attributed to non-renin-angiotensin system effects (notably angioedema and cough) may be less frequent in patients treated with an Ang II antagonist. ACE inhibitors act within the renin-angiotensin system to prevent the conversion of Ang I to Ang II. Recently, however, enzymes have been described which are capable of producing Ang II via metabolic pathways independent of the classical renin-angiotensin system route. CONCLUSIONS: At the tissue level, Ang II may still be generated in a patient receiving systemic ACE inhibitor therapy. Ang II blockade at the receptor level may thus be more efficient than ACE inhibition in blocking the undesirable cardiovascular actions of Ang II.

Sympathomimetic amines: potential clinical applications in ischemic heart disease.

Sympathomimetic amines are useful in the treatment of patients with ischemic heart disease complicated by heart failure and shock. These agents influence the cardiovascular system by action on alpha-adrenergic, beta-adrenergic, and dopamine receptors. Recent evidence has demonstrated the existence of subtypes of the classic adrenergic and dopamine receptors that mediate distinct physiologic effects. The relative actions of sympathomimetic amines on these receptors differ substantially, resulting in considerable variation in their cardiac and peripheral vascular effects. Two classes of sympathomimetic amines are being intensively investigated at present: (1) compounds acting predominantly on beta 1-adrenergic receptors (i.e., they increase cardiac contractile force with little or no peripheral vascular effects) and (2) compounds acting on both beta 1-adrenergic and dopamine receptors. Orally active compounds of these two classes have been synthesized recently and are now under study for the treatment of patients with heart failure. Results of preliminary studies with such components are briefly reviewed.

The use of levodopa, an oral dopamine precursor, in congestive heart failure.

The successful treatment of congestive heart failure with intravenous dopamine in the acute setting has prompted investigation into the development and use of oral dopamine analogs. The administration of dopamine can lead to an improvement in myocardial pump performance through a combination of afterload reduction and augmented contractile state. The ingestion of levodopa, an oral dopamine precursor, is associated with sustained hemodynamic and clinical improvement in patients with congestive heart failure. Improvements in hemodynamic performance correlated with the generation of substantial amounts of dopamine. Current research efforts are directed at developing oral dopamine analogs that exhibit improved bioavailability and do not traverse the blood-brain barrier.

Role of dopamine receptors and the utility of dopamine agonists in heart failure.

The existence of two dopamine receptor subtypes (DA1 and DA2) has been firmly established. Activation of DA1 receptors is associated with vasodilation, primarily in the renal, mesenteric, cerebral, and coronary arterial beds, and a natriuresis. DA2 receptors located on postganglionic sympathetic nerves and sympathetic ganglia mediate a decrease in the release of norepinephrine from sympathetic nerve terminals. The DA receptor activity of dopamine (which activates beta 1- and alpha-adrenoceptors as well as DA receptors) plays a prominent role in determining the beneficial hemodynamic responses to this drug in patients with heart failure. As a result, recent research efforts have been directed toward the development of dopamine analogues, which are orally effective and exhibit more selective agonist activity at DA receptors. Limited clinical experience in heart failure is now available for analogues with different spectra of receptor activity than dopamine, including selective DA1 and DA2 agonists. A review of these data is presented with an attempt to define the clinical relevance of the DA receptor-agonist properties of the compounds. Although the results of early clinical studies with some of these first-generation dopamine congeners are encouraging, analysis of ongoing large-scale placebo-controlled trials will provide valuable insight into their utility as therapeutic agents for patients with heart failure.

Contractile actions of racemic and d-propranolol on isolated canine mesenteric and coronary arteries.

This investigation was undertaken to determine whether propranolol exerts a direct vasoconstriction action which contributes to the increased systemic and regional vascular resistance observed after its acute administration. Helically cut strips of canine mesenteric and coronary arteries were exposed to cumulative concentrations of racemic propranolol, d-propranolol, metoprolol and sotalol. Racemic and d-propranolol were equipotent in eliciting concentration-related increments in tension in the mesenteric (3 x 10(-6)-3 x 10(-5) M) and coronary (3 x 10(-7)-3 x 10(-5) M) arterial strips. Metoprolol and sotalol did not cause contractions in concentrations up to 10(-4) M. Phenoxybenzamine, 10-(-6) M, did not alter the contractile responses elicited by racemic and d-propranolol. Upon exposure of mesenteric strips to calcium-free media or 10(-6) M verapamil, the contractile responses to propranolol (3 x 10(-5) M) and KCl (30 mM) were markedly reduced (not significantly different), whereas norepinephrine (10(-6) M)-induced responses were inhibited to a significantly lesser degree. In coronary arteries exposed to calcium-free media or 10(-6) M verapamil, the responses to propranolol, KCl and methoxamine (10(-5) M) were all extensively decreased (not significantly different). These results indicate that propranolol exerts a direct contractile effect on canine mesenteric and coronary arteries, which is unrelated to its beta adrenergic blocking activity and is not mediated through action on alpha adrenergic receptors. The propranolol-induced contraction appears to be associated predominantly with an influx of calcium ion.

Metabolic responses to exercise in patients with heart failure.

Metabolic and hemodynamic responses to exercise were evaluated in 10 patients with chronic congestive heart failure. We utilized an exercise protocol in which the work rate was increased continuously and oxygen uptake (VO2) kinetics were characterized by linear, first-order dynamics. VO2 at peak exercise (VO2max) was depressed at 12.8 +/- 2.3 ml/min/kg and the anaerobic threshold occurred at 63 +/- 10% of the VO2max. A significant correlation was observed between the VO2 at the anaerobic threshold and the resting cardiac index (r = .74, p less than .05). Ventilation-perfusion relationships improved during exercise, despite the presence of a widened alveolar-arterial gradient in oxygen tension and elevation of the physiologic dead space/tidal volume ratio. At peak exercise, a large breathing reserve (maximal voluntary ventilation-minute ventilation), a decline in arterial carbon dioxide tension, and a slight increase in arterial oxygen tension were observed. Plasma epinephrine levels at peak exercise correlated directly with VO2max (r = .74, p less than .05). Thus, although disturbances in ventilation-perfusion relationships occur in association with heart failure, exercise is not limited by an impairment in pulmonary function. The glycogenolytic action of epinephrine may play an important role in determining peak exercise capacity since glycogen stores are increasingly utilized at work rates above the anaerobic threshold.

Role of adrenoceptors and dopamine receptors in modulating left ventricular diastolic function.

Although both dopamine and dobutamine are potent positive inotropic agents, multiple studies indicate that dopamine may produce a rise in left ventricular (LV) filling pressure, while dobutamine often has the opposite effect. To ascertain the pharmacological and hemodynamic mechanisms responsible for the elevation in LV filling pressure observed with dopamine, we administered incremental infusions (2, 4, and 6 micrograms/kg/min) of dopamine to 18 open-chest, anesthetized dogs in the presence and absence of rauwolscine (selective alpha 2-adrenoceptor antagonist) (n = 7), terazosin (selective alpha 1-antagonist) (n = 6), and domperidone (selective dopamine2 antagonist) (n = 5), while measuring pressures in the LV and left atrium and changes in dimension in the LV short-axis (with ultrasonic piezo crystals). Dobutamine (2, 4, and 6 micrograms/kg/min) was infused in five additional dogs before and after administration of rauwolscine. The time constant of isovolumic pressure decay, peak lengthening rate (mm/sec), LV end-diastolic pressure, and diastolic pressure-dimension relation were computed. A significant elevation in LV end-diastolic pressure and a parallel increase in LV end-diastolic chamber size was observed with dopamine, while a decline in LV end-diastolic pressure occurred with dobutamine. Yet both dopamine and dobutamine caused a dose-related acceleration of pressure decay and augmentation of peak lengthening rate. Furthermore, heart rate declined during the administration of dopamine but rose with dobutamine. In the presence of either rauwolscine or terazosin, dopamine infusion resulted in a positive chronotropic effect and dose-dependent reductions in LV end-diastolic pressure and end-diastolic chamber dimension; arterial pressure fell only after terazosin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic mechanisms governing hemodynamic responses to positive inotropic therapy in patients with dilated cardiomyopathy.

Clinical trials in patients with dilated cardiomyopathy (DCM) have shown a wide disparity in the hemodynamic responses to positive inotropic therapy. In addition, the response of the failing left ventricle to positive inotropic agents reflects the net interaction of multiple factors, including the magnitude of contractile abnormality and compensatory mechanisms. In the current study, left ventricular geometry, loading conditions, and contractile state were assessed in 13 patients with nonischemic DCM with the use of simultaneous high-fidelity pressure measurements and echocardiographic recordings. Comparisons were made with echocardiographic and calibrated carotid pulse data acquired in nine age-matched normal subjects. The patients with DCM were divided according to the left ventricular end-diastolic wall thickness-to-dimension ratio into groups with "appropriate" hypertrophy (i.e., less than or equal to 2 SDs from mean normal; n = 5; group 1) and "inadequate" hypertrophy (i.e., greater than 2 SDs from mean normal; n = 8; group 2). Age, New York Heart Association functional class, left ventricular wall mass index, and left ventricular end-diastolic pressure and dimension were similar for the DCM groups. Baseline left ventricular afterload (defined as circumferential end-systolic wall stress, sigma es) was 168% and 203% greater than normal in groups 1 and 2, respectively. The administration of the beta-adrenoceptor agonist dobutamine decreased left ventricular afterload by 12% in the normal subjects and by 10% in group 1 patients, while augmenting afterload by 5% in group 2 patients. The latter response occurred despite a 17% fall in systemic vascular resistance. Overall left ventricular performance, as assessed by the rate-corrected mean velocity of fiber shortening (Vcfc), was related to left ventricular afterload (i.e., sigma es). The resultant sigma es -Vcfc relationship, a sensitive measure of left ventricular contractility, was determined over a wide range of afterload conditions generated by methoxamine (normal subjects) or nitroprusside (DCM). Baseline left ventricular contractile state was 61% of normal for group 1 and 44% of normal for group 2. The contractile response to dobutamine infusion was 52% of normal for group 1 and only 22% of normal for group 2. Thus, positive inotropic therapy with dobutamine in patients with DCM is limited by (1) an attenuated contractile response and (2) elevated left ventricular afterload, which may be augmented further during its administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of long-term therapy with oral ibopamine on resting hemodynamics and exercise capacity in patients with heart failure: relationship to the generation of N-methyldopamine and to plasma norepinephrine levels.

N-Methyldopamine (epinine), one of the few modifications of the dopamine (DA) molecule that retains agonist activity at the DA1 receptor, was administered orally as the diisobutyric ester, ibopamine (100, 200, and 300 mg), to 15 patients with congestive heart failure. An increase in cardiac index and decline in systemic vascular resistance was observed with each dose, and these hemodynamic effects persisted for 3 to 6 hr. Small transient increments in right atrial and pulmonary capillary wedge pressures occurred 0.5 hr after ingestion of 200 and 300 mg of ibopamine, but these pressures returned to baseline or lower levels within 30 min. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of epinine peaked 0.5 hr after administration of drug and then declined to minimal levels at 3 hr. Ten patients enrolled in a trial to evaluate the efficacy of long-term therapy with ibopamine; after 8 weeks of treatment, the initial hemodynamic responses to the drug were attenuated and no significant improvement in oxygen uptake at peak exercise was observed. A decline in plasma norepinephrine concentrations, which could be attributed to activation of alpha 2-adrenoceptors and/or DA2 receptors on sympathetic nerves, was observed after initial administration of ibopamine and persisted after long-term drug ingestion; no long-term hemodynamic benefit could be ascribed to the reduction in sympathetic activity.