Early impairment of renal hemodynamic reserve in patients with asymptomatic heart failure is restored by angiotensin II antagonism.

BACKGROUND: The early/asymptomatic stages of heart failure (HF) are characterized by sodium retention secondary to derangement of sodium reabsorption at the proximal nephron level. Because this phenomenon is reversed by ACE inhibition, abnormalities of renal sodium handling may depend on intrarenal changes of angiotensin II (AII)/nitric oxide (NO) levels. Renal hemodynamic reserve (ie, the glomerular vasodilatory response to amino acid infusion) has been proposed as a reliable test to assess in vivo AII/NO balance. METHODS AND RESULTS: In this study, the effects of 6 weeks of treatment with 5 mg/d of enalapril or with 50 mg/d of losartan on systemic hemodynamics and renal function were assessed, at baseline and after amino acid infusion (AA), in patients with mild HF (NYHA class I) and in healthy volunteers. Untreated HF patients showed a basal renal function comparable to that of healthy subjects. After AA, glomerular filtration rate and renal plasma flow significantly increased in healthy subjects (+29.0% and +30.4%, respectively), whereas no vasodilatory response was observed in HF. Although they did not affect basal renal hemodynamics, both enalapril and losartan restored a normal response to AA in HF patients. Blood pressure and heart rate were comparable in HF subjects and healthy subjects at baseline and were not modified by either treatment. Left ventricular ejection fraction was depressed in HF but did not change after either drug. Urinary excretions of cGMP and nitrate (indexes of NO activity in the kidney), comparable in healthy subjects and in HF patients, were unchanged by either enalapril or losartan and did not correlate with renal reserve. CONCLUSIONS: (1) Renal functional reserve is absent in patients with early/asymptomatic HF and normal renal function and (2) both enalapril and losartan restore a normal vasodilatory response to AA in these patients without affecting basal systemic and renal hemodynamics. These data suggest a major role of AII in the development of early abnormalities in patients with HF.

Impaired vasorelaxant responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats.

BACKGROUND: We have previously shown that a locus on rat chromosome 5, termed STR 2, co-localizes with the genes encoding atrial natriuretic and brain natriuretic peptides, and is closely linked to the development of strokes in rats of a F2 hybrid cohort obtained by crossing stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats. We also demonstrated that there are significant differences in vascular functioning that are co-segregated with stroke latency of stroke-prone spontaneously hypertensive rats. OBJECTIVE: To investigate the vascular responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats. DESIGN AND METHODS: In view of the important vasoactive properties of natriuretic peptides, we tested the vascular responses to 10(-11)-10(-9) mol/l atrial natriuretic peptide and to 10(-11)-10(-7) mol/l brain natriuretic peptide in isolated rings of aortas and internal carotid arteries obtained from stroke-prone and stroke-resistant spontaneously hypertensive rats. The 6-week-old rats were exposed for 4 weeks either to their regular diet (n = 15 of both strains) or to the stroke-permissive Japanese-style diet (n = 14 of both strains). A group of 14 normotensive, age-matched and sex-matched Wistar-Kyoto rats was also studied. RESULTS: Systolic blood pressures in stroke-prone and stroke-resistant spontaneously hypertensive rats were similar, and were significantly higher than those in Wistar-Kyoto rats. Vascular responses to nitroglycerin, atrial natriuretic peptide, and brain natriuretic peptide in rats of the two hypertensive strains and in Wistar-Kyoto rats fed their regular diet were comparable. In contrast, the vasorelaxant responses to atrial natriuretic peptide in stroke-prone spontaneously hypertensive rats fed Japanese diet were lower both in aortas and in internal carotid arteries than were those in spontaneously hypertensive rats (both P < 0.05 by analysis of variance) and in Wistar-Kyoto rats (both P < 0.05). Similarly, vasorelaxant responses to brain natriuretic peptide were lower both in aortas and in internal carotid arteries of stroke-prone spontaneously hypertensive rats than they were in spontaneously hypertensive rats (both P < 0.05) and in Wistar-Kyoto rats (P < 0.05). The responses to nitroglycerin in the stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats fed Japanese-style diet were also similar. CONCLUSION: The vasorelaxant effects of natriuretic peptides are impaired in stroke-prone spontaneously hypertensive rats. This abnormality could play a role in the pathogenesis of stroke incidence in this hypertensive model.

Intrarenal determinants of sodium retention in mild heart failure: effects of angiotensin-converting enzyme inhibition.

The onset and the mechanisms leading to Na+ retention in incipient congestive heart failure (CHF) have not been systematically investigated. To investigate renal Na+ handling in the early or mild stages of CHF, Na+ balance and renal clearances were assessed in 10 asymptomatic patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (HF) off treatment (left ventricular ejection fraction, 29.7+/-2%) and in 10 matched normal subjects during a diet containing 100 mmol/d of NaCl and after 8 days of high salt intake (250 mmol/d). Six patients were studied again after 6 weeks of treatment with enalapril (5 mg/d P.O.). At the end of the high salt diet, in patients with mild HF the cumulative Na+ balance exceeded by 110 mmol that of normal subjects (F=3.86, P<.001). During high salt intake, renal plasma flow and glomerular filtration rate were similarly increased in both normal subjects and mild HF patients. In spite of comparable increases of filtered Na+ in the two groups, fractional excretion of Na+, fractional clearance of free water, and fractional excretion of K+ (indexes of distal delivery of Na+) increased in normal subjects and were reduced in patients with mild HF. During enalapril treatment, in the mild HF patients the cumulative Na+ balance was restored to normal; furthermore, enalapril significantly attenuated the abnormalities in the distal delivery of Na+. Our results indicate that a defective adaptation of Na+ reabsorption in the proximal nephron is associated with Na+ retention in response to increased salt intake in the early or mild stages of HF. These abnormalities of renal Na+ handling are largely reversed by enalapril.

Transition from asymptomatic left ventricular dysfunction to congestive heart failure.

One of the main goals of modern management and care of heart failure is to prevent the disease to progress toward congestion and death. The achievement of such an objective may, in fact, guarantee a sufficient quality of life and reduce the exposure of patients to the most common life-threatening complications associated with the congestive stage of the disease. Early identification of left ventricular dysfunction as well as a better knowledge of the mechanisms that favor the progression to more advanced stages of heart failure are fundamental requirements for the proper treatment of asymptomatic heart failure and for preventing the transition to symptomatic and more severe heart failure. The authors reviewed the literature on this topic, with emphasis on a series of studies they performed, to characterize the pathophysiologic profile of mild heart failure and the mechanisms that are possibly involved in the progression to congestive heart failure.

Radionuclide monitoring of cardiac adaptations to volume loading in patients with dilated cardiomyopathy and mild heart failure. Effects of angiotensin-converting enzyme inhibition.

BACKGROUND: Cardiac adaptations to volume overload have been poorly investigated in heart failure. The aim of this study was to assess dynamic left ventricular responses to acute volume loading by continuous radionuclide monitoring in patients with asymptomatic to mildly symptomatic left ventricular dysfunction. METHODS AND RESULTS: Left ventricular end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), and peak filling rate (PFR) were monitored by a radionuclide detector (Vest) before and during volume expansion (sodium chloride, 0.9%, 0.25 mL.kg-1.min-1 for 2 hours) in 10 patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (New York Heart Association class I or II, ejection fraction < 50%). The patients were studied off treatment and after 6 to 8 weeks of oral treatment with enalapril (5 mg/d). A control group of 11 age- and sex-matched healthy volunteers (N group) was also studied. In the N group, volume loading caused prompt and sustained increases of EDV, EF, and PFR (all P < .001), whereas ESV was progressively reduced (P < .001), and heart rate and blood pressure did not change. In contrast, in DCM, EDV showed a smaller increase than in the N group (two-way ANOVA: F = 5.98, P < .001), ESV increased (P < .001), and EF and PFR remained unchanged. After enalapril, the cardiac adaptations to volume loading were restored to normal. In particular, EDV, EF, and PFR increased (P < .001), and ESV was reduced (P < .001). In 6 additional DCM patients studied before and after 6 to 8 weeks of placebo treatment, left ventricular responses to volume loading remained unchanged. CONCLUSIONS: Left ventricular dynamic adaptations to acute volume loading are compromised in patients with idiopathic DCM and mild heart failure. These impaired responses are ameliorated by treatment with enalapril.

Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure.

BACKGROUND: Sodium retention and hormonal activation are fundamental hallmarks in congestive heart failure. The present study was designed to assess the ability of patients with asymptomatic to mildly symptomatic heart failure and no signs or symptoms of congestion to excrete ingested sodium and to identify possible early abnormalities of hormonal and hemodynamic mechanisms related to sodium handling. METHODS AND RESULTS: The effects of a high salt diet (250 mEq/day for 6 days) on hemodynamics, salt-regulating hormones, and renal excretory response were investigated in a balanced study in 12 untreated patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (NYHA class I-II, ejection fraction < 50%) (HF) and in 12 normal subjects, who had been previously maintained a 100 mEq/day NaCl diet. In normal subjects, high salt diet was associated with significant increases of echocardiographically measured left ventricular end-diastolic volume, ejection fraction, and stroke volume (all P < .001) and with a reduction of total peripheral resistance (P < .001). In addition, plasma atrial natriuretic factor (ANF) levels increased (P < .05), and plasma renin activity and aldosterone concentrations fell (both P < .001) in normals in response to salt excess. In HF patients, both left ventricular end-diastolic and end-systolic volumes increased in response to high salt diet, whereas ejection fraction and stroke volume failed to increase, and total peripheral resistance did not change during high salt diet. In addition, plasma ANF levels did not rise in HF in response to salt loading, whereas plasma renin activity and aldosterone concentrations were as much suppressed as in normals. Although urinary sodium excretions were not significantly different in the two groups, there was a small but systematic reduction of daily sodium excretion in HF, which resulted in a significantly higher cumulative sodium balance in HF than in normals during the high salt diet period (P < .001). CONCLUSIONS: These results show a reduced ability to excrete a sodium load and early abnormalities of cardiac and hemodynamic adaptations to salt excess in patients with mild heart failure and no signs or symptoms of congestion.

Effects of angiotensin converting enzyme inhibitors on left ventricular hypertrophy.

It is well known that, in patients with essential hypertension, left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular disease. However, it has been demonstrated that normalisation of arterial pressure, by therapy with antihypertensive drugs, is associated with regression of LVH, although the extent and time-course of this phenomenon depend on the antihypertensive drug used. In particular, angiotensin converting enzyme (ACE) inhibitors seem capable of inducing a faster and more complete reversal of LVH in patients with essential hypertension than other antihypertensive drugs. The mechanisms underlying this property of ACE inhibitors remain unclear, although 2 features of ACE inhibitors may be particularly relevant. The first is their ability to improve large artery compliance, this being a major determinant of LVH. Arterial compliance is reduced in essential hypertension, resulting in increased left ventricular end-systolic stress, which then contributes to the development of LVH. The second possible mechanism by which ACE inhibitors reverse LVH to a greater degree than other antihypertensive drugs may relate to their ability to interfere with the cardiopulmonary receptor control of the circulation. Thus, ACE inhibitors may counteract the neural and hormonal abnormalities that contribute to the maintenance of LVH in hypertensive patients.

Angiotensin converting enzyme inhibition restores cardiac and hormonal responses to volume overload in patients with dilated cardiomyopathy and mild heart failure.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibition exerts a favorable effect on the response to exercise in heart failure. This study was planned to define the influence of ACE inhibition on the adaptation to volume overload. METHODS AND RESULTS: We studied the hemodynamic, hormonal, and renal responses to acute volume expansion (sodium chloride, 0.9%, 0.25 ml.kg-1.min-1 for 2 hours) in patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (New York Heart Association class I or II, ejection fraction < or = 50%). The patients were studied without any pretreatment (n = 14) or after 1 week of treatment with the oral ACE inhibitor quinapril at a dosage of 10 mg/day (n = 11). Seven patients were studied during constant intravenous infusion with nitroglycerin (0.1 micrograms.kg-1.min-1). The study groups had similar hemodynamic and clinical characteristics and hormonal profile at baseline evaluation. In the untreated patients, volume expansion did not increase left ventricular end-diastolic volume measured by echocardiography and was associated with a reduction in ejection fraction (p < 0.05) and with a paradoxical increase in forearm vascular resistance (p < 0.05) estimated by plethysmography. In addition, plasma atrial natriuretic factor did not change, and plasma norepinephrine was increased by saline loading. In contrast, in the patients treated with quinapril, volume expansion induced an increase of both left ventricular volumes (p < 0.001) without changing ejection fraction and reduced forearm vascular resistance (p < 0.05). In addition, in this group, plasma atrial natriuretic factor levels increased (p < 0.05) and plasma norepinephrine did not change during volume overload. During nitroglycerin infusion, volume expansion was associated with peripheral vasodilatation, increases of left ventricular volumes, and no change in ejection fraction. In this group, however, plasma atrial natriuretic factor levels did not change in response to volume overload. CONCLUSIONS: We conclude that pretreatment with the ACE inhibitor quinapril significantly improves compromised responses to acute isotonic volume overload in patients with dilated cardiomyopathy and mild heart failure. The favorable influence of ACE inhibition on cardiovascular and hormonal responses to volume expansion seems to be related to the cardiac unloading produced by this treatment.

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

To investigate whether the response of atrial natriuretic factor (ANF) to volume expansion is impaired in the early stages of dilated cardiomyopathy, the effects of saline load (SL; 0.25 ml/kg.min for 120 min) were assessed in 12 patients with dilated cardiomyopathy and asymptomatic to mildly symptomatic heart failure (HF) and in nine normal subjects (N). SL increased plasma ANF levels in N (from 14.3 +/- 2 to 19.5 +/- 3 and 26 +/- 4 pg/ml, at 60 and 120 min, respectively, P less than 0.001), but not in HF (from 42.9 +/- 9 to 45.9 +/- 9 and 43.9 +/- 8 pg/ml). Left ventricular end-diastolic volume (LVEDV) and stroke volume were increased (P less than 0.001) by SL in N but not in HF. Urinary sodium excretion (UNaV) increased in N more than in HF during SL, whereas forearm vascular resistance (FVR) did not change in N and increased in HF (P less than 0.001). In five HF patients SL was performed during ANF infusion (50 ng/kg, 5 ng/kg.min) that increased ANF levels from 37.1 +/- 10 to 146 +/- 22 pg/ml. In this group, SL raised both LVEDV (P less than 0.01) and ANF (P less than 0.05), whereas FVR did not rise. In addition, the UNaV increase and renin and aldosterone suppressions by SL were more marked than those observed in HF under control conditions. Thus, in patients with dilated cardiomyopathy and mild cardiac dysfunction, plasma ANF levels are not increased by volume expansion as observed in N. The lack of ANF response is related to the impaired cardiac adaptations. The absence of an adequate increase of ANF levels may contribute to the abnormal responses of HF patients to saline load.

Modulatory role of angiotensin-II in the secretion of atrial natriuretic factor in rabbits.

This study was designed to investigate whether the increase in circulating atrial natriuretic factor (ANF) levels produced by angiotensin II (Ang II) is a consequence of the hemodynamic changes or whether it occurs also in the absence of pressor changes. For this purpose in anesthetized and awake rabbits we evaluated the effects of Ang II (0.1 micrograms/kg.min) alone or during the simultaneous infusion of sodium nitroprusside (NP) at a dose titrated to abolish the pressor effects. Systemic blood pressure increased from 76 +/- 4 to 113 +/- 5 mm Hg (P less than 0.001) during Ang II and from 76 +/- 2 to 75 +/- 3 mm Hg (P = NS) during Ang II plus NP. The alpha-adrenergic agonist phenylephrine, used as a control, raised blood pressure from 65 +/- 2 to 101 +/- 8 mm Hg (P less than 0.001), and its pressor effect was abolished by the concomitant infusion of NP (64 +/- 2 to 61 +/- 1 mm Hg; P = NS). The increase in plasma ANF levels produced by Ang II alone (from 36.5 +/- 5 to 237 +/- 57 pg/ml; P less than 0.001) was not different from that observed during Ang II plus NP (from 46 +/- 10 to 207 +/- 88 pg/ml; P less than 0.001). In contrast, the stimulatory effect on ANF release of phenylephrine (from 56.1 +/- 9 to 202 +/- 40 pg/ml; P less than 0.001) was completely abolished when its pressor effects were prevented by the combined infusion of NP (from 58.5 +/- 15 to 42.3 +/- 10 pg/ml; P = NS). These results show that the stimulatory effect of Ang II on ANF release can be clearly dissociated from its pressor effect, whereas the increase in plasma ANF levels caused by phenylephrine is strictly related to its hemodynamic effect. Therefore, Ang II is capable of modulating ANF secretion in a manner that is independent of its pressor actions. In addition, our results suggest that ANF release is not solely linked to myocyte stretch.

[The early hemodynamic and hormonal changes in patients with left ventricular dysfunction]. / Alterazioni emodinamiche ed ormonali precoci in pazienti con disfunzione ventricolare sinistra.

The aim of this study was to highlight a different hormonal and hemodynamic pattern in patients with mild cardiomyopathy. For this purpose, we studied subjects with mild heart failure (CHF; NYHA class I and II; post-ischemic and idiopathic) who underwent an isotonic saline load (SL) (0.22 ml/kg/min of 0.9% NaCl for 120 min). A second group of age- and sex-matched normal subjects (C) was studied as a control. Basal hormonal and hemodynamic values of the 2 groups differed only in atrial natriuretic factor (ANF), left ventricular end-diastolic diameter and ejection fraction (EF). There were, on the contrary, no differences in basal plasma renin activity (PRA) and plasma aldosterone (PA) values. After SL, in C, percent changes in EF, cardiac output and ANF values were significantly higher than in CHF while total peripheral resistances increased only in CHF but not in C. In both groups there were decrements of PRA and PA, but these responses were significantly higher in C than in CHF. In conclusion, our results show that hormonal, renal and hemodynamic responses to salt/volume load are compromised in the early asymptomatic phase of heart failure. These abnormalities may predict the progressive deterioration of cardiac function, and may indicate appropriate therapeutic interventions since the early phases of the disease.

Effects of atrial natriuretic peptide on glomerular filtration rate in essential hypertension: a radionuclide study.

A number of studies show that atrial natriuretic peptide (ANP) raises renal sodium excretion with a concomitant increase in glomerular filtration rate (GFR) in both experimental animals and normal humans. Studies using indirect evaluation of GFR have provided less consistent results in hypertensive patients. We studied the effects of intravenously administered (iv) alpha-human ANP on GFR in patients with hypertension by a radionuclide technique using technetium 99m diethylenetriaminepenta-acetic acid. In six patients (ANP group), GFR was determined under control conditions, during iv ANP (initial bolus of 0.5 micrograms/kg followed by a 21-min maintenance infusion at 0.05 micrograms.kg-1.min-1) and during a recovery phase. In six other patients (control group), GFR was determined under control conditions, during saline iv infusion and during recovery. The two groups did not differ with respect to age, sex, basal blood pressure, heart rate or GFR. In the ANP group, the infusion of the peptide induced a significant decrease of mean blood pressure (from 133 +/- 5 to 120 +/- 5 mmHg, P less than 0.01), no change in heart rate and a significant increase in GFR (from 104 +/- 4 to 125 +/- 5 ml/min, P less than 0.01). During recovery, blood pressure, heart rate and GFR were not different from the values recorded under control conditions. No changes in blood pressure, heart rate or GFR (from 106 +/- 5 to 108 +/- 5 ml/min, n.s.) were detected during saline infusion in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hormonal control of the endocrine function of the heart]. / Controllo ormonale della funzione endocrina del cuore.

Previous studies demonstrate that high doses of angiotensin II (Ang II) increase the release of ANF from atrial cells but it is not known whether this is a direct effect of Ang II or due to the induced hemodynamic changes. We report the effects of low doses of Ang II (1, 2.5, 5, 10 ng/kg/min) in anesthetized, instrumented dogs after volume load (2.5% body weight) and converting enzyme inhibition. During Ang II infusion we found an increase in mean blood pressure (from 147 +/- 3 to 160 +/- 3 mmHg, p less than 0.05) and arterial ANF (from 32 +/- 6 to 80 +/- 23 fmol/ml, p less than 0.05), while left and right atrial pressures did not change significantly. In a second group of dogs (n = 4) that underwent a similar protocol with the infusion of vehicle alone we failed to find any statistical difference in the above mentioned parameters. The Ang II induced ANF release was not related to the hemodynamic changes. Changes in plasma ANF levels were, in turn, related to the effects of Ang II on hormones and kidney, thus suggesting a role for endogenous ANF. In a separate study we found an increase of ANF production (+129 +/- 18, +176 +/- 46, +210 +/- 66% basal value) from isolated atrial minces exposed to Ang II concentration of 1, 10, and 100 nM, respectively.

Hemodynamic and hormonal effects of atrial natriuretic factor in patients with essential hypertension.

Hemodynamic and hormonal effects of two graded infusions of alpha-human-(1-28)-atrial natriuretic factor (0.5 microgram/kg prime followed by 0.05 microgram/kg per min for 20 minutes and by 0.1 microgram/kg per min for 20 minutes) were evaluated in 13 patients with mild to moderate essential hypertension. The lower dose of atrial natriuretic factor did not change significantly any of the considered variables, although it tended to reduce aortic mean blood pressure (from 132.6 +/- 5.3 to 125.5 +/- 4.6 mm Hg), cardiac index (from 3.67 +/- 0.2 to 3.54 +/- 0.18 liters/min per m2) and forearm vascular resistance (from 178.6 +/- 15 to 148.3 +/- 10 mm Hg/ml per s). The higher dose of atrial natriuretic factor significantly reduced mean aortic pressure (118.6 +/- 5 mm Hg), cardiac index (3.29 +/- 0.16 liters/min per m2) and stroke volume index (from 45.9 +/- 2.6 to 38.9 +/- 3 ml/m2) and slightly decreased pulmonary wedge pressure, whereas both total peripheral resistance and forearm vascular resistance were not modified. With this latter dose a reduction in aortic pressure was observed in all patients at the steady state, and this was associated with a fall in stroke volume index in 10 of the 13 patients and with a reduction in total peripheral resistance in only 6 patients. Heart rate and right atrial and pulmonary pressures did not change during infusion of atrial natriuretic factor. Plasma renin activity was only slightly reduced by atrial natriuretic factor, whereas plasma norepinephrine rose significantly (from 233 +/- 34 to 330 +/- 58 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Vagal mediation of the effects of atrial natriuretic factor on blood pressure and arterial baroreflexes in the rabbit.

We investigated the hemodynamic effect of synthetic atrial natriuretic factor Auriculin A (ANF) and its influence on arterial baroreflex control of heart rate, systemic blood pressure, and perfusion pressure in the hind limb (perfused at constant flow) in rabbits anesthetized with alpha-chloralose and urethane. The neural mechanisms underlying these effects were also studied. In the intact animal, a 45-minute constant infusion of ANF (2 micrograms/kg prime, 0.2 microgram/kg/min) significantly reduced mean blood pressure and increased mean perfusion pressure, while heart rate did not change. Comparable data were obtained with lower (0.5 microgram/kg + 0.05 microgram/kg/min; 1 microgram/kg + 0.1 microgram/kg/min) or higher (4 micrograms/kg + 0.4 microgram/kg/min; 8 micrograms/kg + 0.8 microgram/kg/min) doses of ANF. In addition, ANF enhanced bradycardic reflex responses to phenylephrine i.v. bolus administration, while it did not change baroreflex-mediated responses to nitroglycerin i.v. bolus administration and to 30-second bilateral carotid occlusion. The specificity of the influence of ANF on arterial baroreflex responses was confirmed by the observation that no significant change in reflex responses to phenylephrine or carotid occlusion was detectable during a comparable decrease in blood pressure induced by a constant infusion of nitroglycerin. Bilateral vagotomy prevented both the fall in blood pressure and the increase in perfusion pressure induced by ANF, while cholinergic blockade (atropine, 0.5 mg/kg i.v.) or adrenergic blockade (propranolol, 0.3 mg/kg i.v. + phentolamine, 0.3 mg/kg i.v.) did not modify the hemodynamic response to ANF observed in the intact animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of coronary occlusion on arterial baroreflex control of heart rate and vascular resistance.

This study was planned to assess whether circumflex coronary occlusion (CO) impairs the arterial baroreflex control of heart rate (HR) and hindlimb vascular resistance (HVR), and to determine the mechanisms involved in the mediation of these phenomena. Increasing doses of phenylephrine and nitroglycerin were given intravenously to anesthetized dogs with a constant flow-perfused hindlimb before and during 30-s CO. The reflex responses were assessed by the changes in HR and hindlimb perfusion pressure evoked by changes in arterial pressure following phenylephrine and nitroglycerin administration. During CO, there was an attenuation of the reflex control of HR and HVR as compared with control conditions. The application of lidocaine on the left ventricular epicardial surface was able to prevent the effect of CO on both the baroreflex responses. The intravenous administration of atropine prevented only the impairment in arterial baroreflex control of HR induced by CO. After the injection of phentolamine into the perfused hindlimb, the baroreflex had no effect on HVR either before or during CO. Finally, intravenous administration of propranolol failed to modify the effect of CO on both the baroreflex responses. These data indicate that CO attenuates the arterial baroreflex control of both HR and HVR through the stimulation of left ventricular receptors. The effect on HR is mediated by the parasympathetic system, whereas the effect on HVR is due to sympathetic efferents.

Carotid baroreceptor unloading decreases plasma atrial natriuretic factor in hypertensive patients.

Atrial natriuretic factor (ANF) release is known to be regulated by distension of the atrial wall; other factors affecting ANF secretion have not yet been defined. In order to evaluate the effects of the reflex activation of the sympathetic nervous system on ANF plasma levels, in 11 patients with essential hypertension progressive deactivation of carotid baroreceptors was induced by 4-min graded increases in external neck tissue pressure. Carotid sinus hypotension induced progressive increases in blood pressure (BP), heart rate (HR) and forearm vascular resistance (FVR), while plasma renin activity and catecholamine concentrations did not change significantly. Despite the lack of changes in right atrial pressure during this manoeuvre, plasma ANF levels showed a progressive and significant reduction, which was correlated with the increase in FVR. Although a contribution by other factors cannot be ruled out, our data suggest that the reflex activation of sympathetic nervous system is associated with reduced ANF release, independent of changes in atrial pressure.

Impaired responsiveness of the ventricular sensory receptor in hypertensive patients with left ventricular hypertrophy.

We studied the control of forearm vascular resistance (FVR) by cardiopulmonary receptors in seven patients with hypertension and left ventricular hypertrophy (LVH) and in seven normotensive control subjects. Increasing levels of lower body negative pressure (LBNP) (-10 and -40 mm Hg) induced a progressive decrease in central venous pressure (CVP) and an increase in FVR. The changes in these two variables were correlated both in normal subjects and patients with hypertension (slope for normal subjects = -29.9, for patients with hypertension = -40.3, NS). After propranolol, there was a significant reduction in the increase in FVR induced by -40 mm Hg LBNP in normal subjects (+107 +/- 5 vs +129 +/- 15 mm Hg/ml/sec, p less than .05) but not in patients with hypertension. Consequently, the slope of the delta CVP/delta FVR regression was reduced in normal subjects (-20.6, p less than .01) but not in patients with hypertension. In another seven normal subjects and seven patients with hypertension and LVH we assessed the effects of -10 and -40 mm Hg LBNP on left ventricular filling pressure (LVFP). LBNP induced similar changes in CVP, LVFP, and total peripheral resistance both in normal subjects and in patients with hypertension. Propranolol failed to modify the effects of LBNP on CVP and LVFP in both groups and reduced the response of total peripheral resistance to -40 mm Hg LBNP only in normal subjects. Propranolol did not reduce the response of FVR to the cold pressor test and sustained handgrip or the arterial baroreflex response to the injection of phenylephrine and increased neck tissue pressure. Thus, hypertension-induced LVH seems to be associated with a selective impairment of the left ventricular sensory receptors.