Atrial natriuretic peptide attenuates the reflex sympathetic responses to lower body negative pressure

The authors studied the effect of intravenous infusion of atrial natriuretic peptide (ANP) on the plasma catecholamine and forearm vasoconstrictor responses to cardiopulmonary baroreflex deactivation in six normal, male volunteers in order to determine whether ANP influences reflex forearm vasoconstriction in humans. Unloading of low-pressure cardiopulmonary baroreceptors (CPBR) was accomplished by application of low levels (-10 and -20 mm Hg) of lower body negative pressure (LBNP). The authors measured the plasma norepinephrine (NE) and epinephrine, the mean arterial pressure (MAP), and the forearm vascular resistance (FVR) responses to reflex sympathetic activation by LBNP. ANP infusion (0.1 microgram.kg-1.min-1) decreased (p less than 0.01) basal MAP, as well as plasma renin activity and plasma aldosterone levels (p less than 0.05). ANP infusion also reduced (p less than 0.01) plasma NE responses to both levels of LBNP and tended to decrease both epinephrine and FVR during ANP infusion at -20 mm Hg LBNP (p = 0.8). These data suggest that exogenous ANP inhibits the reflex sympathetic responses that occur with CPBR unloading. The blunted plasma NE responses to CPBR unloading parallel the attenuation of FVR response to LBNP during ANP infusion, despite significant LBNP-induced hypotension.     

Effects of hydrochlorothiazide and diltiazem on reflex vasoconstriction in hypertension

The purpose of our study was to determine the effects of treatment with hydrochlorothiazide (n = 10) or diltiazem (n = 8) on reflex humoral, hemodynamic, and vascular responses to graded lower body negative pressure in subjects with mild to moderate hypertension (supine diastolic pressure, 95-114 mm Hg). All subjects received placebo for 2 to 4 weeks followed by either hydrochlorothiazide (25-50 mg b.i.d.) or diltiazem (120-180 mg b.i.d.) to achieve a reduction in supine diastolic pressure of 10 mm Hg or more and a final pressure below 90 mm Hg. Mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and renin responses to graded lower body negative pressure (-10, -20, -40 mm Hg) and head-up tilt were examined before and after 12 weeks of treatment with either drug. Pretreatment basal values of mean arterial pressure (114 +/- 2 vs 117 +/- 2 mm Hg), forearm vascular resistance (29 +/- 3 vs 35 +/- 7 units), and plasma renin activity (0.7 +/- 0.2 vs 0.6 +/- 0.2 ng angiotensin I/ml/hr) were not significantly different between groups. There were no significant differences in basal plasma norepinephrine or in the increases of norepinephrine in response to lower body negative pressure before and after treatment in either group. Forearm vascular resistance responses to lower body negative pressure were virtually abolished in the diltiazem-treated group but not in the hydrochlorothiazide-treated group despite similar levels of mean arterial pressure and basal forearm vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Blunted sympathetic response to cardiopulmonary receptor unloading in hypertensive patients with left ventricular hypertrophy. A possible compensatory role of atrial natriuretic factor

To investigate whether or not hypertension with left ventricular hypertrophy (LVH) modifies the mechanisms underlying the vascular adjustments to orthostatic stress, we evaluated the hemodynamic and hormonal effects of graded lower-body negative pressure (LBNP) (-10 and -40 mm Hg) before and after sympathetic blockade in 10 hypertensive patients with LVH and in five age- and sex-matched normotensive subjects. In control conditions, LBNP elicited comparable vasoconstrictor responses in the forearm in the two groups. In normotensive subjects, graded increases in plasma norepinephrine and plasma renin activity (PRA) and reductions in plasma immunoreactive atrial natriuretic factor (irANF) were recorded. In hypertensive patients, a significant increase in plasma norepinephrine and plasma renin activity was obtained only with the higher level of LBNP, whereas irANF plasma levels decreased progressively. In both groups, sympathetic blockade abolished the increase in plasma renin activity and did not modify the changes in plasma irANF induced by both levels of LBNP in control conditions. The vascular response to -10 mm Hg LBNP remained unchanged after sympathetic blockade in both groups. However, after sympathetic blockade, the vasoconstrictor response to -40 mm Hg LBNP in normal subjects was no longer different from that elicited by -10 mm Hg LBNP, whereas in hypertensive patients the vasoconstrictor response was still significantly higher than that induced by -10 mm Hg LBNP. Direct correlations between the percent changes in forearm vascular resistance and those in plasma norepinephrine and plasma renin activity were found only in normal subjects in control conditions but were not observed after sympathetic blockade. On the contrary, the inverse correlation between changes in irANF plasma levels and in forearm vascular resistance found in control conditions in both groups was still observed after sympathetic blockade. In a separate group of hypertensive patients with left ventricular hypertrophy, exogenous infusion of ANF induced an increase in venous irANF plasma levels of the same magnitude of the decrease evoked by LBNP and significantly reduced forearm vascular resistance. These data show that in hypertensive patients with left ventricular hypertrophy, sympathetic activation does not contribute to the vascular response to cardiopulmonary receptor unloading (-10 mm Hg LBNP). They also suggest that in these patients inhibition of ANF secretion may play a role in the response to a low level of LBNP so that the peripheral vasoconstriction induced by cardiopulmonary receptor unloading is comparable to that observed in normal subjects despite the lack of appropriate sympathetic reflex vasoconstriction.     

Effects of diltiazem on hormonal and hemodynamic responses to lower body negative pressure and tilt in patients with mild to moderate systemic hypertension

Mean arterial blood pressure, forearm vascular resistance, plasma norepinephrine, plasma renin activity and aldosterone responses to graded lower body negative pressure and tilt at 80 degrees were examined in 10 men with mild to moderate essential hypertension before and after 12 weeks of diltiazem (240 to 360 mg/day) therapy. Diltiazem therapy lowered basal supine systolic and diastolic blood pressures without affecting basal heart rate. Mean arterial blood pressure and forearm vascular resistance were decreased from 114 +/- 1.5 to 105 +/- 1 mm Hg, p less than 0.01 and from 29.3 +/- 3.5 to 18.9 +/- 2.1 units, p less than 0.01, respectively. Diltiazem therapy had no effect on basal supine levels of norepinephrine, plasma renin activity or aldosterone, nor on the responses of these hormones to lower body negative pressure. Diltiazem did decrease the forearm vascular resistance responses to lower body negative pressure and tilt. Diltiazem abolished an orthostatic increase (10 +/- 0.3 mm Hg) in mean arterial blood pressure and this was associated with a greater plasma norepinephrine response to tilt. These results suggest that diltiazem decreases vascular resistance through a reduction in the postjunctional effects of norepinephrine on vascular smooth muscle.     

Relationship of cardiac chamber volume to baroreflex activity in normal humans

The objectives of this study were to examine the effect of incremental lower body negative pressure (LBNP) on cardiac chamber volume and assess the relationship between cardiac chamber volume and baroreflex activation of the neurohormonal axis. Accordingly, echocardiographic determination of cardiac chamber volume and neurohormonal responses were studied in 14 normal subjects during incremental LBNP. LBNP -10 mm Hg decreased left atrial diameter and left ventricular systolic volume index, but did not alter heart rate, systolic or pulse pressure, or stroke volume. During LBNP -10 mm Hg, plasma norepinephrine levels increased, suggesting activation of the sympathetic nervous system. LBNP -40 mm Hg caused a significant decrease in left atrial diameter and left ventricular systolic, diastolic, and stroke volume indices. During LBNP -40 mm Hg, heart rate increased, and systolic and pulse pressure fell. With this more negative level of LBNP, norepinephrine, angiotensin II, aldosterone, and arginine vasopressin concentrations and PRA all increased. The findings that left atrial diameter decreased and plasma norepinephrine concentration increased during LBNP -10 mm Hg suggest that the sympathetic nervous system is sensitive to changes in atrial receptor activity. At higher levels of LBNP (-40 mm Hg), activation of the renin-angiotensin system and release of vasopressin were associated with a fall in left ventricular diastolic volume as well as a decrease in the pressure input to the arterial baroreceptors. Under this condition, the differential contribution of the cardiopulmonary and arterial baroreceptors to the regulation of the renin-angiotensin system and vasopressin release cannot be distinguished.     

Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.     

The acute response of plasma norepinephrine, renin activity, and arginine vasopressin to short-term nitroprusside and nitroprusside withdrawal in patients with congestive heart failure

Activation of the sympathetic nervous system, manifested by an increase in heart rate and circulating plasma norepinephrine, can occur in normal subjects when they are given vasodilators. The extent to which this activation occurs in patients with congestive heart failure (CHF) and whether this activation could account for the hemodynamic rebound sometimes observed following abrupt withdrawal of nitroprusside in such patients are unclear. We prospectively and retrospectively studied the effects of nitroprusside on plasma norepinephrine in 38 patients with CHF to determine if acute vasodilator therapy activates this vasoconstrictor system during or following such treatment. Thirty-six of these patients also had plasma renin activity (PRA) measured and plasma arginine vasopressin was measured in 12 patients. Baseline supine plasma norepinephrine (714 +/- 72 pg/ml, +/- SEM), PRA (15 +/- 2 ng/ml/hr), and arginine vasopressin (10 +/- 1 pg/ml) were increased at least twofold in the CHF patients. Nitroprusside (96 +/- 11 micrograms/min) was infused for 63 +/- 5 minutes after achieving an optimal hemodynamic response: cardiac index increased (2.01 +/- 0.08 to 2.67 +/- 0.1 L/min/m2, p less than 0.001), pulmonary artery wedge pressure decreased (25 +/- 1 to 16 +/- 1 mm Hg, p less than 0.001), mean arterial pressure decreased (83 +/- 1 to 72 +/- 1 mm Hg, p less than 0.001), and heart rate was unchanged. Plasma norepinephrine (632 +/- 43 pg/ml), PRA (18 +/- 3 ng/ml/hr), and arginine vasopressin (11 +/- 1 pg/ml) did not change significantly for the group during peak effect of the vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for structural alterations in resistance arteries of patients with severe congestive heart failure.

Congestive heart failure (CHF) is characterized by an increase in total peripheral resistance. It was the specific aim of this study to investigate whether structural factors participate in the increased peripheral resistance that can be observed in severe heart failure. We determined forearm vascular resistance (FVR) at rest and after 10 min ischemia (Rmin; mm Hg/ml/min/100 ml) using venous occlusion plethysmography. Rmin was studied since it is largely dependent on the structural characteristics of resistance arteries. 24 patients with CHF [71.5 +/- 2.3 years; New York Heart Association (NYHA) functional class I-IV] with no history of arterial hypertension and casual arterial blood pressure < 140/90 mm Hg and 24 normotensive healthy control subjects (52.5 +/- 4.1 years) were included in our study. The patients were subdivided into those with 'mild' (NYHA class I and II; n = 10) and 'severe' (NYHA class III and IV; n = 14) heart failure. There were no significant differences between the two groups for echocardiographically determined ejection fraction and mean arterial blood pressure. Resting FVR averaged 40.5 +/- 4.4 mm Hg/ml/min/100 ml in control subjects and was 43.6 +/- 7.9 (nonsignificant vs. control) and 51.0 +/- 5 mm Hg/ml/min/100 ml (p < 0.05 vs. control) in patients with mild and severe CHF, respectively. No significant correlation between age and Rmin could be demonstrated in either the patient or the control group. Furthermore, Rmin did not differ between patients with mild CHF and control subjects. However, Rmin was significantly elevated in patients with severe CHF (5.7 +/- 0.39 mm Hg/ml/min/100 ml) as compared to patients with mild CHF (4.0 +/- 0.39 mm Hg/ml/min/100 ml; p < 0.05) and controls (4.5 +/- 0.26 mm Hg/ml/min/100 ml; p < 0.05). In conclusion, our study supports the concept that structural alterations contribute to the increased peripheral resistance in patients with heart failure. These changes are correlated with the severity of clinical symptoms.     

Norepinephrine and forearm vascular resistance responses to tilt and cold pressor test in essential hypertension: effects of aging

Heart rate, blood pressure, forearm vascular resistance (FVR), and catecholamine and renin responses to head-up tilt at 80 degrees and cold pressor test were investigated in 15 hypertensive men aged less than fifty-five (mean 44 +/- 7 years; M +/- SD) and 13 similarly hypertensive men aged more than fifty-five (mean 62 +/- 4 years; M +/- SD). Baseline plasma norepinephrine levels, as well as norepinephrine responses to tilt and cold pressor stress, were similar in the two groups, suggesting a lack of age-related increase in plasma norepinephrine (NE) responses in patients with essential hypertension. Normalized FVR responses (% change) to tilting (28 +/- 21 vs 95 +/- 36; M +/- SE) and cold pressor test (33 +/- 12 vs 64 +/- 21; M +/- SE) were significantly less (p less than 0.01) in older hypertensives. These results, but not the plasma NE responses to reflex sympathetic activation by tilt and cold pressor testing in older hypertensives, suggest an impaired forearm vasoconstriction.     

Renal denervation does not abolish sustained baroreflex-mediated reductions in arterial pressure

Recent studies indicate that suppression of renal sympathetic nerve activity and attendant increments in renal excretory function are sustained baroreflex-mediated responses in hypertensive animals. Given the central role of the kidneys in long-term regulation of arterial pressure, we hypothesized that the chronic blood pressure-lowering effects of the baroreflex are critically dependent on intact renal innervation. This hypothesis was tested in 6 dogs by bilaterally activating the carotid baroreflex electrically for 7 days before and after bilateral renal denervation. Before renal denervation, control values for mean arterial pressure and plasma norepinephrine concentration were 95+/-2 mm Hg and 96+/-12 pg/mL, respectively. During day 1 of baroreflex activation, mean arterial pressure decreased 13+/-1 mm Hg, and there was modest sodium retention. Daily sodium balance was subsequently restored, but reductions in mean arterial pressure were sustained throughout the 7 days of baroreflex activation. Activation of the baroreflex was associated with sustained decreases in plasma norepinephrine concentration ( approximately 50%) and plasma renin activity (30% to 40%). All of the values returned to control levels during a 7-day recovery period. Two weeks after renal denervation, control values for mean arterial pressure, plasma norepinephrine concentration, plasma renin activity, and sodium excretion were comparable to those measured when the renal nerves were intact. Moreover, after renal denervation, all of the responses to activation of the baroreflex were similar to those observed before renal denervation. These findings demonstrate that the presence of the renal nerves is not an obligate requirement for achieving long-term reductions in arterial pressure during prolonged activation of the baroreflex.     

Impaired control of vasopressin release in hypertensive subjects with cardiac hypertrophy

The effects of graded lower body negative pressure (-10 and -40 mm Hg) on vascular resistance and plasma vasopressin, norepinephrine, and renin activity were assessed in seven hypertensive subjects with left ventricular hypertrophy and seven sex-matched and age-matched normotensive subjects. In both groups increasing levels of lower body negative pressure induced a progressive decrease in right atrial pressure and an increase in vascular resistance. In normal subjects plasma vasopressin, norepinephrine, and renin activity were progressively raised, whereas only the higher level of stimulation increased plasma renin activity, norepinephrine, and vasopressin in hypertensive subjects. Propranolol induced a significant increase in plasma vasopressin in normal subjects (from 1.3 +/- 0.1 to 2.0 +/- 0.1 pg/ml; p less than 0.05) but not in hypertensive subjects. In this latter condition -10 mm Hg lower body negative pressure failed to increase plasma vasopressin, norepinephrine, and renin activity in normal subjects. Propranolol abolished the change in plasma renin activity in both groups, reduced the increase in vascular resistance induced by -40 mm Hg lower body negative pressure in normotensive subjects, but did not modify the rise in vasopressin elicited by this stimulus in normal subjects or the humoral and hemodynamic reflex responses evoked in hypertensive subjects. These results suggest that cardiopulmonary receptors are involved in the control of vasopressin release in normal subjects, whereas in hypertensive subjects with left ventricular hypertrophy, this control is altered because of an impaired function of cardiopulmonary receptors.     

Effects of renal medullary and intravenous norepinephrine on renal antihypertensive function

Increasing renal arterial pressure activates at least 3 antihypertensive mechanisms: reduced renin release, pressure natriuresis, and release of a putative renal medullary depressor hormone. To examine the role of renal medullary perfusion in these mechanisms, we tested the effects of the infusion of norepinephrine, either infusion into the renal medullary interstitium or intravenous infusion, on responses to increased renal arterial pressure in pentobarbital-anesthetized rabbits. We used an extracorporeal circuit, which allows renal arterial pressure to be set to any level above or below systemic arterial pressure. With renal arterial pressure initially set at 65 mm Hg, intravenous and medullary interstitial norepinephrine (300 ng. kg(-1). min(-1)) similarly increased mean arterial pressure (by 12% to 17% of baseline) and reduced total renal blood flow (by 16% to 17%) and cortical perfusion (by 13% to 19%), but only medullary norepinephrine reduced medullary perfusion (by 28%). When renal arterial pressure was increased to approximately 160 mm Hg, in steps of approximately 65 mm Hg, urine output and sodium excretion increased exponentially, and plasma renin activity and mean arterial pressure fell. Medullary interstitial but not intravenous norepinephrine attenuated the increased diuresis and natriuresis and the depressor response to increased renal arterial pressure. This suggests that norepinephrine can act within the renal medulla to inhibit these renal antihypertensive mechanisms, perhaps by reducing medullary perfusion. These observations support the concept that medullary perfusion plays a critical role in the long-term control of arterial pressure by its influence on pressure diuresis/natriuresis mechanisms and also by affecting the release of the putative renal medullary depressor hormone.     

Impairment of cardiopulmonary baroreflex after cardiac transplantation in humans

There is ample evidence for efferent cardiac denervation in patients after cardiac transplantation. However, little is known regarding the effects of the cardiac deafferentation that also results. We examined responses to graded lower-body negative pressure and thus cardiopulmonary baroreceptor unloading in 23 patients 3 to 12 months after cardiac transplantation and compared their responses with those of nine normal subjects. Responses of mean arterial pressure, forearm vascular resistance, and plasma norepinephrine were assessed during lower-body negative pressure and the cold pressor test. Reflex increases in forearm vascular resistance (1.5 +/- 1, 5.0 +/- 1.4, and 6.4 +/- 2.1 vs 14.5 +/- 4.5, 20.3 +/- 6.5, and 34 +/- 11 units) and plasma norepinephrine (42 +/- 12, 58 +/- 15, and 62 +/- 13 vs 49 +/- 14, 94 +/- 25, and 173 +/- 36 pg/ml) during lower-body negative pressure (at -10, -20, and -40 mm Hg) were strikingly smaller in cardiac transplant patients than in normal subjects. The impaired responses of the cardiac transplant patients were not the result of a nonspecific depression of cardiovascular reflexes, since increases in mean arterial pressure (12 +/- 3 vs 10 +/- 2 mm Hg), forearm vascular resistance (19.5 +/- 3.4 vs 18 +/- 5.8 units), and plasma norepinephrine (56 +/- 8 vs 42 +/- 11 pg/ml) during cold pressor test were not significantly different in the two groups. Furthermore, the impaired responses were not caused by the immunosuppressive agents used to treat the cardiac transplant patients, since patients with renal transplants on similar regimens had augmented forearm vasoconstrictor responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of reducing atrial pressure on atrial natriuretic factor and vasoactive hormones in congestive heart failure secondary to ischemic and nonischemic dilated cardiomyopathy

The effect of an acute and sustained reduction in atrial pressure on atrial natriuretic factor (ANF) and vasoactive hormone secretion was studied in 9 patients with congestive heart failure (CHF). Intravenous nitroglycerin was titrated to reduce the pulmonary artery wedge pressure by 30 to 50% and maintain this reduction for 4 hours. After 60 minutes of nitroglycerin administration, the mean decrement in wedge pressure was 10.0 +/- 1.7 (standard error) mm Hg (35%) and plasma ANF was 65.3 +/- 13.9 pmol/liter (35%). The initial decrease, sustained reduction and later increase in plasma ANF levels closely paralleled the changes in pulmonary arterial wedge (r = 0.94, p less than 0.0001) and right atrial pressures (r = 0.91, p less than 0.0001) during and immediately after the nitroglycerin infusion. Plasma aldosterone and cortisol levels increased during the first 2 hours of the nitroglycerin infusion, but there was little change in plasma norepinephrine or plasma renin activity. Although levels were elevated in CHF, plasma ANF still responded rapidly to changes in atrial pressure. A sustained reduction in pressure produced a sustained reduction in ANF levels. These findings provide further support for a regulatory role of ANF, even in chronic CHF.     

Baroreceptor-mediated release of vasopressin in patients with chronic congestive heart failure and defective sympathetic responsiveness.

In patients with congestive heart failure (CHF), overactivity of the sympathetic nervous system may be accompanied by an impairment of the baroreflex control mechanism. To evaluate the reflex responses of the sympathetic nervous system, the renin-angiotensin system and vasopressin release to baroreceptor unloading, 38 patients with left ventricular dysfunction were studied. Hemodynamic data, and plasma norepinephrine, renin activity and vasopressin concentrations were measured before and 60 minutes after administration of high-dose hydralazine (0.4 mg/kg intravenously). On the basis of blood pressure response to vasodilator administration, patients were divided arbitrarily into those with a decrease in mean arterial blood pressure greater than or equal to 15 mm Hg (group A; n = 12) and those with a decrease less than 15 mm Hg (group B; n = 26) compared with control values. In response to hydralazine, heart rate decreased in group A from 100 to 92 beats/min (p less than 0.001) and increased in group B from 90 to 96 beats/min (p less than 0.05). In group A, hemodynamic changes induced by hydralazine were accompanied by a decrease in plasma norepinephrine from 822 to 518 pg/ml (p less than 0.01) and an increase in plasma vasopressin from 8.4 to 45.2 pg/ml (p less than 0.001). In group B, plasma norepinephrine and vasopressin did not change significantly (407 vs 447, and 8.4 vs 8.3 pg/ml, respectively). Plasma renin activity remained unchanged in group A and increased in group B (p less than 0.001). The data show that baroreceptor-mediated release of vasopressin is not impaired in patients with CHF and a defective sympathetic reflex control mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased renal sympathetic activity in response to cardiac unloading with nitroglycerin in patients with heart failure

AIMS: To examine changes in renal sympathetic outflow in response to cardiac unloading with nitroglycerin (GTN) in patients with chronic heart failure (CHF) and healthy subjects (HS). METHODS AND RESULTS: Renal (RNAsp) and total body (TBNAsp) noradrenaline (NA) spillover were measured with radiotracer methods in 16 patients with CHF (50+/-3 years, LVEF 20+/-1%) and nine HS (57+/-2 years) during right heart and renal vein catheterisation. Low dose GTN decreased mean pulmonary artery pressure (PAm: CHF -7+/-2 mm Hg, HS -4+/-1 mm Hg, p<0.05 vs. baseline) but not mean arterial pressure (MAP: CHF -2+/-1 mm Hg, HS -2+/-1 mm Hg) and did not affect RNAsp in any of the study groups. High dose GTN lowered MAP (CHF -12+/-1 mm Hg, HS -12+/-2 mm Hg, p<0.05 vs. baseline) and PAm (CHF -13+/-2 mm Hg, HS -5+/-1 mm Hg, p<0.05 vs. baseline) and was accompanied by a significant reduction in RNAsp only in CHF (1.3+/-0.1 nmol/min baseline to 0.9+/-0.2 nmol/min, p<0.05), whereas RNAsp in HS remained unchanged. CONCLUSIONS: In spite of a reduction in both arterial pressure and cardiac filling pressures, renal sympathetic activity decreased in CHF and did not increase in HS. These findings suggest that the altered loading conditions resulting from high-dose GTN infusion have renal sympathoinhibitory effects.     

Oral calcium treatment lowers blood pressure in renovascular hypertensive rats by suppressing the renin-angiotensin system

The effects of calcium supplementation on blood pressure and its mechanisms were investigated in two-kidney, one clip renovascular hypertensive rats. Two series of experiments were performed: one was begun just after renal artery constriction, the other after the onset of hypertension. Calcium supplementation significantly attenuated the development of hypertension (systolic blood pressure: 183 +/- 8 vs 130 +/- 2 mm Hg) and was found to abate existing renovascular hypertension (systolic blood pressure: from 183 +/- 8 to 151 +/- 4 mm Hg). Calcium treatment did not cause significant alterations in fluid intake, urine volume, or urinary sodium excretion in either study. However, increased plasma renin activity and plasma aldosterone concentration were suppressed to the basal levels at the end of 3 weeks of calcium treatment (14 +/- 3 vs 8 +/- 2 ng angiotensin I/ml/hr; 530 +/- 50 vs 380 +/- 40 pg/ml). Blood pressure of calcium-treated renovascular hypertensive rats responded poorly to blockade of the renin-angiotensin system with captopril injection and angiotensin II analogue (saralasin) infusion. Further, in rats with chronic established renovascular hypertension, calcium treatment attenuated the enhanced pressor response to norepinephrine, but not to angiotensin II. These results suggest that the blood pressure-lowering actions of calcium supplementation are related primarily to suppression of renin secretion and secondarily to alteration of pressor response to norepinephrine in two-kidney, one clip renovascular hypertensive rats.     

Isometric exercise in patients with chronic advanced heart failure: hemodynamic and neurohumoral evaluation

We evaluated the hemodynamic effects of isometric exercise in 53 patients with congestive heart failure (CHF) and compared them with those found in 10 normal subjects. In both groups, isometric exercise increased heart rate and blood pressure. Systemic resistance increased in patients with CHF (1862 +/- 520 vs 2126 +/- 642 dyne-sec-cm-5; p less than .001) but not in normal subjects (1359 +/- 268 vs 1380 +/- 252 dyne-sec-cm-5). Cardiac index and stroke volume index increased mildly but not significantly in the normal subjects (2.8 +/- 0.5 vs 3.1 +/- 0.7 liters/min/m2 and 46 +/- 8 vs 47 +/- 7 ml/m2) and showed a significant fall in the patients with CHF (2.1 +/- 0.6 to 1.9 +/- 0.6 liters/min/m2, p less than .01 and 23 +/- 7 vs 20 +/- 7 ml/m2, p less than .01). Mean pulmonary arterial wedge pressure increased in patients with CHF from 26 +/- 7 to 30 +/- 8 mm Hg (p less than .001). Although no significant change was found in mean value for stroke work index (21 +/- 9 vs 20 +/- 9 g-m/m2), the individual changes were variable, with marked decrease (greater than 15%) in 17 of the patients. This hemodynamic deterioration could not be predicted from resting hemodynamics, left ventricular ejection fraction, or functional classification. Isometric exercise resulted in no significant change in circulatory catecholamine levels or plasma renin concentration in our 10 normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preservation of renal function by angiotensin during chronic adrenergic stimulation

The purpose of the present study was to determine the role of angiotensin II (Ang II) in mediating renal responses to chronic intrarenal norepinephrine infusion. Norepinephrine was continuously infused for 5 days into the renal artery of unilaterally nephrectomized dogs at progressively higher daily infusion rates: 0.05, 0.10, 0.20, 0.30, and 0.40 micrograms/kg/min. In three additional groups of dogs, norepinephrine infusion was repeated during chronic intravenous captopril administration to fix plasma Ang II concentration at 1) low levels (no Ang II infused), 2) high levels in the renal circulation (Ang II infused intrarenally at a rate of 1 ng/kg/min), and 3) high levels in the systemic circulation (Ang II infused intravenously at a rate of 5 ng/kg/min). In the control group of animals with intact renin-angiotensin systems, there were progressive increments in mean arterial pressure (from 96 +/- 4 to 141 +/- 6 mm Hg) and plasma renin activity (from 0.4 +/- 0.1 to 10.9 +/- 4.5 ng angiotensin I/ml/hr) and concomitant reductions in glomerular filtration rate and renal plasma flow to approximately 40% of control during the 5-day norepinephrine infusion period. In marked contrast, when captopril was infused chronically without Ang II, mean arterial pressure was 20-25 mm Hg less than that under control conditions, and the renal hemodynamic effects of norepinephrine were greatly exaggerated; by day 3 of norepinephrine infusion, both glomerular filtration rate (16 +/- 2% of control) and renal plasma flow (12 +/- 4% of control) were considerably lower than values in control animals (86 +/- 4% and 80 +/- 8% of control, respectively). Similarly, when a high level of Ang II was localized in the renal circulation during captopril administration, mean arterial pressure was depressed, and again there were pronounced renal responses to norepinephrine. Conversely, when Ang II was infused intravenously during captopril administration, mean arterial pressure was not reduced, and the glomerular filtration rate and renal plasma flow responses to norepinephrine were similar to those that occurred under control conditions. These findings indicate that the renin-angiotensin system prevents exaggerated renal vascular responses to chronic norepinephrine stimulation by preserving renal perfusion pressure.