Activity of [Des-Aspartyl1]-Angiotensin II and Angiotensin II in Man: DIFFERENCES IN BLOOD PRESSURE AND ADRENOCORTICAL RESPONSES DURING NORMAL AND LOW SODIUM INTAKE

This study was designed to compare the effect of [des-Aspartyl(1)]-angiotensin II ([des-Asp]-A II) and angiotensin II (A II) on blood pressure and aldosterone production in man under conditions of normal and low sodium (Na) intake. Seven normal male subjects in balance on constant normal Na intake (U(Na) V 160.3+/-5.0 meq/24 h) for 5 days received A II and [des-Asp]-A II infusions on two consecutive days; 1 mo later they were restudied after 5 days of low Na intake (U(Na) V 10.5+/-1.6 meq/24 h). Each dose was infused for 30 min, sequentially. During normal Na intake, [des-Asp]-A II from 2 to 18 pmol/kg per min increased mean blood pressure from 85.2+/-3 to 95.3+/-5 mm Hg and plasma aldosterone concentration from 5.2+/-1.1 to 14.3+/-1.9 ng/100 ml. During low Na intake, the same dose of [des-Asp]-A II increased mean blood pressure from 83.7+/-3 to 86.7+/-3 mm Hg and plasma aldosterone concentration from 34.4+/-6.0 to 51.0+/-8.2 ng/100 ml. In contrast, A II from 2 to 6 pmol/kg per min during normal Na intake increased mean blood pressure from 83.3+/-4 to 102.3+/-4 mm Hg and plasma aldosterone concentration from 7.0+/-2.2 to 26.8+/-2.0 ng/100 ml; during low Na intake, A II increased mean blood pressure from 83.0+/-3 to 96.0+/-4 mm Hg and plasma aldosterone concentration from 42.0+/-9.7 to 102.2+/-15.4 ng/100 ml. A II and [des-Asp]-A II were equally effective in suppressing renin release. Plasma cortisol and Na and K concentration did not change.The effects of two doses (2 and 6 pmol/kg per min) of each peptide on blood pressure and aldosterone production were evaluated. During normal Na intake, [des-Asp]-A II had 11-36% of the pressor activity and 15-30% of the steroidogenic activity of A II. Na deprivation attenuated the pressor response and sensitized the adrenal cortex to both peptides, but the increase in steroidogenesis was greater with [des-Asp]-A II than with A II. The dose-response curves for [des-Asp]-A II with respect to blood pressure and aldosterone production were not parallel, and although no maximum was established for A II, [des-Asp]-A II was less efficacious.In summary, (a) [des-Asp]-A II has biologic activity in man, (b) [des-Asp]-A II is less efficacious than A II in stimulating aldosterone production, (c) Na deprivation sensitizes the adrenal cortex more markedly to [des-Asp]-A II than A II, and (d) dose-response curves for the two peptides differ, suggesting the possibility that they act at different receptor sites in vascular smooth muscle and the adrenal cortex.     

Abnormal Adrenal Responsiveness and Angiotensin II Dependency in High Renin Essential Hypertension

Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na(+)/100 meq K(+) diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24+/-6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 +/- 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 +/- 1 ng/ml per h; plasma aldosterone = 87 +/- 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 mug/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (-15 +/- 3 mm Hg) was significantly greater than in the normal adrenal responsive group (-3 +/- 2 mm Hg) (P < 0.02).It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes.     

Peripheral dopaminergic blockade for the treatment of diabetic orthostatic hypotension

This study was designed to evaluate the effects of domperidone, a peripheral dopaminergic antagonist, in diabetic patients with symptomatic orthostatic hypotension. Nine patients were admitted to the hospital, placed on a diet containing 150 mEq sodium, and studied for periods of 4 hours, on different days, in the following conditions: (1) supine position, (2) upright posture (UP), (3) UP after 10 mg domperidone, intravenously in bolus, and (4) UP after 3 days of domperidone, 30 mg orally. Before domperidone the mean blood pressure observed in supine position of 132 +/- 37/75 +/- 6 mm Hg fell to 75 +/- 22/57 +/- 13 mm Hg after 2 hours in UP. Acute domperidone did not change the blood pressure response to UP. After 3 days of oral domperidone and in UP for 2 hours, the mean blood pressure value of 89 +/- 21/61 +/- 8 mm Hg was higher than that before domperidone (p less than 0.05), with relief of symptoms in all patients. This blood pressure response to UP has been maintained in six patients who completed 6 months of therapy. No differences were observed in plasma renin activity, aldosterone, sodium, and potassium and in 4-hour urinary excretion of aldosterone, epinephrine, norepinephrine, and dopamine, determined during the UP tests. Administration of domperidone for 3 days reduced the falls in creatinine clearance and the urinary excretion of sodium and potassium induced by UP but did not alter the blood pressure and aldosterone dose-response curves to angiotensin II. Although the mechanism of action is not defined, it is concluded that domperidone is effective for the treatment of orthostatic hypotension in patients with diabetes.     

Effect of positive and negative pressure breathing on sodium and water excretion

Positive and negative pressure breathing purportedly alter renal sodium and water excretion by modifying hemodynamics and/or hormonal regulators of sodium and water homeostasis. To test this hypothesis we monitored hemodynamic and hormonal responses in seven normal men to (1) continuous positive pressure breathing (19 +/- 1 mm Hg for 30 minutes) after water loading (urine volume = 15 +/- 1 ml/min); and (2) continuous negative pressure breathing (11 +/- 1 mm Hg for 30 minutes) after maintenance water ingestion (urine volume = 4 +/- 1 ml/min), in random order. Each study was repeated on a control day without pressure breathing. Results were as follows (mean +/- SE, p less than 0.05): (1) continuous positive pressure breathing decreased urinary sodium from 0.28 +/- 0.07 to 0.17 +/- 0.04 mEq/min, increased atrial natriuretic peptide from 34.2 +/- 4.9 to 48.5 +/- 6.9 pg/ml, and had no effect on osmolar and free water clearances, cardiac output, plasma renin activity, or plasma aldosterone and plasma arginine vasopressin levels; and (2) continuous negative pressure breathing increased free water clearance from 0.6 +/- 0.7 to 4.5 +/- 1.2 ml/min, urine volume from 4.0 +/- 0.8 to 8.9 +/- 1.3 ml/min, and cardiac output from 5.1 +/- 0.4 to 7.0 +/- 0.6 L/min in a proportional manner (r = 0.40, p less than 0.01) and had no effect on osmolar clearance, urinary volumes of sodium and potassium, plasma renin activity, plasma aldosterone, atrial natriuretic peptide, and arginine vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered pressor responses in long-term nitrendipine treatment

The effect of long-term treatment with nitrendipine on systemic pressor responses to norepinephrine (NE) and angiotensin II (AII) was evaluated in 11 subjects with mild, uncomplicated hypertension. Pressor responses to NE and AII were measured at the end of a 4-wk placebo period and after 5 wk treatment with nitrendipine (final dose 16 mg twice daily; range 5 to 20 mg/day) or placebo. In subjects who received nitrendipine, clinic supine blood pressure was reduced from 152 +/- 12/96 +/- 4 mm Hg to 134 +/- 11/84 +/- 5 mm Hg and pressor responses to NE but not to AII were attenuated. Endogenous plasma levels of NE and renin activity were not changed by nitrendipine. Data suggest that noradrenergic blood pressure control mechanisms depend more on cellular calcium transport than do AII-mediated ones and may help explain the greater effectiveness of calcium entry blockers in the treatment of low-renin hypertension.     

Alpha-1-adrenergic blockade and lipoprotein metabolism in essential hypertension

The effect of the selective alpha 1-antagonist terazosin on serum lipoproteins and certain blood pressure-regulating factors was assessed in 15 patients with essential hypertension. Terazosin given during 8 weeks reduced arterial pressure (from 153/103 +/- 3/2 (SE) to 143/96 +/- 5/2 mm Hg; P less than 0.02) but did not modify body weight, heart rate, blood volume, plasma renin activity, aldosterone and catecholamine levels, or serum cholesterol, triglycerides, and their lipoprotein fractions. In nine of the patients, blood pressure control was not achieved with terazosin monotherapy and the diuretic methyclothiazide, 2.5 mg, was added. After 8 weeks of combined treatment, blood pressure decreased further (P less than 0.05); serum lipids and lipoprotein fractions did not change as compared with placebo or terazosin conditions. These findings indicate that terazosin in monotherapy does not unfavorably influence lipid metabolism.     

Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension

An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117+/-2 (mean+/-SE) mm Hg to 108+/-3 mm Hg after 4 days of aminoglutethimide therapy and further to 99+/-3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6+/-7.2 kg in the control period to 80.6+/-7.0 kg after 4 days of drug treatment and to 80.1+/-6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18-hydroxydeoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16beta-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17-hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16beta-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62+/-0.5 (mean+/-SE) in the control period to 0.9+/-0.2 mug/24 h after 4 days and to 1.1+/-0.3 mug/24 h at the termination of aminoglutethimide treatment.The gradual lowering of blood pressure and body weight during aminoglutethimide therapy is consistent with the view that the antihypertensive effect of the drug is mediated through a reduction in the patients' extracellular fluid volume, probably secondary to the persistent decrease in aldosterone production. The observation that chronic administration of aminoglutethimide lowered blood pressure in these patients and elevated their plasma renin activity to the normal range without decreasing production of the adrenal steroids, deoxycorticosterone, 18-hydroxydeoxycorticosterone, and 16beta-hydroxydehydroepiandrosterone, makes it unlikely that these steroids are responsible either for the decreased renin or the elevated blood pressure in patients with low renin essential hypertension.     

Blood pressure dependency on vasopressin and angiotensin II in prazosin-treated conscious normotensive rats

The role of the sympathetic nervous system, angiotensin II and vasopressin in limiting the hypotensive effect of prazosin (0.25 mg i.v.) was investigated in conscious normotensive rats. Within 45 min, mean blood pressure fell from 120 +/- 1 to 98 +/- 1 mm Hg (mean +/- S.E.M., P less than .001) while pulse rate rose from 463 +/- 9 to 500 +/- 9 beats/min (P less than .01). The blood pressure response to prazosin tended to be most pronounced in the rats with the smallest increase in heart rate (r = 0.58, P less than .001). Plasma norepinephrine and epinephrine levels were higher in prazosin-treated rats than in the controls (P less than .001). In the animals receiving prazosin, plasma renin activity was 4 times (P less than .001) and plasma vasopressin 7 times (P less than .01) higher than in the controls. Blockade of angiotensin II with saralasin (10 micrograms/min) further decreased blood pressure of the prazosin-treated rats by 22 +/- 4 mm Hg (P less than .001). In contrast, dPVDAVP (25 micrograms), a vasopressin antagonist, had no effect. Prazosin decreased the pressor response to methoxamine (10 micrograms) by 80% (P less than .001) but not to angiotensin II (60 ng). However, prazosin enhanced the reflex bradycardia induced by angiotensin II (P less than .001). These data demonstrate that both the sympathetic and the renin angiotensin system are markedly stimulated by prazosin; they both appear to limit its acute hypotensive action. In contrast, although plasma vasopressin is also increased, its pressor action is effectively buffered, probably due to enhanced baroreflex sensitivity.     

Static exercise-induced increase in blood pressure in individuals with cervical spinal cord injury

OBJECTIVE: To compare the pressor response to static exercise in subjects with cervical spinal cord injury (SCI) at the C6 to C8 level with that in able-bodied control subjects. In these SCI subjects, the descending supraspinal sympathetic neurons and afferent pathways from the contracting muscles to peripheral vessels via the medullary cardiovascular center are damaged. DESIGN: Mean arterial blood pressure, heart rate, and plasma concentrations of norepinephrine, epinephrine, renin activity, vasopressin, aldosterone, and human atrial natriuretic peptide were measured during a 2-minute period of sustained contraction of elbow flexor group muscle in 7 SCI subjects and 7 age-matched able-bodied control subjects. RESULTS: Static exercise resulted in a significant increase in mean blood pressure (p<.05) in both SCI subjects (pre-exercise. 74.7+/-2.2 mm Hg; static exercise, 81.9+/-4.1 mm Hg) and control subjects (pre-exercise, 101.0+/-4.2 mm Hg; static exercise, 117.0+/-4.9 mm Hg). In SCI subjects, there was no change in heart rate during exercise, whereas in control subjects heart rate increased during exercise (p<.05) (pre-exercise, 8.7+/-3.8 beats/min: static exercise, 76.0+/-3.1 beats/min). There were no significant changes in the hormone levels in the SCI subjects throughout the experiment. CONCLUSION: The significant increase in mean blood pressure observed in the present study indicates the presence of peripheral control from muscle receptors and evoked pressor response during static exercise in SCI subjects.     

Nadolol antihypertensive effect and disposition in young and elderly adults with mild to moderate essential hypertension

Nadolol was effective and well tolerated as once-daily monotherapy for mild to moderate essential supine diastolic hypertension (SDBP) in 10 young (mean age, 39 years) and 12 elderly (mean age, 68 years) patients in a single-blind, placebo-baseline, escalating-dose study. Doses required to reduce SDBP to 90 mm Hg were not different in young (1.08 +/- 0.21 mg/kg/day) and elderly (0.82 +/- 0.14 mg/kg/day) patients (mean +/- SE). Trough plasma nadolol concentrations at steady state were similar and were linearly related to dose in both groups. More unchanged nadolol was recovered in 24-hour urine samples from young subjects (15.6% +/- 1.9%) than from elderly ones (10.7% +/- 1.1%) (p = 0.028). With increasing nadolol doses, plasma norepinephrine concentration increased and isoproterenol sensitivity decreased in both young and elderly subjects, and creatinine clearance and plasma active renin levels were unchanged; plasma inactive renin levels increased in the young, and aldosterone concentration declined in the elderly with the lowest nadolol dose.     

Antihypertensive mechanism of amlodipine in essential hypertension: role of pressor reactivity to norepinephrine and angiotensin II.

Calcium entry blockade may affect the pressor reactivity to vasoconstrictors. The pressor response to norepinephrine and angiotensin II, as well as several other blood pressure modulating factors, were studied in normal subjects (n = 9) and patients with essential hypertension (n = 10) before and after 8 weeks of treatment with the long-acting dihydropyridine amlodipine. In control subjects, calcium entry blockade did not modify blood pressure, the pressor and aldosterone response to angiotensin II, the activity of the renin-angiotensin and sympathetic nervous systems, or urinary dinoprostone (prostaglandin E2) excretion; however, the pressor response to norepinephrine was significantly decreased (p less than 0.01). In patients with hypertension, amlodipine decreased blood pressure (p less than 0.01) and the pressor response to both norepinephrine and angiotensin II (p less than 0.01), without changes in body weight, plasma renin, angiotensin II and catecholamine levels, dinoprostone excretion, or aldosterone responsiveness to angiotensin II. These findings suggest that calcium entry blockade modifies sympathetic-dependent vasoconstriction in both normal subjects and in patients with hypertension. Angiotensin II pressor response may be selectively decreased in essential hypertension.     

Sequential changes in atrial pressures, dimensions, and plasma atrial natriuretic factor concentrations during volume loading in hemodynamically normal human subjects.

The effects of volume loading on atrial pressures and dimensions, plasma levels of atrial natriuretic factor (ANF), and other neurohormonal variables were studied in 11 patients with normal hemodynamics with the patients in a supine -15 degree left decubitus posture by infusing 750 ml of normal saline solution over 30 minutes. Right and left atrial areas were measured by two-dimensional echocardiography. Plasma ANF level was sampled simultaneously from the pulmonary artery, aorta, and femoral artery and vein. At 30 minutes into the infusion, pulmonary capillary wedge pressure and right atrial pressure increased from 5.6 +/- 2.8 mm Hg (mean +/- SD) and 6.4 +/- 2.2 mm Hg to 10.2 +/- 3.2 and 9.5 +/- 2.2 mm Hg, respectively (both p less than 0.01). Left atrial area increased from 12.6 +/- 2.2 cm2 to 15.0 +/- 2.1 cm2 (p less than 0.05), whereas right atrial area did not change. Plasma ANF levels from all sampling sites increased significantly (e.g., 43 +/- 21 pg/ml to 71 +/- 62 pg/ml in the femoral artery, p less than 0.05). Plasma norepinephrine and renin levels were unchanged, whereas aldosterone level declined significantly. At 30 minutes after termination of the infusion, atrial pressures declined to baseline values in all patients. However, left atrial area remained significantly increased, and a trend for systemic arterial plasma ANF level to remain increased was seen. Plasma aldosterone level remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. METHODS AND RESULTS: Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. RESULTS: The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). CONCLUSIONS: Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.     

Cardiovascular and endocrine responses during the cold pressor test in subjects with cervical spinal cord injuries

OBJECTIVE: To investigate cardiovascular regulation and endocrine responses during the cold pressor test in patients with chronic spinal cord injury (SCI). DESIGN: Experimental and control study. SETTING: University laboratory, department of rehabilitation medicine, in Japan. PARTICIPANTS: Eight quadriplegic subjects with complete spinal cord transection at the C6 to C8 level and 6 age-matched healthy subjects. INTERVENTIONS: Cardiovascular and endocrine responses were examined during 2 minutes of control, 3 minutes of ice-water immersion of the foot, followed by a 3-minute recovery. MAIN OUTCOME MEASURES: Blood pressure, heart rate, the Borg 15-point Rating of Perceived Pain Scale, and blood samples for measurement of plasma norepinephrine, epinephrine, plasma renin activity, plasma aldosterone, and arginine vasopressin. RESULTS: The rise in the mean arterial blood pressure during the cold pressor test in patients with SCI (baseline, 81.6+/-3.7mmHg; increased by 30%+/-6.1%) was significantly (P<.05) higher than that in healthy subjects (baseline, 101.2+/-4.5mmHg; increased by 20%+/-4.5%). The SCI subjects had no change in heart rate throughout the test, in contrast to the tachycardia noted in normal subjects. Baseline plasma norepinephrine in SCI subjects (63.0+/-18.3pg/mL) was significantly lower than in normal subjects (162.3+/-19.6pg/mL) and plasma norepinephrine increased significantly during the cold pressor test in both groups. CONCLUSIONS: In the SCI subjects, a reflex sympathetic discharge through the isolated spinal cord results in a more profound rise in mean blood pressure during ice-water immersion. This response was free of inhibitory impulses from supraspinal center and baroreceptor reflexes, either of which might restrain the increase in blood pressure.     

Regional blood flow and neurohormonal responses to milrinone in congestive heart failure

We measured systemic hemodynamics, regional blood flow, and neurohormonal parameters in 13 patients with severe chronic congestive heart failure before and after 1 month of therapy with oral milrinone, a bipyridine cardiotonic agent. After milrinone there were significant reductions in pulmonary wedge pressure (27 +/- 2 to 19 +/- 3 mm Hg; P less than 0.02) and systemic vascular resistance (1866 +/- 152 to 1393 +/- 93 dyne X sec/cm5; P less than 0.05) that were associated with increases in cardiac index (1.85 +/- 0.15 to 2.47 +/- 0.20 L/min/m2; P less than 0.02). There was a marked improvement in forearm blood flow (1.98 +/- 0.14 to 3.02 +/- 0.16 ml/min/dl; P less than 0.01) and a reduction in forearm vascular resistance (45 +/- 3 to 30 +/- 3 U; P less than 0.01). Overall there was no significant change in renal blow flow, renal vascular resistance, or glomerular filtration rate. However, there was a heterogeneous response of renal blood flow and glomerular filtration rate, such that both were directly correlated with the magnitude of increase of cardiac index (r = 0.587 [P less than 0.05] and r = 0.721 [P less than 0.01], respectively). After milrinone there were no significant overall or subgroup changes in urinary sodium excretion, blood volume, plasma renin activity, urinary aldosterone levels, plasma or platelet vasopressin levels, or plasma norepinephrine levels. Thus 1 month of therapy with milrinone improves systemic and forearm hemodynamics, but its effects on renal blood flow and function were heterogeneous. These heterogeneous effects on regional blood flow may depend on the relative vasodilator and inotropic effects of milrinone.     

Effects of perfusion pressure on tissue perfusion in septic shock

OBJECTIVE: To measure the effects of increasing mean arterial pressure (MAP) on systemic oxygen metabolism and regional tissue perfusion in septic shock. DESIGN: Prospective study. SETTING: Medical and surgical intensive care units of a tertiary care teaching hospital. PATIENTS: Ten patients with the diagnosis of septic shock who required pressor agents to maintain a MAP > or = 60 mm Hg after fluid resuscitation to a pulmonary artery occlusion pressure (PAOP) > or = 12 mm Hg. INTERVENTIONS: Norepinephrine was titrated to MAPs of 65, 75, and 85 mm Hg in 10 patients with septic shock. MEASUREMENTS AND MAIN RESULTS: At each level of MAP, hemodynamic parameters (heart rate, PAOP, cardiac index, left ventricular stroke work index, and systemic vascular resistance index), metabolic parameters (oxygen delivery, oxygen consumption, arterial lactate), and regional perfusion parameters (gastric mucosal Pco2, skin capillary blood flow and red blood cell velocity, urine output) were measured. Increasing the MAP from 65 to 85 mm Hg with norepinephrine resulted in increases in cardiac index from 4.7+/-0.5 L/min/m2 to 5.5+/-0.6 L/min/m2 (p < 0.03). Arterial lactate was 3.1+/-0.9 mEq/L at a MAP of 65 mm Hg and 3.0+/-0.9 mEq/L at 85 mm Hg (NS). The gradient between arterial P(CO2) and gastric intramucosal Pco2 was 13+/-3 mm Hg (1.7+/-0.4 kPa) at a MAP of 65 mm Hg and 16+/-3 at 85 mm Hg (2.1+/-0.4 kPa) (NS). Urine output at 65 mm Hg was 49+/-18 mL/hr and was 43+/-13 mL/hr at 85 mm Hg (NS). As the MAP was raised, there were no significant changes in skin capillary blood flow or red blood cell velocity. CONCLUSIONS: Increasing the MAP from 65 mm Hg to 85 mm Hg with norepinephrine does not significantly affect systemic oxygen metabolism, skin microcirculatory blood flow, urine output, or splanchnic perfusion.     

Comparison of sympathetic modulation induced by single oral doses of mibefradil, amlodipine, and nifedipine in healthy volunteers

OBJECTIVE: Our objective was to compare the sympathetic modulation induced by oral administration of a single dose of 20 mg of standard nifedipine, of 10 mg of amlodipine, and of 100 mg of mibefradil. METHODS: Sixteen healthy male volunteers participated in this double-blind, randomized, placebo-controlled, crossover four-period study. The sympathetic modulation induced by treatments was evaluated during 24 hours after drug administration by neurohormonal dosages, hemodynamic parameter measurements, and spectral analysis of heart rate and blood pressure. RESULTS: We observed a significant (P <.05) decrease in diastolic blood pressure 1 hour after the administration of nifedipine (62 +/- 9 to 59 +/- 5 mm Hg) with concomitant increases in heart rate (59 +/- 5 to 74 +/- 8 bpm) and neurohormones (53 +/- 18 to 83 +/- 50 pg/mL for aldosterone, 157 +/- 56 to 282 +/- 119 pg/mL for norepinephrine, and 9.8 +/- 5.5 to 40.2 +/- 97.1 pg/mL for active renin). No significant modification of these parameters was observed with amlodipine and mibefradil, except an isolated increase of norepinephrine plasma level 2 hours after the administration of mibefradil (133.1 +/- 67.1 to 210.9 +/- 92.5 pg/mL). The spectral analysis over 24 hours of Mayer waves of systolic blood pressure did not show any significant change over time in the different groups. When the analysis was performed during the first 4 hours after treatment administration, we observed a decrease of Mayer waves of systolic blood pressure with nifedipine (2.21 +/- 1.45 mm Hg(2) versus 3.53 +/- 1.85 mm Hg(2) with placebo). These results indicate that oral single doses of mibefradil and amlodipine do not induce baroreflex-mediated clinical changes in healthy volunteers. The single oral dose of nifedipine resulted in a marked increase in sympathetic tone and a decrease in systolic blood pressure variability early after oral administration. CONCLUSION: Mibefradil, the nondihydropyridine calcium antagonist, exerts much less sympathetic stimulation than nifedipine.     

Endogenous bradykinin and the renin and pressor responses to furosemide in humans

In humans, bradykinin contributes to the acute renin response after ACE inhibition. To further explore the role of endogenous bradykinin in human renin regulation, we determined the effect of HOE 140, a specific bradykinin B(2) receptor antagonist, on the renin response to 0.5 mg/kg i.v. furosemide in a randomized, single blind, crossover design study of 10 healthy, salt-replete volunteers. HOE 140 did not affect basal plasma renin activity, aldosterone, mean arterial pressure, or heart rate. Furosemide administration increased plasma renin activity from 1.0 +/- 0.2 to 4.5 +/- 1.2 ng of angiotensin I/ml/h and there was no effect of HOE 140 (from 1.1 +/- 0.2 to 3.9 +/- 0.8 ng of angiotensin I/ml/h). Similarly, there was no effect of HOE 140 on the diuretic response to furosemide. Mean arterial pressure increased in response to furosemide after HOE 140 (82 +/- 2 to 94 +/- 2 mm Hg), but not after vehicle (81 +/- 3 to 85 +/- 2 mm Hg), whereas heart rate was unchanged. In conclusion, activation of the B(2) receptor by endogenous bradykinin does not contribute to the renin response to acute furosemide treatment in humans. However, bradykinin may contribute to blood pressure regulation under conditions in which the renin-angiotensin system is stimulated.     

Systemic vascular effects of cyclosporin A treatment in normotensive rats

The immunosuppressive drug cyclosporin A (CsA) frequently induces hypertension, but the mechanism(s) is unknown. Thus, we examined the mechanism(s) by which CsA increases arterial blood pressure (MAP) in the normotensive rat. Three different treatment modalities were used. First, chronic CsA treatment (20 mg/kg/day, s.c., for 1 week) significantly increased MAP from 109.6 +/- 2.3 mm Hg to 125.8 +/- 2.9 mm Hg (P less than .05). Second, subacute i.v. infusion of CsA (20 mg/kg daily for 3 days) increased MAP to even higher values (140.5 +/- 2.3 mm Hg), which correlated significantly with the highest circulating values of the drug. The pressor effect after i.v. infusion appears to be unrelated to endogenous release of catecholamines, because phentolamine, which abolishes the response to exogenous norepinephrine, failed to prevent the CsA-induced pressor response. Third, i.v. bolus injections of CsA (10-20 mg/kg) evoked immediate, dose-dependent and short-lasting increases in MAP (+15-25 mm Hg) in both anesthetized and conscious rats. Ganglionic blockade did not prevent this effect, rather, a 2- to 3-fold increase in amplitude (+40-60 mm Hg) and duration (+30-45 min) of the CsA-induced pressor response was observed in anesthetized rats. Heart rate was not increased significantly by either acute or chronic administration of CsA. Our results suggest that both CsA-induced pressor responses and hypertension are due to a peripheral action unrelated to sympathetic outflow. Furthermore, CsA's hypertensive effect is accompanied by severe morphological changes in the vascular endothelium and smooth muscle cells. In addition, CsA-treated rats showed significantly attenuated vasodilatory responses to prostacyclin and sodium nitroprusside, and increased pressor responses to norepinephrine. Thus, a direct vascular action of CsA is likely to contribute to the alterations on systemic vascular responsiveness, as well as to the hypertensive effect of the drug.     

The role of epinephrine in the circulatory effects of coffee

The circulatory response to coffee was studied in 10 normotensive, 10 bilaterally adrenalectomized, and 10 hypertensive subjects. In the normotensive group, drinking coffee exerted a rise in blood pressure (+5.1/+11.5 mm Hg), a fall in heart rate (-6.0 bpm), a rise in plasma epinephrine (+257.2%), and no change in plasma norepinephrine. The response to coffee in the hypertensive group was similar or even enhanced. In the patients who had undergone adrenalectomy, the coffee-induced rise of diastolic blood pressure was attenuated (+7.9 mm Hg; P less than 0.05), whereas plasma norepinephrine showed a fall (-20.8%) and plasma epinephrine remained undetectable throughout all tests. Additionally, a fall of plasma renin activity after coffee was observed in all three groups. We conclude that the pressor response to coffee is not purely a result of circulating epinephrine or to stimulation of the renin-angiotensin-aldosterone system. On the other hand, the coffee-induced increase of plasma epinephrine may increase the pressor response to coffee.