Cardiovascular and Hormonal Effects of Domperidone, A Peripheral Dopaminergic Blocker, in Bromocriptine-Treated Hypertensive Patients

Nine patients with mild or moderate essential hypertension were studied at the Vargas Hospital of Caracas, Venezuela. After antihypertensive treatment discontinuation, all patients were placed on placebo during a 1-week period, after which domperidone, a peripheral DA(2) dopaminergic blocker, was orally administered at the dose of 20 mg every 12 h during a period of 1 week. A final 1-week period of bromocriptine, 2.5 mg orally every 8 h, followed the domperidone period. Cold pressor test caused an increase of mean blood pressure and of heart rate, which was more accentuated after adding bromocriptine. Domperidone also caused an increase of serum aldosterone levels. Our results suggest that a dopaminergic mechanism is acting during the cold pressor test and during aldosterone secretion.     

Effect of Domperidone on the Bromocriptine-Induced Antihypertensive Action in Hypertensive Patients

Dopaminergic receptors have been involved in the cardiovascular and renin-angiotensin systems (RAS). We have recently reported that bromocriptine is an effective antihypertensive drug by stimulating DA(2) dopaminergic receptors. However, the nature of the dopaminergic receptors in RAS has not been established. Ten outpatients with essential hypertension were treated at the Vargas Hospital with bromocriptine (BR) (11.25 mg day(minus sign1)), a DA(2) dopaminergic agonist, for a 2-week period, after which an oral dose of 30 mg day(minus sign1) of domperidone (DO), a peripheric DA(2) dopaminergic antagonist, was added for 2 additional weeks. The active period was preceeded by a 2-week placebo period. Bromocriptine decreased blood pressure (BP) significantly by 19/9 mm Hg (systolic/diastolic BP). Bromocriptine did not cause heart rate (HR) changes. Bromocriptine decreased plasma aldosterone (ALD) without altering plasma renin activity (PRA). Domperidone partially blocked bromocriptine-induced antihypertensive submaximal treadmill effects and reversed ALD decrease. Exercise response was not significantly altered by BR + DO. We conclude the following: (1) BR is an effective antihypertensive agent; (2) BR seems to be acting at both the central and peripheric nervous systems, and (3) the nature of the dopaminergic receptor involved in renin secretion does not seem to be DA(2).     

Effect of bromocriptine treatment on prolactin, noradrenaline and blood pressure in hypertensive haemodialysis patients

Bromocriptine (2.5 mg/day orally) produced a significant fall in supine mean arterial pressure in nine hypertensive haemodialysis patients with high serum prolactin levels, without causing significant changes in heart rate. On bromocriptine, there was a significant decrease in the mean value of both serum prolactin and plasma noradrenaline, without significant changes in the mean value of plasma renin activity. A significant relationship was found between the changes in supine plasma noradrenaline and the changes in supine mean arterial pressure induced by bromocriptine. The increase in mean arterial pressure in response to the tilt test was greater on bromocriptine than on placebo although the changes in plasma noradrenaline were reduced by bromocriptine. Similar results were observed during the cold pressor test. These findings suggest that the arterial pressure-lowering effect of bromocriptine is related to the reduction in sympathetic out-flow. The parallel decrease in serum prolactin raises the question of the possible involvement of dopaminergic mechanisms in the development of hypertension in our patients. Moreover, bromocriptine seems to enhance the vascular response to endogenous noradrenaline.     

Dopaminergic regulation of aldosterone secretion: assessment in different subtypes of primary aldosteronism and in essential hypertension.

The inhibitory effect of dopamine on aldosterone secretion was investigated in patients with different types of primary aldosteronism, six with idiopathic hyperaldosteronism (IHA) and four with dexamethasone-suppressible hyperaldosteronism (DSH), and in 10 patients with essential hypertension. The effects of 10 mg metoclopramide given intravenously, 10 mg bromocriptine given orally and 100 micrograms adrenocorticotrophic hormone given intravenously on plasma aldosterone and renin activities were investigated in all patients. Metoclopramide induced a rise in plasma aldosterone activity only in patients with IHA and not in those with DSH and essential hypertension. After bromocriptine plasma aldosterone concentrations decreased in patients with IHA only, and after adrenocorticotrophic hormone plasma aldosterone concentrations increased in patients with DSH only. Plasma renin activity was unaffected in all cases. These results provide evidence of increased endogenous dopaminergic inhibition of aldosterone secretion in IHA and of a blunted aldosterone response in both DSH and essential hypertension.     

Dopamine: pharmacologic and therapeutic aspects

Dopamine is a biogenic amine synthesized in the hypothalamus, in the arcuate nucleus, the caudad, and various areas of the central and peripheral nervous system. It has been widely established that dopamine and its agonists play an important role in cardiovascular, renal, hormonal, and central nervous system regulation through stimulation of alpha and beta adrenergic and dopaminergic receptors. There are several agonists of dopamine-2 (DA 2 ) dopaminergic receptors, such as bromocriptine, pergolide, lisuride, quinpirole, and carmoxirole, which inhibit norepinephrine release and produce a decrease in arterial blood pressure; in some cases, bromocriptine and pergolide also reduce heart rate. From a therapeutic point of view, the above-mentioned agonists are used for treating Parkinson's disease, acting over DA 2 dopaminergic receptors of the nigrostriatal system. Bromocriptine and the other dopaminergic agonists mentioned act over DA 2 receptors of the tuberoinfundibular system, inhibiting prolactin release and decreasing hyperprolactinemia and tumor size. Among DA 1 receptor agonists, we can mention fenoldopam, piribedil, ibopamine, SKF 3893, and apomorphine (nonspecific). Activation of these receptors decreases peripheral resistance, inducing lowering of arterial blood pressure and increases in heart rate, sympathetic tone, and activity of the renin aldosterone system. Among DA 2 receptor antagonists, we can mention metoclopramide, domperidone, sulpiride, and haloperidol. From a therapeutic point of view, metoclopramide and domperidone are used in gastric motility disorders, and haloperidol is used in psychotic alterations. Antagonists of DA 1 receptors are SCH23390 and clozapine. Clozapine is used for treating schizophrenia.     

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.     

Mechanism of the depressor effect of bromocriptine in the spontaneously hypertensive rat

Bromocriptine, a dopamine (DA) agonist which passes the bloodbrain barrier, has been shown to have a depressor effect in the spontaneously hypertensive rat of the Okamoto strain. To elucidate the mechanism of this depressor effect, the responses of mean arterial blood pressure and plasma epinephrine (EP), norepinephrine, prolactin and renin activity to i.v. administration of bromocriptine (500 micrograms/kg), alone and after pretreatment with i.v. metoclopramide, a DA antagonist which crosses the blood-brain barrier, and domperidone, a DA antagonist which does not cross the blood-brain barrier, were examined in conscious unrestrained spontaneously hypertensive rats. Metoclopramide attenuated the depressor action of bromocriptine in a dose-related manner, but domperidone had no effect. Neither metoclopramide nor domperidone given alone altered mean arterial blood pressure. Bromocriptine given alone decreased plasma prolactin and increased plasma EP without altering plasma norepinephrine or plasma renin activity. Pretreatment with either metoclopramide or domperidone completely blocked the EP-stimulating effects of bromocriptine. Neither DA antagonist given alone had an effect on plasma EP, norepinephrine or plasma renin activity; both agents stimulated prolactin release. These results suggest that the depressor action of i.v. administered bromocriptine is mediated mainly through a central dopaminergic mechanism rather than by peripheral effects and that plasma EP responses to bromocriptine do not directly contribute to its depressor action.     

Metoclopramide and domperidone block the antihypertensive effect of bromocriptine in hypertensive patients

This study was conducted in normotensive and hypertensive subjects at the Vargas Hospital of Caracas. Normotensive subjects received, in a cross-over fashion, placebo, metoclopramide (MTC), or domperidone (DOMP), 40 mg of each drug, daily for 1 week. The first group of patients under placebo for 1 week received a single 2.5-mg oral dose of bromocriptine (Br). The second group of patients received 30 mg MTC daily (divided into three doses) for 1 week. At the end of the period a single dose of 2.5 mg Br was administered to each patient. The third group of eight hypertensive patients received DOMP for 1 week at 30 mg/d and then a single 2.5-mg Br dose. Cardiovascular and biochemical parameters including arterial pressure, heart rate, plasma renin activity, and plasma aldosterone were evaluated during the 6-hour period before and after the administration of Br. Neither DOMP nor MTC significantly modified blood pressure and heart rate in normotensive patients. Br reduced both systolic and diastolic arterial pressure in hypertensive subjects. The peak of the antihypertensive effect appeared 3 hours after drug administration, but reduction of arterial pressure lasted approximately 6 hours. At the same time, Br reduced plasma aldosterone levels and plasma renin activity. MTC and DOMP reversed the antihypertensive effect of Br and its effect on aldosterone levels and plasma renin activity. We conclude from these findings that Br acts as an antihypertensive agent at peripheral and central levels by stimulating dopamine-2 receptors, which are involved in the aldosterone and renin secretion.     

Cardiovascular effects of verapamil in essential hypertension

Calcium antagonists may affect the regulation of body sodium and adrenergic-dependent mechanisms. Exchangeable sodium, blood volume, plasma norepinephrine, renin, aldosterone, pressor responsiveness to norepinephrine, heart rate responses to isoproterenol, and lipid metabolism were studied in 15 patients with essential hypertension after 8 weeks of treatment with verapamil (348 +/- 68 (SD) mg/day). Supine blood pressure decreased from 153/103 +/- 19/12 mm Hg to 140/95 +/- 14/12 mm Hg (P less than 0.01). Exchangeable sodium, blood volume, plasma norepinephrine, renin and aldosterone, serum total cholesterol, the lipoprotein fractions, and apoprotein levels were unchanged. The norepinephrine pressor and the isoproterenol chronotropic doses tended to increase, whereas the dose-response curve of blood pressure related to plasma norepinephrine was significantly displaced to the right (F = 5.34; P less than 0.05). The antihypertensive effect of verapamil is associated with a decreased cardiovascular pressor responsiveness to norepinephrine without changes in endogenous noradrenergic activity. Moreover, verapamil does not modify the sodium/fluid volume state, the activity of the renin-angiotensin aldosterone axis, or lipid metabolism.     

EFFECTS OF KETANSERIN ON CARDIOVASCULAR, SYMPATHO-ADRENAL AND ENDOCRINE SYSTEMS DURING PHYSICAL EXERCISE IN MAN

Blood pressure, heart rate, oxygen consumption, plasma concentrations of catecholamines, renin, aldosterone and lactate were measured in 6 normotensive volunteers during a randomized cross-over study of oral ketanserin (20 mg X 7) and placebo; measurements were made at rest and during maximal dynamic exercise on a bicycle ergometer. At rest ketanserin reduced blood pressure without modifying heart rate or plasma noradrenaline and adrenaline. Duration of exercise and blood lactate levels did not differ between the ketanserin and the control group. During exercise only systolic blood pressure was significantly decreased on ketanserin at maximal work rate whereas heart rate did not change. Plasma noradrenaline was significantly increased and plasma aldosterone significantly decreased during exercise in ketanserin-treated subjects whereas plasma renin activity and plasma adrenaline remained unchanged. Finally, under ketanserin oxygen consumption during exercise was reduced. The results suggest that ketanserin might interfere with the sympathetic nervous system and aldosterone secretion in man.     

Effects of Metoclopramide and Bromocriptine on the Renin-Angiotensin-Aldosterone System in Man: DOPAMINERGIC CONTROL OF ALDOSTERONE

This study was designed to investigate the possible role of dopaminergic mechanisms in the control of the renin-angiotensin-aldosterone system in normal man. Six normal male subjects in metabolic balance at 150 meq sodium, 60 meq potassium constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. or placebo followed by angiotensin II infusion 1 h later on 2 consecutive days. Metoclopramide increased plasma aldosterone concentration from 8.2+/-2.2 to 21.0+/-3.3 ng/100 ml (P < 0.005) and plasma prolactin concentration from 18.0+/-4.0 to 91.7+/-4.0 ng/ml (P < 0.001) within 15 min of its administration. At 1 h, plasma aldosterone and prolactin concentrations remained elevated at 16.8+/-2.1 ng/100 ml (P < 0.01) and 86.8+/-15.9 ng/ml (P < 0.005), respectively. Angiotensin II at 2, 4, and 6 pmol/kg per min further increased plasma aldosterone concentration to 27.2+/-3.4, 31.9+/-5.7, and 36.0+/-6.7 ng/100 ml (P < 0.02), respectively. Placebo did not alter plasma aldosterone or prolactin concentrations, but angiotensin II increased plasma aldosterone concentration to 13.7+/-2.4, 19.0+/-1.9, and 23.3+/-3.2 ng/100 ml (P < 0.005). The increment of plasma aldosterone concentration in response to angiotensin II was similar after metoclopramide or placebo.The six subjects also received the dopamine agonist, bromocriptine, 2.5 mg or placebo at 6 p.m., midnight, and 6 a.m. followed by angiotensin II infusion on 2 consecutive d. Bromocriptine suppressed prolactin to <3 ng/ml. After placebo, plasma aldosterone concentration increased from 5.2+/-1.4 to 12.3+/-1.7, 17.2+/-2.2, and 21.8+/-3.5 ng/100 ml (P < 0.01) and after bromocriptine from 7.2+/-1.0 to 14.7+/-3.0, 19.8+/-3.2, and 23.4+/-1.6 ng/100 ml (P < 0.001) with each respective angiotensin II dose. No difference in the response to angiotensin II after bromocriptine or placebo was observed. Plasma renin activity, free 11-hydroxycorticoid concentration, and serum potassium concentration were unchanged by metoclopramide or bromocriptine.The results suggest that aldosterone production is under maximum tonic dopaminergic inhibition which can be overridden with stimulation by angiotensin II in normal man.     

Unaltered dopaminergic modulation of aldosterone secretion in cirrhosis

1. The responses of plasma aldosterone and plasma prolactin concentrations to metoclopramide (10 mg intravenously) were evaluated over 2 h in eight healthy controls and in 23 patients with cirrhosis (10 without and 13 with ascites). Plasma renin activity, glomerular filtration rate and renal sodium excretion were also determined. 2. Metoclopramide did not significantly influence plasma renin activity, whereas both plasma aldosterone and plasma prolactin rose significantly. The incremental areas under the curves did not differ among controls and cirrhotic patients without and with ascites. No significant correlations between plasma prolactin and aldosterone, either under basal conditions or after metoclopramide administration, were found in either controls or patients. 3. Glomerular filtration rate did not change after metoclopramide. Renal sodium excretion in controls and cirrhotic patients without ascites was also unaffected, whereas it decreased significantly in cirrhotic patients with ascites. In the latter, renal sodium excretion was inversely correlated with plasma aldosterone both under basal conditions and after metoclopramide administration. 4. The dopaminergic control of aldosterone secretion does not appear to be significantly altered in cirrhosis. Metoclopramide administration to cirrhotic patients with ascites leads to an increase in plasma aldosterone that may enhance renal sodium retention.     

Metoclopramide-Induced Vascular Hyperreactivity: A Comparative Study Between Normotensive and Hypertensive Subjects

In the present study, we have evaluated the cardiovascular responses to the cold pressor test (CPT) under intravenous metoclopramide (MTC) treatment (7.5 &mgr;g kg(minus sign1) min(minus sign1)) during a 30-min period and two additional periods, before and after MTC by using 5% glucose solution. There was a vascular hyperreactivity induced by MTC, Delta mm Hg was 21.4/24/1 mm Hg (systolic/diastolic blood pressure [BP]) during MTC versus Delta 17.2/17.9 mm Hg during 5% glucose infusion. In nine hypertensive subjects, Delta mm Hg was 36.8/25.7 during MTC versus Delta 31/24 mm Hg during 5% glucose. Bromocriptine pretreatment (7.5 mg daily for 7 days) antagonized MTC-BP increase during CPT. We conclude the following: (1) MTC induces a greater BP response during CPT which is blocked by using bromocriptine, a known DA(2) dopaminergic agonist. (2) A dopaminergic influence is present during CPT in normotensive and hypertensive subjects.     

Adrenergic regulation of blood pressure in chronic renal failure.

Previous investigations have suggested that significant hypotension during hemodialysis may result from abnormalities of sympathetic nervous system activity. To further evaluate these phenomena, plasma dopamine beta-hydroxylase (D beta H) and cold pressor test (proposed indexes of efferent sympathetic nervous system activity) and amyl nitrite inhalation (an index of the entire baroreceptor reflex arc) were studied in two groups of patients: group I, patients exhibiting a mean arterial pressure decrease to less than 70 mm Hg during less than 10% of dialyses; group II (hemodialysis hypotension), patients with a mean arterial pressure decrease to less than 70 mm Hg during more than 90% of dialyses. The groups were similar with respect to plasma renin activity, renin response to ultrafiltration, age, duration of dialysis, nerve conduction velocity, plasma protein concentration, hematocrit, dialysis weight change, resting heart rate, sex, race, blood pressure and heart rate response to cold pressor test, and 125I-albumin plasma volume. Supine mean arterial pressure was higher in patients with hemodialysis hypotension than in patients without hemodialysis hypotension (group I) both before and after dialysis. Plasma D beta H activity was significantly higher in patients with hemodialysis hypotension (group II) than in group I both before and after dialysis. Amyl nitrite inhalation, expressed as change in delta R-R interval/mean arterial pressure decrease, was less in hemodialysis hypotension patients. These results suggest that hemodialysis hypotension may result from a lesion in the baroreceptors, cardiopulmonary receptors, or visceral afferent nerves. Furthermore, elevated mean arterial pressure in patients with hemodialysis hypotension may be neurogenic in origin, as reflected by plasma D beta H activity, and appears similar to the hypertension that follows baroreceptor deafferentation of experimental animals.     

Lack of effect of naloxone in a moderate dosage on the exercise-induced increase in blood pressure, heart rate, plasma catecholamines, plasma renin activity and plasma aldosterone in healthy males

There is evidence that opioid peptides influence blood pressure and heart rate in animals and man. In the present investigation the effect of naloxone on the exercise-induced increase in blood pressure, heart rate, plasma catecholamines, plasma renin activity (PRA) and plasma aldosterone was investigated in nine healthy men. A submaximal work test was performed on two occasions. The test consisted of ergometer bicycling for 10 min on 50% of maximal working capacity immediately followed by 10 min on 80% of maximal working capacity. Ten minutes before exercise the subjects received in a randomized manner a bolus dose of naloxone (10 micrograms/kg) or a corresponding volume of saline followed by a slow infusion (15 ml/h) of naloxone (5 micrograms h-1 kg-1) or saline, respectively. After exercise systolic blood pressure, heart rate, plasma catecholamines, PRA and plasma aldosterone increased during both saline and naloxone infusion. The changes were similar in both studies. Accordingly, opiate receptors sensitive to naloxone in a moderate dosage seem not to be involved in the cardiovascular response and the increase in plasma catecholamines, PRA and plasma aldosterone induced by exercise.     

Plasma noradrenaline and dopamine in renin-mediated hypertension

Summary. Noradrenaline (NA) and dopamine (DA) have opposite effects on the kidney; NA causes vasoconstriction and increased sodium reabsorption while DA promotes vasodilation and natriuresis. In 15 patients investigated for renin-mediated hypertension measurements of plasma renin activity (PRA), NA and DA concentrations were made in arterial and renal venous blood from both kidneys before and after acute stimulation of renin release by i.v. dihydralazine. Nine patients had unilateral renin secretion and were classified as renin-positive, while the remaining six patients were renin-negative. Renin-positive patients had higher arterial and renal venous PRA, NA and DA levels than the negative ones. In the renin-positive group V-A differences for NA and DA were present on both sides despite unilateral secretion of renin. NA but not DA levels were higher in the renin-secreting kidney, which can partly be explained by the reduced plasma flow to the involved kidney. After dihydralazine the arterial NA and DA rose similarly in renin-positive and renin-negative patients, while PRA rose only in the renin-positive cases. In the renin-positive patients where stimulation of renin secretion caused a marked increase of the PRA gradient on the affected side only, renal gradients for NA and DA increased bilaterally. The increase in DA was more pronounced than that of NA yielding a rise in DA/NA ratio on the affected side. Arterial PRA was positively correlated to the plasma concentrations of NA and DA. V-A differences for PRA and NA or DA were positively correlated on the involved renin-secreting side. In summary, patients with renin-dependent hypertension have elevated plasma NA and DA concentrations. Stimulation of renin release by dihydralazine increases the DA/NA ratio in arterial and renal venous blood indicating release of ‘precursor dopamine’ from noradrenergic fibres and/or activation of dopaminergic nerves. There seems to be a relationship between renal nerve activity and renin release in renin-dependent hypertension.     

Acute hemodynamic and humoral effects of metoclopramide on blood pressure control improvement in subjects with diabetic orthostatic hypotension

Metoclopramide (MCP), a dopaminergic antagonist, is effective in postural hypotension, but the mechanisms of action have not been well defined. We studied responses of mean arterial pressure (MAP), heart rate, cardiac output (CO), and total peripheral resistance (TPR) after 5 min of increasing degrees of head tilt (15 degrees to 90 degrees) before and after MCP (20 mg IV) in seven subjects with diabetic postural hypotension. Plasma renin activity (PRA) and plasma aldosterone levels (PA) were determined at each degree of tilt; responses to the cold pressor test were also assessed before and after MCP. Before MCP, the maximal degree of tilt tolerated was 75 degrees, while after MCP four subjects were able to support 90 degrees tilt. At 45 degrees tilt, the decreases in MAP were smaller after than before MCP (-7.6 +/- 3.3 and -28.1 +/- 8.5 mm Hg; means +/- SE). This was associated with responses of TPR to tilt after (from 18.6 +/- 2.6 to 24.0 +/- 3.9 arbitrary units [AU]) but not before (from 22.9 +/- 4.0 to 25.6 +/- 4.5 AU) MCP. Reductions in CO were of the same order before and after MCP. PRA responded to tilt better after than before MCP. Supine PA levels increased with MCP (delta PA = 5.4 +/- 0.7 ng/dl), but its response to tilt was unaltered. There were significant rises in MAP and HR during the cold pressor test after but not before MCP. Our data suggest that vasoconstriction is the main mechanism of MCP improvement in blood pressure response to an orthostatic stimulus in diabetic postural hypotension, possibly because of its antidopaminergic property.     

Prostacyclin attenuates both the pressor and adrenocortical response to angiotensin II in human pregnancy

1. The effects of angiotensin II (ANG II) infusion without and with simultaneous infusion of prostacyclin (PGI2; 1.4 pmol min-1 kg-1; 5 ng min-1 kg-1) have been studied in 16 women in second-trimester pregnancy. Ten received one infusion of ANG II alone, followed by its infusion together with PGI2; the remainder received two identical infusions of ANG II alone as controls. 2. PGI2 administration was associated with a small fall in diastolic pressure (P less than 0.01) and a proportionally greater rise in heart rate (P less than 0.001). Small rises in basal plasma renin and ANG II concentrations and a fall in aldosterone concentration were not statistically significant. 3. The diastolic pressor response to ANG II was blunted during PGI2 infusion by comparison with controls (P less than 0.025); this diminution in response was greatest in patients who had initially been most sensitive to ANG II (P less than 0.02). 4. The evoked increment in plasma aldosterone during ANG II infusion was considerably reduced (P less than 0.005) in the presence of PGI2. 5. These data further support the hypothesis of a role for PGI2 in relation to the blunted pressor response to ANG II of normal pregnancy. The apparent inhibitory effects of PGI2 on aldosterone secretion may partly explain the previously described dissociation between the renin-angiotensin system and aldosterone in pregnancy.     

The role of adrenal medulla in endogenous dopaminergic inhibition of aldosterone secretion

Evidence has accumulated that aldosterone secretion is under endogenous dopaminergic inhibition. To examine potential sources of the dopamine thus inhibitorily acting in the adrenal zona glomerulosa, the responsiveness of aldosterone, plasma renin activity, prolactin, and plasma catecholamines to haloperidol, a dopaminergic antagonist, was studied in rats 6 weeks after unilateral adrenalectomy (Group B), 6 weeks after unilateral adrenal demedullation followed by contralateral adrenalectomy 5 days later (Group C), and in controls without any pretreatment (Group A). In Group C, there were increases in basal levels of norepinephrine (P less than 0.01), prolactin (P less than 0.02), and aldosterone (P less than 0.01). Basal plasma renin activity was also increased (P less than 0.05), epinephrine concentrations were decreased. Two hours after haloperidol 1 mg/kg b.wt. i.p., aldosterone levels were increased in Groups A + B (P less than 0.01) but unresponsive in Group C. Haloperidol-induced stimulation of prolactin and norepinephrine was not impaired by the surgical procedures. Epinephrine levels were increased by haloperidol only in groups A + B (P less than 0.002). In none of the groups were plasma renin activity or dopamine levels influenced by haloperidol. It is concluded that dopaminergic inhibition of aldosterone production is brought about neither by circulating dopamine nor by potential dopaminergic nerves accompanying arterial blood supply of the adrenal cortex but by dopamine originating directly in adrenal medulla.     

Effects of opioid antagonism on the haemodynamic and hormonal responses to exercise

1. Physical effort involves, along with an increase in the plasma concentration of beta-endorphin, profound adaptations of the circulation and the endocrine system. The effects of opioid antagonism on the responses of blood pressure, heart rate and several hormones to exercise were therefore studied in 10 normal men. They exercised in the supine position up to 33% and 66% of their maximal exercise capacity and received in a randomized double-blind cross-over protocol, either saline or naloxone (10 mg intravenously, followed by a continuous infusion of 10 mg/h). 2. Intra-arterial pressure and heart rate were continuously monitored, but were not affected by naloxone. 3. At rest, opioid antagonism produced a rise in plasma renin activity and in plasma adrenocorticotropin, cortisol and aldosterone, but only the stimulation of the two adrenocortical hormones differed significantly from the control experiments; at rest naloxone also prevented the fall in plasma adrenaline, which occurred with saline infusion. Furthermore, the exercise-induced rises in plasma angiotensin II, aldosterone, cortisol, noradrenaline and adrenaline were higher on naloxone than on saline, while a similar tendency was also present for the increases with exercise in plasma renin activity and plasma adrenocorticotropin. Neither at rest nor during exercise did opioid antagonism alter plasma lactate and glucose and serum insulin and growth hormone. 4. In conclusion, (1) endogenous opioids are not involved in the responses of blood pressure and heart rate to supine exercise; (2) at rest and during exercise, the endogenous opioids inhibit the secretion of adrenocorticotropin, aldosterone, cortisol, noradrenaline and adrenaline; (3) they also inhibit the plasma renin-angiotensin II system indirectly via the catecholamines.