Pressor effect of arginine vasopressin in progressive autonomic failure

The blood pressure (BP) and heart rate (HR) responses to 5 min incremental intravenous infusions of noradrenaline (NA) and arginine vasopressin (AVP) were investigated both in patients with progressive autonomic failure (PAF) and in normal volunteers. Stepwise infusion of NA at rates of 300-3000 pmol min-1 kg-1 produced a bradycardia and a dose related increase in BP in normal subjects. In subjects with PAF there was no significant HR response but the dose-BP response was shifted to the left with significant pressor responses at infusion rates of 60-300 pmol min-1 kg-1. Stepwise infusion of AVP at 0.2-5.0 pmol min-1 kg-1 caused transient bradycardia but no pressor response in seven normal volunteers. Further increases in AVP infusion in three other subjects achieved plasma AVP levels as high as 3000-4000 pmol/l, and still no significant pressor response was observed. Stepwise infusion of AVP at 0.05-2.0 pmol min-1 kg-1 in the eight subjects with PAF resulted in a pressor response without any change in HR. During this infusion plasma AVP increased from 0.8 +/- 0.2 (mean +/- SEM) to 30 +/- 2 pmol/l. A significant pressor response was already apparent at a plasma AVP level of 5.5 +/- 1.8 pmol/l.     

Plasma catecholamines, plasma renin activity and plasma aldosterone in tetraplegic man, horizontal and tilted.

1. Plasma catecholamines, plasma renin activity, plasma aldosterone and haematocrit were measured in four subjects with physiologically complete cervical spinal cord transections, before, during and after head-up tilt to 45 degrees for 30 min. Plasma catecholamines were measured in five normal male volunteers in the supine position and after head-up tilt to 45 degrees for 10 min. 2. After 10 min of head-up tilt, the plasma noradrenaline rose 14% in the tetraplegic patients and 115% in the control subjects. These findings indicate a failure of sympathetic activity in response to head-up tilt in the tetraplegic patients, probably caused by interruption of pathways by which the brain normally controls sympathetic outflow. 3. In the tetraplegic patients the resting plasma renin activities were above normal, and rose more quickly and greater on head-up tilt than in published studies of normal subjects. It is likely that the renal baroreceptors are important in the control of renin release. 4. In the tetraplegic patients, there was a late rise in plasma aldosterone which was probably due to the elevation in plasma renin activity.     

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

gamma-L-Glutamyl-L-dopa is a dopamine pro-drug, relatively specific for the kidney in normal subjects

gamma-L-Glutamyl-L-dopa was given by intravenous infusion to eight normal subjects at doses of 12.5 and 100 micrograms min-1 kg-1. Both doses of the dipeptide resulted in an increase in mean urinary sodium excretion. Mean effective renal plasma flow rose at both doses, but mean glomerular filtration rate increased only at the lower dose. There was a fall in mean plasma renin activity after the infusion of both 12.5 and 100 micrograms min-1 kg-1. Mean urine free dopamine excretion increased by 280- and 2500-fold at infusion rates of 12.5 and 100 micrograms min-1 kg-1 respectively. Mean plasma free dopamine rose at both doses but the increase at 12.5 micrograms min-1 kg-1 was not to a level previously associated with systemic effects of the catecholamine. On administration of the dipeptide at 12.5 micrograms min-1 kg-1 there were no changes in blood pressure or heart rate, but at the higher dose there was a fall in diastolic blood pressure. At a dose of 12.5 micrograms min-1 kg-1 in man, there is kidney specific conversion of gludopa to dopamine.     

Neuronal re-uptake of noradrenaline by sympathetic nerves in humans.

1. Plasma concentrations of [3H]dihydroxyphenylglycol, the intraneuronal metabolite of noradrenaline, were examined during intravenous infusion of [3H]noradrenaline in 43 subjects, to assess the nature of its formation. Noradrenaline re-uptake by sympathetic nerves was estimated in 11 subjects from the effects of neuronal uptake blockade with desipramine on noradrenaline clearance and plasma concentrations of [3H]dihydroxyphenylglycol and endogenous dihydroxyphenylglycol. In seven subjects noradrenaline re-uptake and spillover into plasma were examined before and during mental arithmetic or handgrip exercise. 2. During infusion of [3H]noradrenaline, plasma [3H]dihydroxyphenylglycol increased progressively, indicating its formation from previously stored [3H]noradrenaline leaking from vesicles as well as from [3H]noradrenaline metabolism immediately after removal into sympathetic nerves. Thus, to estimate noradrenaline re-uptake, the amount of [3H]dihydroxyphenylglycol derived from [3H]noradrenaline metabolized immediately after removal into the sympathetic axoplasm must be isolated from that derived from [3H]noradrenaline sequestered into vesicles. 3. At rest in the supine position the rate of noradrenaline re-uptake was 474 +/- 122 pmol min-1 kg-1, 9.5-fold higher than the rate of spillover of noradrenaline into plasma (49.6 +/- 6.4 pmol min-1 kg-1). Noradrenaline re-uptake and spillover into plasma were both increased during mental arithmetic and isometric handgrip exercise.     

Blood pressure response to chronic low-dose intrarenal noradrenaline infusion in conscious rats

Sodium chloride solution (0.9%) or noradrenaline in doses of 4, 12 and 36 micrograms h-1 kg-1 was infused for five consecutive days, either intrarenally (by a new technique) or intravenously into rats with one kidney removed. Intrarenal infusion of noradrenaline caused hypertension at doses which did not do so when infused intravenously. Intrarenal compared with intravenous infusion of noradrenaline caused higher plasma noradrenaline concentrations and a shift of the plasma noradrenaline concentration-blood pressure effect curve towards lower plasma noradrenaline levels. These results suggest that hypertension after chronic intrarenal noradrenaline infusion is produced by relatively higher levels of circulating noradrenaline and by triggering of an additional intrarenal pressor mechanism.     

The actions of saralasin on the renal circulation of man and dog; evidence for a sympathetic neural component to vasoconstriction

Abstract. The mechanism of renal vasoconstriction produced by saralasin and its dependence on the sympathetic nervous system was investigated in subjects with mild essential hypertension and in anaesthetized dogs. Fluid or saline was given to maximize agonist vasoconstrictor responses. The changes in renal hae-modynamics produced by intravenously infused saralasin (doses 0.01–10 μg kg^-1 min^-1) were assessed by clearance methods. In the patients, it induced a dose-related renal vasoconstriction which correlated with a rise in plasma noradrenaline levels. In dogs with innervated kidneys it also caused vasoconstriction. But in dogs with denervated kidneys it caused vasodilatation. Infusion at the highest dose directly into the renal artery of denervated kidneys induced only vasodilatation. We conclude that one component of the renal vasoconstriction that occurs with intravenous saralasin infusions is mediated by the renal nerves.     

Absence of adrenergic mediation of agonist response to [Sar1,Ala8]angiotensin II in conscious normotensive and hypertensive dogs.

1. In the conscious normotensive and two-kidney Goldblatt hypertensive dog a transient agonist response to the intravenous infusion of saralasin (1 microgram min-1 kg-1)was manifested by a small increase in blood pressure (6-12) mmHg) and 28-30% increase in renal vascular resistance. 2. These increases in blood pressure and renal vascular resistance were unaffected by administration of either phentolamine or guanethidine. 3. The agonist response in the conscious dog is most likely accounted for by a direct action of saralasin on vascular angiotensin receptors.     

Metabolic effects of low-dose dopamine infusion in normal volunteers

1. Dopamine in 5% (w/v) D-glucose was infused into five healthy male volunteers at doses of 2, 5 and 10 micrograms min-1 kg-1 over three sequential periods of 45 min each. 2. Oxygen consumption, respiratory exchange ratio, blood glucose concentration and plasma levels of free fatty acids, glycerol, lactate, dopamine, adrenaline and noradrenaline were measured. The results were compared with values obtained during infusion over the same time period of the corresponding volumes of 5% (w/v) D-glucose alone. 3. Energy expenditure calculated from the oxygen consumption and the respiratory exchange ratio was higher than control values during infusion of dopamine (P less than 0.001, analysis of variance) specifically at a rate of 10 micrograms min-1 kg-1 (P less than 0.05) when it was 14% higher, but not at a rate 2 of or 5 micrograms min-1 kg-1. The plasma noradrenaline concentration was 74 and 230% and the blood glucose concentration was 21 and 36% higher than control values at 5 and 10 micrograms of dopamine min-1 kg-1, respectively (P less than 0.01). At 10 micrograms of dopamine min-1 kg-1 the plasma free fatty acid concentration was 70% and the plasma glycerol concentration was 80% higher than during the control infusion (P less than 0.01). The respiratory exchange ratio and the plasma lactate concentration were the same in the two groups and did not alter during the dopamine infusion. The plasma adrenaline concentration rose significantly (P less than 0.01), but only transiently, during dopamine infusion at a rate of 2 micrograms min-1 kg-1. 4. Dopamine at low doses has metabolic effects. It increases the blood glucose concentration and the circulating noradrenaline level at an infusion rate of 5 micrograms min-1 kg-1. It increases energy expenditure and circulating free fatty acid and glycerol levels at an infusion rate of 10 micrograms min-1 kg-1, presumably due to stimulation of lipolysis.     

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.     

Cardiac and whole-body [3H]noradrenaline kinetics during adrenaline infusion in man.

1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system, the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min-1 kg-1) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization, in whom beta-adrenoceptor antagonists had been discontinued for 72 h. 2. At rest and compared with placebo, infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 +/- 29 pg/ml to 245 +/- 29 pg/ml (P less than 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 +/- 40 ng min-1 m-2 to 358 +/- 41 ng min-1 m-2, P less than 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion, but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease. 3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions. 4. Infusion of adrenaline to produce 'physiological' increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release, as assessed by whole-body noradrenaline spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma and Urinary Dopamine: Studies During Fasting and Exercise and in Tetraplegic Man

Dopamine, noradrenaline and adrenaline were measured in plasma and in urine, using double-isotope derivative techniques, in 46 normal subjects and in 17 tetraplegic patients with physiologically complete cervical spinal cord transections above the sympathetic outflow. Dopamine was present in plasma in normal subjects in a concentration of 0.33 μg/1 ± 0.06 (SEM). Twenty-four hour urinary excretion of dopamine averaged 248 yg ± 22. There was a significant correlation between the 24 h urinary excretion of dopamine and of noradrenaline. In the normal subjects plasma dopamine and the urinary excretion of dopamine did not change during three days of fasting while urinary excretion of adrenaline increased twofold. In the normal subjects exercise significantly increased plasma dopamine from 0.25 μg/1 to 0.43 μg/1, but significantly decreased the urinary excretion of dopamine. Exercise significantly increased the excretion of noradrenaline. In the tetraplegic patients the plasma dopamine concentration and the urinary excretion of dopamine were lower but not significantly different from the corresponding values in the normal subjects. Plasma noradrenaline and the urinary excretion of noradrenaline and adrenaline were significantly lower in the tetraplegic patients. It is concluded that dopamine is present in human plasma in concentrations similar to that of noradrenaline. Free dopamine in plasma and urine of normal subjects is not dependent on food intake. Urinary dopamine may be derived from circulating dopamine. Urinary dopamine does not necessarily appear to reflect changes in plasma dopamine. The relationship between plasma dopamine and changes in adrenergic nervous activity deserves further investigation.     

The effect of tyramine, noradrenaline, and angiotensin on the blood pressure in hypertensive patients with aldosteronism and low plasma renin

Abstract The reactivity to the pressor action of tyramine, noradrenaline, and angiotensin was determined in 9 patients with hypertension, aldosteronism and low plasma renin concentration (4 patients with solitary adrenal adenomas, 3 patients with nodular adrenal hyperplasia, 2 patients with unknown adrenal status). In 7 patients tests were repeated following unilateral or subtotal adrenalectomy respectively. For comparison, 5 patients with phaeochromocytoma, 10 patients with benign essential hypertension, and 12 normotensive control subjects were studied. — In the hypertensive patients with aldosteronism and low plasma renin, responsiveness to tyramine was significantly reduced. In contrast, pressor response to noradrenaline was in the normal range, and sensitivity to angiotensin was increased. Following adrenal surgery, sensitivity to tyramine increased in all cases but one, sensitivity to noradrenaline did not change significantly, and responsiveness to angiotensin decreased in all cases but one. — It is discussed that the reduced pressor effect of tyramine in the hypertensive patients with aldosteronism is due to a disturbance of adrenergic function which may be of importance for the diminished production of renin in these forms of hypertension.     

Plasma dihydroxyphenylglycol for estimation of noradrenaline neuronal re-uptake in the sympathetic nervous system in vivo

1. Neuronal re-uptake is the primary means for terminating the actions of endogenously released noradrenaline. A portion of the recaptured noradrenaline is deaminated to form dihydroxyphenylglycol. The present report describes a technique using plasma dihydroxyphenylglycol for estimation of the rate of neuronal reuptake of endogenous noradrenaline in vivo. 2. Neuronal re-uptake of noradrenaline in the sympathetic nervous system of the rat was estimated from the effects of neuronal uptake blockade with desipramine on three variables: (i) the plasma clearance of intravenously infused 3H-labelled noradrenaline, (ii) the plasma concentration of endogenous dihydroxyphenylglycol, and (iii) the plasma concentration of 3H-labelled dihydroxyphenylglycol formed from infused 3H-labelled noradrenaline. 3. Desipramine decreased plasma dihydroxyphenylglycol by 36%, this representing the fraction of dihydroxyphenylglycol in plasma that was derived from recaptured noradrenaline. After desipramine, the decrease in the rate of neuronal uptake of 3H-labelled noradrenaline was 9.7 times that of the decrease in the plasma spillover of 3H-labelled dihydroxyphenylglycol. Since the appearances in plasma of dihydroxyphenylglycol from unlabelled and 3H-labelled noradrenaline were similar, the neuronal re-uptake of endogenous noradrenaline could be assumed to be 9.7 times as much as the plasma spillover of dihydroxyphenylglycol that was derived from recaptured noradrenaline (0.15 nmol min-1 kg-1). 4. The rate of neuronal re-uptake of endogenous noradrenaline was estimated to be 1.45 nmol min-1 kg-1, whereas the plasma spillover of noradrenaline was 0.127 nmol min-1 kg-1. Thus, only a small fraction (less than 9%) of the noradrenaline released into the synaptic cleft spills over into the circulation.     

Metabolic effects of dobutamine in normal man.

1. Dobutamine in 5% (w/v) D-glucose was infused at sequential doses of 2, 5 and 10 micrograms min-1 kg-1, 45 min at each dose, into eight healthy male subjects, and the effects were compared with those produced by infusion of the corresponding volumes of 5% (w/v) D-glucose alone. 2. The energy expenditure increased and was 33% higher than control (P less than 0.001) at 10 micrograms of dobutamine min-1 kg-1. The respiratory exchange ratio decreased from 0.85 (SEM 0.02) before infusion to 0.80 (SEM 0.01) at 10 micrograms of dobutamine min-1 kg-1, but did not alter during the placebo infusion (P less than 0.001). 3. Plasma noradrenaline concentrations were lower during the dobutamine infusion compared with during the infusion of D-glucose alone (P less than 0.025). Plasma dopamine concentrations remained below 0.1 nmol/l throughout both infusions. 4. Compared with during the placebo infusion, the blood glucose concentration decreased (P less than 0.001), the plasma glycerol and free fatty acid concentrations increased by 150 and 225%, respectively (both P less than 0.001), and the plasma potassium concentration decreased from 3.8 (SEM 0.07) to 3.6 (SEM 0.04) mmol/l (P less than 0.01) during dobutamine infusion. The plasma insulin concentration increased at 2 and 5 micrograms of dobutamine min-1 kg-1 (P less than 0.001) with no further rise at 10 micrograms of dobutamine min-1 kg-1. 5. Compared with during the placebo infusion, the systolic and diastolic blood pressures and the heart rate increased during dobutamine infusion (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute and chronic administration of idazoxan on blood pressure and plasma catecholamine concentrations of rats

To test the hypothesis that alpha-2 adrenoceptor antagonists can modulate sympathetic nerve release of norepinephrine in vivo through blockade of peripheral prejunctional alpha-2 adrenoceptors, acute and chronic effects of the alpha-2 adrenoceptor antagonist idazoxan on mean arterial pressure (MAP), heart rate and plasma catecholamine concentrations have been investigated in conscious and anesthetized rats. In normotensive rats, a single i.v. dose of idazoxan (300 micrograms kg-1) caused an immediate 2-fold increase in plasma concentration of norepinephrine and epinephrine, a transient increase in heart rate but no significant change in MAP. Plasma norepinephrine concentration of conscious normotensive rats increased significantly during a 4-hr i.v. infusion of idazoxan (300 micrograms kg-1 hr-1) with no concomitant changes in MAP or heart rate. In anesthetized spontaneously hypertensive rats, the increases in plasma norepinephrine concentration and heart rate caused by i.v. idazoxan (300 micrograms kg-1) were accompanied by a significant decrease in MAP. The increase in plasma norepinephrine after idazoxan in spontaneously hypertensive rats was much greater than that produced by an equihypotensive dose of the vasodilator hydralazine. Normotensive rats treated continuously for 7 days with s.c. idazoxan (7.5 mg kg-1 day-1) had similar blood pressures and plasma catecholamine concentrations to vehicle-treated rats. These results suggest that idazoxan causes a greater increase in plasma norepinephrine concentration than that which can be attributed to baroreceptor stimulation. Blockade of prejunctional alpha-2 adrenoceptors by idazoxan may, therefore, increase release of norepinephrine from peripheral sympathetic nerves of anesthetized and conscious rats. This effect is short-lived and does not influence blood pressure of normotensive rats.     

Captopril enhances vascular and adrenal responsiveness to angiotensin II in essential hypertension

The converting-enzyme inhibitor captopril (25-50 mg orally every 6 h for 66 h) was used to dissociate the circulating levels of angiotensin II (ANG II) from changes in sodium balance in 11 patients with normal renin essential hypertension on 10 mmol of sodium/day intake. Pressor, renal vascular and adrenal responses to graded infusions of ANG II (0.3, 1 and 3 pmol kg-1 min-1) were measured before and after captopril administration. Systemic vascular responses were assessed by measuring diastolic blood pressure (DBP), renovascular responses by measuring p-aminohippurate (PAH) clearance and adrenal responses by measuring plasma aldosterone. After receiving captopril for 66 h the hypertensive subjects showed a significantly (P less than 0.004) enhanced blood pressure response to the infused ANG II but not to noradrenaline when compared with the response before captopril. ANG II (3 pmol kg-1 min-1) also produced a significantly (P less than 0.03) greater reduction in PAH clearance after (-194 +/- 40 ml/min) compared with before (-104 +/- 15 ml/min) captopril. These results suggest that the responsiveness to ANG II in these two target tissues is determined by the circulating ANG II level. In the adrenal gland the aldosterone responses to ANG II also were significantly greater after (P less than 0.01) than before captopril (increment at 3 pmol kg-1 min-1: 660 +/- 88 vs 381 +/- 94 pmol/l). These results are in distinct contrast with the responses previously reported for normotensive subjects and support the hypothesis that the regulation of aldosterone secretion is altered in subjects with essential hypertension.     

Effect of bromocriptine on neurogenic vasoconstriction in the isolated autoperfused hindquarters of the rat

The effects of local administration of bromocriptine were studied in the isolated autoperfused hindquarters of the rat, and compared to the actions of apomorphine and pergolide. Local injection of bromocriptine (1 microgram kg-1) (into the hindquarters) did not alter perfusion pressure, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains at all frequencies used (0.5-10 Hz; 5 ms; 35 V). Bromocriptine (1 microgram kg-1) did not alter the increases in perfusion pressure induced by local administration of noradrenaline. The effects of local administration of apomorphine (1 microgram kg-1) and pergolide (1 microgram kg-1) were similar to that of bromocriptine. The inhibitory effect by bromocriptine, apomorphine and pergolide of the stimulation-evoked pressor responses was completely antagonized by intravenous administration of the dopamine receptor antagonist sulpiride (0.3 mg kg-1) but was not by the alpha 2-adrenoceptor antagonist yohimbine (1 mg kg-1). In this dose, yohimbine antagonized the inhibitory effect of the alpha-adrenoceptor agonist clonidine (1 microgram kg-1). The inhibitory effect of clonidine was not altered by sulpiride but was antagonized by yohimbine. The results indicate that bromocriptine like apomorphine and pergolide inhibit neurally-induced pressor responses in the autoperfused hindquarters of the rat by stimulation of presynaptic dopamine receptors. Stimulation of these receptors leading to a fall in noradrenaline release and consequently of vasomotor tone, might at least in part explain the vasodilatator effects of bromocriptine in the rat.     

Effects of the angiotensin II antagonist 1-sar-8-ala-angiotensin II in hypertension in man

The angiotensin II antagonist 1-sar-8-ala-angiotensin II (saralasin) was infused in forty-six patients with hypertension of various aetiology (essential, renal arterial or parenchymal disease, primary hyperaldosteronism), before and/or during sodium volume depletion obtained by chlorthalidone and low sodium diet. When saralasin was infused in twenty-five patients ingesting 130 mmol of sodium per day, including patients with proven renovascular hypertension, the changes in mean arterial pressure and ranged from +10 to -7 mmHg (mean: +0.20 mmHg) and were not related to the plasma renin concentration (PRC) (r = -0.11). During sodium volume depletion, saralasin induced changes in mean arterial pressure, ranging from +21 to -76 mmHg, which were closely related to log PRC (n = 32; r = -0.87). Combined sodium depletion and antagonism of angiotensin II 'normalized' mean arterial pressure (less than or equal to 100 mmHg) in twenty-one of the thirty-two patients, while pressure remained between 106 and 147 mmHg in eleven 'poor' responders, so that pressor mechanisms other than sodium volume and angiotensin must be responsible for the remaining elevation of pressure in these patients. The study indicates that arterial pressure is not dependent on the immediate pressor effects of angiotensin II in sodium replete patients, and in sodium deplete subjects whose PRC remains low, while it is at least partly angiotensin II dependent during sodium volume depletion in the others. The results cast doubts on the clinical usefulness of saralasin in the investigation of patients with hypertension, when studied in the conditions of the present study.     

Subcutaneous and muscle blood flow during dopamine infusion in man

Subcutaneous fat tissue and skeletal-muscle blood flow was measured in six male volunteers using the local 133Xe-washout method. Measurements were obtained before and during intravenous dopamine infusion in non-pressor (1 microgram kg-1 min-1) and pressor infusion rates (3-6 micrograms kg-1 min-1). During non-pressor infusion rate the systolic and diastolic arterial pressure and heart rate remained unchanged. When pressor dose dopamine was infused the systolic and mean arterial pressures increased significantly, whereas the diastolic pressure and the heart rate were left unchanged. The blood flow increased progressively from control values in both subcutis (control: 2.9 +/- 0.2, non-pressor: 5.0 +/- 1.6, pressor: 9.1 +/- 0.4 ml min-1 100 g-1, mean +/- SEM) and in skeletal muscle (control: 1.2 +/- 0.2, non-pressor: 1.5 +/- 0.2, pressor: 1.9 +/- 0.4 ml min-1 100 g-1, mean +/- SEM) and was significantly different from baseline values at any dopamine infusion rate. Side-effects were observed only at pressor dose infusion. It is concluded that dopamine in humans seems to possess vasodilatoric properties in subcutaneous fat tissue, and in skeletal muscles.