Plasma adenosine 3′,5′ -cyclic monophosphate in human hypertension

In a previous study we observed an increase in urinary cyclic AMP in labile hypertension in the upright position and during isoproterenol infusion, in contrast to a decrease in control subjects. In the present study we measured the plasma level of cyclic AMP in control subjects and patients with various types of hypertension. We obtained the following results: (1) plasma cyclic AMP increases in response to upright posture in control subjects and hypertensive patients; (2) values of cyclic AMP in the recumbent and upright positions are comparable in control subjects and patients with essential hypertension, but are significantly higher in those with true renovascular hypertension due to bilateral renal artery stenosis; (3) propranolol inhibits the increase of plasma cyclic AMP in response to posture in control subjects, but has an opposite effect in labile hypertension where there is a further increase; (4) the rise in blood pressure in pheochromocytoma is associated with a considerable increase in plasma cyclic AMP.Present and previous data suggest that kidney handling of cyclic AMP is abnormal in hypertension, and that the specific defect may be related to the type of hypertension.     

Renal vein plasma adenosine 3',5'-cyclic monophosphate in renovascular hypertension.

The concentration of plasma adenosine 3'',5''-cyclic monophosphate (cyclic AMP) and plasma renin activity (PRA) were measured concomitantly in blood from both renal veins and in arterial blood in 22 hypertensive patients. In the nine patients with true renovascular hypertension the concentration of plasma cyclic AMP was greater in the venous effluent of the kidney affected by the renal artery stenosis than in that of the unaffected or less affected kidney. The arteriovenous difference in cyclic AMP concentration was less on the affected side in all but one patient. The arteriovenous differences in PRA identified the affected kidney as the source of hyper-reninemia and showed that renin release from the other kidney was suppressed. In the 13 patients with hypertension associated with but unrelated to renal artery stenosis there were no consistent patterns of cyclic AMP concentration or PRA in the venous effluent of the kidneys or of their arteriovenous differences. In renovascular hypertension the venous effluent of the kidney affected by renal artery stenosis contains not only more renin but also more cyclic AMP, owing to either increased cyclic AMP production or decreased excretion or extraction of cyclic AMP by the affected kidney. This unilateral increase in cyclic AMP concentration may become a complementary diagnostic feature of true renovascular hypertension.     

Comparison of atenolol and propranolol during insulin-induced hypoglycaemia.

The effects of atenolol, a new beta1-blocking drug, on pulse rate, sweating, and blood glucose levels during insulin-induced hypoglycaemia were studied in a double-blind crossover trial in eight normal subjects using placebo and propranolol as reference agents. The intensity of induced hypoglycaemia was identical for atenolol, propranolol, and placebo. Propranolol prolonged hypoglycaemia, but atenolol did not. Atenolol may therefore be safe for use in patients receiving insulin.     

Acute Intermittent Porphyria: Response of Tachycardia and Hypertension to Propranolol

In four young adult patients with acute attacks of acute intermittent porphyria tachycardia and hypertension were prominent features of the illness. Urinary catecholamine excretion was increased in both patients in whom it was measured. The effect of the beta-adrenergic blocking drug propranolol was assessed in each case. The dose varied from 40 to 240 mg daily. A response in the form of a reduction in heart rate and blood pressure was noted in each case, and in one case a marked alleviation of abdominal pain followed administration of the drug.Propranolol, when given in high dosage to rats, did not induce an increase in hepatic delta-aminolaevulic acid synthetase, an enzyme which is raised in human and drug-induced animal porphyria. The use of propranolol is therefore unlikely to aggravate or precipitate an attack of acute intermittent porphyria.     

Influence of electrically induced tachyarrhythmia on the release of cyclic AMP and PGE in canine coronary sinus blood and on the level of cyclic AMP in myocardial tissue

In anaesthetized open-chest dogs tachyarrhythmia (TA) was electrically induced by above-threshold stimuli via the right ventricle. During TA a significant increase in the release of PGE and cyclic AMP of 20% and 40% of the control levels, respectively, was observed in the canine coronary sinus blood (CSB), whereas the level of PGF2 alpha remained nearly unchanged under these conditions. The efflux of cyclic AMP corresponded with a concomitant increase in the left ventricular tissue level of this nucleotide by 59% during TA. Pretreatment with the beta-adrenergic blocking agent propranolol (1.0 mg/kg i.v.) prevented the TA induced changes in the level of PGE as well as cyclic AMP in the CSB and in the tissue levels of cyclic AMP. Propranolol alone was without any effect on the efflux of cyclic AMP, but decreased significantly the efflux of PGE by 32%. There was an increase in the activity of phosphorylase a in the myocardial tissue from 10% to 20% of the total (a + b) activity of this enzyme during TA, which could be abolished by propranolol pretreatment. The results suggest possible interrelationships between catecholamines, cyclic AMP and PGE.     

Renin--angiotensin antagonists and the regulation of blood pressure.

The role of the renin--angiotensin system in the regulation of blood pressure in dogs and in human subjects was assessed by the use of the nonapeptide converting enzyme inhibitor (CEI), permitting the following conclusions: 1) In the normal, sodium replete dog, the renin--angiotensin system plays little role in the regulation of blood pressure. 2) As sodium depletion progresses, the renin--angiotensin system becomes increasingly important in the maintenance of blood pressure. In the markedly hypovolemic animal, blocking the conversion of angiotensin I to angiotensin II leads to prolonged hypotension of shock-like levels. 3) The renin--angiotensin system is responsible for the initiation of renovascular hypertension. Blood pressure does not rise during chronic renal artery constriction when the generation of angiotensin II is prevented by the CEI. Although angiotensin II is essential for the initiation of the elevated blood pressure, the renin--angiotensin system plays a decreasing role in the maintenance of the chronic hypertension as sodium and water are retained, and plasma volume increases. 4) In congestive failure induced in the conscious dog by circulatory impairment, the renin--angiotensin--aldosterone system plays an essential role in the compensatory response. During chronic administration of the CEI, the animal cannot compensate even for a relatively mild degree of constriction, and remains hypotensive. In the dog with congestive failure, as in the dog with renovascular hypertension, plasma renin activity (PRA) and plasma aldosterone are elevated early in the syndrome; during this phase, injection of the nonapeptide produces a marked drop in blood pressure. With the retention of sodium and water, and expansion of plasma and extravascular fluid volumes, PRA and plasma aldosterone return to control levels in the new steady state. The inhibitor no longer produces a drop in blood pressure. Thus, the sequential changes in the renin--angiotensin--aldosterone system are remarkably similar in renovascular hypertension and congestive failure. 5) In the normal, salt replete human subject the renin--angiotensin system plays little role in the regulation of blood pressure either in the recumbent or upright posture. However, with relatively mild sodium depletion, the CEI transiently lowers blood pressure even in the recumbent subject. In the absence of angiotensin II such sodium-depleted subjects are unable to compensate when tilted upright, and faint within minutes.     

Increased resting metabolic rate and lipid oxidation in exercise-trained individuals: evidence for a role of beta-adrenergic stimulation.

This study investigated the contribution of beta-adrenergic stimulation to the increase in resting metabolic rate (RMR) and lipid oxidation observed in exercise-trained individuals. Nine trained and eight sedentary men were subjected to two testing sessions, during which these variables were measured before and for 3 h after the oral administration of propranolol or placebo. As expected, RMR and lipid oxidation were significantly higher in the trained subjects before the administration of propranolol and throughout the placebo test in comparison with sedentary controls. A significant decrease in RMR and lipid oxidation was induced by propranolol in the trained subjects, whereas no change was observed in the untrained group, and this effect of propranolol was sufficient to abolish the difference between the two groups at baseline and under the placebo condition. Propranolol also induced a significant reduction in heart rate and systolic blood pressure, but the response was comparable in the two groups. In conclusion, the results of this study show that beta-adrenergic stimulation is involved in the increase in RMR and lipid oxidation observed in highly trained individuals. Moreover, the absence of a training-propranolol interaction effect on heart rate and systolic blood pressure suggests the existence of some dissociation between the metabolic and cardiovascular effects of prolonged exercise training.     

Controlled Trial of Propranolol in Hypertension

A trial of oral propranolol as a hypotensive agent was designed to provide adequate treatment periods. Twenty-eight patients with essential hypertension, with a mean blood pressure of 190/111 mm. Hg, were controlled on 120-320 mg. of propranolol daily. Their mean treated blood pressure was 153/91. They then entered, on a randomized and double-blind basis, a cross-over trial of two 16-week periods, blood pressure being measured fortnightly. Propranolol caused a statistically significant fall in blood pressure when compared with placebo. When propranolol was withdrawn blood pressures rapidly rose to hypertensive levels, though not to untreated levels. No postural hypotension was found, but a small change in blood pressure levels on exercise was noted.     

Plasma immunoreactive N-terminal parathyroid hormone and cyclic AMP and cyclic GMP urinary levels in man after I. M. administration of two different doses of porcine calcitonin

The effects of acute porcine calcitonin (pCT) administration were studied in 11 healthy volunteers with no metabolic disease. Each subject was given, intramuscularly, 1 MRC unit of pCT in glycine vehicle, 160 units of pCT in gelatine vehicle, and placebo, according to a crossover design. The following parameters were studied: blood calcium, phosphorus and immunoreactive parathyroid hormone (iPTH); urine calcium, phosphorus, cyclic AMP and GMP. Both the pCT preparations produced, at the same time after administration, a hypocalcemic effect (P less than 0.01) which was not dose related, without any modification of urinary calcium excretion, implying that both doses are able to inhibit completely bone destruction. Despite the blood calcium decrease, no significant modifications in plasma iPTH levels were observed. pCT administration did not modify the urinary excretion of cyclic AMP, while it increased the urinary levels of cyclic GMP, particularly at the higher dose employed. Blood phosphorus decrease and urinary phosphate excretion increase were observed only after the administration of 160 MRC units of pCT. These observations suggest that the effects on urinary cyclic GMP and on blood and urine phosphorus are not mediated by PTH but could be the result of a direct action of calcitonin seen only when high doses are employed. In conclusion, one MRC unit of pCT is sufficient to inhibit bone resorption.     

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.     

Renin concentrations and effects of propranolol and spironolactone in patients with hypertension.

In a crossover study 32 patients with hypertension were randomly allocated to treatment with spironolactone 200 mg/day for two months, propranolol 320 mg/day for two months, and a combination of both drugs at half the dose. Between the treatments placebo was given for two months. Both spironolactone and propranolol lowered the blood pressure significantly in both positions. The initial plasma renin activity (PRA) levels ranged from 0-4 to 5-0 mug angiotensin I l-1 h-1, and there was a close correlation between these levels and the effects of the drugs: with increasing PRA the response to propranolol was better while the opposite was true for spironolactone. Spironolactone reduced the blood pressure more at eight than at four weeks, while no such difference could be shown for propranolol. Spironolactone and propranolol together decreased the blood pressure still further irrespective of the initial PRA. All patients achieved a normal supine blood pressure.     

Hemodynamic response to converting enzyme inhibition at rest and exercise in humans

The response of the systemic circulation to acute inhibition of the converting enzyme with 25 mg of oral Captopril (Squibb) was studied in six normal sodium-replete male volunteers at rest and during exercise, together with its effects on exercise capacity for graded uninterrupted exercise. In recumbent subjects at rest Captopril did not affect arterial pressure or heart rate, and plasma renin activity rose 2.5-fold (P less than 0.05). In subjects in the sitting position, at rest and during exercise until exhaustion, Captopril reduced mean brachial intra-arterial pressure by an average of 7 Torr in comparison to placebo (P less than 0.001). Captopril's hypotensive effect was caused by a reduction of systemic vascular resistance (P less than 0.01), without changes of cardiac output (measured by CO2 rebreathing), heart rate, or stroke volume. Plasma renin activity was significantly higher during Captopril (P less than 0.001). Peak oxygen uptake and exercise duration were the same after administration of Captopril or placebo. The data demonstrate that the renin-angiotensin system is not involved in the homeostasis of blood pressure in supine sodium-replete humans, but has a modest role in blood pressure regulation when posture is changed from supine to upright. The orthostatic effect of Captopril is maintained during upright exercise. Furthermore the reduction of systemic vascular resistance by Captopril does not affect peak oxygen uptake.     

An electron microscopic and biochemical study of the effects of propranolol on the glycogen autophagy in newborn rat hepatocytes

The effects of propranolol on the glycogen autophagy in newborn rat hepatocytes were studied by using biochemical determinations, electron microscopy and morphometric analysis. Propranolol lowered the liver cyclic AMP and cyclic AMP-dependent protein kinase activity. It also decreased the formyl-methionyl-leucyl-phenylalanine (FMLP)-inhibitable Ca2+-ATPase activity including lysosomal calcium uptake pump. The normal postnatal increase in the volume of autophagic vacuoles and the activity of acid glycogen-hydrolyzing alpha glucosidase were inhibited. Also, the degradation of glycogen inside the autophagic vacuoles was apparently inhibited. The activity of acid mannose 6-phosphatase was increased. These findings indicate that propranolol influences several steps in the sequence of events leading to the breakdown of glycogen in the autophagic vacuoles of newborn rat hepatocytes. This supports our previous studies suggesting that cyclic AMP regulates glycogen autophagy.     

Effect of nifedipine and propranolol on blood flow,venous compliance and blood pressure in essential hypertension

To determine the efficacy of nifedipine combined with propranolol in the treatment of hypertension, 23 patients with essential hypertension uncontrolled while they were receiving propranolol, 120 mg/d, entered a dose response trial of four 8-week periods while continuing propranolol therapy. Therapy during the four periods consisted respectively of a placebo, 30 mg/d of nifedipine, 30 or 60 mg/d of nifedipine, and 30 or 60 mg/d of nifedipine along with only 60 mg/d of propranolol. Studies of forearm blood flow and venous compliance were carried out in nine of the patients. Ten patients dropped out after the first period. The mean blood pressures while the patients were recumbent after the first, second and third periods were 163 ± 17/100 ± 6, 147 ± 13/89 ± 10 and 141 ± 19/84 ± 10 mm Hg respectively. There was no evidence of tolerance in the four patients who received 30 mg/d of nifedipine during the third period. There was a significant dose-diastolic pressure response (p < 0.0006) without a change in heart rate in the eight who received 60 mg/d of nifedipine during this period. After 16 weeks of therapy with nifedipine 11 patients had a diastolic pressure less than 90 mm Hg while recumbent. While mean blood pressure and heart rate for the group were not significantly increased at the end of the fourth period, in three of the patients the diastolic pressure while recumbent increased to over 90 mm Hg. This suggests that 120 mg/d of propranolol is the minimum dose required for concomitant therapy. Adverse symptoms were mild and transient. Forearm plethysmography showed that nifedipine induced arteriolar but not venous dilation and that propranolol attenuated the vasodilator effect of nifedipine. The author concludes that nifedipine was safe and effective in combination with propranolol in this group of patients with essential hypertension.     

Effect of prostaglandin E1 on renin and aldosterone in hypertensive patients.

The effect of prostaglandin E1 (PGE1) on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was studied in the hypertensive subjects treated with or without 75 mg indomethacin or 60 mg propranolol for a week. Subsequent to the treatment with indomethacin for a week, PRA and PAC levels were decreased as compared to the control, without changes in the blood pressure and heart rate. During the infusion of PGE1, the blood pressure was decreased and the pulse rate was increased. PRA and PAC levels were also elevated. These changes of parameters were not different between the control and the indomethacin-treated subjects. PRA and PAC were suppressed after the treatment with propranolol. With the infusion of PGE1, the level of PRA was not significantly elevated, while, PAC was significantly increased by the infusion of 100 ng/Kg/min of PGE1. During the infusion of PGE1, the blood pressure was decreased while the pulse rate was increased in the subjects treated with propranolol. However, the elevation of the pulse rate was less remarkable than the control. These data indicate that PGE1 have important roles in the regulation of the release of renin and aldosterone. These findings also suggest that PGE1 may act to stimulate the secretion of aldosterone in man.     

Circadian Variation of Cyclic AMP in the Rat Pineal Gland

Abstract: This study was carried out to investigate circadian variation of cyclic AMP contents in the rat pineal glands, using the high-energy microwave radiation technique. The pattern of cyclic AMP concentration in the pineal gland showed a distinct circadian variation, with the maximum level at 0200 and the lowest at 1400. The administration of propranolol completely blocked the dark-induced increase in the pineal cyclic AMP level at 0200, and the administration of isoproterenol induced a threefold, rapid increase in the cyclic AMP level at 1400, although it did not change the level at 0200.     

Effects of catecholamines on ammoniagenesis and gluconeogenesis by renal cortex in vitro

Norepinephrine (arterenol) and a synthetic catecholamine, isoproterenol, increase the production of ammonia and glucose from glutamine and glutamate by rat renal cortical slices in vitro. The stimulation of both ammonia and glucose production by isoproterenol was greater than that observed with identical molar concentrations of arterenol. Isoproterenol markedly increased the concentration of cyclic AMP in rat renal cortical slices. Addition of propranolol, a β-adrenergic blocking agent, prevented the increase of cyclic AMP levels induced by isoproterenol. Cyclic AMP increased both ammoniagenesis and gluconeogenesis by kidney cortex. Thehe increase in ammonia production produced by isoprotenol was blocked by the addition of propranolol. It is concluded that the increase in ammonia and glucose production caused by isoproterenol is mediated through the release of cyclic AMP.     

An electron microscopic and biochemical study of the effects of cyclic 3', 5'-AMP, ergotamine or propranolol on the lysosomes of newborn rat hepatocytes.

The effects of cyclic 3',5'-AMP, ergotamine or propranolol on newborn rat liver were studied by using biochemical assays, electron microscopy and quantitative morphometry. Cyclic AMP enhanced the normal postnatal rise in the glycogen-hydrolysing activity of acid alpha 1, 4 glucosidase but had no effect on the maltose-hydrolysing activity of the enzyme. The results suggest that these activities may be due to different enzymes. Propranolol prevented the postnatal increase in the glycogen-hydrolysing activity of acid glucosidase and the breakdown of lysosomal glycogen, indicating that these phenomena represent beta-adrenergic functions in newborn rats. Ergotamine also inhibited the postnatal increase in this activity and the lysosomal glycogen mobilization. A reasonable explanation for these results is that ergotamine interferes with the action or formation of cyclic AMP.     

Role of the renal nerve in glucocorticoid hypertension

The present study was designed to investigate the involvement of the renal nerve in glucocorticoid hypertension and to assess the role of the renin-angiotensin system in dexamethasone-induced hypertension. The elevated blood pressure in dexamethasone treated rats showing a significant increase in plasma renin concentration (PRC) and activity (PRA) was attenuated dose-dependently by the angiotensin I converting enzyme (ACE) inhibition. Bilateral renal denervation caused a partial decrease in the elevated blood pressure, abolished the increased PRC and PRA, and reduced the dose-dependent decrease in blood pressure with ACE inhibition in dexamethasone treated rats. Although the reduction in body weight and increases in urine volume, urinary sodium excretion and hematocrit were clearly seen following dexamethasone administration, dexamethasone-treated renal denervated rats showed the same degree of change in any of the variables as dexamethasone-treated sham-operated rats. Thus, our results indicate that the stimulation of the renin-angiotensin system through the activation of the renal nerve may be partially responsible for the dexamethasone-induced high blood pressure and, therefore, bilateral renal denervation reduces, partially but significantly, the elevated blood pressure, suggesting that the attenuation of oversecretion of renin contributes to the lowering of the blood pressure.     

Enhanced response of plasma prolactin to metoclopramide during chronic converting enzyme inhibition

The effect of chronic converting enzyme inhibition with enalapril on the PRA, PRL and plasma aldosterone responses to metoclopramide was studied in 10 patients with mild to moderate essential hypertension. Enalapril reduced supine blood pressure and increased heart rate significantly. PRA and urinary sodium excretion rose significantly. PRA levels did not change after metoclopramide neither during placebo nor during enalapril. The aldosterone response to metoclopramide was not altered by enalapril, indicating that this response is independent of the renin-angiotensin system. The PRL response to metoclopramide was considerably enhanced after 4 weeks of treatment with enalapril. It is proposed that enalapril, by decreasing the formation of angiotensin II, increases the prolactin reserve.