Discontinuation syndrome after continuous infusion of clonidine in the spontaneously hypertensive rat

In conscious spontaneously hypertensive rats prepared with permanent indwelling aortic catheters the continuous infusion of clonidine (500 μg/kg/day) via an ALZET miniosmopump induced significant reductions in blood pressure and heart rate. These effects were well sustained during 12 days of treatment. A marked overshoot in heart rate was observed following withdrawal of clonidine administration. The tachycardia persisted for more than 36 hours. Mean arterial pressure exceeded control level slightly in the immediate withdrawal period only, whereas significant blood pressure lability was observed for more than 36 hours. These withdrawal symptoms were accompanied by an elevation of plasma noradrenaline concentration. The present study shows the consistent antihypertensive and bradycardic activities of clonidine during 12 days of infusion in spontaneously hypertensive rats. Furthermore, this model may provide a useful tool in the study of withdrawal phenomena of antihypertensive drugs.     

Arterial hypertension caused by low renin: comparison of the calcium antagonist nifedipine and the ACE-inhibitor enalapril as to antihypertensive efficacy

The aim of this study was to compare the clinical effects of calcium-entry blocker Nifedipine and ACE-inhibitor Enalapril in hypertensive patients with glucose intolerance that have lower plasma renin activity. A blood sample for basal PRA was obtained from 21 subjects; then, 11 patients received Nifedipine (20 mg. b.i.d.) and 10 Enalapril (20 mg. q.d.). The extent of blood pressure fall after 12 weeks of treatment was inversely related to basal PRA levels in Nifedipine treated group only; however, the hypotensive effect of both drugs was comparable.     

Renin-dependency of glycyrrhizin-induced pseudoaldosteronism

A prospective study was carried out on 12 patients with chronic hepatitis who were taking 546 mg/day of glycyrrhizin for 4 weeks in order to identify the factors responsible for the development of hypertension and hypokalemia. In 5 patients, blood pressure increased and serum potassium decreased after the treatment (responders). In the remaining 7 patients, these values were unchanged (nonresponders). There were no significant differences in age, plasma aldosterone, the catecholamine concentrations or serum transaminases. The basal plasma renin activity (PRA) in the responders was more than 1.5 ng/m/h (2.5 +/- 0.3 ng/m/h), while that in the non-responders was less than 1.5 ng/m/h (0.7 +/- 0.1 ng/ml/h). Furthermore, a positive correlation between the basal RPA and the changes in blood pressure, and a negative correlation between the basal PRA and the changes in potassium were found. These results suggest that patients with higher PRA levels are more likely to develop hypertension and hypokalemia when treated with glycrrhizin.     

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.     

The effects of acebutolol alone and in combination with furosemide or hydralazine in experimentally induced hypertensive G-minipigs

Experimentally induced hypertensive G-minipigs were used for assessing the antihypertensive effects of acebutolol, a cardioselective beta-adrenergic blocking agent. In the acute experiment, six females were used. Acebutolol (3 mg/kg, i.v.) alone or in combination with furosemide (1 mg/kg, i.v.) or hydralazine (1 mg/kg, i.v.) was administered through an implanted catheter. In the chronic experiments, five females received oral acebutolol (100-200 mg/day). The blood pressure, heart rate, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were used as parameters. In the acute experiment, there were no marked changes in the blood pressure or heart rate during the nondosing period. Acebutolol alone caused a marked decrease in the blood pressure and heart rate. In the two combination tests, combined administration with acebutolol and furosemide had a greater effect on the blood pressure and heart rate than did acebutolol alone. A combined acebutolol and hydralazine regimen caused a slight reduction not only in the blood pressure, but also in the heart rate compared with acebutolol alone. PRA and PAC remained essentially constant, with minor fluctuations, throughout the nondosing period. Following the injection of acebutolol alone, PRA showed an elevation with a significant rise after three hours and PAC showed a tendency to increase. PRA and PAC generally tended to increase in the case of combined administration with furosemide or hydralazine, but these tendencies were less conspicuous than with acebutolol alone. On the other hand, chronic treatment with acebutolol produced a significant decrease in the heart rate from two weeks after the administration and in the blood pressure from four weeks.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Use of nonlinear methods to assess effects of clonidine on blood pressure in spontaneously hypertensive rats

In spontaneously hypertensive rats (SHR),chronic infusion of clonidine failed to decrease blood pressure andblood pressure variability. We used nonlinear methods to get a deeperinsight on the effects of clonidine on blood pressure dynamics. For 24 h and 4 wk, clonidine (0.1 mg · kg¹ · day¹sc) was infused by minipumps in the conscious SHRs, and, for comparison, a vehicle was infused in SHRs and in Wistar-Kyoto rats.Blood pressure was recorded for 30 min before and after treatments. Weused the Lyapunov exponent, approximated by the inverse of thel_max indexderived from the recurrence plot method, to characterize nonlineardynamics. Before treatment,l_max index ofblood pressure was lower (P < 0.01)in the SHRs than in the Wistar-Kyoto rats. Clonidine significantlyincreased l_max(P < 0.01) to the level observed innormotensive rats, at 24 h and up to 4 wk after infusion. We concludethat clonidine has a significant chronic effect on blood pressuredynamics, as evidenced by nonlinear methods. Our study also suggeststhat the mechanisms governing blood pressure variations are nonlinear.

     

Adrenergic and dopaminergic regulation of circulating beta-endorphin-like immunoreactivity in hypertension.

The central alpha-2-adrenergic receptor agonist, clonidine (300 micrograms daily) significantly increased the plasma beta-endorphin-like immunoreactivity (beta ELI) in 12 patients with mild to moderate essential hypertension in a randomized, crossover study. A significant linear correlation between the increase in plasma beta ELI and the decrease in blood pressure (both systolic and diastolic) was found after clonidine administration. The role of the reduced central sympathetic tone, induced by alpha-2-adrenoceptor stimulation, in the elevation of circulating beta ELI can be suggested. The plasma beta ELI increased also significantly after the dopaminergic D-2 receptor agonist, bromocryptine treatment, (5 mg, daily) in 13 patients with borderline and mild essential hypertension in a randomized, crossover study. A significant drop in circulating noradrenaline and in arterial blood pressure and a significant linear correlation between the changes of plasma noradrenaline level and blood pressure was found after bromocryptine administration. There was no correlation between the rise in plasma beta ELI and the decrease in blood pressure after bromocryptine. The importance of the central sympathetic activity and not only a direct pituitary dopaminergic agonist effect on the beta-endorphin secretion can be stressed in the effect of bromocryptine on the immunoreactive beta-endorphin level.     

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30?mg/kg), celecoxib (3?mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.     

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.     

Clonidine reduces elevated cerebrospinal fluid catecholamine levels in patients with essential hypertension

Cerebrospinal fluid (CSF) catecholamines were measured in normotensive patients and in patients with mild to moderate essential hypertension. CSF-norepinephrine (NE) concentrations were 50% lower in the normotensive individuals (127 ± 28 vs. 240 ± 23 pg/m1) (P<0.01). In hypertensive patients, CSF-NE was inversely related to age (r =-0.68; P<0.01) and directly related to plasma NE (r = 0.61; P<0.05). Clonidine (450 mcg/day for 2 weeks) significantly reduced CSF-NE (?40%) in hypertensive patients. In addition, it decreased blood pressure, plasma and urinary NE. Urinary VMA was not affected by clonidine. No correlation was observed between clonidine effects on BP and on plasma or CSF catecholamines. This study indicates that patients with essential hypertension have elevated levels of CSF-NE which are reduced after treatment with clonidine. The elevation of CSF-NE suggests that central (spinal?) noradrenergic activity may be increased in patients with mild to moderate essential hypertension, and that can be reduced by treatment with clonidine.     

Effect of insulin administration on water drinking in children

The effect of insulin administration on water intake, was studied in children submitted to standard protocols for stimulation of secretion of hypophyseal hormones by i.v. treatment with several different drugs: insulin, insulin plus TRH and LH-RH; and propranolol, clonidine or LH-RH. Drinking was measured from 0 to 90 min after drug administration; from blood samples taken at 60 min for hypophyseal hormones analysis, microhaematocrit values were measured, as well as plasma renin activity (PRA) and glycaemia. Water intake was significantly higher in both groups of patients receiving insulin than in the control group (no insulin). Haematocrit values did not change after 60 min. There was a significant correlation of glycaemia of individuals from all three groups and water intake at 60 min. PRA was significantly higher in insulin treated individuals.     

Possible change in noradrenergic receptor sensitivity following methylphenidate treatment: Growth hormone and MHPG response to clonidine challenge in children with attention deficit disorder and hyperactivity

Growth hormone (GH) and 3-methoxy-4-hydroxyphenelethylene glycol (MHPG) response was measured hourly for 4 hours in 8 children with Attention Deficit Disorder with Hyperactivity (ADD+H) following an acute single-dose of clonidine. The clonidine challenge was repeated before, during, and one day after 12 weeks of treatment with methylphenidate (MPH). Before MPH treatment, the plasma growth hormone (GH) rose to 31.3 ± 4.6 (Mean ± SE) ng/ml; during MPH treatment, the GH peak was only 14.8 ± 3.2 ng/ml; one day after discontinuation of MPH, GH rose to only 20.8 ± 3.9 ng/ml. MHPG release was inhibited by clonidine in all treatment conditions but tended to be more decreased during MPH treatment. Some children with ADD+H may have hypersensitivity of the post-synaptic alpha-1 noradrenergic receptor which is diminished by MPH treatment. The extent to which these effects are pharmacological or represent a change in receptor sensitivity requires further study.     

Long-term lisinopril dihydrate application decreases plasma noradrenaline but not adrenaline levels in chickens

Little is known about the effect of chronic angiotensin-converting enzyme inhibition on the catecholamine levels in fowls. In this study, we investigated the effects of chronic lisinopril dihydrate (Ld) application on the plasma levels of adrenaline and noradrenaline and on the blood pressure. Lisinopril was given in different concentrations (25, 75 and 250 mg/l drinking water) to the white Leghorn chickens for 9 weeks, while the control group drank tap water only. Twenty-eight hours after the last lisinopril application, arterial blood pressure (BP), plasma adrenaline and noradrenaline levels, plasma renin (PRA) and plasma angiotensin-converting enzyme (ACE) activities were determined. In all concentrations, lisinopril significantly increased PRA and decreased ACE activities. Arterial BP was decreased only in the group receiving high lisinopril concentration (Controls 119+/-10.27, Ld3 98+/-5.4 mm Hg). However, the lower lisinopril concentrations did not alter arterial BP compared to the control group. Plasma noradrenaline levels were decreased in a concentration-dependent manner (47-58%), but plasma adrenaline levels remained unchanged. The heart weight/body weight ratio was not changed in any of the lisinopril-treated groups. The persistent decrease in the blood pressure after lisinopril treatment was not directly related to a decrease of plasma ACE activity or plasma noradrenaline levels. Its mechanism still remains to be elucidated.     

Analysis of preincisional and postincisional treatment with alpha2-adrenoreceptor agonist clonidine regarding analgesic consumption and hemodynamic stability in surgical patients

Preemptive analgesia aims to prevent the sensitization of central nervous system, hence the development of pathologic pain after tissular injury. The aim of the study was to assess the effect of preincisional clonidine treatment on analgesic consumption and hemodynamic stability compared to clonidine administered at the end of the operation and control group. Ninety-one patients undergoing elective colorectal surgery were randomly assigned to four groups: peroral clonidine before operation, epidural clonidine before operation, epidural clonidine at the end of operation, and epidural saline before operation as a control group. After the operation, patient-controlled analgesia with epidural morphine was instituted. Analgesic consumption, blood pressure and heart rate were obtained at 1, 2, 6 and 24 h postoperatively, and the cumulative consumption of analgesics was assessed at the end of the study period. Significant differences (p < 0.05) in postoperative systolic blood pressure, with highest hemodynamic stability was observed at 1 h and 6 h in the group of patients administered epidural clonidine before operation. In this group of patients we found significant reduction in analgesic consumption during the study period (p < 0.05), compared to other groups. The cumulative consumption of analgesics assessed at the end of the study period was significantly reduced (p < 0.05) in the group of patients administered epidural clonidine before operation (8.40 +/- 3.74, respectively) as compared with the peroral clonidine before operation (16.79 +/- 5.75, respectively), epidural clonidine at the end of the operation (11.11 +/- 4.24, respectively) and control group of patients (18.00 +/- 6.45, respectively). Preincisional administration of epidural clonidine was associated with a significantly lower analgesic use, lower cumulative analgesic consumption and greater hemodynamic stability, in comparison with other groups.     

Plasma levels of renin, angiotensin II, and 6-ketoprostaglandin F1 alpha in endurance athletes

Twelve male runners and 12 matched nonathletes performed a prolonged uninterrupted graded exercise test on the bicycle ergometer up to exhaustion to study blood pressure and plasma levels of renin (PRA), vasoconstrictor angiotensin II (ANG II), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of the vasodilator prostacyclin. In the athletes work load was increased by 30 W/4 min, and in the control subjects the increments of work load were adjusted to their lower exercise capacity to equalize total exercise duration. Blood was drawn, and blood pressure and O2 uptake (VO2) were measured at rest and at the fourth, eighth, and last steps of exercise. Peak VO2 averaged 60 +/- 1.6 ml . min-1 . kg-1 in the runners and 46.8 +/- 1.5 in the nonathletes. To evaluate differences between athletes and controls, PRA, ANG II, and 6-keto-PGF1 alpha were first adjusted for significant confounding factors, such as age, weight, hematocrit, 24-h urinary sodium excretion, and O2 uptake. PRA was significantly lower in the athletes (F = 11.2; P less than 0.01); ANG II was not different at rest, but its rise with exercise was less steep in the runners (F = 8.2; P less than 0.01), whereas 6-keto-PGF1 alpha was not different between the groups (F = 1.3; NS). Despite the differences in PRA and ANG II, however, blood pressure was similar in athletes and nonathletes (F = 0.0; NS).     

Systemic arterial pressure response to two weeks of Tempol therapy in SHR: involvement of NO, the RAS, and oxidative stress

The roles of nitric oxide (NO) and plasma renin activity (PRA) in the depressor response to chronic administration of Tempol in spontaneously hypertensive rats (SHR) are not clear. The present study was done to determine the effect of 2 wk of Tempol treatment on blood pressure [mean arterial pressure (MAP)], oxidative stress, and PRA in the presence or absence of chronic NO synthase inhibition. SHR were divided into four groups: control, Tempol (1 mmol/l) alone, nitro-L-arginine methyl ester (L-NAME, 4.5 mg x g(-1).day(-1)) alone, and Tempol + L-NAME or 2 wk. With Tempol, MAP decreased by 22%: 191 +/- 3 and 162 +/- 21 mmHg for control and Tempol, respectively (P < 0.05). L-NAME increased MAP by 16% (222 +/- 2 mmHg, P < 0.01), and L-NAME + Tempol abolished the depressor response to Tempol (215 +/- 3 mmHg, P < 0.01). PRA was not affected by Tempol but was increased slightly with L-NAME alone and 4.4-fold with L-NAME + Tempol. Urinary nitrate/nitrite increased with Tempol and decreased with L-NAME and L-NAME + Tempol. Tempol significantly reduced oxidative stress in the presence and absence of L-NAME. In conclusion, in SHR, Tempol administration for 2 wk reduces oxidative stress in the presence or absence of NO, but in the absence of NO, Tempol is unable to reduce MAP. Therefore, NO, but not changes in PRA, plays a major role in the blood pressure-lowering effects of Tempol. These data suggest that, in hypertensive individuals with endothelial damage and chronic NO deficiency, antioxidants may be able to reduce oxidative stress but not blood pressure.     

Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity

There is a perception that phentermine pharmacotherapy for obesity increases blood pressure and heart rate (HR), exposing treated patients to increased cardiovascular risk. We collected data from phentermine‐treated (PT) and phentermine‐untreated (P0) patients at a private weight management practice, to examine blood pressure, HR, and weight changes. Records of 300 sequential returning patients were selected who had been treated with a low‐carbohydrate ketogenic diet if their records included complete weight, blood pressure, and HR data from seven office examinations during the first 12 weeks of therapy. The mean time in therapy, time range, and mode was 92 (97.0), 12–624, and 52 weeks. 14% were normotensive, 52% were prehypertensive, and 34% were hypertensive at their first visit or had a previous diagnosis of hypertension. PT subjects systolic blood pressure/diastolic blood pressure (SBP/DBP) declined from baseline at all data points (SBP/DBP ?6.9/?5.0 mm Hg at 26, and ?7.3/?5.4 at 52 weeks). P0 subjects' declines of SBP/DBP at both 26 and 52 weeks were ?8.9/?6.3 but the difference from the treated cohort was not significant. HR changes in treated/untreated subjects at weeks 26 (?0.9/?3.5) and 52 (+1.2/?3.6) were not significant. Weight loss was significantly greater in the PT cohort for week 1 through 104 (P = 0.0144). These data suggest phentermine treatment for obesity does not result in increased SBP, DBP, or HR, and that weight loss assisted with phentermine treatment is associated with favorable shifts in categorical blood pressure and retardation of progression to hypertension in obese patients.     

Response of plasma renin activity to postural change in vasovagal syncope in children, with observations on syncope

37 children aged 7-14 years with a history of repetitive fainting (vasovagal syncope) were studied. Plasma renin activity (PRA), blood pressure and heart rate were measured before and after standing for 15 min. Standing PRA was significantly higher in cases of fainting (n = 14) than in cases of nonfainting (n = 23). A significant positive correlation was observed between PRA and fall in systolic blood pressure on standing in cases of fainting, but not in cases of nonfainting. These findings suggest that the renin-angiotensin system may respond to the fall in blood pressure in children subject to fainting, unlike their adult counterparts previously reported.     

Circulating endothelin parallels arterial blood pressure during sleep in healthy subjects

OBJECTIVE: To characterize plasma endothelin 1 (ET-1) and arterial blood pressure (ABP) time courses during the first complete non-rapid eye movement (NREM)-REM sleep cycle in healthy subjects, together with plasma renin activity (PRA) and plasma atrial natriuretic peptide (ANP). METHODS: Heart rate (HR), intra-arterial blood pressure and sleep electroencephalographic activity were recorded continuously during the night in eight healthy 20-28-year-old males. Blood was sampled every 10 min during their first complete sleep cycle for simultaneous measurements of plasma ET-1, PRA and ANP. RESULTS: Circulating ET-1 demonstrated significant variations during the sleep cycle (p<0.0001) that paralleled those of ABP (p<0.05) and HR (p<0.005), with a minimum during NREM sleep and a maximum during REM sleep. ET-1 time course opposed that of PRA which increases during NREM sleep and decreases during REM sleep (p<0.0005). Plasma ANP did not demonstrate systematic variation in relation with the sleep cycle. CONCLUSION: Circulating ET-1, which parallels variations of ABP, may participate in ABP regulation during sleep in healthy subjects, in association with the renin-angiotensin system.