Reduce Blood Pressure Variability Research Articles

Very low frequency blood pressure fluctuations: not only myogenic responsiveness

Very low frequency blood pressure fluctuations: not only myogenic responsiveness

Synergism of Hydrochlorothiazide and Nifedipine on Blood Pressure Variability Reduction and Organ Protection in Spontaneously Hypertensive Rats

This study was designed to investigate the effects of a hydrochlorothiazide-nifedipine combination on blood pressure (BP), blood pressure variability (BPV), baroreflex sensitivity (BRS), and organ protection in spontaneously hypertensive rats (SHR). The doses used were 10 mg/kg/d for both hydrochlorothiazide and nifedipine, and 10+10 mg/kg/d for the combination of these two drugs. Drugs were mixed into rat chow at the aforementioned doses. SHR were treated for 4 months, and then BP was continuously recorded for 24 h. After the determination of BRS, rats were killed for organ-damage evaluation. It was found that long-term treatment with hydrochlorothiazide, nifedipine or both significantly decreased BP and BPV, enhanced BRS and conferred organ protection in SHR. The combination of hydrochlorothiazide and nifedipine had a significant synergistic effect on BPV reduction, BRS enhancement and organ protection in SHR, whereas no obvious synergism on BP reduction was found. Multiple-regression analysis showed that the decrease in left ventricular and aortic hypertrophy was most closely associated with the decrease in systolic BPV and the increase in BRS, and the amelioration of renal lesions was most closely associated with the increase in BRS. In conclusion, long-term treatment with a combination of hydrochlorothiazide and nifedipine yielded a significantly synergistic effect on BPV reduction, BRS restoration and organ protection in SHR. In addition to BP reduction, the decrease in BPV and the enhancement of BRS may have made important contributions to the observed organ protection.

Blood Pressure Variability Reduction and Organ Protection in Hypertension Treatment

It is estimated that approximately 1 billion individuals worldwide have hypertension, and more than 7 million deaths per year may be attributable to hypertension-induced complications and organ damage (1). The mechanisms underlying hypertension are complex and incompletely understood. To better control hypertension-induced end-organ damage, it is important to investigate new and effective targets for therapeutic intervention. Besides blood pressure level itself, recent studies have demonstrated that the spontaneous variation in blood pressure, called blood pressure variability (BPV), is another key determinant of hypertensive end-organ damage. Clinical trials have demonstrated that, for nearly any level of 24-h mean arterial blood pressure, hypertensive subjects with low 24-h BPV had a significantly lower prevalence and severity of organ damage than those with high BPV (2). Furthermore, the cardiovascular complications of hypertension may in fact depend on the degree of 24-h BPV (3). Tatasciore et al. showed that awake systolic BPV, via non-invasive ambulatory blood pressure monitoring, correlates with subclinical target-organ damage that is independent of mean blood pressure level in hypertensive subjects (4). In contrast, ambulatory blood pressure levels and BPV are closely associated with carotid artery alteration, as found in the Ohasama study, suggesting that these parameters are independent risk

Reduction of blood pressure variability by combination therapy in spontaneously hypertensive rats

To test the hypothesis that combination therapy might be a powerful tool to reduce blood pressure variability (BPV) in the treatment of hypertension. In chronic studies, male spontaneously hypertensive rats were given drugs in their rat chow for 18 weeks (n = 9 or 10 for each group of rats). Doses were as follows: atenolol (10 mg/kg per day), amlodipine (1 mg/kg per day), a combination of atenolol and amlodipine (2.5 + 0.25, 5 + 0.5, and 10 + 1 mg/kg per day), hydrochlorothiazide (8 mg/kg per day), enalapril (3.2 mg/kg per day), and a combination of hydrochlorothiazide and enalapril (2 + 0.8, 4 + 1.6, and 8 + 3.2 mg/kg per day). In acute studies, drugs were perfused through the left femoral vein in conscious rats. In chronic studies, compared with monotherapy, the combinations of two antihypertensive drugs were more effective in reducing the blood pressure (BP), BPV, and organ damage. The indexes of organ damage were all positively related to BP and/or BPV. In acute studies, the constant infusion of phenylephrine (6.25 microg/kg per min) markedly increased the BP, but showed no significant effects on BPV. The infusion of a combination of atenolol and amlodipine (62.5 + 6.25 microg/kg per min) or a combination of hydrochlorothiazide and enalapril (500 + 200 microg/kg per min) significantly reduced the BP and BPV; moreover, a significant reduction in BPV was still found when the rat's BP was restored to control levels by a concomitant infusion of phenylephrine. Combination therapy may be a powerful and useful tool for BPV reduction in the treatment of hypertension. In addition to the BP reduction, the decrease in BPV may contribute significantly to the prevention of organ damage in hypertension.

Chapter 19 - Mechanosensitive Ion Channels in Blood Pressure‐Sensing Baroreceptor Neurons

Baroreceptors (BRs) are mechanosensitive nerve endings in carotid sinuses and aortic arch that function as arterial blood pressure (BP) sensors. Changes in BR activity evoke reflex circulatory adjustments that reduce BP variability and its adverse consequences. BR activation during increases in BP involves three processes: (1) vascular distension and deformation of BR nerve endings, (2) depolarization of the nerve terminals consequent to the opening of mechanosensitive ion channels (mechanoelectrical transduction), and (3) translation of mechanically induced depolarization into action potential discharge mediated by voltage-dependent Na(+) and K(+) channels. This chapter discusses the mechanism of mechanoelectrical transduction. A variety of physiological, pharmacological, and molecular approaches to this problem, including studies in animals and isolated BR neurons in culture is presented. The chapter provides an overview of the molecular basis of BR mechanoelectrical transduction. Emerging evidence points to the members of three evolutionarily conserved ion channel families in mediating BR activation: epithelial Na channels (ENaCs), acid-sensing ion channels (ASICs), and transient receptor potential (TRP) channels.

Synergism of hydrochlorothiazide and nitrendipine on reduction of blood pressure and blood pressure variability in spontaneously hypertensive rats

To investigate the possible synergism of hydrochlorothiazide and nitrendipine on reducing both blood pressure (BP) and blood pressure variability (BPV) in spontaneously hypertensive rats (SHR). Seventy animals were randomly divided into seven groups. The doses were 5 and 10 mg/kg for nitrendipine, 10 and 20 mg/kg for hydrochlorothiazide and 10 + 5, 20 + 10 mg/kg, respectively, for the combination of these two drugs and 0.8% carboxymethylcellulose as control. The drugs were given via a catheter of gastric fistula. BP was then continuously recorded for 5 h from 1 h before drug administration to the end of 4th hour after drug administration, in conscious and freely moving rats. The effects on both BP and BPV reduction of the combination of hydrochlorothiazide and nitrendipine were greater than the single drug in SHR. The two drugs possessed an obvious synergism on both systolic blood pressure (q = 1.79 with small dose and q = 1.23 with large dose) and systolic blood pressure variability reduction (q = 1.79 with small dose and q = 1.39 with large dose) in SHR. The present work clearly demonstrated that there was a synergistic effect between hydrochlorothiazide and nitrendipine in lowering and stabilizing BP in SHR.

Treatment of hypertension based on measurement of blood pressure variability: lessons from animal studies

Blood pressure variability, a quantitative index for the spontaneous variation in blood pressure, has been proposed as a risk factor for end-organ damage and to determine the efficacy of hypertension treatment. Animal studies indicate that blood pressure variability is as important as blood pressure level in determining end-organ damage, and that high blood pressure variability is associated with end-organ damage, including myocardial lesions, aortic hypertrophy, vascular remodeling and renal damage. Although the organ damage induced by high blood pressure variability was similar to that induced by hypertension, comparative studies in sinoaortic-denervated and spontaneously hypertensive rats revealed that aortic hypertrophy is a sensitive index of high blood pressure variability, and left ventricular hypertrophy is a sensitive index of high blood pressure level. The possible mechanisms for high blood pressure variability-induced end-organ damage include: direct endothelial lesions, renin-angiotensin system activation, inflammation initiation and cardiomyocyte apoptosis augmentation. Blood pressure variability reduction contributes importantly to the organ-protective effect of some antihypertensive drugs. Although animal studies suggest some advantages in blood pressure variability measurements, clinical trials are necessary before the widespread use of blood pressure variability as a predictor of hypertensive organ damage and a new strategy for the treatment of hypertension.

Effects of amlodipine and valsartan on vascular damage and ambulatory blood pressure in untreated hypertensive patients

The present study was performed to compare the long-term effects of 24-h ambulatory blood pressure (BP) control with amlodipine versus valsartan on vascular damage in untreated hypertensive patients. Amlodipine and valsartan have benefits on cardiovascular mortality and morbidity in hypertensive patients. Although ambulatory BP is associated with severity of target-organ damage in hypertensive patients, beneficial effects of ambulatory BP control with amlodipine versus valsartan on vascular damage have not been compared. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE) and 24-h ambulatory BP were determined in 100 untreated hypertensive patients before and 12 months after the start of antihypertensive therapy with amlodipine or valsartan. Amlodipine and valsartan decreased ambulatory BP similarly, but the variability of 24-h and daytime ambulatory systolic BP was significantly reduced by amlodipine but not by valsartan. The reduced variability of ambulatory systolic BP caused by amlodipine significantly contributed to the improvement of PWV, although both drugs decreased PWV similarly. Carotid IMT was unaffected by treatment with either drug. Valsartan significantly decreased UAE independently of its depressor effect, but amlodipine had no effect on UAE. These results suggest that the 24-h control of ambulatory BP with amlodipine had functionally improved the stiffened arteries of hypertensive patients by the end of 12 months of treatment, in part through reducing BP variability, whereas ambulatory BP control with valsartan decreased the arterial stiffness to the same degree as amlodipine without affecting BP variability maybe through some pleiotropic effects.

Blood pressure variability, baroreflex sensitivity and organ damage in spontaneously hypertensive rats treated with various antihypertensive drugs

Besides blood pressure, blood pressure variability and baroreflex sensitivity maybe important factors determining organ damage in hypertension. This study was designed to investigate the effects of various antihypertensive drugs on blood pressure and blood pressure variability reductions, baroreflex sensitivity, and target organ damage in spontaneously hypertensive rats (SHR). The dose is 20 mg/kg/day for atenolol, and 10 mg/kg/day for nifedipine, irbesartan and hydrochlorothiazide. We used relatively low doses of drugs to avoid a very remarkable normalization of blood pressure in the treatment, which would make it much difficult to distinguish the contribution of blood pressure variability and baroreflex sensitivity to organ protection from that of blood pressure. Drugs at the aforementioned doses were mixed into rat chow. SHR were treated for 4 months. Blood pressure was then continuously recorded for 24 h. After the determination of baroreflex sensitivity, rats were killed for organ-damage evaluation. It was found that long-term treatment with atenolol, nifedipine, irbesartan or hydrochlorothiazide all markedly reduced blood pressure variability, enhanced baroreflex sensitivity, and produced significant organ protection. Compared with blood pressure level, blood pressure variability and baroreflex sensitivity values showed a much closer or similar relationship with organ-damage parameters in every treatment group of rats. Multiple-regression analysis showed that the decrease in left ventricular hypertrophy, the decrease in aortic hypertrophy and the amelioration in renal lesion were all most closely correlated with the increase in baroreflex sensitivity and the decrease in systolic blood pressure variability. In conclusion, long-term treatment with atenolol, nifedipine, irbesartan or hydrochlorothiazide produced organ protection in SHR. Besides the blood pressure reduction, the decrease in blood pressure variability and the restoration of baroreflex sensitivity may contribute to this organ protection.

BLOOD PRESSURE VARIABILITY

Introduction: Our previous work in heart rate variability explores "uncoupling" (low variability) & autonomic dysfunction in ICU patients. We expand this work to include 4 blood pressure (BP) parameters (systolic, diastolic, mean, pulse). Hypothesis: BP measure is a robust predictor of mortality. Methods: Data Sources: SIMON captures second-by-second bedside physiologic data. TRACS records 250 fields of demographic & outcome data. Study Group: Of 3,187 trauma ICU admissions, 1852 (58.1%) had invasive integer BP data. 308 patients (16.6%) died. Measurements: Data 3 hours prior to death & non-physiologic abnormalities (2.52% of data) was excluded. The remaining 180 million BP data points (132,000 monitored hours) were grouped into 5-minute intervals (N = 1.55 million) and each BP parameter was analyzed for variability (mmHg difference between the 10th & 90th percentile) & central tendency (median). Outcome was defined as hospital death. Statistics: Individual logistic regression models for death were constructed for each BP parameter. Areas under ROC were computed and validated (expressed as mean±SE). P-values are from Walds χ2 test corrected for repeated measures. Results: Mortality is associated with reduction in variability of all four BP parameters, but not with central tendency.TableConclusions: Reduced blood pressure variability may: Predict mortality more robustly than central tendency Signal autonomic dysfunction Provide a new class of vital signs for ICU patients

Myogenic vascular function selectively affects low frequency blood pressure variability while sympathetic modulation of vascular tone selectively affects mid frequency blood pressure variability

High doses of the Ca++-channel blocker nifedipine reduce blood pressure variability (BPV) at low (LF, 0.02-0.2 Hz) and mid frequencies (MF, 0.2-0.6 Hz) in rats. We tested the hypothesis that these effects are due to inhibition of myogenic vascular function and reduced vascular sympathetic responsiveness, respectively. Normotensive Wistar Kyoto rats were instrumented with catheters in the femoral artery and vein. After 24 h of recovery, blood pressure and heart rate were recorded in conscious rats during baseline conditions and i.v. infusion of nifedipine at 6 doses (0.05 mg/kg/h to 25.0 mg/kg/h). Nifedipine caused a dose-dependent decrease in blood pressure and increase in heart rate. Increasing doses of nifedipine gradually decreased LF BPV from 55.2±5.4 % during baseline conditions to 30.3±5.8 % at 25 mg/kg/h (P<0.05). In contrast, relative MF BPV increased from 19.9±4.0 % at baseline conditions to 27.0±3.1 % at a dose of 0.5 mg/kg/h (P<0.05) and then declined to 12.3±2.1 % at 25 mg/kg/h. At low doses of nifedipine (0.5 mg/kg/h), MF BPV increased most likely due to baroreflex activation of sympathetic nerve activity. At higher doses, MF BPV declined probably due to reduced vascular sympathetic responsiveness. The lack of an increase in LF BPV at low doses of nifedipine indicates that sympathetic modulation of vascular tone does not affect LF BPV. Instead, inhibition of myogenic vascular function may explain the decrease in LF BPV with increasing doses of nifedipine. These results suggest that myogenic vascular function is exclusively reflected in LF BPV, while sympathetic modulation of vascular tone is exclusively reflected in MF BPV.

Synergistic effects of atenolol and amlodipine for lowering and stabilizing blood pressure in 2K1C renovascular hypertensive rats1

To test the synergistic effects of atenolol and amlodipine on lowering blood pressure (BP) and reducing blood pressure variability (BPV) in 2-kidney, one-clip (2K1C) renovascular hypertensive rats. Forty-eight 2K1C renovascular hypertensive rats were randomly divided into 6 groups. They were respectively given 0.8% carboxymethylcellulose sodium (control), atenolol (10.0 mg/kg), amlodipine (1.0 mg/kg), and combined atenolol and amlodipine (low dose: 5.0+0.5 mg/kg; intermediate dose: 10.0+1.0 mg/kg; high dose: 20.0+2.0 mg/kg). The drugs were given via a catheter in a gastric fistula. BP was recorded for 25 h from 1 h before drug administration to 24 h after administration. Compared with BP before medication, all 3 doses of combined atenolol and amlodipine significantly decreased the BP at 24 h after administration, except for the low dose on diastolic BP. Compared with the control group, all 3 doses of combined atenolol and amlodipine significantly reduced the average BP levels for the 24 h period after administration; furthermore, the high and intermediate doses also significantly decreased the BPV levels for the same period. The q values calculated by probability sum analysis for systolic and diastolic BP for the 24 h period after administration were 2.29 and 1.45, respectively, and for systolic and diastolic BPV for the same period they were 1.41 and 1.60, respectively. There is significant synergism between atenolol and amlodipine in lowering and stabilizing BP in 2K1C renovascular hypertensive rats.

Reduction of blood pressure variability: a new strategy for the treatment of hypertension

The main aims of the treatment of hypertension are to prevent end-organ damage (EOD) and to avoid consequent lethal complications associated with hypertension. Blood pressure level is a well-known determinant of EOD. However, recent studies suggest that blood pressure variability (BPV) is as important as blood pressure level in determining EOD. The reduction of BPV is an important contributory factor of the organ protection provided by some antihypertensive drugs. Thus, reduction of BPV might represent a new strategy for the treatment of hypertension.

Synergism of atenolol and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats

This study was designed to investigate the possible synergism of atenolol and nitrendipine on blood pressure (BP) and blood pressure variability (BPV) reductions, baroreflex sensitivity (BRS) amelioration, and organ protection in hypertensive rats. The dose was 20 mg/kg for atenolol, 10 mg/kg for nitrendipine and 20 + 10 mg/kg for the combination of these two drugs. In an acute study, a single dose was given via a catheter previously inserted into the stomach in spontaneously hypertensive rats (SHR). In a subacute study, SHR, deoxycorticosterone acetate (DOCA)-salt rats, and two-kidney, one-clip (2K1C) rats were used. They received the same dose by gavage daily for 10 days. BP was measured 24 h after drug administration. In chronic studies, these drugs at the aforementioned dose were mixed into rat chow. SHR were treated for 4 months. BP was then continuously recorded for 24 h. After the determination of BRS, rats were killed for organ-damage evaluation. In the acute study, it was found that the combination of atenolol and nitrendipine had an obviously greater and longer BP reduction than treatment with each of these two drugs separately. In the subacute study, an effective decrease in BP 24 h after administration was found only in the rats treated with the combination. In chronic studies, it was found that the combination possessed the obvious synergism on BP and BPV reduction, BRS amelioration and organ protection in SHR. Multiple-regression analysis showed that the decrease in left ventricular hypertrophy was most significantly related to the decrease in systolic BPV and BP, the decrease in aortic hypertrophy was most significantly related to the increase in BRS and the decrease in systolic BPV, and amelioration in the renal lesion was most significantly associated with the restoration of BRS. Treatment with a combination of atenolol and nitrendipine exhibited a rapid and persistent antihypertensive effect and possessed an obvious synergism on BP and BPV reduction, BRS restoration and organ protection in hypertensive rats. The decrease in BPV and the restoration of BRS may importantly contribute to organ protection in SHR with chronic treatment.

Acute and chronic stress influence blood pressure variability in mice

There is evidence that alterations in heart rate and blood pressure variability (BPV) are associated with cardiovascular disease. We used a mice model to investigate the effects of acute and chronic stress on blood pressure variability (BPV) and heat rate variability (HRV). Shaker stress was given acutely (5 min, 150 cycles/min) and chronically (3 days, 2 min stress, 150 cycles/min, 45 sessions/day) in male C57BLJ mice. Systolic arterial pressure (SAP) and pulse interval (PI) time series were submitted to autoregressive spectral analysis with variability measured in the low-frequency (LF, 0.1–1.0 Hz) and high-frequency (HF, 1–5 Hz) ranges. In the acute experiment, MAP was increased significantly in the first 10 min poststress period (99±2 vs. 113±2 mm Hg) and returned to control levels 30 min poststress. HR was significantly higher in the initial poststress period (537±12 vs. 615±20 bpm). These alterations were associated with a marked increase in BPV (21±4 vs. 55±11 mm Hg2) and in power of LF oscillations (18±3 vs. 42±7 mm Hg2). On the other hand, chronic stress exposure produced a reduction in BPV (16±4 vs. 6±1 mm Hg2) and LF oscillations (11±3 vs. 3±1 mm Hg2). HRV was not altered after either acute or chronic stress. Spontaneous baroreflex sensitivity (SBS), determined by cross-spectral analysis between PI and BP, was reduced significantly in acute stress (−50%), but unchanged in chronic stress. Our results show that acute stress produced changes in BPV that may be associated with increased sympathetic activity and a reduction in blood pressure buffering. Under chronic conditions, there is no alteration in baroreflex sensitivity while BPV is reduced. This is likely related to the combination of sympathetic activation in the face of vasculature alterations.

Acute and chronic stress influence blood pressure variability in mice

There is evidence that alterations in heart rate and blood pressure variability (BPV) are associated with cardiovascular disease. We used a mice model to investigate the effects of acute and chronic stress on blood pressure variability (BPV) and heat rate variability (HRV). Shaker stress was given acutely (5 min, 150 cycles/min) and chronically (3 days, 2 min stress, 150 cycles/min, 45 sessions/day) in male C57BLJ mice. Systolic arterial pressure (SAP) and pulse interval (PI) time series were submitted to autoregressive spectral analysis with variability measured in the low-frequency (LF, 0.1–1.0 Hz) and high-frequency (HF, 1–5 Hz) ranges. In the acute experiment, MAP was increased significantly in the first 10 min poststress period (99±2 vs. 113±2 mm Hg) and returned to control levels 30 min poststress. HR was significantly higher in the initial poststress period (537±12 vs. 615±20 bpm). These alterations were associated with a marked increase in BPV (21±4 vs. 55±11 mm Hg 2) and in power of LF oscillations (18±3 vs. 42±7 mm Hg 2). On the other hand, chronic stress exposure produced a reduction in BPV (16±4 vs. 6±1 mm Hg 2) and LF oscillations (11±3 vs. 3±1 mm Hg 2). HRV was not altered after either acute or chronic stress. Spontaneous baroreflex sensitivity (SBS), determined by cross-spectral analysis between PI and BP, was reduced significantly in acute stress (−50%), but unchanged in chronic stress. Our results show that acute stress produced changes in BPV that may be associated with increased sympathetic activity and a reduction in blood pressure buffering. Under chronic conditions, there is no alteration in baroreflex sensitivity while BPV is reduced. This is likely related to the combination of sympathetic activation in the face of vasculature alterations.

ATP-sensitive potassium channels are involved in adenosine-induced reduction of blood pressure variability in spontaneously hypertensive rats.

With a computerized analysis system, blood pressure was recorded continuously in conscious unrestrained spontaneously hypertensive rats. The effects of different adenosine receptor agonists and ATP-sensitive potassium channel opener and blocker on blood pressure variability in spontaneously hypertensive rats were studied. It was found that adenosine, 5'-N-cyclopropyl-carboxamidoadenosine (CPCA, a selective adenosine A2-receptor agonist) and pinacidil (a nonselective ATP-sensitive potassium channel opener) decreased blood pressure variability when one of them was used alone, whereas N -cyclopentyladenosine (CPA, a selective adenosine A1-receptor agonist) had no significant effects on blood pressure variability. When pretreated with glibenclamide (a nonselective ATP-sensitive potassium channel blocker), the inhibitory effects of adenosine and CPCA on blood pressure variability were significantly prevented. By itself, however, glibenclamide had no influence on blood pressure variability. These results suggest that the effect of adenosine on blood pressure variability in spontaneously hypertensive rats is due to activation of ATP-sensitive potassium channels mediated by adenosine A2-receptor.

Effects of long-term treatment with ketanserin on blood pressure variability and end-organ damage in spontaneously hypertensive rats.

It has been proposed that instability of blood pressure may produce organ damage. Ketanserin is an anti-hypertensive drug with an ability to reduce blood pressure variability (BPV) in acute experiments in spontaneously hypertensive rats (SHRs). The present work was designed to observe the effects of long-term treatment with ketanserin on BPV and end-organ damage in SHRs. Ketanserin was mixed in rat chow at an estimated dose of 10 mg/kg/d. After 5 months of drug administration, BP was continuously recorded in conscious, freely moving rats for 24 h. The heart, kidneys, and abdominal aorta were then isolated and examined by using histologic methods and computer image analysis. In another work, the effects of hydralazine (40 mg/kg/d, for 5 months) on BP, BPV, and organ damage were observed in SHRs. Ketanserin significantly decreased BP and BPV, ameliorated impaired arterial baroreflex function, and significantly prevented the target organs of SHRs from being damaged. This preventive effect was characterized by decrease in left ventricular hypertrophy, diminution of glomerulus damage, and amelioration in vascular lesion. Hydralazine decreased BP but did not lower BPV. No organ protection was found in hydralazine-treated rats. In conclusion, long-term treatment with ketanserin reduced hypertensive organ damage. Lowering BP, decreasing BPV, and ameliorating arterial baroreflex function may contribute together to this effect.

Increased Postoperative Arterial Blood Pressure Stability with Continuous Epidural Infusion of Clonidine in Children

To the Editor: We want to add additional information to our previous study published in Anesthesia & Analgesia(1). This information concerns the variability of postoperative hemodynamic variables associated with continuous postoperative epidural infusion of clonidine and ropivacaine in children. Following Ethical Committee approval and written parental informed consent, 60 boys (ASA physical status 1–2) aged 1–4 yr undergoing hypospadias repair were randomized to receive one of the following four postoperative epidural infusions after the induction of a standardized isoflurane based anesthetic: Group R: plain ropivacaine 0.1%, 0.2 mg kg−1h−1; Group RC1: ropivacaine 0.08% 0.16 mg kg−1 h−1 + clonidine 0.04 μg −1 h−1; Group RC2: ropivacaine 0.08% 0.16 mg kg−1 h−1 + clonidine 0.08 mg kg−1 h−1; or Group RC3: ropivacaine 0.08% 0.16 mg kg−1 h−1, + clonidine 0.12 μg kg−1 h−1. Further details are given in the original article (1). No difference in overall heart rate or arterial blood pressure levels could be detected between the four study groups during the 48-h observation period. However, the systolic blood pressure variability, measured as the coefficient of variation (CV%) as described by Ghignone et al. (2) was significantly lower than in groups RC2 and RC3 compared with the other two groups (P < 0.001) (Table 1) (Fig. 1). No such difference was observed regarding heart rate variability (Table 1).Table 1: Intrapatient Variability of Hemodynamic VariablesFigure 1: Individual systolic blood pressure recordings in patients receiving a postoperative epidural infusion of either plain ropivacaine 0.1% (group R) or a co-infusion of ropivacaine 0.08% + clonidine 0.12 μg kg−1 h−1 (group RC3). Please note the difference in individual variability and the lack of difference regarding overall blood pressure levels between the two groups.The improved arterial blood pressure stability we observed associated with epidural clonidine administration is most likely explained by two interacting mechanisms. First, systemic uptake of clonidine from the epidural space into the systemic circulation will cause secondary interactions with centers in the brain stem (e.g., locus coeruleus and the vasomotor center) that affect central sympathetic discharge. Second, epidural clonidine in the dose range of 0.08–0.12 μg −1 h−1 is associated with improved postoperative pain relief (1). A reduced nociceptive input is likely to result in reduced blood pressure variability due to a reduction of the pain-generated stress response. However, if improved pain relief would be the main mechanism behind the observed reduction of blood pressure variability, then it is difficult to explain why heart rate variability did not show a similar pattern. Although strict cardiovascular control might not be essential after urogenital surgery in children, improved hemodynamic stability could be of potential benefit in other clinical situations (e.g., after major thoracic or abdominal surgery). We have previously shown that the bioavailability of clonidine is not restricted by epidural administration (3). Thus, one could postulate a similar hemodynamic effect if clonidine instead was administered as an intravenous infusion. Intravenous administration of clonidine would obviously make this property of clonidine useful in situations where epidural administration of clonidine is not an option (i.e., neurosurgery). H. T. G. Bergendahl P. A. Lonnqvist P. De Negri G. Ivani S. Eksborg

Mecamylamine (Inversine): an old antihypertensive with new research directions.

Mecamylamine (Inversine), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30-90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5-5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the treatment of hypertension. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. Though currently untested, the available evidence suggests that low-dose mecamylamine therapy might reduce blood pressure variability and atherogenetic lipid profile in smokers. With this in mind, mecamylamine should be an important research tool in the field of hypertension research, particularly in recalcitrant smokers with mild to moderate hypertension.