Influence of metoprolol and cilazapril on blood pressure and on sleep apnea activity.

Up to 50% of hypertensive men are subject to sleep apnea (SA). With a prevalence in men of up to 10%, SA is a common illness and hypertension (HT) one of its early symptoms. It is important to have available a drug treatment that will effectively control blood pressure (BP) without exacerbating symptoms of SA. Twelve patients with SA and HT were investigated in a double-blind, comparative trial. Patients were randomly allocated to either metoprolol (M) 100 mg daily or cilazapril (C) 2.5 mg daily. Polysomnographic measurements under standardized conditions including intraarterial BP monitoring were taken on two consecutive nights each before and after the 1-week treatment. Values in the M group were (mean +/- 95% CI) systolic BP 161 +/- 2.1 vs. 148 +/- 2.2 mm Hg (p less than 0.01); diastolic BP 98 +/- 1.8 vs. 93 +/- 1.8 mm Hg (p less than 0.01); and HR 73 +/- 1.2 vs 65 +/- 1.1 beats/min (p less than 0.01). Corresponding figures for the C group were systolic BP 140 +/- 2.1 vs. 127 +/- 2.1 mm Hg (p less than 0.01); diastolic BP 95 +/- 1.7 vs. 78 +/- 1.7 mm Hg (p less than 0.01); and HR 82 +/- 1.1 vs. 79 +/- 1.2 beats/min (p less than 0.01). Whereas C reduced both BP and HR in all sleep phases, M produced no changes during REM sleep. SA activity was 45 (range 15-91) vs. 34 (range 2-57) apneas per hour of sleep in the M group and 54 (range 21-84) vs. 40 (range 8-72) apneas per hour in the C group (p less than 0.01). There were no changes in total sleep time or in the proportions of non-REM to REM sleep. Both M and C reduce nocturnal BP in SA patients, but the effect of C is seen in all sleep phases. C has a more favorable effect on the disturbed nocturnal blood pressure of SA patients.     

Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.     

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2. Basal mean BP and HR were 115 +/- 2 and 165 +/- 3 mmHg and 345 +/- 10 and 410 +/- 14 beats min in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys-desArg9-BK significantly increased the BP of WKY and SHR by 7+/-1 and 19+/-2 mmHg, respectively. One nmol Sar[D-Phe8]-desArg9-BK, a kininase-resistant B1 agonist, increased the BP of WKY and SHR by 19+/-2 and 17+/-2 mmHg, respectively and reduced HR in both strains. 3. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8-desArg9-BK or AcLys[D-betaNal7,Ile8]-desArg9-BK (R715), significantly decreased mean BP in SHR (by 9+/-2 mmHg the former and 14+/-3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. 4. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. 5. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein-conjugated ODNs was detected in brain areas surrounding cerebral ventricles. 6. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.     

In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-alpha-methyl-histamine and its prodrug BP 2.94 in the dog

1. The aim of this study was to investigate whether histamine H3-receptor agonists could inhibit the effects of cardiac sympathetic nerve stimulation in the dog. 2. Catecholamine release by the heart and the associated variation of haemodynamic parameters were measured after electrical stimulation of the right cardiac sympathetic nerves (1-4 Hz, 10 V, 10 ms) in the anaesthetized dog treated with R-alpha-methyl-histamine (R-HA) and its prodrug BP 2.94 (BP). 3. Cardiac sympathetic stimulation induced a noradrenaline release into the coronary sinus along with a tachycardia and an increase in left ventricular pressure and contractility without changes in mean arterial pressure. Intravenous administration of H3-receptor agonists significantly decreased noradrenaline release by the heart (R-HA at 2 micromol kg(-1) h(-1): +77 +/- 25 vs +405 +/- 82; BP 2.94 at 1 mg kg(-1): +12 +/- 11 vs +330 +/- 100 pg ml(-1) in control conditions, P < or = 0.05), and increases in heart rate (R-HA at 2 micromol kg(-1) h(-1): +26 +/- 8 vs +65 +/- 10 and BP 2.94 at 1 mg kg(-1): +30 +/- 8 vs 75 +/- 6 beats min(-1), in control conditions P < or = 0.05), left ventricular pressure, and contractility. Treatment with SC 359 (1 mg kg(-1)) a selective H3-antagonist, reversed the effects of H3-receptor agonists. Treatment with R-HA at 2 micromol kg(-1) h(-1) and BP 2.94 at 1 mg kg(-1) tended to decrease, while that with SC 359 significantly increased basal heart rate (from 111 +/- 3 to 130 +/- 5 beats min(-1), P < or = 0.001). 4. Functional H3-receptors are present on sympathetic nerve endings in the dog heart. Their stimulation by R-alpha-methyl-histamine or BP 2.94 can inhibit noradrenaline release by the heart and its associated haemodynamic effects.     

Acute electrophysiologic effects of intravenous amiodarone are independent of a sympatholytic action in humans

Previous experiments in animals demonstrated a novel sympatholytic action of acute intravascular amiodarone (AM). It is not known if this action also occurs in humans. Twelve male volunteers performed handgrip for 10 min before and after 300 mg intravenous (IV) AM over 60 min. The effect of handgrip was determined from changes in blood pressure (BP), heart rate (HR), and cardiac noradrenaline (NA) spillover. Changes in cardiac spillover of dihydroxyphenylglycol (DHPG), the metabolite of NA, were measured during AM infusion. The electrophysiological effects of AM were determined from changes to the A-H intervals during right atrial stimulation (100 beats/min). Handgrip increased HR (63 +/- 2 to 84 +/- 5 beats/min and 65 +/- 3 to 84 +/- 4 beats/min), systolic BP (141 +/- 4 to 179 +/- 6 mm Hg and 140 +/- 4 to 179 +/- 7 mm Hg), and cardiac NA spillover (11.9 +/- 4 to 44.3 +/- 13 ng/min and 17.3 +/- 4 to 55.5 +/- 11 ng/min) before and after AM, respectively (P < 0.02 in all groups). There was good correlation between increases in cardiac NA spillover and HR (r2 = 0.86) and systolic BP (r2 = 0.87). AM increased the A-H interval (95.5 +/- 18 to 107.8 +/- 20 ms, P < 0.02). There was no difference in hemodynamic or NA response to handgrip before or after the AM infusion. There was also no change in DHPG cardiac spillover during AM infusion. Acute IV AM did not exert a sympatholytic action in humans, with no attenuation in hemodynamic or NA response to handgrip or increase in DHPG production, despite producing an electrophysiologic response.     

Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat.

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.     

Central vasopressin impairs the baroreceptor heart rate reflex in conscious rats.

In conscious, unrestrained rats, the resting values of mean arterial blood pressure (BP) and heart rate (HR) as well as the baroreceptor heart rate reflex (BHR) were measured before and after intracerebroventricular (i.c.v.) application of arginine vasopressin (AVP). The BHR was induced by intravenous (i.v.) injection of different doses of phenylephrine. Basal values of BP and HR were 114 +/- 2.4 mm Hg and 376 +/- 13 beats/min (mean +/- SE). These values were not altered by i.c.v. application of vehicle or 5, 10, 30, 300, 3,000 pg AVP or 1 pg AVP antagonist [(D(CH2)5Tyr(Me)-AVP)]. Ten and 30 pg AVP administered i.c.v. attenuated the phenylephrine-induced decrease in HR. Lower or higher doses of AVP were not effective. Administration of the AVP antagonist i.c.v. sensitized the BHR. When the BHR was rechecked 24 h after treatment, the influence of the i.c.v.-administered peptides had disappeared. We conclude that AVP through the cerebrospinal fluid impairs the baroreflex regulation.     

Protection of CGS 10078B against ouabain-induced arrhythmia in the cat

CGS 10078B (CGS; 1-[2,3-dihydro-1,4-(2S)-benzodioxin-2-yl]-5-[2,3-dihydro-1,4-(2R)- benzodioxin-2-yl]-3-(1R,5S)-aza-1,5-pentanediol methane sulfonate) is an agent with alpha- and beta-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with alpha-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 micrograms/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p less than 0.05) from control (165 +/- 6 vs. 96 +/- 7, and 136 +/- 5 vs. 90 +/- 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p less than 0.05) from 225 +/- 17 to 166 +/- 14 and from 193 +/- 8 to 152 +/- 6 beats/min. 11 min after T, BP and HR had decreased (p less than 0.05) from 133 +/- 6 to 103 +/- 7 mm Hg and from 134 +/- 4 to 104 +/- 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p less than 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.     

Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro.

1. The release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) from the dorsal horn of the rat spinal cord in vitro in response to dorsal root stimulation was measured by radioimmunoassay. 2. Stimulation of the dorsal roots (3 or 4 roots on each side) at 10 Hz for 5 min evoked a mean release (R1) of 134.3 +/- 17.5 (n = 10) fmol CGRP-LI; the release (R2) evoked by a second stimulation period 30 min later under control conditions was 77 +/- 10% (n = 10) of R1. Test compounds were applied to the preparation following release R1, and their effect calculated from the value of R2/R1. 3. Bradykinin (0.01-10 microM) had no significant effect on the basal release of CGRP-LI, but at 0.1-10 microM it increased 2-3 fold the release evoked by dorsal root stimulation. 4. This effect of bradykinin was prevented by indomethacin (10 microM), or by the B2-receptor antagonist, Hoe140 (1-10 microM). In the presence of Hoe140, bradykinin significantly reduced R2/R1; the explanation for this is not clear. 5. The B1-receptor agonist, Des-Arg9-bradykinin (10 microM), did not affect CGRP-LI release nor was the effect of bradykinin blocked by the B1-receptor antagonist, Des-Arg9-Leu8-bradykinin (10 microM). 6. Various prostaglandins were found to mimic the effect of bradykinin on CGRP-LI release. Their approximate order of potency was prostaglandin D2 (PGD2) = PGE1 > PGF2 alpha = PGE2; PGI2 was ineffective at 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

ULFS-49 causes bradycardia without decreasing right ventricular systolic and diastolic performance.

The effects of ULFS-49, a new calcium channel blocker, on right ventricular (RV) systolic and diastolic performance were evaluated in nine anesthetized, closed-chest dogs by load-insensitive indexes. ULFS-49 (0.3 mg/kg) decreased heart rate (HR) from 76 +/- 25 to 47 +/- 11 beats/min (p less than 0.01) and cardiac output (CO) from 1.89 +/- 0.62 to 1.42 +/- 0.72 L/min (p less than 0.01), as RV free wall end-diastolic area increased from 486 +/- 126 to 581 +/- 45 mm2 (p less than 0.01) and RV end-diastolic volume increased from 66.6 +/- 26.4 to 85.3 +/- 28.5 ml (p less than 0.05). Pacing at 100 beats/min ablated these hemodynamic and dimensional changes. RV free wall contractility was assessed by the slope and midrange intercept values of the relation between RV end-systolic pressure (Pes) and end-systolic free wall area (Aes) and between RV free wall segmental work (SW) and end-diastolic area (Aed). RV free wall stiffness was measured by exponential fit of the RV end-diastolic pressure (Ped)-Aed points during caval occlusion. With pacing at 100 beats/min, the slope of the Pes-Aes relationship was unchanged by ULFS-49 (0.52 +/- 0.29 vs. 0.60 +/- 0.35 mm Hg/mm2) as was the midrange intercept (382.3 +/- 114.7 vs. 387.1 +/- 121.5 mm2). After administration of ULFS-49, the slope of the SW-Aed relation increased from 31.8 +/- 14.4 to 37.3 +/- 17.7 mm Hg.mm2 (p less than 0.05) without changing the midrange intercept (410.5 +/- 108.1 mm2 vs. 413.0 +/- 107.0 mm2). Similarly, neither the position nor curvature of the Ped-Aed relation was changed by ULFS-49. These data demonstrate that ULFS-49 causes significant bradycardia and increases the size of the right ventricle without directly depressing RV free wall systolic or diastolic performance.     

Systemic and pulmonary hemodynamic effects of indapamide in patients with mild arterial hypertension

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.     

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.     

Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy

The cardioprotective properties of carvedilol (a vasodilating beta-adrenoceptor blocking agent) were studied in a rat model of dilated cardiomyopathy induced by autoimmune myocarditis. Twenty-eight days after immunization, surviving Lewis rats (32/43=74%) were divided into three groups to be given 2 mg kg(-1) day(-1) (Group-C2, n=10) or 20 mg kg(-1) day(-1) (Group-C20, n=10) of carvedilol, or vehicle (0.5% methylcellulose, Group-V, n=12). After oral administration for 2 months, body weight, heart weight (HW), heart rate (HR), rat alpha-atrial natriuretic peptide (r-ANP) in blood, central venous pressure (CVP), mean blood pressure (mean BP), peak left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), +/-dP dt(-1) and area of myocardial fibrosis were measured. Values were compared with those for normal Lewis rats (Group-N, n=10). Two out of 12 (17%) rats in Group-V died from day 28 to day 42 after immunization. No rat died in Groups-C2, -C20 and -N. Although the CVP, mean BP, LVP and +/-dP dt(-1) did not differ among the three groups, the HW, HR and r-ANP in Group-C2 (1.14+/-0.03, 339+/-16 and 135+/-31) and Group-C20 (1.23+/-0.04, 305+/-8 and 156+/-24) were significantly lower than those in Group-V (1.36+/-0.04 g, 389+/-9 beats min(-1) and 375+/-31 pg ml(-1), respectively). The LVEDP in Group-C2 was significantly lower than that in Group-V (7.4+/-1.4 and 12.2+/-1.2 mmHg, respectively, P<0. 05). The area of myocardial fibrosis in Group-C2 was smaller than that in Group-V (12+/-1 and 31+/-2%, P<0.01). These results indicate that a low dose of carvedilol has beneficial effects on dilated cardiomyopathy.     

Effects of icatibant on the ramipril-induced decrease in renal lithium clearance in the rat

The interaction between an inhibitor of angiotensin I converting enzyme (ramipril) and renal lithium handling was analysed in conscious, normotensive Wistar rats in the absence or the presence of a specific bradykinin B2 receptor antagonist, icatibant. The rats were treated for 5 days with ramipril (1 mg/kg/day p.o.) or its vehicle, alone or together with icatibant (0.1 mg/kg/day, s.c. infusion). Lithium chloride (8.3 mg/kg i.p.) was given as a single dose on day 5. Systolic blood pressure and heart rate were measured by tail plethysmography on day 3 (3, 9 and 15 h after ramipril administration) and renal function on day 4 (0-6 and 6-24 h urine sampling) and day 5 (0-6 h urine sampling). In another group of rats, 24 h sodium excretion was assessed during the first 4 days of ramipril treatment. Ramipril decreased renal lithium clearance (90+/-8 vs. 142+/-10 microl/min/100 g, P<0.001, n=24) and increased the fractional lithium reabsorption (74.3+/-1.9 vs. 66.7+/-1.7%, P<0.05) and plasma lithium concentration (0.108+/-0.006 vs. 0.085+/-0.004 mM, P<0.01). Alteration of renal lithium handling by ramipril was associated with a decrease in systolic blood pressure (-15% 3 h after ramipril administration) and sodium excretion (0-6 h after ramipril). The 24-h sodium excretion, however, tended to increase. Icatibant had no effect per se on renal function but attenuated the ramipril-induced decrease in renal lithium clearance (118+/-16 vs. 90+/-8 microl/min/100 g, n=12 and 24 respectively, P<0.05 one-tailed test) and systolic blood pressure. These results suggest that endogenous bradykinin contributes to the ramipril-associated alteration in renal lithium handling. Bradykinin B2 receptor-mediated vasodilation seems to be involved.     

Centrally produced neuronal nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and spontaneously hypertensive rats

We studied the effect of chronic nitric oxide synthase (NOS) blockade in the brain on mean arterial pressure [MAP (mmHg)], heart rate [HR (bpm)] and baroreceptor reflex sensitivity [BRS (mean slope: bpm/mmHg)] in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Intracerebroventricular (i.c.v.) infusion of the nonselective NOS inhibitor N-Nitro-L-arginine-methylester (L-NAME) (50 microg/kg per day, 11-12 days) increased MAP in WKY and SHR (125+/-2.1 vs 118+/-1.1 controls, P<0.01 and 179+/-3.59 vs 156+/-4.0 controls, P<0.001, respectively) without affecting HR. In L-NAME-treated WKY, BRS to bradycardia was suppressed (-0.79+/-0.09 vs -1.76+/-0.17 controls, P=0.001), whereas in SHR, L-NAME did not affect BRS to bradycardia. BRS to tachycardia remained unaffected in either strain. In WKY, 7-nitroindazole (7-NI x Na+) (34 microg i.c.v./kg per day, 11-12 days), a selective nNOS inhibitor, did not affect MAP or HR, but BRS to bradycardia and tachycardia was decreased (-0.37+/-0.20 vs -0.97+/-0.41 controls, P<0.01 and -1.78+/-0.20 vs -2.52+/-0.40 controls, P=0.05, respectively). In SHR, the same dose of 7-NI x Na+ increased resting MAP (171+/-5.00 vs 150+/-7.00 controls, P<0.05) without affecting HR or BRS to bradycardia or tachycardia. Thus in WKY, BRS to acute changes in systemic blood pressure (BP) is regulated by NO produced by nNOS in the brain, serving as a neurotransmitter in sympathetic and parasympathetic efferent pathways. In SHR, systemic BP is regulated in part by NO released by the type I NOS isoenzyme in the brain.     

帕瑞昔布钠对导尿引起的全麻患者苏醒期躁动的影响

目的探讨帕瑞昔布钠对全麻患者苏醒期躁动的影响。方法将120例全麻手术患者随机均分为三组:A组麻醉诱导前20min静脉注射帕瑞昔布钠40mg,麻醉诱导后10min插入导尿管;B组和C组麻醉诱导前20min静脉注射生理盐水10ml;C组麻醉诱导前插入导尿管,B组麻醉诱导后10min插入导尿管。记录导尿管插入前、后的HR、BP。用Riker镇静-躁动评分(SAS)评估全麻苏醒期躁动发生情况。结果与留置导尿管前比较,C组患者置尿管后BP明显升高[(14.8±3.6/9.5±3.3)kPa vs.(15.9±3.7/10.4±3.4)kPa]、HR明显增快[(88.3±18.6)次/分vs.(96.0±20.7)次/分](P<0.05),而A、B组无明显改变(P>0.05)。C组全麻苏醒期SAS评(3.7±1.3)分,明显优于A组的(4.1±1.2)分和B组的(5.2±1.1)分(P<0.01);A组躁动程度明显低于B组(P<0.05)。结论全麻诱导后插入导尿管能降低BP、HR的波动,但明显增加全麻苏醒期躁动的发生;预先静脉给予帕瑞昔布钠且于麻醉诱导后导尿,既可维持循环稳定,又可有效减少全麻患者苏醒期躁动的发生。     

心肺运动试验在心肌缺血早期诊断中的应用价值探讨

目的 研究心肺运动试验(CPET)相关指标在心肌缺血患者诊断中的价值。方法 52例胸痛患者患者分别行CPET、99Tcm-MIBI心肌灌注显像检查及心脏彩色多普勒超声检查。根据心肌灌注显像检查结果分为心肌缺血组（30例）及非缺血组（22例）。比较2组患者的CPET相关指标如每千克体重峰摄氧量( VO2 peak/kg)、峰摄氧最(VO2 peak)、峰氧脉搏(VO2 peak/HR)、最大呼吸频率、氧斜率、呼吸储备、最大心率、心率储备和无氧阈、无氧阈时氧气通气当最、无氧阈时二氧化碳通气当量、无氧阈时氧脉搏以及心脏彩色多普勒超声检查二尖瓣口血流舒张早期峰值速度(E)与舒张晚期峰值速度(A)的比值（E/A值）和左心室射血分数(LVEF)。结果 2组患者之间年龄、性别、BMI、E/A值及EF值差异均无统计学意义。心肌缺血组与非缺血组比较、VO2 peak/kg[(27±6) ml/(kg·min)比(33±7)ml/(kg·min),P＜0.01],vO2 peak[(1.5±0.5) L/min比(2.1±0.5) L/min,P＜0.01]、VO2 peak/HR[(10.7±2.6) ml/次比(14.1±3.0)ml/次,P＜0.01]、最大心率[(143±15)次/min比(154±17)次/min,P＜0.05]和无氧阈[(16.4±3.0)ml/(kg·min)比(20.6±5.0)ml/(kg·min),P＜0.01]、无氧阈时氧脉搏[(9.0±1.8)ml/次比(11.3±2.3) ml/次,P＜0.01]均明显为低,差异具有统计学意义。结论 采用心肺运动试验检测心肌缺血患者的VO2 peak/kg、VO2 peak、VO2 peak/HR、无氧阚和无氧阈时氧脉搏等指标对早期发现心肌缺血具有一定价值。     

Acute renal response to the non-peptide vasopressin V2-receptor antagonist SR 121463B in anesthetized rats

Vasopressin V2-receptor antagonists are promising agents for the use in water-retaining diseases. Potential renal mechanisms of action include effects on water permeability in the collecting duct as well as on electrolyte transport in the thick ascending limb of Henle's loop (TALH). To elucidate sites of action upstream of the distal tubule, e.g., in TALH, micropuncture experiments were performed in anesthetized rats during application of the V2-receptor antagonist SR 121463B. As compared to vehicle-treated rats, SR 121463B (0.3 mg/kg i.v.) did not affect mean arterial blood pressure (means +/- SEM, n=10 rats per group: 108+/-4 mmHg vs. 107+/-4 mmHg), whole kidney GFR (1.1+/-0.1 ml/min vs. 1.1+/-0.1 ml/min), or whole kidney fractional reabsorption (FR) of potassium (66+/-5% vs. 68+/-4%). The drug, however, reduced whole kidney FR of fluid (92+/-1% vs. 99+/-1%), increased urinary flow rate (84+/-7 microl/min vs. 8+/-1 microl/min) and electrolyte-free-water clearance (72+/-8 microl/min vs. 2+/-1 microl/min), and reduced urinary osmolality (148+/-11 mosmol/kg vs. 1,200+/-185 mosmol/kg). This pronounced diuretic response was associated with a minor reduction in whole kidney FR of sodium (99.6+/-0.1% vs. 99.9+/-0.1%) and chloride (98.3+/-0.2% vs. 98.9+/-0.1%). As compared to vehicle application, SR 121463B did not significantly alter single nephron GFR (39+/-2 nl/min vs. 39+/-1 nl/min, n=22 and 23 nephrons, respectively) or the FR up to the early distal tubule of fluid (76+/-2% vs. 76+/-1%), sodium (92+/-1% vs. 93+/-1%), potassium (91+/-1% vs. 90+/-1%) or chloride (90+/-1% vs. 91+/-1%). Together these data indicate a predominant aquaretic effect of SR 121463B which is located downstream of the early distal tubule. This response is compatible with blockade of vasopressin V2-receptors in the collecting duct and, as directly demonstrated by immunohistochemistry, subsequent retrieval of aquaporin-2 from apical plasma membrane, which inhibits water permeability and transport.     

Impaired vagal reflex activity in insulin-resistant rats

Insulin resistance, without frank diabetes, is associated with sudden cardiac death. We postulated that a potential mechanism for this association is autonomic dysfunction. Male Sprague-Dawley rats were randomized into one of two groups: (a) insulin resistant (IR; n = 15), or (b) control (n = 11). Animals were made insulin resistant with a fructose-rich diet, whereas control animals received standard rat chow. Four weeks after randomization, arterial pressure and baroreceptor reflex were assessed. Baroreflex sensitivity was defined as the heart-rate response to acute blood pressure changes caused by nitroprusside (0.5-18 micrograms) or phenylephrine (0.2-3 micrograms). To determine the role of vagal stimulation specifically, each animal was randomized to receive atropine sulfate (1 mg/kg) or vehicle (normal saline) before administration of phenylephrine. Mean arterial pressure and fasting insulin concentrations were increased in the insulin-resistant group, whereas there were no differences in body weight, fasting glucose concentrations, or resting heart rate. Phenylephrine increased arterial blood pressure to a maximum of 54 +/- 2 mm Hg for control and 45 +/- 6 mm Hg for IR, p = 0.7. The maximal heart-rate change response to the increased blood pressure was markedly blunted in IR as compared with control (-88 +/- 12 beats/min for IR vs. -238 +/- 18 beats/min for control; p < 0.001). Thus the baroreflex sensitivity (BRS) was threefold less in IR versus the control group (-1.8 +/- 0.2 vs. -4.6 +/- 0.7 beats/min/mm Hg; p = 0.001). Pretreatment with atropine sulfate decreased the BRS in both groups, eliminating the difference between groups (-0.96 +/- 0.5 beats/min/mm Hg for control and -0.56 +/- 0.3 beats/min/mm Hg for IR; p = 0.2). Thus atropine sulfate caused the phenylephrine-induced heart rate and arterial blood pressure response to be equal between groups. On the other hand, BRS to nitroprusside-induced blood pressure changes were similar between groups. Insulin resistance, without the confounding factors of obesity, diabetes, and significant hypertension, is associated with a large reduction in vagal activity, which occurs via attenuation in reflex activity. In contrast, the insulin-resistant syndrome does not affect baroreflex sensitivity via sympathetic reflex.     

A comparative study of cardiovascular stress during different swimming strokes

The study was aimed: (i) to compare maximum heart rate during exhaustive running (HRmasr) and swimming (HRmaxs), (ii) to compare heart rate (HR) in various modes of swimming-front crawl (FC), butterfly (BF), breast stroke (BRS) and back stroke (BS). HRmaxr (192.3 +/- 4.9 beats/min) of the swimmers (N = 7) was higher, although not significantly (P < 0.05), than their HRmaxs (183.7 +/- 3.8). Peak HR of the swimmers in FC, BF, BRS and BS (each of 100 m distance) were 179.9 +/- 7.2, 180.3 +/- 7, 178.6 +/- 6.2 and 177.3 +/- 5.4 beats/min respectively. Average HR in the respective events were 167.3 +/- 15.8, 166.6 +/- 14.1, 163.3 +/- 13.5 and 165.8 +/- 14.6 beats/min. Differences were not significant between any two modes, either in peak HR or mean HR. The results conclude that: (i) maximum HR in swimming is approximately 8 beats/min lower than maximal running and (ii) when the effort is maximum, cardiovascular stress remains unaltered in different swimming modes.