Role of heme-oxygenase pathway on vasopressin deficiency during endotoxemic shock-like conditions

The septic shock is characterized by decrease in median arterial pressure; many researchers have been related a deficiency in vasopressin release during the septic shock. Lipopolysaccharide administration is used to induce septic shock model in animals. We investigated the heme-oxygenase (HO) inhibition during the endotoxemic shock-like conditions. The LPS administration induced a significant decrease in MAP (-15.4 +/- 1.2 mmHg at second hour, -25.8 +/- 8.7 mmHg at fourth hour, and -22.3 +/- 8.6 mmHg at sixth hour) with a concomitant increase in heart rate (486.3 +/- 55.0, 531.8 +/- 53.8, and 510.0 +/- 55.3 bpm, respectively), a significant decrease in diuresis (from 1.1 +/- 0.7 to 0.4 +/- 0.3/100g body weight at fourth hour), and a transitory decrease in body temperature (from 37.0 +/- 0.5 to 35.4 +/- 0.8 degrees C at second hour). An increase in plasma arginine vasopressin (AVP) concentration (from 3.2 +/- 0.9 to 19.0 +/- 5.7 pg/mL at the first hour) occurred in these animals and was present for 2 h after LPS administration, returning close to basal levels thereafter and remaining unchanged until the end of the experiment. When LPS was combined with the i.c.v. administration of HO inhibitor, we observed a sustained increase in plasma AVP concentration, attenuation in the drop of MAP, and increase in antidiuresis induced by LPS treatment. These data suggest that central HO pathway may activate a control mechanism that attenuates AVP secretion during endotoxemia and may consequently regulate the MAP and diuretic output.     

Haemodynamic responses to static and dynamic handgrip before and after autonomic blockade

1. Six healthy men performed static and dynamic handgrip to local muscular fatigue in approximately 6 min under control conditions, i.e. without drugs and after combined parasympathetic and beta-adrenergic blockade with atropine and metoprolol. 2. From rest to exercise at fatigue, systolic, diastolic and mean arterial pressures increased by 32 +/- 4 and 39 +/- 3 mmHg, 24 +/- 3 and 26 +/- 4 mmHg, and 26 +/- 3 and 30 +/- 3 mmHg respectively for static and dynamic handgrip. There were no significant differences between the pressor responses for the two modes of contraction. Cardiac output increased significantly only during dynamic exercise. Total peripheral resistance increased by 2.3 +/- 1.0 units for static handgrip (P less than 0.05) and by 0.7 +/- 0.8 unit (P greater than 0.05) for dynamic handgrip. Autonomic blockade abolished the heart rate response to both static and dynamic handgrip. For both modes of contraction the systolic arterial pressure responses were 9-12 mmHg lower (P less than 0.05) after autonomic blockade, but the diastolic and mean pressure responses were not significantly affected. A significant increase in cardiac output persisted during dynamic exercise. The increase in peripheral resistance during static exercise tended to be greater after blockade. Plasma noradrenaline and adrenaline levels showed only minor elevations in response to static and dynamic handgrip and were not changed by autonomic blockade. 3. These data indicate that when performed to a common end-point with identical small muscle groups static and dynamic exercise produce an equally large pressor response, which is only slightly attenuated by autonomic blockade.     

Decreased large artery distensibility in borderline hypertension is related to increased in vivo low-density lipoprotein oxidation

The present study tested the hypothesis that reduced arterial elasticity seen in hypertension is related to increased oxidation of LDL. Fifteen men with borderline hypertension (BHT), with blood pressure values classified as high normal (systolic blood pressure 130-140 mmHg or diastolic blood pressure 85-89 mmHg) were included. The control group comprised 22 men with normal blood pressure values (<135/80 mmHg) matched for age, body size and LDL-cholesterol level. Distensibility of aorta was measured using magnetic resonance imaging, and distensibility of the common carotid artery using ultrasound. Baseline LDL diene conjugation was used as a marker for ox-LDL. Aortic and carotid distensibilities were lower in the BHT men than in controls (1.4 +/- 0.6 vs. 1.9 +/- 0.6%/10 mmHg, p<0.05 for aortic distensibility; 2.9 +/- 0.9 vs. 3.6 +/- 0.6%/10 mmHg, p<0.05 for carotid distensibility). Ox-LDL was significantly higher in the BHT men than in controls (44 +/-15 vs. 28 +/- 8 micromol/L, p<0.01). In univariate analysis, ox-LDL associated with aortic distensibility (r=-0.43, p<0.05). In multivariate analysis, the differences in distensibilities between the groups disappeared when the values were adjusted for ox-LDL. These data show decreased arterial elasticity and increased LDL oxidation in young men with borderline hypertension, and suggest that oxidative modification of LDL particles may play a pathophysiological role in the development of reduced arterial distensibility in hypertension.     

The preoptic anterior hypothalamic area mediates initiation of the hypotensive response induced by LPS in male rats

The mechanism responsible for the initiation of endotoxic hypotension is not fully understood, although it is often attributed to a direct effect of LPS and other vasoactive mediators on the vasculature. Alternatively, recent evidence raises the possibility that endotoxic hypotension may be initiated through a central mechanism. Previous studies have shown that LPS initiates fever, sickness behavior, and other aspects of the inflammatory response through a neural pathway that sends peripheral inflammatory signals to the preoptic anterior hypothalamic area (POA). It is also well known that the POA plays a role in the regulation of cardiovascular function, but its involvement in LPS-induced hypotension has not been examined previously. Therefore, the aim of the present paper was to investigate whether the initial abrupt fall in arterial pressure evoked by LPS in septic shock is mediated by the POA. LPS (1 mg/kg, i.v.) administration to halothane-anesthetized or conscious rats lowered arterial blood pressure by 24.8+/-2.9 and 25.1+/-5.8 mmHg, respectively. Bilateral lidocaine (2%; 1 microL) injection into the POA, but not the lateral hypothalamus, prevented the hypotension evoked by LPS entirely in both anesthetized and conscious animals. Remarkably, this blockade significantly inhibited the second, delayed fall in arterial pressure induced by LPS, and simultaneously decreased TNF-alpha plasma levels. Together, these data indicate that the initial phase of endotoxic hypotension is mediated by the POA and suggest that the initiation of the hypotensive response induced by LPS can be essential for the development of the late fall in blood pressure.     

Glutamate-evoked pain and mechanical allodynia in the human masseter muscle

The present study examined the effect of peripheral administration of the excitatory amino acid (EAA) glutamate on the intensity of perceived pain and pressure pain thresholds (PPTs) in healthy young women (n=17) and men (n=18). Two injections separated by 25 min of 0.2 ml, 1.0M glutamate into the masseter muscle produced significantly higher scores of pain on 0-10 cm visual analogue scales (VAS) in women than in men (analysis of variance, ANOVA: P<0.001). There was no significant difference between the VAS scores for the first and the second injections in either men or women. The PPTs determined in the masseter muscle were significantly reduced following the first injection and further significantly reduced after the second injection (ANOVA: P<0.001). Furthermore, the PPTs were reduced to a similar extent in both women and men (maximum 44-56%), suggesting that gender did not influence the process of sensitization. There were no significant difference in VAS scores or PPTs between women taking oral contraceptives (n=9) and those who did not (n=8) (ANOVAs: P=0.709, P=0.153). It is concluded that the VAS scores produced by intramuscular administration of 1.0M glutamate may reflect a gender-dependent activation of nociceptive pathways which, in part, may be mediated through peripheral EAA receptors. The reduction of PPTs in the masseter muscle following administration of glutamate in a concentration of 1.0M may reflect allodynia to mechanical stimuli. This process of sensitization was not gender-dependent. The present results suggest that injection of 1.0M glutamate into the masseter muscle may provide a useful experimental method to test sensitization and efficacy of peripheral EAA receptor antagonists in human subjects.     

Hemorrhage alters neuroendocrine, hemodynamic, and compartment-specific TNF responses to LPS

The aim of the present study was to determine the effects of fixed pressure (40 mmHg) hemorrhage (HEM) followed by fluid resuscitation with Ringer's lactate on the subsequent hemodynamic, neurohormonal, and TNF response elicited by systemic lipopolysaccharide (LPS) administration. Chronically catheterized, conscious, unrestrained male Sprague-Dawley rats were randomized to either HEM (n = 12) or sham (n = 12) groups. HEM and sham animals were randomized to receive either LPS (100 mg/100 g body weight) or an equal volume of intravenous saline 1.5 h after completion of the resuscitation period. LPS administration produced an immediate 20% decrease in mean arterial pressure in sham animals, which was accentuated in HEM animals (40%, P < 0.05 versus sham). Moreover, HEM blunted (75%, P < 0.05) the LPS-induced increase in plasma TNF concentrations. TNF was not detected in bronchoalveolar lavage fluid (BALF) obtained from sham LPS-treated animals. In contrast, TNF levels were significantly elevated (35 +/- 17 pg/mL) in HEM LPS-treated animals. A 400% increase in lung TNF content following LPS treatment was not affected by prior HEM. LPS administration produced a marked increase in plasma epinephrine, norepinephrine, and corticosterone levels in sham animals. HEM blunted the LPS-induced rise in circulating levels of epinephrine and corticosterone without altering that of norepinephrine. Our second set of studies showed that the increase in BALF TNF was associated with a 30% increase in wet-to-dry lung weight ratios, suggesting that this is most likely the result of leaky endothelium following hemorrhage and LPS. Furthermore, alterations in LPS-induced alveolar macrophage TNF production following HEM were not detected. These results indicate that HEM altered the hemodynamic, neurohormonal, and circulating TNF responses to systemic LPS administration. In addition, our results suggest that HEM impaired the compartmentalization of the inflammatory response to LPS, without affecting alveolar macrophage responses to LPS. The role of altered neuroendocrine responses to a second challenge in modulating proinflammatory responses remains to be elucidated.     

Effects of age on body temperature and blood pressure in cold environments

Mean deep body temperature fell by 0.4 +/- 0.1 (SD) degrees C in five sedentary, clothed 63-70 year old men and by 0.1 +/- 0.1 degrees C in four young adults after 2 h exposure in still air at 6 degrees C (P less than 0.001). The mean increase in systolic and diastolic pressure was significantly greater (P less than 0.002) in the older subjects (24 +/- 4 mmHg systolic, 13 +/- 4 mmHg diastolic) than in the young (14 +/- 6 mmHg systolic, 7 +/- 3 mmHg diastolic) after 2 h at 6 degrees C. A small rise in blood pressure occurred in the older men at 12 degrees C, but there was no increase in either group at 15 degrees C. The association of variables is particularly marked between systolic blood pressure and core temperature changes at 6 degrees C. There were no appreciable cold-adaptive changes in blood pressure or thermoregulatory responses after 7-10 days repeated exposure to 6 degrees C for 4 h each day. Blood pressure elevation in the cold was slower but more marked in the older men. These changes in blood pressure may provide a possible basis for delineating low domestic limiting temperature conditions.     

Cardiopulmonary and splanchnic blood flow during 48 hours of a continuous infusion of endotoxin in conscious pigs: a model of hyperdynamic shock

Hyperdynamic shock can be modeled in pigs by chronic administration of a continuous, low-dose infusion of endotoxin. Lipopolysaccharide (LPS, E. coli 0111:B4, 80 ng/kg/min i.v.) initially resulted in a hypodynamic shock state with significant decreases in mean arterial pressure (112+/-3 mmHg at baseline to 94+/-4 mmHg at 8 h) and cardiac index (5.35+/-0.32 L/min/m2 at baseline to 4.07+/-0.32 L/min/m2 at 4 h). Eight hours after the initiation of the LPS infusion, cardiac index rose to above baseline values (5.82+/-0.4 L/min/m2 at 8 h) and remained elevated for the duration of the 48-h study (6.54+/-0.39 L/min/m2 at 48 h). Similarly, systemic vascular resistance fell significantly by 8 h (1640+/-100 dyne sec cm(-5) at baseline to 1239+/-80 dyne sec cm(-5) at 8 h) and remained decreased for the duration of the study. Blood flow in major abdominal vessels, including the left renal artery, the cranial mesenteric artery, and the portal vein, paralleled changes in the cardiac index. Serum concentrations of tumor necrosis factor were increased after 2 h of LPS infusion, but did not remain elevated above baseline concentrations for more than about 4 h despite continuous LPS challenge. Concentrations of tumor necrosis factor did not differ between arterial and portal venous samples. This model of hyperdynamic shock should be useful to assess potential therapies for septic shock.     

Disparities in circulatory adjustment to standing between young and elderly subjects explained by pulse contour analysis.

1. The circulatory adjustment to standing was investigated in two age groups. Young subjects consisted of 20 healthy 10-14-year-old girls and boys. Elderly subjects consisted of 40 70-86-year-old healthy and active females and males. Continuous responses of blood pressure and heart rate were recorded by Finapres. A pulse contour algorithm applied to the finger arterial pressure waveform was used to assess stroke volume responses. 2. During the first 30s (initial phase), an almost identical drop in mean blood pressure was found in both age groups (young, 16 +/- 10 mmHg; old, 17 +/- 10 mmHg), but the initial heart rate increase was attenuated in the elderly subjects (young, 29 +/- 7 beats/min; old, 17 +/- 7 beats/min). 3. During the period from 30 s to 10 min of standing, mean blood pressure increased from 96 +/- 12 to 106 +/- 12 mmHg in the elderly subjects compared with almost no change in the young subjects (from 82 +/- 8 to 84 +/- 7 mmHg). In the elderly subjects a progressive increase in total peripheral resistance (from 114 +/- 14% to 146 +/- 29%) was found, compared with an initial rapid increase in total peripheral resistance (126 +/- 18% after 30 s) with no further change during prolonged standing (124 +/- 17% after 10 min) in the young subjects. In this age group the decrease in stroke volume and the increase in heart rate after 10 min of standing were large (young, -37 +/- 11% and 27 +/- 11 beats/min; old, -31 +/- 9% and 7 +/- 6 beats/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome

Both antioxidant supplementation and exercise training have been identified as interventions which may reduce oxidative stress and thus improve cardiovascular health, but the interaction of these interventions on arterial BP (blood pressure) and vascular function has not been studied in older humans. Thus in six older (71+/-2 years) mildly hypertensive men, arterial BP was evaluated non-invasively at rest and during small muscle mass (knee-extensor) exercise with and without a pharmacological dose of oral antioxidants (vitamins C and E, and alpha-lipoic acid). The efficacy of the antioxidant intervention to decrease the plasma free radical concentration was verified via EPR (electron paramagnetic resonance) spectroscopy, while changes in endothelial function in response to exercise training and antioxidant administration were evaluated via FMD (flow-mediated vasodilation). Subjects were re-evaluated after a 6-week aerobic exercise training programme. Prior to training, acute antioxidant administration did not change resting arterial BP or FMD. Six weeks of knee-extensor exercise training reduced systolic BP (from 150+/-8 mmHg at pre-training to 138+/-3 mmHg at post-training) and diastolic BP (from 91+/-5 mmHg at pre-training to 79+/-3 mmHg at post-training), and improved FMD (1.5+/-1 to 4.9+/-1% for pre- and post-training respectively). However, antioxidant administration after exercise training negated these improvements, returning subjects to a hypertensive state and blunting training-induced improvements in FMD. In conclusion, the paradoxical effects of these interventions suggest a need for caution when exercise and acute antioxidant supplementation are combined in elderly mildly hypertensive individuals.     

Inhibition of theophylline metabolism by mexiletine in young male and female nonsmokers

The influence of mexiletine (200 mg every 8 hours) on theophylline metabolism was studied in young male (n = 7) and female (n = 8) nonsmokers. A single-dose study of theophylline kinetics was performed at baseline and after 5 days of mexiletine treatment. With mexiletine the plasma clearance of theophylline decreased from 33.5 +/- 2.6 (mean +/- SEM) to 17.9 +/- 1.0 ml/kg per hour in the female group (p less than 0.001) and from 32.3 +/- 2.6 to 19.3 +/- 1.3 ml/kg per hour in the male group (p less than 0.001). The elimination half-life was prolonged by 74% and 103% in the male and female groups, respectively. Mexiletine decreased the formation of all theophylline metabolites in both groups. Within each group, the demethylation pathways were affected more than the hydroxylation pathway. These data indicate that mexiletine is a potent inhibitor of theophylline metabolism. This effect is not influenced by gender. Concurrent administration of these drugs may require a dose reduction of theophylline by as much as 50% to minimize the risk of toxicity.     

Autonomic mechanisms underlying intraocular pressure changes during insulin-induced hypoglycaemia in normal human subjects: effects of pharmacological blockade.

1. A fall in intraocular pressure is induced by acute hypoglycaemia in humans. The role of the autonomic nervous system in mediating this response was investigated in 24 normal volunteers in whom hypoglycaemia was induced with intravenous soluble insulin, under four experimental conditions: (1) control (n = 6), (2) non-selective alpha-adrenoceptor blockade (phentolamine) (n = 6), (3) non-selective beta-adrenoceptor blockade (propranolol) (n = 6) and (4) cholinergic blockade (atropine) (n = 6). Intraocular pressure was measured by using an applanation tonometer. In 12 subjects intraocular pressure was measured during each type of pharmacological blockade of similar duration without induction of hypoglycaemia, to assess the effects of individual antagonists. 2. In the control study intraocular pressure fell during hypoglycaemia from 15 +/- 1.0 to 10 +/- 1.3 mmHg (P less than 0.01) 10 min after the autonomic reaction. beta-Adrenoceptor blockade caused a reduction in intraocular pressure from 15 +/- 1.1 to 9 +/- 1.0 mmHg (P less than 0.001) before the administration of insulin, and when hypoglycaemia was induced intraocular pressure decreased further to 7 +/- 1.0 mmHg (P less than 0.05, compared with immediately before insulin). A decrease in intraocular pressure of similar magnitude was observed with propranolol alone (16 +/- 1.0 to 10 +/- 1.0 mmHg, P less than 0.05). 3. Cholinergic blockade had no immediate effect on intraocular pressure, and the reduction in intraocular pressure during hypoglycaemia was of similar magnitude to that observed during the control study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monophosphoryl lipid A blocks the hemodynamic effects of lethal endotoxemia

Monophosphoryl lipid A (MPL) is a "nontoxic" derivative of lipid A. We hypothesized that, because of the structural similarity between MPL and the lipid A portion of lipopolysaccharide (a "toxic" moiety of endotoxin), hemodynamic events occurring during endotoxemia could be attenuated by administration of MPL. Lipopolysaccharide (LPS) from Salmonella minnesota wild type S and MPL from S. minnesota R595 were used for the study. Fifteen Sprague-Dawley rats were randomized to receive either (1) 0.50 mg LPS per 100 gm body weight intravenously, (2) 0.50 mg MPL per 100 gm body weight intravenously, or (3) 0.5 mg MPL per 100 gm body weight intravenously followed in 15 minutes by 0.50 mg LPS per 100 gm body weight intravenously. Arterial pressure, thermodilution cardiac output, and central venous oxygen saturation were measured before and 30 and 60 minutes after LPS administration. In LPS-treated animals, cardiac output decreased from 448 +/- 28 ml/kg/min to 336 +/- 15 ml/kg/min (p less than 0.02), and central venous oxygen saturation decreased from 71% +/- 1% to 62% +/- 2% (p less than 0.05). Mean arterial pressure decreased from 134 +/- 5 mm Hg to 90 +/- 6 mm Hg (p less than 0.01). In MPL-treated and MPL + LPS-treated animals, no significant changes were observed in cardiac output, central venous oxygen saturation, or arterial pressure. These data indicate that MPL is not associated with the adverse cardiovascular responses observed after LPS administration. Furthermore, administration of MPL blocks the development of acute circulatory failure during endotoxemia.     

Increased uterine arterial pressure and contractility of perfused swine uterus after treatment with serum from pre-eclamptic women and endothelin-1

The present study was designed to examine the effects of ET-1 (endothelin-1) and serum from PE (pre-eclamptic), HP (healthy pregnant) and HNP (healthy non-pregnant) women on uterine arterial perfusion pressure and uterine contractility. Swine uteri (n = 25) were perfused for a period of up to 11 h, with the aim being to preserve a viable organ. Various concentrations of ET-1 as well as serum from PE, HP and HNP women (n = 10 per group) were administered to the perfused swine uteri and IUP (intrauterine pressure) and IAP (intra-arterial pressure) were recorded. ET-1 produced dose-dependent increases in IUP and IAP. The ET-1 concentration in serum was higher in serum from PE women than in HP and HNP women (P > 0.05). Administration of all serum samples had a contractile effect on the swine uterus, with the greatest effect being seen in HNP women (12.8 +/- 5.3 mmHg), followed by PE (9.06 +/- 4.2 mmHg) and HP (6.1 +/- 4.1 mmHg) women. Statistically significant differences were observed between HNP and PE women (P = 0.048), and PE and HP women (P = 0.021). Increases in IAP following administration of serum from PE women (48.8 +/- 20.0 mmHg) were significantly higher (P = 0.024) compared with the effect of serum from HP women (28.4 +/- 13.7 mmHg). In conclusion, the findings show that serum from PE women has significant vasoconstrictive and oxytocic effects compared with serum from HP women. In pre-eclampsia, the balance between vasorelaxing and vasoactive substances is disturbed.     

Endocrine and haemodynamic responses to graded dopamine infusion in essential hypertension

Hormonal, mean arterial blood pressure, forearm blood flow and heart rate responses to graded dopamine infusion (0.5-2.0 micrograms/kg/min) were examined in 10 men with untreated essential hypertension WHO group I (147 +/- 4/100 +/- 1 mmHg, means +/- SE), and in 10 normotensive men (129 +/- 2/85 +/- 1 mmHg), all 40 years old. Another 12 normotensive men (126 +/- 3/80 +/- 2 mmHg) were given only saline infusion. Dopamine increased heart rate significantly in the hypertensive group (8 +/- 2 beats/min, p less than 0.001), but the heart rate remained unchanged in the normotensive group (1 +/- 1 beats/min, NS). Although dopamine infusion tended to decrease mean blood pressure, the changes were not significantly different from those observed in the control group. No change in forearm blood flow was observed in either group. In the groups given dopamine, prolactin levels decreased only slightly compared to the control group given saline, the decrement tending to be more pronounced in the hypertensive group. Plasma vasopressin remained unchanged in both groups during dopamine infusion. These results indicate that hypertensive patients exhibit increased sensitivity to the cardiovascular effects of dopamine.     

Oral contraceptive steroids impair the elimination of theophylline

The influence of OCS and sex differences on the disposition of theophylline has been studied in 12 healthy young men (29 +/- 4 years old), 13 healthy young women (29 +/- 12), and 10 healthy young women (24 +/- 3) receiving OCS for a period greater than 6 months. The elimination t1/2 was longer in women taking oral contraceptives (523 +/- 110 min) than in women not on oral contraceptives (386 +/- 157). Weight-normalized plasma clearance of theophylline was less in women taking oral contraceptive steroids (0.70 +/- 0.15 ml X min-1 X kg-1) than in women not on oral contraceptive steroids (0.98 +/- 0.32). Plasma binding and volume of distribution were not different between the two groups of women. Weight-normalized clearance, weight-normalized volume of distribution, plasma t1/2, and plasma binding were not different between men and women not taking OCS.     

Arterial baroreflex function determines the survival time in lipopolysaccharide-induced shock in rats

Lipopolysaccharide (LPS) mimics many of the effects of septic shock. LPS-induced death has been attributed to systemic hypotension, hyporeactiveness to vasoconstrictors, metabolic acidosis, and organ damage. However, there is no research directed to the involvement of the baroreflex sensitivity (BRS) in LPS-induced death. The purpose of this study was to evaluate the effect of BRS on the survival time after lethal LPS challenge. Four groups of rats were used. Each rat received an equivalent dose of intravenous LPS (50 mg/kg). It was found that the anesthetized sinoaortic-denervated (SAD) rats (representative of the lowest BRS, BRS = 0.022 +/- 0.015 ms/mmHg) survived the shortest time (36 +/- 11.1 min). The conscious SAD rats (BRS = 0.198 +/- 0.035 ms/mmHg) and the anesthetized sham-operated rats (BRS = 0.304 +/- 0.072 ms/mmHg) were alive a relatively long time (101 +/- 11.5 min and 110 +/- 12.4 min, respectively). The conscious sham-operated rats (BRS = 0.943 +/- 0.097 ms/mmHg) survived the longest time (148 +/- 6.5 min). These results demonstrated that arterial baroreflex function determined the survival time in the LPS-induced lethal shock.     

A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade

BACKGROUND: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. METHODS AND RESULTS: Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. CONCLUSIONS: There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.     

Effects of head-up tilting on baroreceptor control in subjects with different tolerances to orthostatic stress

During orthostatic stress, an increase in peripheral vascular resistance normally results in arterial blood pressure being well maintained, despite a decrease in cardiac output. The present study was undertaken to determine whether the sensitivity of the carotid baroreceptor reflex was increased during orthostatic stress and whether failure to develop this increase was associated with poor orthostatic tolerance. Three groups of subjects were studied: asymptomatic controls; patients investigated for suspected posturally related syncope but who had normal responses to an orthostatic stress test (normal patients); and patients who were shown to have low orthostatic tolerance (early fainters). We determined responses of R-R interval and forearm vascular resistance (mean arterial pressure/brachial artery velocity by Doppler ultrasonography) to the loading and unloading of carotid baroreceptors by application of pressures of -30 and +30 mmHg to a chamber fitted over the neck. Responses were determined after 20 min of supine rest and after 10 min of head-up tilt at 60 degrees. Responses of cardiac interval were not significantly different between the three groups, and they were not altered by the postural change. Vascular responses also did not differ between the groups during supine rest. However, in healthy volunteers and in normal patients, responses to both neck suction and pressure were significantly enhanced during head-up tilt. In controls, responses to suction were increased by tilt from 0.04+/-0.1 to -1.01+/-0.2%.mmHg(-1) (means+/-S.E.M.; P<0.001) and those to neck pressure from -0.6+/-0.3 to -3.1+/-1.1%.mmHg(-1) (P<0.05). In the normal patients, the corresponding changes were: during suction, from -0.2+/-0.1 to -0.7+/-0.1%.mmHg(-1) (P<0.05); during pressure, from -0.7+/-0.1 to -1.5+/-0.3%.mmHg(-1) (P<0.05). In contrast, in patients with low orthostatic tolerance, posture had no effect on the reflex (neck suction, from -0.3+/-0.1 to -0.3+/-0.1%.mmHg(-1); neck pressure, from -1.0+/-0.3 to -0.9+/-0.2%.mmHg(-1)). We suggest that an increase in the sensitivity of the carotid baroreceptor/vascular resistance reflex may be important in the maintenance of blood pressure during orthostatic stress, and that failure of this to occur in patients with posturally related syncope may go some way towards explaining their poor orthostatic tolerance.     

Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats.

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.