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INTEGRATIVE |
1 Department of Anaesthesiology
2 Department of Biostatistics
3 Division of Cardiovascular Diseases, Department of Internal Medicine
4 Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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Abstract |
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(Received 21 April 2006;
accepted after revision 31 May 2006;
first published online 1 June 2006)
Corresponding author John H. Eisenach: Anesthesia Research, Mayo Clinic and Foundation, 200 1st Street, SW Rochester, MN 55905, USA. Email: eisenach.john{at}mayo.edu
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Introduction |
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In the ‘pregenomic’ era, intermediate physiological characteristics of ß2AR function were described for both hypertension and dietary sodium intake. In individuals with essential hypertension, ß2AR responsiveness is reduced (Feldman et al. 1984; Feldman, 1987); likewise, normotensive individuals at increased risk of developing hypertension have impaired vasodilator responses to ß2AR agonists (Lang et al. 1995; Stein et al. 1995). Studies of the effects of sodium intake on sensitivity to ß2AR-mediated vasodilatation have established that a normal response to increased sodium intake, consisting of increased sensitivity to ß2AR-mediated vasodilatation, is decreased in hypertensive compared to normotensive individuals (Naslund et al. 1990). Furthermore, ß2AR-mediated responsiveness is reduced selectively in peripheral veins of borderline hypertensive subjects, an effect that is potentially reversible by a low-Na+ diet (Feldman, 1990).
We previously reported that, in a group of healthy normotensive subjects, following 5 days of normal dietary Na+ intake (150 mmol day–1), Gly16 homozygotes demonstrated greater forearm arterial vasodilatation in response to isoprenaline (isoproterenol) than Arg16 homozygotes, and the effect appeared to be dependent on the generation of NO, while responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were not different in the two genotype groups (Garovic et al. 2003). Additionally, increased ß2AR-mediated venodilatation in response to isoprenaline is 3-fold greater in Gly16 than Arg16 subjects (Cockcroft et al. 2000). However, in contrast to regional vascular studies, systemic infusions of selective ß2AR agonists have been shown to evoke greater systemic vasodilatation in Arg16 than Gly16 subjects receiving an unrestricted dietary sodium intake of 8–12 g salt (137–205 mmol sodium) per day (Gratze et al. 1999; Hoit et al. 2000).
With this information as background, the purpose of the present study was to investigate mechanistically the vasodilator pathways by which dietary sodium restriction might affect intermediate physiological characteristics and cardiovascular function in individuals homozygous for the Gly16 versus Arg16 polymorphism of the ß2AR. We reasoned that effects of dietary sodium restriction would differ between genotypes of the ß2AR. Since normotensive Gly16 subjects previously demonstrated augmented forearm ß2AR-mediated vasodilatation while receiving a normal sodium dietary intake (Garovic et al. 2003), and dietary sodium intake has substantial effects on ß2AR-mediated function, we tested the following hypotheses: (1) increased ß2AR, NO-mediated forearm vasodilatation in Gly16 versus Arg16 homozygotes is dependent on normal dietary sodium intake, and therefore differences would not be apparent after a low-Na+ diet; (2) non-ß2AR-mediated vasodilator responses to ACh and SNP in individuals homozygous for Gly16 and Arg16 would be similar after a low-Na+ diet; (3) systemic vasodilatation in response to intravenous ß2AR agonist stimulation would be different in the Arg16 and Gly16 subjects before, but not after the low-Na+ diet; and (4) indices of myocardial function (cardiac output (CO) and stroke volume (SV)) would also be different in the Arg16 and Gly16 subjects before, but not after, receiving the low-Na+ diet. Our findings, and those in a companion paper in this issue by Snyder et al. (2006c) suggest the possibility that the Arg16Gly polymorphism influences salt sensitivity and cardiovascular function.
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Methods |
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Thirty-two normotensive, unrelated, non-Hispanic white individuals in Rochester, MN, USA were recruited and grouped according to the Arg16Gly polymorphism, genotyped as previously described (Garovic et al. 2003). Men were under 40 years of age, women were under 50 years and premenopausal, and neither had a history of tobacco use or any acute or chronic disorder associated with alterations in cardiovascular structure or function. Subjects made up two genotype groups: homozygous for the Arg16 variant (n = 15) or homozygous for the Gly16 variant (n = 17). Nine of the Arg16 homozygotes and 12 of the Gly16 homozygotes had participated in a previous study following a normal sodium diet (Garovic et al. 2003).
One of the investigators reviewed each subject's medical history and performed a physical examination including blood pressure (by random zero sphygmomanometer). Three blood pressure readings taken 2 min apart were recorded after the subject had been seated quietly for at least 5 min. The second and third readings were averaged and used in the analyses. Women of childbearing potential were required to have a negative pregnancy test before participation. This study was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board. Each participant gave written, informed consent.
Study protocol
Subjects fasted on the morning of study day 0, and checked into the General Clinical Research Center (GCRC) Physiology Core Laboratory (Fig. 1). Subjects were familiarized with the testing equipment while supine. After administration of subcutaneous local anaesthesia, an 18-gauge peripheral intravenous catheter was placed in either arm. CO was measured non-invasively by using an open-circuit acetylene gas method described in detail elsewhere (Johnson et al. 2000). Measurements of CO were acquired in duplicate for each experimental condition.
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On day 6, seated blood pressure measurements were repeated, followed by the forearm blood flow (FBF) protocol in the integrative physiology core of the GCRC. The volume of the non-dominant arm was measured by water displacement, followed by placement of a 20-gauge, 4.45-cm catheter in the brachial artery under aseptic conditions after administration of local anaesthetic (2% lidocaine). A three-port connector was placed in series with a catheter–transducer system so that drugs could be infused and arterial pressure measured simultaneously. FBF was measured using venous occlusion plethysmography with a mercury-in-silastic strain gauge placed around the non-dominant forearm at its greatest circumference (Greenfield et al. 1963). During recording, a wrist cuff was continuously inflated to suprasystolic pressure (250 mmHg) to occlude arterial blood flow to the hand while a venous occlusion cuff around the upper arm was inflated to 50 mmHg for 7.5 s of every 15 s, providing one blood flow measurement every 15 s. FBF values were expressed as ml (100 ml limb volume)–1 min–1.
Drug infusion protocol and drug doses. All drug infusions were administered at rates of 2–3 ml min–1. Infusions of SNP, isoprenaline and ACh were administered before and after NG-mono-methyl-L-arginine (L-NMMA). Each dose of each drug was administered for 2–3 min and the dose–response determinations were separated by a period of quiet rest for 20 min. To test NO-mediated endothelium-independent vasodilatation, the NO donor SNP was infused for 2 min at 1.0 µg (100 ml limb volume)–1 min–1. To test ß2AR-mediated vasodilatation, isoprenaline was infused for 2 min at 1.0, 3.0, 6.0 and 12.0 ng (100 ml limb volume)–1 min–1. To test endothelium-dependent vasodilatation, ACh was infused for 2 min at 4.0 µg (100 ml limb volume)–1 min–1.
After the initial drug infusions and return of FBF to baseline levels, the wrist cuff was re-inflated and the NO synthase (NOS) inhibitor L-NMMA (50 mg) was infused over 10 min, followed by a ‘maintenance’ dose of L-NMMA (1 mg min–1) throughout the remainder of the protocol. Administration of the three vasodilator drugs was then repeated in reverse order (ACh, isoprenaline and SNP). We reasoned that if any differences between the groups were due to NO production, then the responses after administration of L-NMMA would be similar. The order of drug administration was not randomized so that the repeat doses of ACh could be given immediately after L-NMMA, to assess the magnitude of the NOS inhibition. Following FBF measurements, the arterial catheter was removed. Subjects walked to the GCRC Physiology Core Laboratory for placement of an intravenous catheter for systemic TRB infusion and the CO protocol was repeated exactly as described above for day 0 of the study.
Data analysis. Data were digitized at 200 Hz and stored on computer. Data were analysed off-line with signal processing software (Windaq, Dataq Instruments, Akron, OH, USA). FBF was determined from the derivative of the forearm plethysmogram during the last minute of each drug dose. FBF was reported rather than forearm vascular conductance because it was the primary measured variable in the pharmacological dose–response curves and because there were negligible changes in arterial pressure during the isolated forearm drug infusions. HR was derived from the electrocardiogram waveform, and mean arterial pressure (MAP) was derived from the arterial pressure waveform during plethysmography, and from an automated oscillometric brachial cuff during the TRB trials.
Statistical analysis
Baseline patient characteristics were summarized by calculating means and standard deviations for continuous variables and proportions for categorical variables. These characteristics were compared between Arg16 and Gly16 groups using the two-sample t test for continuous variables, and Fisher's exact test for categorical traits (sex). For MAP, HR, SV, CO and systemic vascular resistance (SVR), the paired t test was used to compare baseline values between day 0 (normal sodium) and day 6 (low sodium). In addition, repeated measures ANOVA models were used to assess differences between genotype groups for the within-subject responses to increasing doses of TRB. Separate models were used to analyse data collected on day 0 (normal Na+) and day 6 (low Na+) diets and an overall model was used to assess whether genotype effects were dependent on diet. For FBF, analogous models were used to assess differences between genotype groups for the within-subject responses to increasing doses of ACh, SNP or isoprenaline, both before and after administration of L-NMMA. In addition, an overall model was fitted for each of the individual drugs in which L-NMMA was included as a subject effect to assess whether the effect of L-NMMA was dependent on genotype. The sample size for this study was determined to provide statistical power of 80% to detect differences in the FBF response to isoprenaline based on the Arg16Gly polymorphism, consistent with previous observations (Garovic et al. 2003). Data are presented as means ± S.D. In all cases, two-tailed P values of 0.05 were considered statistically significant.
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Results |
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As shown in Fig. 3, resting CO was 5.8 ± 1.3 and 6.4 ± 1.4 l min–1 in the Arg16 and Gly16 groups, respectively, before dietary sodium restriction (P = 0.24). Following dietary sodium restriction, CO was 5.6 ± 1.0 and 5.5 ± 1.2 l min–1 in the Arg16 and Gly16 groups, respectively, representing a significant decrease in the Gly16 group (P = 0.003) but not in the Arg16 group (P = 0.38). TRB increased CO before and after dietary sodium restriction (P < 0.001). However, there was no evidence that diet or genotype affected the response to TRB (P = 0.33, genotype-by-dose interaction; P = 0.87, diet-by-dose interaction; P = 0.65, genotype-by-diet-by-dose interaction).
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Before dietary sodium restriction, resting SVR was 1165 ± 226 and 1106 ± 246 dynes s cm–5 in the Arg16 and Gly16 groups, respectively (P = 0.49). Following dietary sodium restriction, SVR was 1216 ± 209 and 1246 ± 222 dynes s cm–5 in the Arg16 and Gly16 groups, respectively, representing a significant increase in the Gly16 group (P = 0.02) but not in the Arg16 group (P = 0.47). TRB decreased SVR in all subjects before and after dietary sodium restriction (P < 0.001). However, there was no evidence that diet or genotype affected the dose–responses to TRB (P = 0.623, genotype-by-dose interaction; P = 0.66, diet-by-dose interaction; P = 0.72, genotype-by-diet-by-dose interaction).
Baseline FBF did not differ between groups (Arg16, 2.28 ± 0.92 ml (100 ml limb volume)–1 min–1; Gly16, 1.93 ± 0.43 ml (100 ml limb volume)–1 min–1; P = 0.17). SNP evoked an increase in FBF (P < 0.001), but there was no evidence of a difference between genotype groups (P = 0.76, main effect of genotype; P = 0.45, genotype-by-SNP interaction). L-NMMA significantly decreased baseline FBF (Arg16, 1.73 ± 0.48 ml (100 ml limb volume)–1 min–1, P = 0.04; Gly16, 1.49 ± 0.38 ml (100 ml limb volume)–1 min–1, P = 0.002), while the difference was not dependent on genotype (P = 0.67). L-NMMA did not affect the vasodilator responses to SNP (P = 0.07, SNP-by-L-NMMA interaction; P = 0.29, genotype-by-SNP-by-L-NMMA interaction).
Isoprenaline caused an increase in FBF (P < 0.001, main effect of isoprenaline dose) that did not differ between groups (P = 0.51, main effect of genotype; P = 0.72, genotype-by-dose interaction, Fig. 4). For example, the response to isoprenaline at 12 ng (dl limb volume)–1 min–1 was 10.3 ± 5.5 ml (100 ml limb volume)–1 min–1 in the Arg16 group and 12.0 ± 4.4 ml (100 ml limb volume)–1 min–1 in the Gly16 group (P = 0.33, unpaired t test). L-NMMA significantly blunted the vasodilator response to isoprenaline (P < 0.001), but there was no evidence that this effect was influenced by genotype (P = 0.89, genotype-by-dose-by-L-NMMA interaction).
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As nine Arg16 and 12 Gly16 homozygotes were participants in a preceding study (Garovic et al. 2003), we performed an analysis of the effect of dietary sodium restriction on these individuals (Fig. 5). In the previous study, with a normal dietary sodium intake, the FBF responses of the Gly16 subjects to isoprenaline at 3, 6 and 12 ng (100 ml limb volume)–1 min–1 were 9.6 ± 3.6, 11.7 ± 4.6 and 15.9 ± 6.4 ml (100 ml limb volume)–1 min–1, respectively. In the present study, the FBF responses to the same doses in these individuals were 7.3 ± 2.6, 9.4 ± 4.1 and 11.2 ± 4.9 ml (100 ml limb volume)–1 min–1, respectively (P
= 0.04, 0.08, 0.007, respectively, paired t test). Furthermore, the Arg16 subjects did not display a significant change in the FBF response to isoprenaline at any of the dosages after the low-Na+ diet (P
0.2 for all).
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Discussion |
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Clinical significance of the Arg16Gly polymorphism has been demonstrated in genomic analyses of hypertension, but as yet there is no conclusive evidence that the Gly16 rather than the Arg16 variant is most important (Kotanko et al. 1997; Bray et al. 2000; Busjahn et al. 2000; Xie et al. 2000; Ranade et al. 2001; Herrmann et al. 2002; Jindra et al. 2002; Snieder et al. 2002; Ge et al. 2005). Despite this, recent studies have suggested that the Gly16 allele may actually be favourable in cardiovascular health. A study of 5888 people 65 years of age or older, suggested a decreased risk of coronary events in Gly16 compared to Arg16 carriers (Heckbert et al. 2003). A prospective cohort study of patients with acute coronary syndrome who received ß-blockers, predicted lower 3-year cumulative mortality in Gly16 than in Arg16 subjects (Lanfear et al. 2005). Bao et al. (2005) reported that the haplotype containing the Gly16 allele was found to be protective against hypertension in European American adults below age 50. Healthy Gly16 homozygotes have enhanced left ventricular function compared to Arg16 homozgygotes (Tang et al. 2003; Eisenach et al. 2004, 2005; Snyder et al. 2006a), while decreases in ejection fraction increase the odds ratio of death in patients with acute coronary syndrome with non-ST-segment elevation (Bosch & Theroux, 2005). Taken together, the Arg16Gly polymorphism appears to have powerful pharmacogenetic and disease-modifying implications.
Because essential hypertension is a heterogeneous disorder caused by both genetic and environmental factors, we sought to determine whether intermediate physiological characteristics of cardiovascular function would clarify the understanding of the functional relevance of ß2AR gene variation. Along these lines, we previously reported that Gly16 subjects demonstrated a greater vasodilator response to isoprenaline than Arg16 subjects, independent of amino acid position 27, and the difference was dependent on endothelial production of NO (Garovic et al. 2003); that study was performed after a controlled normal sodium diet (150 mmol day–1) for 5 days. As ß2AR function in the vasculature (Feldman, 1990) and lymphocytes (Feldman, 1987) is affected by dietary sodium intake, we hypothesized that dietary sodium restriction would blunt the greater ß2AR-mediated vasodilator responsiveness seen in Gly16 than in Arg16 subjects.
Naslund et al. (1990) placed normotensive subjects on a low-Na+ diet and found decreased forearm vasodilator sensitivity in response to isoprenaline, a decreased lymphocyte receptor affinity for isoprenaline, and a decrease in the proportion of lymphocyte ß2AR binding agonists with high affinity, implying a decrease in adenylate cyclase coupling but not a difference in absolute receptor number. However, specific to the Arg16Gly polymorphism, lymphocyte assays have demonstrated a greater ß2AR density in individuals homozygous for Gly16 (Snyder et al. 2006b) or in carriers of the most common haplotype associated with Gly16 in European Americans (Bao et al. 2005). Therefore, the present finding that Gly16 subjects no longer possessed the greater ß2AR-mediated vasodilator function after low dietary sodium intake may suggest that low sodium intake affected either ß2AR density, basal NO levels, or adenylate cyclase function. The blunted ß2AR function in the forearm may also relate to the finding that baseline ß2AR function in the heart was reduced after the low-Na+ diet, as CO decreased, systolic blood pressure decreased, SV tended to decrease and SVR increased in the Gly16 group. That ACh-evoked vasodilatation was similar in the groups before administration of L-NMMA, but tended to be blunted to a greater degree in the Gly16 group, also suggests that the polymorphism affects endothelial regulation of NO, but this was unaffected by dietary sodium, as similar findings were present in the previous study after normal dietary sodium intake (Garovic et al. 2003). Moreover, arterial vasodilator responses to ACh and SNP were unaffected by low dietary sodium, which is consistent with experiments performed in Sprague Dawley rats (Sofola et al. 2002).
Another potential explanation for the salt-sensitive ß2AR responsiveness in Gly16 homozygotes may be dependence of the physiological stress response on low sodium intake. Formative work by Green and colleagues (1994) demonstrated in Chinese hamster fibroblasts that the Gly16 allele was associated with agonist-promoted down-regulation or sequestration of the ß2AR. In this context, the sympatho-excitatory effect of dietary sodium restriction increases circulating catecholamines (Naslund et al. 1990; Grassi et al. 2002). Conceivably, a low-Na+ diet may result in down-regulation of the ß2AR in Gly16 homozygotes, thereby decreasing the availability of ß2ARs on the forearm vascular endothelium and abrogating the greater ß2AR-mediated dilatation previously seen while receiving a normal sodium diet. We speculate that the desensitization of ß2ARs in this group may differ in the setting of low dietary sodium for 5 days compared to chronic ß2-agonist exposure. Bruck et al. (2003a,b) reported that following oral administration of the ß2-agonist TRB for 2 weeks, desensitization of cardiac ß2AR responses and down-regulation of lymphocyte ß2ARs were not significantly different in Arg16 compared with Gly16 subjects. Furthermore, these same authors have shown that TRB-induced venodilatation in the dorsal hand vein following 2 weeks of oral TRB evoked the greatest extent of desensitization in the Arg16 homozygotes (Bruck et al. 2005). It remains unclear whether the polymorphisms affect myocardial responses, forearm arterial vasodilatation, and venodilatation differentially, although our study suggests that low dietary sodium affects myocardial function and arterial vasodilatation to a significant extent in Gly16 homozygotes.
Aside from the changes in baseline CO and SVR in the Gly16 group, the similar cardiovascular responses to TRB in the groups were not expected from our hypothesis and are not consistent with prior studies examining the Arg16Gly polymorphism. Gratze et al. (1999) showed that during systemic infusion of salbutamol, the total peripheral resistance index in Arg16 homozygotes decreased to a greater extent than in Gly16 homozygotes, implying a greater systemic vasodilator response in the Arg16 group; this group also had a greater increase in HR, cardiac index and stroke index. Similarly, Hoit et al. (2000) reported that during administration of a high systemic dose of TRB, calf blood flow was lower and SVR was greater in the Gly16 group, whereas HR and blood pressure responses were similar. Finally, Lee et al. (2004) reported that administration of inhaled salbutamol in asthmatics evoked a larger decrease in diastolic blood pressure in Arg16 + Gln27 (glutamine) homozygotes when compared to Gly16 + Glu27 (glutamate) homozygotes. The most likely explanation for the disparities between the findings of their studies and ours is the inability to isolate vascular responsiveness when counter-regulatory baroreflexes are engaged. Further analyses of systemic vasodilatation may require concomitant baroreflex inhibition with Nn-cholinergic blockade to measure adrenergic receptor sensitivity without the confounding influence of baroreflexes (Shannon et al. 1998; Jordan et al. 2002; Jones et al. 2003).
The functional relevance of ß2AR polymorphism and its interaction with sodium intake is also highlighted in the companion paper in this issue by Snyder et al. (2006c). Compared to Arg16 homozygotes, the Gly16 group had a greater baseline CO and lower SVR before an acute intravenous saline infusion that remained following the saline load; furthermore, MAP increased to a greater extent and sodium excretion was less in the Gly16 group after the saline challenge (Snyder et al. 2006c). Whereas the Gly16 subjects who participated in our study did not have a significantly greater CO or lower SVR than the Arg16 subjects at rest, the dietary sodium restriction affected these indices in a direction opposite to that in our sodium loading study (Snyder et al. 2006c). Together, these findings suggest that increases in sodium balance may augment effects of the Gly16 allele on cardiovascular and renal phenotypes, and decreases in sodium balance may reduce ß2AR-mediated cardiovascular function for the Gly16 allele. From an evolutionary viewpoint, the low-Na+ diet in the present study is probably closer to ‘normal’ when compared to the current sodium intake in modern society (Lev-Ran & Porta, 2005). In this context, we postulate that the intermediate physiological characteristics seen in Gly16 individuals are protective while receiving a normal to high-Na+ diet, but return to values similar to those of the Arg16 individuals after the low-Na+ diet. Thus, these studies provide evidence that the Arg16Gly polymorphism may be a genetic marker of salt sensitivity.
Limitations
The main experimental limitation involves the lack of forearm vascular response measurements prior to the low-Na+ diet, which is an important consequence of the inability to safely catheterize the non-dominant brachial artery in human volunteers both before and after a 5-day dietary intervention. From a study design perspective, it would have been ideal to perform these measurements before and after the low-Na+ diet. It was therefore necessary to perform a subanalysis of the 9 Arg16 and 12 Gly16 individuals who participated in the prior study approximately 1–2 years earlier following a controlled sodium diet (Garovic et al. 2003) (see Fig. 5). Moreover, characterization of position 16 in combination with position 27 will require larger sample sizes to associate salt sensitivity with composite haplotypes. Finally, similar studies will be necessary in older adults to extend the functional relevance of our findings to ageing and cardiovascular disease.
In summary, this is the first study to demonstrate that the Arg16Gly polymorphism modulates the effect of dietary sodium restriction on cardiovascular function in healthy, normotensive individuals. We conclude that dietary sodium restriction blunts the increased forearm NO-mediated, ß2AR responsiveness in Gly16 subjects, as previously demonstrated for subjects receiving a normal sodium diet. The low-Na+ diet evoked a baseline decrease in systolic function and increase in peripheral resistance in the Gly16 group, providing evidence that sodium intake affects the influence of the Arg16Gly ß2AR polymorphism on cardiovascular indices.
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  E. M. Snyder, S. T. Turner, M. J. Joyner, J. H. Eisenach, and B. D. Johnson The Arg16Gly polymorphism of the {beta}2-adrenergic receptor and the natriuretic response to rapid saline infusion in humans J. Physiol., August 1, 2006; 574(3): 947 - 954. [Abstract] [Full Text] [PDF]
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P
= 0.06) and increased systemic vascular resistance (SVR, *P
= 0.02), whereas these baseline indices were unaffected in the Arg16 group. Terbutaline increased CO and SV, and decreased SVR (P < 0.001), but there were no differences in the responses to terbutaline based on diet or genotype. Error bars denote S.D.
