Role of β1–3-Adrenoceptors in Blood Pressure Control at Rest and During Tyramine-Induced Norepinephrine Release in Spontaneously Hypertensive Rats
β-Adrenoceptors contribute to hypertension in spite of the fact that β-adrenoceptor agonists lower blood pressure. We aimed to differentiate between these functions and to identify differences between spontaneously hypertensive and normotensive rats. β-Adrenoceptor antagonists with different subtype selectivity or the ability to cross the blood-brain barrier were used to demonstrate β-adrenoceptor involvement in resting blood pressure and the response to tyramine-induced peripheral norepinephrine release. The centrally acting propranolol (β1+2[+3]), CGP20712A (β1), ICI-118551 (β2), and SR59230A (β3), as well as peripherally restricted nadolol (β1+2) and atenolol (β1), were administered intravenously, separately, or in combinations. Blood pressure, cardiac output, heart rate, total peripheral vascular resistance, and plasma catecholamine concentrations were evaluated. β-Adrenoceptor antagonists had little effect on cardiovascular baselines in normotensive rats. In hypertensive rats, antagonist-induced hypotension paralleled reductions in resistance, except for atenolol, which reduced cardiac output. The resistance reduction involved primarily neuronal catecholamine, central β1-adrenoceptors, and peripheral β2-adrenoceptors. Tyramine induced a transient, prazosin-sensitive vascular resistance increase. Inhibition of nerve-activated, peripheral β1/3-adrenoceptors enhanced this α1-adrenoceptor–dependent vasoconstriction in normotensive but not hypertensive rats. In hypertensive rats, return to baseline was eliminated after inhibition of the central β1-adrenoceptor, epinephrine release (acute adrenalectomy), and peripheral β2/3-adrenoceptors. Adrenalectomy eliminated β-adrenoceptor–mediated vasodilation in hypertensive rats, and tyramine induced a prazosin-sensitive vasoconstriction, which was inhibited by combined blockade of central β1- and peripheral β2-adrenoceptors. In conclusion, nerve-activated β1- and β3-adrenoceptor–mediated vasodilation was not present in hypertensive rats, whereas epinephrine-activated β2- and β3-adrenoceptor–mediated vasodilation was upregulated. There was also a hypertensive, nerve-activated vasoconstrictory mechanism present in hypertensive rats, involving central β1- and peripheral β2-adrenoceptors combined.
- blood pressure
- total peripheral vascular resistance
- adrenal glands
- sympathetic nervous system
The adrenergic system is a prime controller of blood pressure (BP). The α-adrenoceptor (AR), composed of α1- and α2-subtypes, elicits constriction in vascular smooth muscle cells (VSMCs).1 In addition, α2-ARs limit adrenergic activity by preventing catecholamine release in the central nervous system, peripheral sympathetic nerves, and the adrenals.1 β-ARs located on VSMCs may oppose an α-AR tension response by activating the adenylyl cAMP pathway.2 β2-ARs on endothelial cells may activate NO synthesis and induce vasodilation.2,3 Also, β3-AR may induce endothelial NO- and VSMC cAMP-dependent vasodilation.4 Deficiencies in β-AR–induced vasodilation may result in hypertension.
Other β-AR–dependent mechanisms may increase BP. Central β-ARs of both the β1 and β2 subtypes are involved in the pressor response to behavioral stress,5 and peripheral, presynaptic β2-ARs enhance norepinephrine release.6 Presynaptic β2-ARs have been suggested to be activated by epinephrine, coreleased with norepinephrine.7 Moreover, β1-ARs in the kidney may activate renin release8 and, consequently, angiotensin II formation with vasoconstriction and norepinephrine release.9 In addition, cardiac β1- and β2-ARs stimulate cardiac function and may elevate BP by increasing cardiac output (CO). Because β-AR antagonists have been used efficiently in the treatment of hypertension for almost half a century, β-ARs most likely play an important role in the development of hypertension. How they do so is still not fully understood.
We aimed to show how β-ARs influence BP homeostasis and how their function differs in spontaneously hypertensive rats (SHRs). We hypothesized that the role of β-AR could be revealed by the effect of β-AR antagonists on resting BP and on a provoked sympathetic response. Through this approach, we were able to differentiate between β-AR–mediated vasodilation and vasoconstriction and to reveal altered β-AR functions in SHRs.
The experiments were approved by the institutional review committee and conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Systolic BP, diastolic BP, mean arterial BP (MBP), heart rate (HR), stroke volume (SV), CO (ascending aorta flow), and total peripheral vascular resistance (TPVR) were monitored in Nembutal-anesthetized (70 to 75 mg/kg IP), artificially ventilated rats. A total of 207 SHRs and 173 normotensive controls (Wistar-Kyoto [WKY]), all male and 12 to 14 weeks old, were included. High-resolution flow data were used to estimate inotropy, that is, time from onset of flow increase to maximum rise in flow (TF). Please see the online Data Supplement at http://hyper.ahajournals.org for detailed description.
Control rats were pretreated with a sham injection containing vehicle (PBS, IV) and infused with tyramine (1.26 μmol/min per kilogram, 217 μL/min per kilogram, 15 minutes).10 Tyramine stimulates norepinephrine release by reverse transport through the norepinephrine reuptake transporter in peripheral sympathetic nerves. To identify the influence of β-ARs on baseline and on the tyramine response, PBS was substituted with β-AR antagonist, alone, or in combination, which included centrally active propranolol (β1+2+, 44 μmol/kg), CGP20712A (β1, 11 μmol/kg), ICI-118551 (β2, 1 μmol/kg start dose+0.3 μmol/kg per minute), and SR59230A (β3, 13.8 μmol/kg), as well as the peripherally restricted nadolol (β1+2, 8.5 μmol/kg) and atenolol (β1, 5.6 μmol/kg). Drug concentration was halved for CGP20712A+nadolol. Adrenal catecholamine contribution was identified by adrenalectomy (AdrX; −30 minutes) and that of neuronal transmitter release by reserpine (8 μmol/kg IP, −48 and −24 hours). Please see the online Data Supplement for further details.
Results are presented as mean±SE. The effects of β-AR antagonists on baselines, on ΔTF after pretreatment or tyramine, and on plasma catecholamine concentrations were evaluated first by overall tests (1-way ANOVA). When the presence of significant differences was indicated, the response in the experimental group was compared with that after PBS in corresponding controls or with other experimental groups, using 2-sample Student t tests and, in the presence of outliers, Kruskal-Wallis tests. The tyramine-response curves were evaluated using repeated-measures ANOVA and ANCOVA, first as overall tests, then between groups or in 1 group separately. When significant responses, group differences, and/or interactions were indicated, contrasts were used to locate significant responses and differences between groups, respectively, at specific times. The P value was for each step and all of the tests adjusted according to Bonferroni, except for the plasma catecholamine levels where P≤0.05 was used.
Effect of β-AR Antagonists on Cardiovascular Baselines
The effects of AdrX and reserpine on the response to propranolol and the TPVR-response to all of the β-AR antagonists are shown in Figures 1 and 2, respectively. For changes in all of the cardiovascular parameters in response to the β-AR antagonist and changes in inotropy (ΔTF), please see Table S1 and S2 in the online Data Supplement.
In WKY rats, the β-AR antagonists had little effect on resting MBP and TPVR, and none of the antagonists influenced resting CO. Only propranolol reduced HR and prolonged TF but increased SV. The propranolol-induced bradycardia was eliminated after reserpine+AdrX (P value not significant; data not shown) but not after reserpine or AdrX alone (Figure 1), suggesting that both neuronal and adrenal catecholamines supported resting HR. SR59230A abbreviated TF by ≈8%, with the same tendency after AdrX, demonstrating the presence of nerve-activated, negative inotropic β3-AR in WKY rats.
In SHRs, all of the β-AR antagonists except SR59230A (β3) reduced baseline MBP. The hypotension was paralleled by reductions in TPVR, except after atenolol (peripheral β1), which reduced CO. The MBP and TPVR responses to propranolol were eliminated after reserpine but not AdrX (Figure 1), indicating that the antihypertensive effect of propranolol primarily involved neuronal catecholamines. This conclusion agreed with the idea that AdrX did not influence the TPVR response to the various β-AR antagonists, although the response was not statistically significant in all of the groups (Figure 2). CGP20712A but not atenolol reduced TPVR, demonstrating involvement of a central β1-AR vasoconstrictory component. A TPVR reduction after nadolol but not atenolol identified a peripheral, vasoconstrictory β2-AR component. However, CGP20712A+nadolol had no effect on TPVR in AdrX SHRs, possibly because of the reduced drug concentrations necessary to prevent death from cardiac failure. All of the antagonists, except SR59230A, reduced resting HR in SHRs. AdrX and reserpine reduced the propranolol-induced bradycardia. SR59230A had no effect on resting TF in SHR.
Effect of β-AR Antagonists on the Cardiovascular Response to Tyramine
Please see Table S1 for cardiovascular baselines after pretreatment, that is, before tyramine. As documented previously,10 tyramine infusion induced a sustained increase in MBP (Figure 3). This pressor response was composed of a transient rise in TPVR, which declined after 3 to 4 minutes and returned to baseline levels (Figure 4). The vasoconstriction was in both strains, also after AdrX, abolished by prazosin, showing that it depended on VSMC α1-AR activation (please see Figure S2). There was also an immediate increase in HR (Figure 5) and CO (please see Figure S3), which remained throughout the infusion period. Tyramine had no effect on SV (Figure S4) but abbreviated TF by ≈30% in both strains (please see Table S2), indicating a positive inotropic effect.
The TPVR Response
In WKY rats, the initial TPVR peak response to tyramine was increased after all of the β-AR antagonists but in AdrX WKY rats only after atenolol and SR59230A (Figure 4). These results demonstrated that nerve-activated peripheral β1- and β3-AR, as well as β2-AR, activated by epinephrine from the adrenals, counteracted the initial vasoconstrictory TPVR response to tyramine. TPVR at the end of the 15-minute infusion period was increased after all of the antagonists except atenolol and SR59230A in WKY rats but not AdrX WKY rats (Figure 4). Thus, the late vasodilation, which returned TPVR to baseline, depended on central β1-AR and peripheral β2-AR, both probably involving adrenal catecholamine(s).
The initial TPVR peak response to tyramine was not influenced by any of the β-AR antagonists in SHRs (Figure 4), in spite of some increase in striated muscle β-AR density in SHRs (Table S3). However, the subsequent return to baseline was prevented by all of the antagonists, except atenolol and CGP20712A+ICI-118551 (Figure 4). AdrX prolonged the TPVR peak response (P=0.0002), and β-AR antagonists did not prevent the return to baseline in AdrX SHRs (Figure 4). These results showed that β-AR–mediated vasodilation did not oppose the immediate, α1-AR–mediated vasoconstriction in SHRs but identified central β1-AR, peripheral β2-AR, and β3-AR, all involving adrenal catecholamine(s), as contributors in returning TPVR to baseline.
In AdrX SHRs, the vasoconstrictory TPVR response to tyramine was totally eliminated by propranolol or CGP+nadolol (P value not significant and P≤0.005 at 4 minutes, 1- and 2-sample Student t tests, respectively) and reduced by CGP20712A+ICI-118551 (P=0.001 and 0.0005, respectively) but not influenced by nadolol alone (Figure 4). These results demonstrated that, when β2-AR–mediated vasodilation had been eliminated by AdrX, tyramine induced an α1-AR–mediated vasoconstrictory response, which was sensitive to combined inhibition of central β1-AR and peripheral β2-AR.
Surprisingly, the return to baseline TPVR was not blocked in SHRs after CGP20712A+ICI-118551, although both antagonists alone and propranolol did. These observations were likely to indicate that CGP20712A+ICI-118551 eliminated β1-/β2-AR vasoconstriction and allowed β3- but not β2-AR–mediated vasodilation, whereas propranolol also inhibited β3-AR–mediated vasodilation.11
The Cardiac Response
β-AR antagonists greatly influenced the cardiac response to tyramine. The tyramine-induced tachycardia (Figure 5) was reduced or eliminated in WKY rats by all of the antagonists that contained a β1-AR inhibitory component. The HR response to tyramine after ICI-118551 (β2) alone was not different from that in the controls, but combinations of β1- and β2-AR blockade reduced ΔHR more efficiently than β1-AR inhibition alone (P<0.0001 for curve interaction; P≤0.0354 at 15 minutes). This difference was not observed in AdrX WKY rats. SR59230A caused some reduction in the tyramine-induced tachycardia in WKY rats and AdrX WKY rats. These results showed that tyramine-induced tachycardia was predominantly mediated through postsynaptic, peripheral β1-AR with some contribution from β3-AR, but, in the presence of β1-AR blockade, through peripheral β2-AR, activated by epinephrine. Tyramine abbreviated TF also in AdrX WKY rats (−32.8±4%; P≤0.004), indicating that neuronal catecholamine activated the positive inotropic response. The TF abbreviation was hampered after CGP20712A+ICI-118551, nadolol, and atenolol but not influenced by ICI-118551 or SR59230A (Table S2), showing that the positive inotropy was mediated through peripheral β1-AR, and that negative inotropic β3-AR did not influence this response. Increased ΔSV (Figure S4) was followed by a reduced tachycardia and not positive inotropy. Except for a reduction in the SR59230A group, there was no difference in the tyramine-induced rise in CO in WKY, but all of the antagonists reduced ΔCO in AdrX WKY rats (Figure S3).
In SHRs, all of the antagonists, except ICI-188551 and SR59230A, reduced the tyramine-induced tachycardia (Figure 5), showing that peripheral β1-AR mediated the HR response. The further reduction in ΔHR after additional inhibition of β2-AR was not as prominent as in WKY rats (Figure 5). Thus, epinephrine-activated β2-ARs were less important in tyramine-induced tachycardia in SHRs, and SR59230A (β3) had no effect on the HR response to tyramine in SHRs or AdrX SHRs (Figure 5). Like in WKY rats, the positive inotropic effect of tyramine (Table S2) was primarily mediated through peripheral β1-AR, activated by sympathetic nerves. Some contribution from epinephrine-activated β2-AR was detected, because ICI-118551 reduced ΔTF in SHRs but not AdrX SHRs. Reduction in the inotropic response to tyramine was paralleled by a reduced ΔSV only in CGP20712A+ICI-118551+SR59230A-treated AdrX SHRs. Otherwise, an augmented SV response to tyramine was paralleled by reductions in ΔHR. In both WKY and SHRs, β-AR antagonist-dependent reductions in the tyramine-induced MBP response (Figure 3) were paralleled by a lower ΔCO (Figure S3), whereas an elevated MBP response was paralleled by an increased ΔTPVR (Figure 4).
Effect of β-AR Antagonists on Tyramine-Induced Catecholamine Release
Tyramine increased the plasma concentration of norepinephrine (Table). The concentration at the end of the 15-minutes tyramine infusion period was higher (P≤0.011) than in blood collected during the initial peak response in SHRs (P=0.006) but not different in WKY rats (P value not significant). CGP20712A and ICI-118551 (P≤0.002), but not propranolol, reduced tyramine-induced norepinephrine overflow in SHRs. These differences were not observed in AdrX SHRs. The concentration of norepinephrine was reduced in WKY rats after propranolol, CGP20712A (P≤0.001), or ICI-118551 (P=0.047) and after propranolol in AdrX WKY rats (P<0.001).
The concentration of epinephrine (Table) increased throughout the experiment in the time controls. This increase was less at the end of the 15-minute tyramine infusion period in WKY rats but not SHRs. The concentration of epinephrine was increased after propranolol in both strains and reduced after CGP20712A (β1) in SHRs (P≤0.037). Epinephrine was almost completely absent in plasma from AdrX rats.
The present experiments demonstrated the role of β-AR in BP control, at rest and during a stimulated adrenergic response in anesthetized WKY rats and SHRs. The experiments identified the β-AR subtype involved, their peripheral or central localization, the source of the catecholamine responsible for their activation, the cardiovascular parameter that they influenced, and their effect on catecholamine release. Our experimental design also allowed us to differentiate between β-AR–mediated vasodilatory and vasoconstrictory mechanisms.
Norepinephrine overflow to plasma remained elevated throughout the tyramine infusion period. The transient nature of the α1-AR–mediated vasoconstrictory TPVR response to tyramine was, therefore, not explained by transmitter exhaustion but involved activation of a vasodilatory response. In WKY rats, this vasodilation was mediated through nerve-activated peripheral β1-AR and β3-AR, subsequently replaced by epinephrine-activated β2-AR. All of the β-ARs may activate the VSMC cAMP pathway, and β2+3-AR may also activate endothelial NO synthesis.2,3 VSMC β1-ARs, unlike β2-ARs, are located within the synapse,12 compatible with the more important role of norepinephrine-activated β1-AR early in the infusion period and the later elevation in the plasma epinephrine concentration. A role of NO was supported by our previous study showing endothelial NO to counteract the TPVR response to tyramine.10 The peripheral β2-AR–dependent vasodilation also involved a central β1-AR component, possibly responsible for the secretion of epinephrine (discussed below). β2-AR-induced vasodilation has also been demonstrated to counteract norepinephrine-induced forearm vasoconstriction in humans, and a reduced vasoconstriction in women compared with men was explained by an augmented β2-AR–mediated vasodilation.13 Epinephrine-activated β2-ARs may also possibly explain why propranolol increased resting forearm vascular resistance in awake humans,14 in contrast to no effect in our anesthetized WKY rats and a reduced TPVR in SHRs, where plasma epinephrine initially was virtually absent.
Peripheral β1-AR did not oppose the initial TPVR peak response in SHRs, nor did β1-AR contribute to the return to baseline or influence baseline TPVR. Indeed, neuronal catecholamine(s) were not involved in β-AR–mediated vasodilation throughout the tyramine infusion period. These results agreed with studies on isolated aorta demonstrating impaired β1-AR–induced relaxation in SHRs, as well as impaired β-AR function in human hypertension.2,15 The subsequent return to TPVR baseline in SHRs depended exclusively on a central β1-AR component and epinephrine-activated VSMC/endothelial β2+3-AR–mediated vasodilation. The absence of epinephrine in plasma collected during the peak response explained why β2+3-AR failed to ameliorate the initial norepinephrine-induced vasoconstriction. VSMC vasodilatory β2-ARs are located remotely from the synaptic cleft and are, thus, accessible by circulating epinephrine, and they have a higher affinity for epinephrine than norepinephrine.12 Endothelial β2- and β3-ARs will be even more easily accessed by circulating epinephrine. Because CGP20712A reduced the plasma epinephrine concentration, the central β1-AR component may be responsible for adrenal epinephrine release.
The tachycardia after tyramine-induced norepinephrine release was primarily mediated through postsynaptic β1-AR in both strains. However, when these were blocked, epinephrine-activated β2-AR mediated tyramine-induced tachycardia in WKY rats. The ability of adrenal catecholamine to replace the neuronally released transmitter was also observed for the effect of propranolol on resting HR in WKY rats. The coexistence of β1- and β2-ARs in the heart is now generally accepted,16 with a 3:1 distribution in both strains (Table S3). However, the ability of β2-AR to replace β1-AR–mediated tyramine-induced tachycardia was detected in SHRs only after AdrX. The reason for this difference was not clear, but ICI-118551 also reduced resting HR and TF in AdrX SHRs.
In resting WKY rats, SR59230A revealed a β3-AR–mediated, neuronally dependent, negative inotropic activity. β3-AR did not influence the tyramine-induced, positive inotropy, which was primarily β1-AR mediated in both strains, with some additional contribution from β2-AR in SHRs. However, β3-AR mediated part of the tyramine-induced tachycardia in WKY rats and AdrX WKY rats, compatible with positive chronotropic β3-AR demonstrated previously in the rat atrium.17 Effects because of negative inotropic or positive chronotropic β3-AR were not detected in SHRs.
Reduced inotropy after the β-AR antagonist was paralleled in both strains by reduced chronotropy, showing a parallel stimulation pattern for these 2 functions. Still, changes in SV were reciprocal to ΔHR, showing that the time for diastolic heart filling was the important factor in determining SV. HR rather than SV determined CO, because reductions in CO at rest or during stimulation were paralleled by bradycardia or reduced tyramine-induced tachycardia, respectively.
Presynaptic control of norepinephrine release was likely to be superimposed on the tyramine-induced, nonexocytotic, norepinephrine reuptake transporter–mediated release. Thus, ICI-118551 (β2) lowered tyramine-induced norepinephrine overflow but not the plasma epinephrine concentration in both strains, compatible with the known role of presynaptic β2-AR to enhance exocytotic norepinephrine release.6 Activation of the presynaptic, release-stimulating β2-AR apparently depended primarily on epinephrine, because a significant ICI-118551–induced reduction in norepinephrine overflow was not detected in AdrX SHRs (WKY rats not tested). The inhibitory effect of CGP20712A (β1) on epinephrine secretion in SHRs may, therefore, explain the concomitant reduced norepinephrine overflow. In WKY rats, CGP20712A had no effect on epinephrine secretion, because tyramine itself reduced epinephrine release. The latter was likely to result from a concomitant activation of α2C-AR in the adrenals, known to inhibit adrenal catecholamine secretion.18 Preliminary data indicated this to occur in WKY rats but not SHRs, thus explaining why norepinephrine release continued to rise throughout the tyramine-infusion in SHRs but not WKY rats. However, CGP20712A reduced norepinephrine overflow also in WKY rats. It is, therefore, possible that central β1-AR increased adrenergic activity not only in the adrenals but also in peripheral sympathetic nerves, thus promoting presynaptic events, which enhanced tyramine-induced norepinephrine reuptake transporter norepinephrine transport. This conclusion was supported by a role of central β1-AR in stress-induced hypertension in the rat.5 The importance of the control of norepinephrine release was demonstrated recently in humans, where family history of hypertension and genetic variations in proteins involved in presynaptic catecholamine synthesis, storage, and metabolism predicted the constrictory response to tyramine in dorsal hand veins.19 Furthermore, ICI-118551 (β2) reduced BP in moderately hypertensive patients.20
Atenolol and Hypertension
Of the β-AR antagonists presently tested, only atenolol reduced baseline MBP in SHRs by lowering CO and not TPVR. As in SHRs, elevated TPVR and low CO characterize the condition in essential hypertension in humans, and long-term use of atenolol did not normalize these hemodynamic changes.21 Compatible with these observations, atenolol has been suggested to be useful in the treatment of angina, myocardial infarction, and heart failure, but its efficacy in hypertension has been questioned.22
β-AR–Dependent TPVR Control and Hypertension
The failing β1-AR–mediated counteraction of tyramine-induced vasoconstriction may represent a hypertensive drive in SHRs, although possibly not in humans, where isoprenaline-induced forearm vasodilation was primarily mediated through β2-AR and NO synthesis.23 However, it could not be excluded that the latter observation reflected a difference in the response to a circulating contra intrasynaptically released agonist.
In spite of enhanced epinephrine secretion and subsequent augmented norepinephrine release in SHRs, epinephrine functioned as an antihypertensive agent by upregulating β2- and β3-AR–mediated vasodilation. As a consequence of the exclusive adrenal contribution, β-AR–mediated vasodilation was totally eliminated in AdrX SHRs, and, in AdrX SHRs, surprisingly, the tyramine-induced, α1-AR–mediated vasoconstriction was blocked after combined inhibition of central β1-AR and peripheral β2-AR. A neural mechanism, also involving central β1-AR and peripheral β2-AR, upheld resting MBP and TPVR in SHRs but not in WKY rats, further indicating that these receptors contributed to the hypertensive condition. Although the central β1-AR may activate peripheral sympathetic nerve activity, it may be speculated that the peripheral β2-AR activated a mechanism that prevented norepinephrine-activated, β-AR–induced VSMC vasodilation but left epinephrine-activated endothelial β2- and β3-AR–mediated NO synthesis intact. This assumption was supported by the fact that nerve-activated β-AR vasodilation was not detected at all in SHRs, whereas neural catecholamine release induced not only β1- but also β3-AR–mediated vasodilation in WKY rats. Additional studies are needed for a better understanding of this potentially hypertensive mechanism.
In SHRs, nerve-activated β1- and β3-AR–mediated vasodilation was not present. A failing β-AR–activated moderation of an α1-AR–mediated vasoconstriction may lead to hypertension, although epinephrine-activated β2- and β3-AR–mediated vasodilation was upregulated in SHRs. Presynaptic stimulation of norepinephrine release was enhanced in SHRs, possibly because of failing control of adrenal epinephrine secretion. In addition, we detected in SHRs a vasoconstrictory, neural mechanism involving central β1-AR and peripheral β2-AR combined. Although this mechanism was not fully understood, it elevated resting TPVR and augmented α1-AR–mediated vasoconstriction in SHRs.
Sources of Funding
This work was supported by the Norwegian Council on Cardiovascular Diseases and Anders Jahres Fond (to T.B.) and the Novo Nordisk Foundation, Denmark (to J.J.).
- Received December 18, 2009.
- Revision received January 9, 2010.
- Accepted February 18, 2010.
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