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Departments of Obstetrics, Gynecology and Reproductive Sciences and Cell Biology and Physiology (K.P.C., J.N.), University of Pittsburgh School of Medicine and Magee-Womens Research Institute, and Department of Bioengineering (D.O.D., S.G.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Pathology (L.A.D.), University of New Mexico School of Medicine, Albuquerque, New Mexico 87131
Address all correspondence and requests for reprints to: Kirk P. Conrad, M.D., Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213. E-mail: rsikpc{at}mwri.magee.edu.
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Introduction |
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One of the major cardiovascular adaptations in human pregnancy is the increase in global AC that reaches a peak by the end of the first trimester just as SVR reaches a nadir (3). The one or more mechanisms of this rapid increase in global AC during pregnancy are presently unknown. At least in theory, the rise in global AC is critical to the maintenance of cardiovascular homeostasis during pregnancy for several reasons: 1) prevents excessive decline in diastolic pressure that otherwise would fall to precariously low levels due to the significant decline in SVR; 2) minimizes the pulsatile or oscillatory work wasted by the heart that otherwise would increase in disproportion to the rise in total work required of and expended by the heart during pregnancy; and 3) preserves steady shear-type (or prevents oscillatory shear-type) stress at the blood-endothelial interface despite the hyperdynamic circulation of pregnancy, thereby favoring production of nitric oxide rather than superoxide and other damaging reactive oxygen species by the endothelium. The increase in AC, along with the reduction in SVR, can result in circulatory underfilling, and thus, contribute to renal sodium and water retention and plasma volume expansion during early pregnancy.
Previous work has implicated a vasodilatory action for relaxin (Refs.4, 5, 6, 7 , and reviewed in Ref.8). Moreover, because circulating relaxin, which emanates from the corpus luteum of the ovary, mediates maternal renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small renal arteries during pregnancy in rats (9), it was logical to consider whether the hormone might also contribute to the broader cardiovascular changes of pregnancy, i.e. the increases in CO and global AC, as well as the reduction in SVR. To begin investigating this question, we tested whether relaxin has the potential to modify the systemic steady and pulsatile load when chronically administered to nonpregnant rats. A method was developed to quantify global AC in conscious, chronically instrumented, unrestrained rats. To determine whether alteration in blood vessel wall structure (e.g. extracellular matrix) contributes to the modification of AC (in addition to reduction in vascular smooth muscle tone), the passive mechanics of small renal arteries were analyzed in a pressure arteriograph.
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Materials and Methods |
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Surgical preparation
Briefly, the rats were habituated to Nalgene metabolism cages for 1 wk (VWR Scientific Products, Bristol, CT), followed by further habituation to a harness/7.5 cm spring assembly for another week while in the metabolism cage (Harvard Apparatus, Holliston, MA). The animals were fitted to the harness under isoflurane anesthesia. After this habituation period, the rats were anesthetized with 60 mg/kg ketamine im and 21 mg/kg pentobarbital ip and placed in the prone position on a heating pad. After application of 70% ethanol and betadine to all exposed skin areas, ampicillin was administered sc (0.2 ml of a 125 mg/ml solution) and atropine was also administered sc (0.075 ml of a 0.4 mg/ml solution).
Next, a sterile tygon catheter (18 in. long; 0.015 inner diameter; 0.030 outer diameter) connected to a syringe containing Ringer’s solution, as well as a sterile thermodilution microprobe (22 cm long, French no. 1.5; Columbus Instruments, Columbus, OH) were threaded through the spring. The tygon catheter was subsequently threaded through the hole in the harness and then tunneled sc from the midpoint between the shoulder blades out a small incision behind the ear using an 18-gauge trocar. The thermodilution catheter was also threaded through the harness assembly and then tunneled sc from the midpoint between the scapulae out a skin incision in the left costal margin. The spring was then reattached to the harness.
The rat was repositioned on the back. A 1.0-cm skin incision was made in the left inguinal region. The external iliac artery was isolated and prepared for catheterization. The thermocouple was then tunneled sc exiting at the inguinal incision. The thermocouple was next inserted into the external iliac artery being directed rostrally, so that it passed easily into the internal iliac artery and subsequently into the aorta. The thermocouple tip lay approximately 1.0 cm below the left renal artery.
Next, a horizontal 2.0-cm incision was made over the trachea, 1.0 cm above the cricoid notch. Through this incision, a large sc pocket was dissected in the neck and above the left shoulder. The right jugular vein and carotid artery were then isolated and prepared for catheterization, the latter facilitated by placing a small roll of gauze under the neck to elevate this deep structure. Using the 18-gauge trocar, the tygon catheter was tunneled sc from the small incision behind the right ear out the incision in the neck. The tygon catheter was implanted in the right jugular vein 3.0 cm, thereby placing the catheter tip at the confluence of the anterior vena cava and the right atrial appendage. The battery/transmitter of a sterile mouse pressure catheter (TA11PA-C20; 
French no. 1.2; Data Sciences International, St. Paul, MN) was inserted in the sc pocket. The mouse pressure catheter was then implanted in the right carotid artery 2.8 cm, thereby placing the catheter tip at the confluence of the right carotid artery and aortic arch. All wounds were closed with 4-0 silk or autoclips. After instilling 0.05 ml of a heparin solution into the jugular catheter and plugging it with a straight pin, the rat was placed in the metabolism cage and given ampicillin by drinking water for 2 d (100 mg/50 ml with 2 tablespoons of dextrose). The spring and catheters that exit the cage top were secured. Terbutrol was given sc for postoperative analgesia as soon as the rats were recovered sufficiently from the anesthesia.
For low-dose administration of recombinant human relaxin (4.0 µg/h rhRLX) for 10 d, two Alzet model 2002 osmotic minipumps (Durect Corp., Cupertino, CA) were inserted sc in the back of the animal under isoflurane anesthesia. For high-dose administration for 10 d (25 µg/h), one Alzet model 2ML2 osmotic minipump was implanted.
After completion of the measurement for the last time point, the rat was anesthetized with 60 mg/kg pentobarbital iv. Blood was obtained from the abdominal aorta for rhRLX levels, osmolality, and hematocrit. The position of the jugular catheter relative to the right atrium, the placement of the pressure catheter relative to the aortic arch, and the position of the thermocouple relative to the left renal artery were recorded.
In vivo studies: hemodynamics and systemic arterial mechanical properties
Time control studies were first performed in five rats, to document the stability of systemic hemodynamics over a 17-d period after surgery. Measurements were recorded on d 4–5, 7–8, 9–10, 13–14, and 16–17 after surgery.
The low- and high-dose rhRLX protocols entailed six and seven rats, respectively. In addition, the vehicle for rhRLX [20 mM sodium acetate (pH 5.0)] was administered to another six rats. After two baseline measurements of systemic hemodynamics on d 5 and 7 after surgery, either low- or high-dose rhRLX or vehicle was administered by osmotic minipump. Systemic hemodynamics were again assessed on d 3, 6, 8, and 10 after initiation of rhRLX or vehicle infusion.
Each measurement consisted of four to six recordings of CO and blood pressure waveforms that were obtained when the rat was either sleeping or resting. At least 10 min was allowed between recordings. These measurements were obtained between 0900 and 1500 h.
CO.
To measure CO, we used the thermodilution technique (10). Ringer’s solution of known volume and temperature was injected into the anterior vena cava using the Micro Injector 400 (Columbus Instruments). The CO was calculated from the change in blood temperature (Cardiotherm 400R, Columbus Instruments). The CO as determined by the Cardiotherm 400R was calculated as CO = [(BT – IT) x VI]/
BT(t) where BT is the blood temperature (recorded by the thermocouple implanted in the abdominal aorta), IT is the injectate temperature (room temperature), VI is the injectate volume (150 µl), and BT(t) is the blood temperature as a function of time.
Blood pressure.
Instantaneous aortic pressure was recorded using a blood pressure telemetry system (Data Sciences International) (11). The aortic pressure was recorded by a pressure catheter implanted in the aortic arch via the right carotid artery and transmitted to an external receiver. Steady-state aortic pressure was digitized online using a PC-based data acquisition system with 16-bit resolution and 2000 Hz sampling rate and stored as text files for off-line analysis. Each measurement consisted of a 30-sec sampling duration.
Aortic pressure analysis.
Analysis of the acquired data and calculation of global AC was performed by a custom computer program developed using MATLAB software (MathWorks Inc., Natick, MA). Briefly, individual beats were selected (3–15 cycles) from the 10 sec of the aortic pressure recording, immediately preceding the measurement of CO. The ensemble was averaged as described by Burattini et al. (12) to yield a single representative beat for each trial. The MAP, peak systolic pressure (Ps), and end diastolic pressure (Pd) were calculated from this averaged beat. Pulse pressure (PP) was calculated as Ps-Pd. SVR was calculated by dividing the MAP by CO.
Global AC.
Two measures of global AC were calculated. The first (ACarea) was calculated from the diastolic decay of the aortic pressure waveform [P(t)] using the area method (2) ACarea = Ad/[SVR(P1 – P2)] where P1 and P2 are the pressures at the beginning and end of the diastolic decay curve, respectively, and Ad is the area under the P(t) waveform over this region. The second measure of global AC was calculated as the stroke volume (SV)-to-pulse pressure (PP) ratio (13). SV was defined as CO/heart rate (HR).
In vitro studies: arterial passive mechanics
Nonpregnant female rats were administered rhRLX (4 µg/h) or vehicle by osmotic minipump for 5 d. A kidney was removed and placed in ice-cold HEPES buffered physiological saline solution (a modified Kreb’s buffer). The HEPES-physiologic saline solution was composed of (in mmol/liter): sodium chloride 142, potassium chloride 4.7, magnesium sulfate 1.17, calcium chloride 2.5, potassium phosphate 1.18, HEPES 10, glucose 5.5, and was pH 7.4 at 37 C. A stereo dissecting microscope, fine forceps and iridectomy scissors were used to isolate interlobar arteries as described by Gandley et al. (14) (unpressurized inner diameter, 100–200 µm). An arterial segment was then transferred to an isobaric arteriograph (Living Systems Instrumentation, Burlington, VT) and mounted on two glass micro-cannulae suspended in the chamber. After the residual blood was flushed from the lumen of the artery, the distal cannula was occluded to prevent flow. The proximal cannula was attached to a pressure transducer, a pressure servo-controller and a peristaltic pump. The servo-controller maintained a selected intraluminal pressure that was changed in a stepwise manner. An electronic dimension analyzing system obtained arterial diameter measures.
The vessels were incubated in the bath with 10–4 M papaverine and 10–2 M EGTA in calcium-free HEPES physiological saline solution. After a 30 min equilibration period, transmural pressure was increased in 14 steps beginning at 0 mm Hg up to 150 mm Hg. Inner and outer diameters as well as wall thickness were measured after each pressure step when the vessel had reached a steady state. Midwall radius (Rm) and circumferential wall stress (
) were calculated from these data as described before (15). Vessel wall elastic properties were quantified in terms of the incremental elastic modulus (Einc), which was calculated from the –Rm relationship (16).
Serum measurements
Serum osmolality was measured using a freezing-point depression instrumentation osmometer (Model 3 MO; Advanced Instruments, Needham Heights, MA). The levels of rhRLX in serum were measured by a quantitative sandwich immunoassay as previously described (17).
Preparation of rhRLX
Two model 2002 osmotic minipumps (Durect Corp., Cupertino, CA) were used to deliver the rhRLX for 10 d at the dose of 4 µg/h which yielded concentrations of circulating relaxin similar to those measured during early to midgestation in rats, i.e. 10–20 ng/ml (7, 17, 18, 19, 20) when pregnancy-induced renal vasodilation is maximal in this species (21). One model 2ML2 osmotic minipump was used to deliver rhRLX at the dose of 25 µg/h for 10 d which we expected to produce concentrations of circulating hormone comparable to those recorded during mid to late gestation (18) when further increases in CO and decreases in SVR are observed in this species (22, 23). The rhRLX (Connetics, Palo Alto, CA) provided as a 5.0 mg/ml solution in 20 mM sodium acetate (pH 5.0) was diluted in the same buffer.
Statistical analysis
Data are presented as means ± SEM. One- or two-factor repeated measures ANOVA (24) was used to compare mean values among various groups. If significant main effects or interactions were observed, comparisons between groups were performed using Fisher’s least significant difference test or Dunnett’s test. The Student’s paired t test was used to compare the composite mean values during infusion of rhRLX (i.e. values averaged over all time points during rhRLX infusion) with baseline. Least squares regression analysis was performed on -Rm and Einc-Rm relationships. Analysis of excess variance (or extra sum of squares) (25) was used to compare these relationships between vehicle and relaxin-treated groups. P < 0.05 was taken to be significant.
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). HR declined significantly due to a training effect as we have previously reported (26). SV reciprocally increased, such that CO was unchanged. All other variables did not change significantly over the 17-d period after surgery; thus, this conscious rat model can be used to obtain meaningful data under the experimental conditions described next (Table 1).
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and 2 depict the percent change from baseline for systemic hemodynamics and other variables. Similar to the time control studies, there was a significant decrease in HR, which was offset by an insignificant rise in SV, such that CO remained unchanged. All other variables remained relatively constant. Combining all of the time points during administration of vehicle yielded overall changes in CO, global AC, and SVR of –1.4 ± 1.3, 2.2 ± 4.6, and 0.4 ± 3.4% of baseline, respectively (all P values were not significant vs. baseline). As expected, there was no measurable rhRLX in the serum, and the osmolality was 309 ± 6 mOsm/kg water.
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, whereas Figs. 1
and 2 show the temporal pattern of percentage change from baseline. Low-dose rhRLX significantly increased CO relative to baseline and to vehicle infusion (Fig. 1A). The infusion of rhRLX prevented the decline normally observed in HR (cf. vehicle, Fig. 1B), and the hormone significantly increased SV (Fig. 1C). Thus, increases in both SV, and to a lesser degree, HR combined to raise the CO relative to vehicle-infused rats. SVR fell significantly relative to baseline and to vehicle infusion (Fig. 2A), whereas MAP remained unchanged (Fig. 2B). Global AC significantly increased relative to baseline and to vehicle infusion (Fig. 2C). There was no significant change in PP; however, the ratio of SV-to-PP, another index of AC, increased significantly during the infusion of low-dose rhRLX relative to baseline and to vehicle infusion (Fig. 2D).
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), there were no significant changes with time in CO beyond d 3 (Fig. 1A). This was a result of a small, but insignificant, fall in HR from d 3 to d 8 (Fig. 1B). SVR and both measures of global AC were significantly altered at d 3; thereafter, there were no further significant changes (Fig. 2). In general, maximal changes in arterial hemodynamics and mechanical properties after low-dose rhRLX administration were observed at the earliest time point examined (d 3), with no further temporal alterations. Combining all of the time points during administration of low-dose rhRLX yielded an overall increase in CO and global AC of 19.2 ± 4.8 and 21.4 ± 3.6% above baseline, respectively, and an overall decrease in SVR of 15.5 ± 2.4% below baseline (all P < 0.01 vs. baseline). Serum rhRLX and osmolality were 14 ± 2 ng/ml and 284 ± 2 mOsm/kg water, respectively. The latter was significantly decreased compared with vehicle infusion.
Rats administered high-dose rhRLX (25 µg/h).
The absolute values for systemic hemodynamics and other variables are presented in Table 3, and Figs. 1 and 2 portray the percent change from baseline. The results for the high-dose infusion were comparable to the low-dose administration in direction, but were somewhat less, although not significantly so, in magnitude.
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), SV (Fig. 1C), SVR (Fig. 2A), and global AC (SV/PP method) (Fig. 2D) were maximally altered by the earliest time point examined (d 3), with no further significant changes thereafter. The temporal response of global AC as calculated by the area method (Fig. 2C) deviated slightly from this general pattern—ACarea at d 6 was not different from that at baseline. Although we do not have a specific explanation, we believe this to be an aberration. This belief is based on the observations that the second measure of global AC at all time points (Fig. 2D) and ACarea at d 3, 8, and 10 (Fig. 2C) were significantly higher than baseline. Combining all of the time points during administration of high-dose rhRLX yielded an overall increase in CO and global AC of 14.1 ± 3.2 and 15.6 ± 4.7% above baseline, respectively, and an overall decrease in SVR of 9.7 ± 2.4% below baseline (all P < 0.02). Serum relaxin and osmolality were 36 ± 3 ng/ml and 287 ± 1 mOsm/kg water, respectively. The latter was significantly decreased compared with vehicle infusion.
Arterial pressure waveforms.
Representative arterial waveforms from a single rat at baseline and after administration of rhRLX are depicted in Fig. 3A. They illustrate that the mouse pressure catheter (TA11PA-C20) provides high-fidelity recordings necessary for determining global AC. Ensemble average arterial pressure waveforms, derived using the methodology proposed by Burattini et al. (12) are shown in Fig. 3B for the three groups of rats on d 10 of infusion. As discussed above, SV significantly increased and SVR significantly decreased after rhRLX administration (Tables 2 and 3). If these were the only alterations, one would expect to see a clear change in pressure waveform morphology: increased PP, and hastened diastolic decay of arterial pressure. However, as illustrated in Fig. 3B, rhRLX administration did not significantly affect pressure waveform morphology, as indicated by unchanged PP and diastolic decay. This invariant pressure waveform morphology, in the presence of increased SV and decreased SVR, is consistent with a simultaneous increase in global AC.
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) and midwall radius (Rm) were calculated from these primary measurements and -Rm relationship was used to quantify vessel wall elastic behavior (e.g. incremental elastic modulus, Einc). -Rm (Fig. 4A) and Einc-Rm (Fig. 4B) relationships for small renal arteries were significantly different between the two groups (P < 0.001 by analysis of excess variance) such that and Einc were smaller for a given Rm in the relaxin-treated group. In contrast, the unstressed Rm, Rmo (i.e. Rm at = 0), was not different between the two groups (relaxin-treated: 105 ± 5 µm; vehicle-treated: 98 ± 6 µm). Thus, the Rm axis can be considered as circumferential wall strain. These data indicate that relaxin treatment significantly reduced vessel wall stiffness (Einc) at matched Rm (strain) values. This reduced passive wall stiffness contributes to the increased global AC seen in conscious animals with relaxin treatment (vide supra).
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Discussion |
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The major findings were 1) chronic administration of rhRLX to conscious, female, nonpregnant rats reduces the steady arterial load by decreasing SVR, 2) rhRLX infusion also reduces the pulsatile arterial load by increasing global AC as reflected by two indices—ACarea and the ratio of SV-to-PP, and 3) rhRLX administration regulates the passive mechanics of small renal arteries by reducing vessel wall stiffness.
We successfully developed a conscious rat model for the assessment of global AC. CO and high-fidelity aortic pressure waveforms are essential to the derivation of global AC. Using the Mouse Pressure catheter from Data Sciences International, high-fidelity aortic pressure waveforms were captured and transmitted by radio-telemetry, and received and analyzed by computer. Because the right carotid artery was used to gain access to the aortic arch for the Mouse Pressure catheter, the thermodilution catheter was implanted in the abdominal aorta via the external iliac artery. Although the placement of the thermocouple was untraditional, this approach yielded excellent temperature differences after bolus injection of room temperature Ringer’s solution into the right atrium (
T > 0.30 C, Tables 1–3) and measurements of CO that are comparable to Osborne et al. (10). Importantly, values for CO, SVR, and global AC were steady over the 2.5-wk period after surgery in the time control studies and in the rats administered the vehicle/diluent for rhRLX.
Analogous to our previous work on relaxin in the renal circulation (7, 17, 19, 20), the hormone proved to be a general vasodilator reducing SVR and increasing CO each by approximately 20%, thereby maintaining MAP. As in pregnancy, this increase in CO was due primarily to an increase in SV with a lesser contribution from HR (23, 27). Although the renal circulation clearly participated in this systemic vasodilatory response (7, 17, 19, 20), other peripheral circulations undoubtedly contributed as well, but their relative contributions remain to be identified. Because relaxin administration reduced the myogenic reactivity of small mesentery, as well as small renal arteries (28), we speculate that the hormone also vasodilated the mesenteric circulation in this study. Others have shown that relaxin is most likely vasodilatory in several organ beds including heart, uterus, breast, liver, and mesentery (see Ref.8 for review); therefore, these are also likely to have contributed to the overall reduction in SVR and rise in CO.
The levels of circulating rhRLX reached in this investigation were comparable to those observed in early to midgestation in the rat (15–40 ng/ml) (18). At this stage of pregnancy, renal hemodynamics are maximally altered in this species (21), and CO is approximately 25% above nonpregnant values (22, 23). Although we reached approximately 15 ng/ml with our low-dose infusion, we anticipated reaching 80–100 ng/ml comparable to late rat pregnancy with our high-dose rhRLX administration, when CO is increased by 50% at this stage of gestation (22, 23). Unfortunately, we only reached a mean plasma concentration of 36 ng/ml, so presently we do not know whether such high blood concentrations of rhRLX will translate into even greater increases in CO (and global AC). We are currently investigating a higher infusion rate of 50 µg/h that should yield circulating levels of approximately 80 ng/ml (20). Nevertheless, there were no significant differences in systemic arterial hemodynamics between the two doses employed in this study. Interestingly, in the case of the renal circulation, a biphasic effect was observed (20). That is, the lower circulating levels as reached in the present study produced marked renal vasodilation, but higher concentrations comparable to late pregnancy were ineffective. In fact, despite the 50% increase in CO near term in the gravid rat (22, 23), renal hemodynamics are returning to nonpregnant values (21).
The pulsatile arterial load fell concurrently with the decline in SVR. Both global ACarea and the ratio of SV-to-PP increased by approximately 20% during infusion of rhRLX. The magnitude of this change is comparable to the rise in global AC observed in human pregnancy, which peaks at about 30% above nonpregnant values during the first trimester (3) and coincides with the rise in circulating relaxin (18). The increase in global AC observed here is also similar to the rise in the compliance coefficient of the descending thoracic aorta measured in conscious pregnant rats that began to increase with the rise in circulating relaxin (29). Finally, consistent with an increase in global AC, PP remained unchanged in the face of an approximately 20% increase in SV.
Because relaxin is a potent vasodilator (Refs.7 , 17 , 19 , and 20 ; and present study), reduced arterial smooth muscle tone likely contributed to the rise in global AC. Relaxin may also exert angiogenic activity, albeit indirectly (reviewed in Ref.8) and thus, the formation of new blood vessels or increased branching of existing blood vessels may be another mechanism contributing to the overall increase in AC. Finally, relaxin increases gelatinase activity in small renal and various other arteries when administered to nonpregnant rats, and pregnancy per se, also stimulates vascular gelatinase activity (17). We reasoned, therefore, that relaxin modifies the arterial extracellular matrix by increasing vascular gelatinase (and perhaps the activity of other matrix metalloprotinases), thereby contributing to the rise in global AC. This alternative mechanism was supported by our results from isolated small renal arteries in which the vascular smooth muscle tone had been eliminated by papaverine and EGTA. That is, we demonstrated that at any given midwall radius, wall stress and stiffness of the small renal arteries from relaxin-treated rats were significantly smaller than those from the vehicleinfused animals. This increase in AC in small arteries, as we observed in the small renal arteries, has been shown to significantly contribute to an overall increase in global AC (30). Similar changes in the passive mechanics of mesenteric resistance arteries have been reported for late gestation in the rat (31). Because vascular gelatinase activity plays a pivotal role in the remodeling of the extracellular matrix and plays a pivotal role in the renal vasodilatory response to relaxin (17), there are overlapping hormonal and cellular signaling mechanisms for vasodilatory and vascular compliance changes during pregnancy. This sharing of molecular mechanisms is one way to ensure a temporal coordination of the decrease in both steady and pulsatile arterial loads that, as described above in the introductory section, is critical to the maintenance of cardiovascular homeostasis during pregnancy.
There are several unresolved questions arising from this work that require future investigation. First, what is the earliest time course of change in systemic hemodynamics in response to relaxin administration? We previously showed that renal vasodilation is detected within 1–2 h of the onset of rhRLX infusion to conscious rats (20). The earliest time point in the current work was 3 d. Second, are the effects of relaxin on systemic hemodynamics gender specific? We reported that relaxin vasodilates the renal circulation irrespective of gender (19). Third, will neutralization or elimination of circulating relaxin prevent the changes in CO and AC observed in conscious pregnant rats as it did for the changes in the renal circulation during pregnancy (9)? Fourth, can other relaxin-like peptides such as Insl-3 modify systemic arterial properties? Finally, taking a novel therapeutic point of view, we speculate that relaxin might be useful in preventing or reversing the reduced compliance of blood vessels that occurs with aging pathology. Moreover, because it can reduce SVR (present study) and antagonize the vascular action of angiotensin II (7), relaxin may also be useful in reducing cardiac afterload during heart failure.
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Acknowledgments |
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Footnotes |
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K.P.C., D.O.D., and J.N. contributed equally to this manuscript.
Abbreviations: AC, Arterial compliance; CO, cardiac output; HR, heart rate; MAP, mean arterial pressure; PP, pulse pressure; rhRLX, recombinant human relaxin; SV, stroke volume; SVR, systemic vascular resistance.
Received December 1, 2003.
Accepted for publication March 9, 2004.
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, P < 0.05 vs. baseline; *, P < 0.05 vs. vehicle at the same time point by Fisher’s or Dunnett’s post hoc tests.
