Reduced baroreceptor sensitivity during hypotension in ANP-knockout mice

We studied baroreflex gain in inactin-anesthetized mice that had been genetically modified to be depleted of atrial natriuretic peptide (ANP -/-). Wild-type mice (ANP +/+) served as controls. ANP -/- mice had a significantly higher basal arterial blood pressure (ABP) than ANP +/+ mice [112+/-7 vs. 80+/-5 mmHg (mean +/- SEM)]. Their basal heart rates were not different (491+/-13 vs. 446+/-19 bpm). A third group, composed of ANP +/+ mice only, was rendered acutely hypertensive by an intravenous infusion of arginine vasopressin acetate (0.3 pg bolus followed by 0.3 pg/h) so as to serve as a control for the elevated ABP in the ANP -/- mice. Transient changes in ABP were caused by bolus injections of oxymetazoline hydrochloride (1.5-3 ng) or sodium nitroprusside (20-100 ng). Baroreflex gain was calculated as the ratio of the peak heart rate change that followed the peak change in mean ABP resulting from injection of oxymetazoline or nitroprusside. There were no significant differences among the groups in their responses to transient hypertension. On the other hand, the ANP -/- mice showed a significantly depressed tachycardic response to transient hypotension when compared with the other two groups. We conclude that the ANP -/- mice are unable to increase efferent sympathetic nervous activity adequately above the high basal activity that is a feature of this animal model.     

Effect of saline infusion on kidney and collecting duct function in atrial natriuretic peptide (ANP) gene "knockout" mice.

Atrial natriuretic peptide (ANP) is thought to play a role in renal regulation of salt balance by reducing tubular reabsorption of sodium and chloride. Therefore, in the chronic absence of this hormone, a defect of salt excretion should be evident. We used an ANP gene deletion model to test this premise. F2 homozygous mutant mice (-/-) and their wild-type littermates (+/+) were fed an 8% NaCl diet prior to an acute infusion of isotonic saline. Arterial blood pressures, renal excretions of salt and water, as well as collecting duct transport of fluid and electrolytes were measured. Pressures were significantly higher in -/- compared with +/+ mice (139 +/- 4 vs. 101 +/- 2 mmHg; 1 mmHg = 133.3 Pa). There was no difference in glomerular filtration rate (-/- = 0.84 +/- 0.06; +/+ = 0.81 +/- 0.04 mL x min(-1) x g(-1) kidney weight). In the collecting duct, sodium and chloride reabsorptions were significantly higher in the -/- group than in the +/+ group. As a result, natriuresis and chloruresis were relatively reduced (U(Na)V: -/- = 8.6 +/- 1.1; +/+ = 14.0 +/- 1.1; U(Cl)V: -/- = 10.1 +/- 1.4; +/+ = 16.0 +/- 1.1 micromol x min(-1) x g(-1) kidney weight). We conclude that the absence of endogenous ANP activity in mice on a high-salt diet subjected to acute saline infusion causes inappropriately high reabsorption of sodium and chloride in the medullary collecting duct, resulting in a relative defect in renal excretory capacity for salt.     

Systemic hemodynamic and regional blood flow changes in response to chronic reductions in uterine perfusion pressure in pregnant rats

Preeclampsia (PE) is associated with increased total peripheral resistance (TPR), reduced cardiac output (CO), and diminished uterine and placental blood flow. We have developed an animal model that employs chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats to generate a "preeclamptic-like" state during late gestation that is characterized by hypertension, proteinuria, and endothelial dysfunction. Although this animal model has many characteristics of human PE, the systemic hemodynamic and regional changes in blood flow that occur in response to chronic RUPP remains unknown. Therefore, we hypothesized that RUPP would decrease uteroplacental blood flow and CO, and increase TPR. Mean arterial pressure (MAP), CO, cardiac index (CI), TPR, and regional blood flow to various tissues were measured using radiolabeled microspheres in the following two groups of conscious rats: normal pregnant rats (NP; n = 8) and RUPP rats (n = 8). MAP was increased (132 +/- 4 vs. 99 +/- 3 mmHg) in the RUPP rats compared with the NP dams. The hypertension in RUPP rats was associated with increased TPR (2.15 +/- 0.02 vs. 0.98 +/- 0.08 mmHg x ml(-1) x min(-1)) and decreased CI (246 +/- 20 vs. 348 +/- 19 ml x min(-1) x kg(-1), P < 0.002) when contrasted with NP dams. Furthermore, uterine (0.16 +/- 0.03 vs. 0.38 +/- 0.09 ml x min(-1) x g tissue(-1)) and placental blood flow (0.30 +/- 0.08 vs. 0.70 +/- 0.10 ml x min(-1) x g tissue(-1)) were decreased in RUPP compared with the NP dams. These data demonstrate that the RUPP model of pregnancy-induced hypertension has systemic hemodynamic and regional blood flow alterations that are strikingly similar to those observed in women with PE.     

Cardiac and hemodynamic responses to synthetic atrial natriuretic factor in rats

To determine the hemodynamic effects of a hypotensive dose of atrial natriuretic factor (ANF), a synthetic peptide containing 26 amino acids of endogenous rat ANF (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH) was studied in two groups of barbiturate anesthetized rats. In the first experiment, a 20-minute infusion of a hypotensive dose, 95 pmole/min i.v., of the synthetic ANF decreased mean arterial pressure (MAP) by 40 +/- 3 mm Hg from a baseline of 128 +/- 5 mm Hg, and cardiac output (CO) (microsphere method) by 7.8 +/- 1.8 ml/min/100 gm from a baseline of 23.5 +/- 1.3 ml/min/100 gm. Synthetic ANF did not significantly affect the total peripheral resistance (TPR) measured at the end of the 20-minute infusion. Sodium nitroprusside (SNP), infused at an equihypotensive dose of 20 micrograms/kg/min i.v., produced the same hemodynamic profile in seven other animals; in contrast, 0.3 mg/kg i.v. of hydralazine (n = 7) lowered MAP by 56 +/- 6 mm Hg and reduced TPR index by 3.0 +/- 0.6 mm Hg/ml/min/100 gm, but did not change CO. Other than an increase in coronary blood during SNF infusion, there were no significant changes in the distribution of cardiac output. Infusion of the saline vehicle had no significant effects on any of these parameters. The results of the second experiment in anesthetized rats confirmed that hypotensive doses of 40 and 100 pmole/kg/min i.v. lowered CO (dye dilution method) from a baseline of 33 +/- 6 to a minimum of 24 +/- 2 ml/min/100 gm (p less than 0.05) without affecting TPR. In addition, synthetic ANF did not significantly affect heart rate (HR) but it slightly reduced cardiac contractility (dp/dt50). These results suggest that the hypotensive dose of synthetic ANF reduced cardiac output, partially by diminishing stroke volume, and perhaps contractility.     

Heart rate deflection point as a strategy to defend stroke volume during incremental exercise.

The purpose of this study was to examine whether the heart rate (HR) deflection point (HRDP) in the HR-power relationship is concomitant with the maximal stroke volume (SV(max)) value achievement in endurance-trained subjects. Twenty-two international male cyclists (30.3 +/- 7.3 yr, 179.7 +/- 7.2 cm, 71.3 +/- 5.5 kg) undertook a graded cycling exercise (50 W every 3 min) in the upright position. Thoracic impedance was used to measure continuously the HR and stroke volume (SV) values. The HRDP was estimated by the third-order curvilinear regression method. As a result, 72.7% of the subjects (HRDP group, n = 16) presented a break point in their HR-work rate curve at 89.9 +/- 2.8% of their maximal HR value. The SV value increased until 78.0 +/- 9.3% of the power associated with maximal O(2) uptake (Vo(2 max)) in the HRDP group, whereas it increased until 94.4 +/- 8.6% of the power associated with Vo(2 max) in six other subjects (no-HRDP group, P = 0.004). Neither SV(max) (ml/beat or ml.beat(-1).m(-2)) nor Vo(2 max) (ml/min or ml.kg(-1).min(-1)) were different between both groups. However, SV significantly decreased before exhaustion in the HRDP group (153 +/- 44 vs. 144 +/- 40 ml/beat, P = 0.005). In the HRDP group, 62% of the variance in the power associated with the SV(max) could also be predicted by the power output at which HRDP appeared. In conclusion, in well-trained subjects, the power associated with the SV(max)-HRDP relationship supposed that the HR deflection coincided with the optimal cardiac work for which SV(max) was attained.     

Cardiovascular responses to an isosterically modified prostaglandin analog in conscious dogs

The cardiovascular effects of oral and intravenous administration of 0.05 and 0.1 mg/kg of the isosterically modified prostaglandin (PG) analog, (+)- 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl] propyl) benzoic acid were ascertained in conscious mongrels. After 0.05 mg/kg p.o., mean arterial pressure (MAP), obtained from indwelling catheters, fell from 105 +/- 1 to 100 +/- 4 mm Hg and total peripheral resistance (TPR) decreased from 0.062 +/- 0.006 to 0.039 +/- 0.002 mm Hg/ml/min. Cardiac output (CO), measured via electromagnetic flow probes, rose from 1.8 +/- 0.2 to 2.6 +/- 0.1 l/min and heart rate from 109 +/- 13 to 128 +/- 8 beats/min. The 0.1 mg/kg p.o. dose produced similar results. Intravenous injection of 0.1 mg/kg immediately dropped MAP from 103 +/- 6 to 58 +/- 3 mm Hg and TPR from 0.049 +/- .006 to .014 +/- .002 mm Hg/ml/min. CO climbed from 2.3 +/- 0.2 to 5.3 +/- 0.5 l/min and HR increased from 126 +/- 9 to 254 +/- 14 beats/min. Stroke volume was not affected by either oral or intravenous administration of the PG analog. Pretreatment with 100 micrograms/kg timolol blunted the CO and HR responses to 0.1 mg/kg iv of the PG analog without affecting the depressor response. Metaraminol infused during injection of 0.1 mg/kg iv of the PG analog diminished all responses. When compared to the cardiovascular effects of hydralazine and nitroprusside, the profile of the PG analog activity closely resembled that produced by the arterial vasodilator, hydralazine; in contrast, nitroprusside (which also dilates veins) reduced stroke volume, but did not significantly affect HR. In conclusion, dilation of the resistance vessels by the PG analog decreased MAP and TPR and reflexly elevated CO and HR in conscious dogs.     

Atrial natriuretic peptide inhibits compensatory responses when cardiac performance is depressed.

We tested the hypothesis that the atrial natriuretic peptide (ANP) mediated decrease in baroreceptor sensitivity that is seen in normal rats is more pronounced in a state of depressed cardiac performance. Holtzman rats (n = 15) were injected with Adriamycin (1 mg/kg i.p. 3 times/week for 8-10 weeks). Control rats (n = 17) were injected with 0.9% saline. Experiments were done in conscious animals that had been catheterized for i.v. infusions and for measurement of arterial blood pressure (ABP) and heart rate (HR). ANP (250 ng.kg-1.min-1) or saline vehicle was infused i.v. Graded periodic bolus injections of phenylephrine or sodium nitroprusside were given to assess baroreceptor sensitivity (beats.min-1.mmHg-1) up to 60 mmHg (1 mmHg = 133.3 Pa) above and below resting ABP. The following day the experiment was repeated with the ANP-vehicle regimen reversed. Finally, the rats were anesthetized and the rate of left ventricular pressure increase (dP/dt) was measured. Data evaluation included calculation of least squares linear regression slopes of peak delta HR vs. peak delta ABP, applying corrections for experimental errors in both the dependent and independent variables. Adriamycin rats (A) did not differ significantly from control rats (C) with respect to either initial ABP (A = 105 +/- 5; C = 100 +/- 3; mean mmHg +/- SEM) or initial HR (335 +/- 9 vs. 312 +/- 13 beats.min-1). However, their indices of cardiac performance were significantly depressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

家兔Bezold—Jarisch反射的血流动力学效应

在40只麻醉兔,观察经冠脉内注射尼古丁诱发Bezold-Jarisch反射时的血流动力学变化。反射效应表现为心率减慢、动脉血压和左心室收缩压降低以及左心室内压微分值减小。切断两侧窦神经和减压神经后,上述效应增强;两侧迷走神经切断后,多数动物反射效应消失。 冠脉内注射尼古丁后,心输出量和总外周阻力均下降。人工起搏心脏以防止心率减慢时,对上述效应无明显影响。动物阿托品化并切除两侧星状神经节后,心率减慢基本消失,但动脉血压降低的程度并无明显变化。结果提示,Bezold-Jarisch反射时所表现的动脉血压降低,可归因于心输出量减少和总外周阻力降低,而以后者为主。     

Chronic intermittent hypoxia impairs baroreflex control of heart rate but enhances heart rate responses to vagal efferent stimulation in anesthetized mice

Chronic intermittent hypoxia (CIH) leads to increased sympathetic nerve activity and arterial hypertension. In this study, we tested the hypothesis that CIH impairs baroreflex (BR) control of heart rate (HR) in mice, and that decreased cardiac chronotropic responsiveness to vagal efferent activity contributes to such impairment. C57BL/6J mice were exposed to either room air (RA) or CIH (6-min alternations of 21% O(2) and 5.7% O(2), 12 h/day) for 90 days. After the treatment period, mice were anesthetized (Avertin) and arterial blood pressure (ABP) was measured from the femoral artery. Mean ABP (MABP) was significantly increased in mice exposed to CIH (98.7 +/- 2.5 vs. RA: 78.9 +/- 1.4 mmHg, P < 0.001). CIH increased HR significantly (584.7 +/- 8.9 beats/min; RA: 518.2 +/- 17.9 beats/min, P < 0.05). Sustained infusion of phenylephrine (PE) at different doses (0.1-0.4 microg/min) significantly increased MABP in both CIH and RA mice, but the ABP-mediated decreases in HR were significantly attenuated in mice exposed to CIH (P < 0.001). In contrast, decreases in HR in response to electrical stimulation of the left vagus nerve (30 microA, 2-ms pulses) were significantly enhanced in mice exposed to CIH compared with RA mice at low frequencies. We conclude that CIH elicits a sustained impairment of baroreflex control of HR in mice. The blunted BR-mediated bradycardia occurs despite enhanced cardiac chronotropic responsiveness to vagal efferent stimulation. This suggests that an afferent and/or a central defect is responsible for the baroreflex impairment following CIH.     

Circadian relations among cardiovascular variables of young adults.

Every 4 hours for 24 hours, 14 clinically healthy young individuals (6 women and 8 men), 26 +/- 4 years of age, measured systolic (S) and diastolic (D) blood pressure (BP) by sphygmomanometer and heart rate by ECG and did impedance cardiography under usual living conditions. Stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) were calculated. Time series of SBP, DBP, HR, SV, CO and TPR were analyzed by single and population-mean cosinor. A circadian cardiovascular rhythm is demonstrated by rejection of the zero amplitude assumption in the population-mean cosinor test for SBP, DBP, HR, SV, CO and TPR (P < 0.01). TPR peaks around 0400 (-61 degrees from local midnight), in antiphase with all other variables, their acrophase occurring around 1600 (-240 degrees). A circadian rhythm of statistical significance or of borderline statistical significance is found for all variables except TPR in women. Circadian rhythm characteristics were otherwise mostly similar in men and women with a statistically significant gender difference found by parameter tests only for the MESOR and amplitude of SBP.     

Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate

For porcine myocardium, ultrasonic regional deformation parameters, systolic strain (epsilon(sys)) and peak systolic strain rate (SR(sys)), were compared with stroke volume (SV) and contractility [contractility index (CI)] measured as the ratio of end-systolic strain to end-systolic wall stress. Heart rate (HR) and contractility were varied by atrial pacing (AP = 120-180 beats/min, n = 7), incremental dobutamine infusion (DI = 2.5-20 microg. kg(-1). min(-1), n = 7), or continuous esmolol infusion (0.5 mg. kg(-1). min(-1)) + subsequent pacing (120-180 beats/min) (EI group, n = 6). Baseline SR(sys) and epsilon(sys) averaged 5.0 +/- 0.4 s(-1) and 60 +/- 4%. SR(sys) and CI increased linearly with DI (20 microg. kg(-1). min(-1); SR(sys) = 9.9 +/- 0.7 s(-1), P < 0.0001) and decreased with EI (SR(sys) = 3.4 +/- 0.1 s(-1), P < 0.01). During pacing, SR(sys) and CI remained unchanged in the AP and EI groups. During DI, epsilon(sys) and SV initially increased (5 microg. kg(-1). min(-1); epsilon(sys) = 77 +/- 6%, P < 0.01) and then progressively returned to baseline. During EI, SV and epsilon(sys) decreased (epsilon(sys) = 38 +/- 2%, P < 0.001). Pacing also decreased SV and epsilon(sys) in the AP (180 beats/min; epsilon(sys) = 36 +/- 2%, P < 0.001) and EI groups (180 beats/min; epsilon(sys) = 25 +/- 3%, P < 0.001). Thus, for normal myocardium, SR(sys) reflects regional contractile function (being relatively independent of HR), whereas epsilon(sys) reflects changes in SV.     

Chronic measurement of cardiac output in conscious mice

We describe the feasibility of chronic measurement of cardiac output (CO) in conscious mice. With the use of gas anesthesia, mice >30 g body wt were instrumented either with transit-time flow probes or electromagnetic probes placed on the ascending aorta. Ascending aortic flow values were recorded 6-16 days after surgery when probes had fully grown in. In the first set of experiments, while mice were under ketamine-xylazine anesthesia, estimates of stroke volume (SV) obtained by the transit-time technique were compared with those simultaneously obtained by echocardiography. Transit-time values of SV were similar to those obtained by echocardiography. The average difference +/- SD between the methods was 2 +/- 7 microl. In the second set of studies, transit-time values of CO were compared with those obtained by the electromagnetic flow probes. In conscious resting conditions, estimates +/- SD) of cardiac index (CI) obtained by the transit-time and electromagnetic flow probes were 484 +/- 119 and 531 +/- 103 ml x min(-1) x kg body wt(-1), respectively. Transit-time flow probes were also implanted in mice with a myocardial infarction (MI) induced by ligation of a coronary artery 3 wk before probe implantation. In these MI mice (n = 7), average (+/- SD) resting and stimulated (by volume loading) values of CO were significantly lower than in noninfarcted mice (n = 15) (resting CO 16 +/- 3 vs. 20 +/- 4 ml/min; stimulated CO 20 +/- 5 vs. 26 +/- 6 ml/min). Finally, using transfer function analysis, we found that, in resting conditions for both intact and MI mice, spontaneous variations in CO (> 0.1 Hz) were mainly due to those occurring in SV rather than in heart rate. These data indicate that CO can be measured chronically and reliably in conscious mice, also in conditions of heart failure, and that variations in preload are an important determinant of CO in this species.     

Cardiovascular responses to voluntary and nonvoluntary static exercise in humans.

We have measured the cardiovascular responses during voluntary and nonvoluntary (electrically induced) one-leg static exercise in humans. Eight normal subjects were studied at rest and during 5 min of static leg extension at 20% of maximal voluntary contraction performed voluntarily and nonvoluntarily in random order. Heart rate (HR), mean arterial pressure (MAP), and cardiac output (CO) were determined, and peripheral vascular resistance (PVR) and stroke volume (SV) were calculated. HR increased from approximately 65 +/- 3 beats/min at rest to 80 +/- 4 and 78 +/- 6 beats/min (P < 0.05), and MAP increased from 83 +/- 6 to 103 +/- 6 and 105 +/- 6 mmHg (P < 0.05) during voluntary and nonvoluntary contractions, respectively. CO increased from 5.1 +/- 0.7 to 6.0 +/- 0.8 and 6.2 +/- 0.8 l/min (P < 0.05) during voluntary and nonvoluntary contractions, respectively. PVR and SV did not change significantly during voluntary or nonvoluntary contractions. Thus the cardiovascular responses were not different between voluntary and electrically induced contractions. These results suggest that the increases in CO, HR, SV, MAP, and PVR during 5 min of static contractions can be elicited without any contribution from a central neural mechanism (central command). However, central command could still have an important role during voluntary static exercise.     

Control of myocardial oxygen consumption in transgenic mice overexpressing vascular eNOS

Our objective was to investigate the potential role of selective endothelial nitric oxide (NO) synthase (eNOS) overexpression in coronary blood vessels in the control of myocardial oxygen consumption (MVO2). Transgenic (Tg) eNOS-overexpressing mice (eNOS Tg) (n=22) and wild-type (WT) mice (n=24) were studied. Western blot analysis indicated greater than sixfold increase of eNOS in cardiac tissue. Echocardiography in awake mice indicated no difference in cardiac function between WT and eNOS Tg; however, systolic pressure in eNOS Tg mice decreased significantly (126 +/- 2.3 to 109 +/- 2.3 mmHg; P <0.05), whereas heart rate (HR) was not different. Total peripheral resistance (TPR) was also decreased (9.8 +/- 0.8 to 7.6 +/- 0.4 4 mmHg.ml(-1).min; P <0.05) in eNOS Tg. Furthermore, female eNOS Tg mice showed even lower TPR (7.2 +/- 0.4 mmHg.ml(-1).min) compared with male eNOS mice (8.6 +/- 0.5, mmHg.ml.min(-1); P <0.05). Left ventricular slices were isolated from WT and eNOS Tg mice. With the use of a Clark-type oxygen electrode in an airtight bath, MVO2 was determined as the percent decrease during increasing doses (10(-10) to 10(-4) mol/l) of bradykinin (BK), carbachol (CCh), forskolin (10(-12) to 10(-6) mol/l), or S-nitroso-N-acetyl penicillamine (SNAP; 10(-7) to 10(-4) mol/l). Baseline MVO2 was not different between WT (181 +/- 13 nmol.g(-1).min(-1)) and eNOS Tg (188 +/- 14 nmol.g(-1).min(-1)). BK decreased MVO2 (10(-4) mol/l) in WT by 17% +/- 1.1 and 33% +/- 2.7 in eNOS Tg (P < 0.05). CCh also decreased MVO2, 10(-4) mol/l, in WT by 20% +/- 1.7 and 31% +/- 2.0 in eNOS Tg (P <0.05). Forskolin (10(-6) mol/l) or SNAP (10(-4) mol/l) also decreased MVO2 in WT by 24% +/- 2.8 and 36% +/- 1.8 versus eNOS 31% +/- 1.8 and 37% +/- 3.5, respectively. N-nitro-L-arginine methyl ester (10(-3) mol/l) inhibited the MVO2 reduction to BK, CCh, and forskolin by a similar degree (P <0.05), but not to SNAP. Thus selective overexpression of eNOS in cardiac blood vessels in mice enhances the control of MVO2 by eNOS-derived NO.     

Diminished baroreflex control of heart rate responses in otoconia-deficient C57BL/6JEi head tilt mice

The maintenance of stable blood pressure during postural changes is known to involve integration of vestibular and cardiovascular central regulatory mechanisms. Sensory activity in the vestibular system plays an important role in cardiovascular regulation. The purpose of this study was to determine the role of vestibular gravity receptors in normal baroreflex function. Baroreflex heart rate (HR) responses to changes in blood pressure (BP) in otoconia-deficient head tilt (het) mice (n = 8) were compared with their wild-type littermates (n = 12). The study was carried out in conscious male mice chronically implanted with arterial and venous catheters for recording BP and HR and for the infusion of vasoactive drugs. Resting HR was higher in the het mice (661 +/- 13 beats/min) than in the wild-type mice (579 +/- 20 beats/min). BP was comparable in the het (113 +/- 4 mmHg) and wild-type mice (104 +/- 4 mmHg). The slopes of reflex decreases in HR in response to phenylephrine (PE) were blunted in the het mice (-5.5 +/- 1.5 beats x min(-1) x mmHg(-1)) compared with the wild-type mice (-8.5 +/- 0.9 beats x min(-1) x mmHg(-1)). Likewise, reflex tachycardic responses to decreases in BP with sodium nitroprusside (SNP) were significantly blunted in the het mice (-0.8 +/- 0.3 beats x min(-1) x mmHg(-1)) versus the wild-type mice (-2.2 +/- 0.6 beats x min(-1) x mmHg(-1)). Frequency-domain analysis of the HR variability suggests that under resting conditions, parasympathetic contribution was lower in the het versus wild-type mice. Mapping of the expression of immediate-early gene product, c-Fos, in forebrain and brain stem nuclei in response to a BP challenge showed no differences between the wild-type and het mice. These results suggest that tonic activity of gravity receptors modulates and is required for normal function of the cardiac baroreflexes.     

Oxytocinergic regulation of cardiovascular function: studies in oxytocin-deficient mice

Oxytocin (OT) has been implicated in the cardiovascular responses to exercise, stress, and baroreflex adjustments. Studies were conducted to determine the effect of genetic manipulation of the OT gene on blood pressure (BP), heart rate (HR), and autonomic/baroreflex function. OT knockout (OTKO -/-) and control +/+ mice were prepared with chronic arterial catheters. OTKO -/- mice exhibited a mild hypotension (102 +/- 3 vs. 110 +/- 3 mmHg). Sympathetic and vagal tone were tested using beta(1)-adrenergic and cholinergic blockade (atenolol and atropine). Magnitude of sympathetic and vagal tone to the heart and periphery was not significantly different between groups. However, there was an upward shift of sympathetic tone to higher HR values in OTKO -/- mice. This displacement combined with unchanged basal HR led to larger responses to cholinergic blockade (+77 +/- 25 vs. +5 +/- 15 beats/min, OTKO -/- vs. control +/+ group). There was also an increase in baroreflex gain (-13.1 +/- 2.5 vs. -4.1 +/- 1.2 beats x min(-1) x mmHg(-1), OTKO -/- vs. control +/+ group) over a smaller BP range. Results show that OTKO -/- mice are characterized by 1) hypotension, suggesting that OT is involved in tonic BP maintenance; 2) enhanced baroreflex gain over a small BP range, suggesting that OT extends the functional range of arterial baroreceptor reflex; and 3) shift in autonomic balance, indicating that OT reduces the sympathetic reserve.     

The relationship of the heart rate deflection point to the ventilatory threshold in trained cyclists

The purpose of this study was to assess the relationship of the heart rate deflection point (HRDP) to the ventilatory threshold (VT) in trained cyclists. Twenty-one endurance-trained cyclists (mean +/- SD: Vo(2)max = 67.6 +/- 4.7 ml x kg x min(-1)) completed a maximal cycle ergometer test of volitional fatigue using a ramped protocol. Ventilatory variables (Ve, Vo(2), Vco(2)) and power were measured online with averages reported every 20 seconds. Heart rate (HR) was recorded every 20 seconds using a Polar monitor. VT was calculated using the excess CO(2) elimination curve. The first derivative of a logistic growth curve fit to the HR-power data produced the HRDP. No significant differences (p > 0.01) existed between HR values at HRDP (171.7 +/- 9.6 b x min(-1)) and VT (169.8 +/- 9.9 b x min(-1)) or between Vo(2) values at HRDP (53.6 +/- 4.2 ml x kg x min(-1)) and VT (52.2 +/- 4.8 ml x kg x min(-1)). But power values at HRDP (318.7 +/- 30.7 W) were significantly different (p < 0.01) from those at VT (334.8 +/- 36.7 W). There were significant relationships between HRDP and VT for the physiological variables of HR (r = 0.92, p < 0.001), Vo(2) (r = 0.72, p < 0.001), and power (r = 0.77, p < 0.001). These findings indicate that HR and Vo(2) at HRDP are not significantly different from the values at VT in trained cyclists. HR values derived from HRDP may be used to set parameters for training intensity. Variability in the speed/power-HRDP relationship across detrained/trained states may be used to evaluate training programs.     

Cerebral and systemic hemodynamic changes during cognitive and motor activation paradigms

Cognitive and/or sensorimotor stimulations of the brain induce increases in cerebral blood flow that are usually associated with increased metabolic demand. We tested the hypothesis that changes in arterial blood pressure (ABP) and arterial Pco(2) also take place during brain activation protocols designed to induce hemispheric lateralization, leading to a pressure-autoregulatory response in addition to the metabolic-driven changes usually assumed by brain stimulation paradigms. Continuous recordings of cerebral blood flow velocity [CBFV; bilateral, middle cerebral artery (MCA)], ABP, ECG, and end-tidal Pco(2) (Pet(CO(2))) were performed in 15 right-handed healthy subjects (aged 21-43 yr), in the seated position, at rest and during 10 repeated presentations of a word generation and a constructional puzzle paradigm that are known to induce differential cortical activation. Derived variables included heart rate, cerebrovascular resistance, critical closing pressure, resistance area product, and the difference between the right and left MCA recordings (CBFV(R-L)). No adaptation of the CBFV(R-L) difference was detected for the repeated presentation of 10 activation tasks, for either paradigm. During activation with the word generation tasks, CBFV changed by (mean +/- SD) 9.0 +/- 3.7% (right MCA, P = 0.0007) and by 12.3 +/- 7.6% (left MCA, P = 0.0007), ABP by 7.7 +/- 6.0 mmHg (P = 0.0007), heart rate by 7.1 +/- 5.3 beats/min (P = 0.0008), and Pet(CO(2)) by -2.32 +/- 2.23 Torr (P = 0.002). For the puzzle paradigm, CBFV changed by 13.9 +/- 6.6% (right MCA, P = 0.0007) and by 11.5 +/- 6.2% (left MCA, P = 0.0007), ABP by 7.1 +/- 8.4 mmHg (P = 0.0054), heart rate by 7.9 +/- 4.6 beats/min (P = 0.0008), and Pet(CO(2)) by -2.42 +/- 2.59 Torr (P = 0.001). The word paradigm led to greater left hemispheric dominance than the right hemispheric dominance observed with the puzzle paradigm (P = 0.004). We concluded that significant changes in ABP and Pet(CO(2)) levels occur during brain activation protocols, and these contribute to the evoked change in CBFV. A pressure-autoregulatory response can be observed in addition to the hemodynamic changes induced by increases in metabolic demand. Simultaneous changes in Pco(2) and heart rate add to the complexity of the response, indicating the need for more detailed modeling and better understanding of brain activation paradigms.     

Human cardiovascular reactions to simulated hypovolaemia, modified by the opiate antagonist naloxone

Six healthy males were exposed to 20 mm Hg lower body negative pressure (LBNP) for 8 min followed by 40 mm Hg LBNP for 8 min. Naloxone (0.1 mg.kg-1) was injected intravenously during a 1 h resting period after which the LBNP protocol was repeated. Systolic, mean, and diastolic arterial blood pressures (SAP, MAP, DAP), and central venous pressure (CVP) were obtained using indwelling catheters. Cardiac output (CO), forearm blood flow (FBF), heart rate (HR), left ventricular ejection time (LVET), and electromechanical systole (EMS) were measured non-invasively. Pulse pressure (PP), stroke volume (SV), total peripheral resistance (TPR), forearm vascular resistance (FVR), systolic ejection rate (SER), pre-ejection period (PEP), PEP/LVET and indices for the systolic time intervals (LVETI, EMSI, PEPI) were calculated. During the second LBNP exposure, only two parameters differed from the pre-injection values: DAP at LBNP = 40 mm Hg increased from 60.0 +/- 4.8 mm Hg to 64.8 +/- 4.1 mm Hg (N = 4, p less than 0.02) and LVETI at LBNP = 20 mm Hg increased from 384.4 +/- 5.2 ms to 396.8 +/- 6.2 ms (N = 6, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

The total cavopulmonary connection resistance: a significant impact on single ventricle hemodynamics at rest and exercise

Little is known about the impact of the total cavopulmonary connection (TCPC) on resting and exercise hemodynamics in a single ventricle (SV) circulation. The aim of this study was to elucidate this mechanism using a lumped parameter model of the SV circulation. Pulmonary vascular resistance (1.96+/-0.80 WU) and systemic vascular resistances (18.4+/-7.2 WU) were obtained from catheterization data on 40 patients with a TCPC. TCPC resistances (0.39+/-0.26 WU) were established using computational fluid dynamic simulations conducted on anatomically accurate three-dimensional models reconstructed from MRI (n=16). These parameters were used in a lumped parameter model of the SV circulation to investigate the impact of TCPC resistance on SV hemodynamics under resting and exercise conditions. A biventricular model was used for comparison. For a biventricular circulation, the cardiac output (CO) dependence on TCPC resistance was negligible (sensitivity=-0.064 l.min(-1).WU(-1)) but not for the SV circulation (sensitivity=-0.88 l.min(-1).WU(-1)). The capacity to increase CO with heart rate was also severely reduced for the SV. At a simulated heart rate of 150 beats/min, the SV patient with the highest resistance (1.08 WU) had a significantly lower increase in CO (20.5%) compared with the SV patient with the lowest resistance (50%) and normal circulation (119%). This was due to the increased afterload (+35%) and decreased preload (-12%) associated with the SV circulation. In conclusion, TCPC resistance has a significant impact on resting hemodynamics and the exercise capacity of patients with a SV physiology.