Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

Despite reductions in beta-adrenoreceptor (beta-AR)-mediated inotropic effects induced by sustained sympathetic activation in cardiac disease, whether these changes necessarily result in reductions in systolic function under resting conditions (baseline function) is not clear. Moreover, possible compensatory mechanisms which might contribute to maintaining the baseline systolic function despite reductions in beta-AR-mediated inotropic effects have not been systematically sought. In the present study, 1 month of daily administration of the beta-AR agonist, isoproterenol (0.05 mg/kg/day, i.p.), to rats resulted in an attenuation of left ventricular inotropic responses to isoproterenol over a wide range of concentrations (10(-8)-10(-4) M), whereas a decline of inotropic responses to norepinephrine, an endogenous inotrope, occurred only at high concentrations (10(-5)-10(-4) M). However, chronic isoproterenol administration failed to modify baseline systolic chamber and myocardial function, as determined in vivo using echocardiography (endocardial and midwall fractional shortening), and in isolated, perfused heart preparations (end-systolic chamber and myocardial elastance) Sustained baseline chamber function despite profound beta-AR-mediated inotropic downregulation was not attributed to alterations in cardiac loading conditions, resting heart rate, chamber remodeling, increased myocardial norepinephrine release, or enhanced contractile responses to alternative receptor/signal transduction pathways mediating positive inotropy (as assessed from histamine, serotonin, forskolin, angiotensin II or phenylephrine responsiveness). These findings indicate that baseline cardiac contractile function might be unaltered despite a profound impairment of beta-AR-induced responsiveness, an effect related to a preserved stimulatory influence of low physiological concentrations of endogenous norepinephrine constituting adrenergic tone at rest.     

Unloading arterial baroreceptors causes neurogenic hypertension

We developed a new model to examine the role of arterial baroreceptors in the long-term control of mean arterial pressure (MAP) in dogs. Baroreceptors in the aortic arch and one carotid sinus were denervated, and catheters were implanted in the descending aorta and common carotid arteries. MAP and carotid sinus pressure (CSP) averaged 104 +/- 2 and 102 +/- 2 mmHg (means +/- 1 SE), respectively, during a 5-day control period. Baroreceptor unloading was induced by ligation of the common carotid artery proximal to the innervated sinus (n = 6 dogs). MAP and CSP averaged 127 +/- 7 and 100 +/- 3 mmHg, respectively, during the 7-day period of baroreceptor unloading. MAP was significantly elevated (P < 0.01) compared to control, but CSP was unchanged. Heart rate and plasma renin activity increased significantly in response to baroreceptor unloading. Removal of the ligature to restore normal flow through the carotid resulted in normalization of all variables. Ligation of the carotid below a denervated sinus (n = 4) caused a significant decrease in CSP but no systemic hypertension. These results indicate that chronic unloading of carotid baroreceptors can produce neurogenic hypertension and provide strong evidence that arterial baroreceptors are involved in the long-term control of blood pressure.     

Central volume expansion is pivotal for sustained decrease in heart rate during seated to supine posture change

During prolonged, static carotid baroreceptor stimulation by neck suction (NS) in seated humans, heart rate (HR) decreases acutely and thereafter gradually increases. This increase has been explained by carotid baroreceptor adaptation and/or buffering by aortic reflexes. During a posture change from seated to supine (Sup) with similar carotid stimulation, however, the decrease in HR is sustained. To investigate whether this discrepancy is caused by changes in central blood volume, we compared (n = 10 subjects) the effects of 10 min of seated NS (adjusted to simulate carotid stimulation of a posture change), a posture change from seated to Sup, and the same posture change with left atrial (LA) diameter maintained unchanged by lower body negative pressure (Sup + LBNP). During Sup, the prompt decreases in HR and mean arterial pressure (MAP) were sustained. HR decreased similarly within 30 s of NS (65 +/- 2 to 59 +/- 2 beats/min) and Sup + LBNP (65 +/- 2 to 58 +/- 2 beats/min) and thereafter gradually increased to values of seated. MAP decreased similarly within 5 min during Sup + LBNP and NS (by 7 +/- 1 to 9 +/- 1 mmHg) and thereafter tended to increase toward values of seated subjects. Arterial pulse pressure was increased the most by Sup, less so by Sup + LBNP, and was unchanged by NS. LA diameter was only increased by Sup. In conclusion, static carotid baroreceptor stimulation per se causes the acute (<30 s) decrease in HR during a posture change from seated to Sup, whereas the central volume expansion (increased LA diameter and/or arterial pulse pressure) is pivotal to sustain this decrease. Thus the effects of central volume expansion override adaptation of the carotid baroreceptors and/or buffering of aortic reflexes.     

Exercise intensity influences cardiac baroreflex function at the onset of isometric exercise in humans.

We sought to examine the influence of exercise intensity on carotid baroreflex (CBR) control of heart rate (HR) and mean arterial pressure (MAP) at the onset of exercise in humans. To accomplish this, eight subjects performed multiple 1-min bouts of isometric handgrip (HG) exercise at 15, 30, 45 and 60% maximal voluntary contraction (MVC), while breathing to a metronome set at eupneic frequency. Neck suction (NS) of -60 Torr was applied for 5 s at end expiration to stimulate the CBR at rest, at the onset of HG (<1 s), and after approximately 40 s of HG. Beat-to-beat measurements of HR and MAP were recorded throughout. Cardiac responses to NS at onset of 15% (-12 +/- 2 beats/min) and 30% (-10 +/- 2 beats/min) MVC HG were similar to rest (-10 +/- 1 beats/min). However, HR responses to NS were reduced at the onset of 45% and 60% MVC HG (-6 +/- 2 and -4 +/- 1 beats/min, respectively; P < 0.001). In contrast to HR, MAP responses to NS were not different from rest at exercise onset. Furthermore, both HR and MAP responses to NS applied at approximately 40s of HG were similar to rest. In summary, CBR control of HR was transiently blunted at the immediate onset of high-intensity HG, whereas MAP responses were preserved demonstrating differential baroreflex control of HR and blood pressure at exercise onset. Collectively, these results suggest that carotid-cardiac baroreflex control is dynamically modulated throughout isometric exercise in humans, whereas carotid baroreflex regulation of blood pressure is well-maintained.     

Cardiovascular effects of static carotid baroreceptor stimulation during water immersion in humans

We hypothesized that the more-pronounced hypotensive and bradycardic effects of an antiorthostatic posture change from seated to supine than water immersion are caused by hydrostatic carotid baroreceptor stimulation. Ten seated healthy males underwent five interventions of 15-min each of 1) posture change to supine, 2) seated water immersion to the Xiphoid process (WI), 3) seated neck suction (NS), 4) WI with simultaneous neck suction (-22 mmHg) adjusted to simulate the carotid hydrostatic pressure increase during supine (WI + NS), and 5) seated control. Left atrial diameter increased similarly during supine, WI + NS, and WI and was unchanged during control and NS. Mean arterial pressure (MAP) decreased the most during supine (7 +/- 1 mmHg, P < 0.05) and less during WI + NS (4 +/- 1 mmHg) and NS (3 +/- 1 mmHg). The decrease in heart rate (HR) by 13 +/- 1 beats/min (P < 0.05) and the increase in arterial pulse pressure (PP) by 17 +/- 4 mmHg (P < 0.05) during supine was more pronounced (P < 0.05) than during WI + NS (10 +/- 2 beats/min and 7 +/- 2 mmHg, respectively) and WI (8 +/- 2 beats/min and 6 +/- 1 mmHg, respectively, P < 0.05). Plasma vasopressin decreased only during supine and WI, and plasma norepinephrine, in addition, decreased during WI + NS (P < 0.05). In conclusion, WI + NS is not sufficient to decrease MAP and HR to a similar extent as a 15-min seated to supine posture change. We suggest that not only static carotid baroreceptor stimulation but also the increase in PP combined with low-pressure receptor stimulation is a possible mechanism for the more-pronounced decrease in MAP and HR during the posture change.     

Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide.

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N(G)-nitro-L-arginine methyl ester (10(-5) M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.     

Nonuniform changes in arteriolar myogenic tone within skeletal muscle following hindlimb unweighting.

Hindlimb unweighting (HLU) has been shown to alter myogenic tone distinctly in arterioles isolated from skeletal muscles composed predominantly of fast-twitch (white gastrocnemius) compared with slow-twitch (soleus) fibers. Based on these findings, we hypothesized that HLU would alter myogenic tone differently in arterioles isolated from distinct fiber-type regions within a single skeletal muscle. We further hypothesized that alterations in myogenic tone would be associated with alterations in voltage-gated Ca(2+) channel current (VGCC) density of arteriolar smooth muscle. After 14 days of HLU or weight bearing (control), first-order arterioles were isolated from both fast-twitch and mixed fiber-type regions of the gastrocnemius muscle, cannulated, and pressurized at 90 cmH(2)O. Mixed gastrocnemius arterioles of HLU rats demonstrated increased spontaneous tone [43 +/- 5% (HLU) vs. 27 +/- 4% (control) of possible constriction] and an approximately twofold enhanced myogenic response when exposed to step changes in intraluminal pressure (10-130 cmH(2)O) compared with control rats. In contrast, fast-twitch gastrocnemius arterioles of HLU rats demonstrated similar levels of spontaneous tone [6 +/- 2% (HLU) vs. 6 +/- 2% (control)] and myogenic reactivity to control rats. Neither KCl-induced contractile responses (10-50 mM KCl) nor VGCC density was significantly different between mixed gastrocnemius arterioles of HLU and control rats. These results suggest that HLU produces diverse adaptations in myogenic reactivity of arterioles isolated from different fiber-type regions of a single skeletal muscle. Furthermore, alterations in myogenic responses were not attributable to altered VGCC density.     

Enhanced baroreflex sensitivity in free-moving calponin knockout mice

Calponin is an actin binding protein in vascular smooth muscle that modifies contractile responses. However, its role in mean arterial pressure (MAP) regulation has not been clarified. To assess this, MAP and heart rate (HR) were measured in calponin knockout (KO) mice, and the results were compared with those in wild-type (WT) mice. The measurements were performed every 100 ms during a 60-min free-moving state each day for 3 days. Mice in both groups rested during approximately 70% of the total measuring period. The mean HR during rest was significantly lower in KO mice than in WT mice but with no significant difference in MAP between the groups. The change in HR response (deltaHR) to spontaneous change in MAP (deltaMAP) varied in a wider range in KO mice with an 80% increase in the coefficient of variation for HR (P < 0.05), whereas MAP in KO mice was controlled in a narrow range similar to that in WT mice. The baroreflex sensitivity (deltaHR/deltaMAP), determined from the change in HR to the spontaneous change in MAP, was twofold higher in KO mice than that in WT mice (P < 0.01), whereas there were no significant differences in the baroreflex sensitivity determined by intravascular administration of phenylephrine and sodium nitroprusside between the two groups (P > 0.1). The MAP response to the administrated doses of phenylephrine in KO mice was reduced to one-half of that in WT mice (P < 0.01) but with no significant difference in the response to sodium nitroprusside between the groups. The differences in HR variability and the spontaneous baroreflex sensitivity between the two groups completely disappeared after carotid sinus denervation. These results suggest that the higher variability in HR for KO mice was caused by the increased spontaneous arterial baroreflex sensitivity, though not detected by the intra-arterial administration of the drug, and that the higher variability of HR may be a compensatory adaptation to the blunted alpha-adrenergic response of peripheral vessels to sympathetic nervous activity.     

Carvedilol Prevents Ovariectomy-Induced Myocardial Contractile Dysfunction in Female Rat

Carvedilol has beneficial effects on cardiac function in patients with heart failure but its effect on ovariectomy-induced myocardial contractile dysfunction remains unclear. Estrogen deficiency induces myocardial contractile dysfunction and increases cardiovascular disease risk in postmenopausal women. Our aim was to investigate whether carvedilol, a beta receptor blocker, would prevent ovariectomy-induced myocardial contractile dysfunction. Female rats (8 weeks old) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with carvedilol (OVX+CAR, 20 mg/kg), placebo (OVX) and SHAM for 58 days. Left ventricle papillary muscle was mounted for isometric tension recordings. The inotropic response to Ca²⁺ (0.62 to 3.75 mM) and isoproterenol (Iso 10⁻⁸ to 10⁻² M) were assessed. Expression of calcium handling proteins was measured by western blot analysis. Carvedilol treatment in the OVX animals: prevented weight gain and slight hypertrophy, restored the reduced positive inotropic responses to Ca²⁺ and isoproterenol, prevented the reduction in SERCA2a expression, abolished the increase in superoxide anion production, normalized the increase in p22^phox expression, and decreased serum angiotensin converting enzyme (ACE) activity. This study demonstrated that myocardial contractile dysfunction and SERCA2a down regulation were prevented by carvedilol treatment. Superoxide anion production and NADPH oxidase seem to be involved in this response.     

Adaptations in beta-adrenergic cardiovascular responses to training in older women.

To determine whether endurance exercise training can alter the beta-adrenergic-stimulated inotropic response in older women, we studied 10 postmenopausal healthy women (65.4 +/- 0.9 yr old) who exercised for 11 mo. Left ventricular (LV) function was evaluated with two-dimensional echocardiography during infusion of isoproterenol after atropine. Maximal O(2) consumption increased 23% in response to training (from 1.35 +/- 0.06 to 1.66 +/- 0.07 l/min; P = 0.004). Training had no effect on baseline LV function, end-diastolic diameter, LV wall thickness, or LV mass. The increase in LV systolic function in response to isoproterenol was unaffected by training. Furthermore, neither the systolic shortening-to-end-systolic wall stress relationship nor the end-systolic wall stress-to-end-systolic diameter relationship during isoproterenol infusion changed with training. We conclude that older postmenopausal women can increase their maximal O(2) consumption with exercise training without eccentric LV hypertrophy or enhancement of beta-adrenergic-mediated LV contractile function. These observations provide an explanation for the finding that maximal cardiac output and stroke volume are not increased in older women in response to training.     

Effect of carotid or aortic baroreceptor denervation on arterial pressure during hemorrhage in conscious dogs

We studied the effect of chronically denervating aortic baroreceptors (ABR; n = 6) or carotid baroreceptors (CBR; n = 7) on mean arterial pressure (MAP) and heart rate (HR) responses to hemorrhage in the dog. Neither denervation had a significant effect on basal MAP, the variability (standard deviation) of MAP, or resting HR. However, the breakpoint of MAP (defined as the volume of blood removed when MAP fell more than 10% below control and declined monotonically thereafter) was significantly reduced in dogs with only ABR functional (12.4 +/- 1.4 ml/kg) compared with the volume in the intact condition (18.9 +/- 1.8 ml/kg). In contrast, there was no difference in the breakpoint or the MAP at any time during hemorrhage in dogs with both CBR functional compared with their intact responses. In a different group of dogs (n = 6), responses were determined with both CBR operating and again after unilateral denervation, leaving only one CBR (1CBR) functional. Basal MAP and the variability of MAP were not altered in dogs with only 1CBR functional, but the breakpoint (11.7 +/- 1.4 ml/kg) during hemorrhage was significantly different compared with responses with two CBR (21.2 +/- 2.3 ml/kg), and MAP fell to much lower levels. These results indicate that the CBR can compensate fully for loss of ABR during hemorrhage but not vice versa; and bilateral CBR inputs are required for normal responses to hemorrhage.     

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic beta-adrenoreceptor activation

There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a beta-adrenoreceptor agonist, for 3 mo to rats (0.1 mg.kg(-1).day(-1)) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic beta-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as beta(1)- and beta(2)-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and beta-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of alpha-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing beta-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.     

Reduced vascular responsiveness after a single bout of dynamic exercise in the conscious rabbit.

We measured agonist-induced changes in the iliac artery blood flow velocity (IFV) independent of baroreflex-mediated compensatory mechanisms in chronically instrumented New Zealand White rabbits (n = 8). Animals were instrumented with a Doppler flow probe around the right common iliac artery. A Teflon catheter was inserted into the right iliolumbar artery for local infusion of the vasoactive agonists. Another Teflon catheter was inserted in the left femoral artery for the measurement of pulsatile and mean arterial (MAP) blood pressures and heart rate (HR). The alpha-adrenergic receptor agonist phenylephrine (PE, 1.32-10.0 micrograms), the beta 1- and beta 2-adrenergic receptor agonist isoproterenol (IP, 0.022-0.11 micrograms), and the purinergic receptor agonist adenosine (AD, 10.0-100.0 micrograms) were injected into the functionally isolated hindlimb, and dose-response curves were generated. Changes in IFV were obtained without changes in MAP or HR. Exercise increased HR, MAP, and IFV (65.3 +/- 7.1 beats/min, 11.1 +/- 2.2 mmHg, and 2.2 +/- 0.3 kHz, respectively). The maximum responses to PE, AD, and IP were reduced 29.0 +/- 6.7, 50.7 +/- 8.5, and 61.0 +/- 8.1%, respectively, after exercise. In conclusion, exercise attenuated adrenergic and purinergic receptor-mediated vascular responses in the intact conscious rabbit.     

Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo

The endothelin (ET) system is involved in the regulation of myocardial function in health as well as in several diseases, such as congestive heart failure, myocardial infarction, and septic myocardial depression. Conflicting results have been reported regarding the acute contractile properties of ET-1. We therefore investigated the effects of intracoronary infusions of ET-1 and of the selective ET(B) receptor-selective agonist sarafotoxin 6c with increasing doses in anesthetized pigs. Myocardial effects were measured through analysis of the left ventricular pressure-volume relationship. ET-1 elicited increases in the myocardial contractile status (end-systolic elastance value of 0.94 +/- 0.11 to 1.48 +/- 0.23 and preload recruitable stroke work value of 68.7 +/- 4.7 to 83.4 +/- 7.2) that appear to be mediated through ET(A) receptors, whereas impairment in left ventricular isovolumic relaxation (tau = 41.5 +/- 1.4 to 58.1 +/- 5.0 and t(1/2) = 23.0 +/- 0.7 to 30.9 +/- 2.6, where tau is the time constant for pressure decay and t(1/2) is the half-time for pressure decay) was ET(B) receptor dependent. In addition, intravenous administration of ET-1 impaired ventricular relaxation but had no effect on contractility. Intracoronary sarafotoxin 6c administration caused impairments in left ventricular relaxation (tau from 43.3 +/- 1.8 to 54.4 +/- 3.4) as well as coronary vasoconstriction. In conclusion, ET-1 elicits positive inotropic and negative lusitropic myocardial effects in a pig model, possibly resulting from ET(A) and ET(B) receptor activation, respectively.     

Transient hypertension and sustained tachycardia in mice housed individually in metabolism cages

The novel environment of a metabolic cage can be stressful for rodents, but few studies have attempted to quantify this stress-response. Therefore, we determined the effects on mean arterial pressure (MAP) and heart rate (HR), of placing mice of both sexes in metabolism cages for 2 days. After surgical implantation of a carotid artery catheter mice recovered individually in standard cages for 5 days. Mice then spent 2 days in metabolism cages. MAP and HR were monitored in the standard cage on Day 5 and in metabolism cages on Days 6-7. MAP increased by 18+/-3 and 22+/-4 %, while HR increased by 27+/-4 and 27+/-6 %, in males and females, respectively, during the first hours after cage switch. MAP decreased to baseline in the fourth and eighth h following metabolism cage switch in males and females, respectively. However, HR remained significantly elevated in both sexes during the entire two-day period in metabolism cages. Females had lower MAP than males both pre- and post-metabolism cage switch, but there were no sex differences in HR. These results demonstrate sustained changes in cardiovascular function when mice are housed in metabolism cages, which could potentially affect renal function.     

兔颈动脉窦和主动脉弓压力感受器反射效应的比较研究

对81只麻醉兔,在静脉注射新福林和硝普钠升降血压而改变动脉压力感受器活动的条件下,观察心率,后肢血管阻力和肾交感神经活动的反射性变化。主要结果如下:(1) 由新福林升高血压时,心率减慢、后肢血管阻力降低和肾交感神经活动抑制;硝普钠降低血压时引起相反效应。各指标的反射性变化有良好的可重复性。(2) 切断两侧减压神经或切断两侧窦神经后,静注新福林和硝普钠诱发的心率反射性变化均显著减弱(P<0.01);切断两侧减压神经较切断两侧窦神经后减弱得更为明显,其中对于新福林升压时的心率减慢反应差异显著(P<(0.05)。相反,对于新福林和硝普钠引起的后肢血管阻力反射性变化,与缓冲神经部分切断之前相比无明显差异;在对照肾交感神经活动已增高的基础上,硝普钠降压时肾交感神经活动的反射性兴奋效应降低,而新福林升压时的肾交感神经活动反射性抑制效应与神经切断前相比无明显差异。(3) 缓冲神经全部切断(SAD)后,新福林和硝普钠引起的平均动脉血压(MAP)变动幅度显著增大(P<0.05)。此时心率、后肢血管阻力和肾交感神经活动的反射调节效应均明显减弱(P<0.001)。(4) 进一步切断两侧迷走神经后,残留的反射效应即行消失。 以上结果表明,颈动脉窦和主动脉弓压力感受器传入以单纯相加的方式对心率进行反射性调节,以主     

Baroreceptor influence on a spinal cardiovascular reflex

A stretch of the walls of the thoracic aorta, performed in vagotomized cats without obstructing aortic flow, induces increases in heart rate, myocardial contractility, and arterial pressure. These reflex responses are still present after high spinal section. Cats under chloralose-urethane anesthesia were vagotomized and one carotid sinus was isolated and perfused with arterial blood at constant flow. The contralateral carotid sinus nerve and both aortic nerves were sectioned. A stretch of the walls of the thoracic aorta between the 7th and 10th intercostal arteries induced a reflex increase in mean arterial pressure 29 +/- 2 mmHg (mean +/- SE). Stepwise increases of carotid sinus pressure (CSP) or electrical stimulation of the carotid sinus nerve induced stepwise decreases of this reflex response. At maximal baroreceptor stimulation (CSP 212 +/- 9 mmHg) the reflex response to aortic stretch was reduced by 42%. These experiments show that this spinal cardiovascular reflex is at least partially under the inhibitory control of the baroreceptor input.     

Sex differences in forebrain and cardiovagal responses at the onset of isometric handgrip exercise: a retrospective fMRI study.

In general, cardiac regulation is dominated by the sympathetic and parasympathetic nervous systems in men and women, respectively. Our recent study had revealed sex differences in the forebrain network associated with sympathoexcitatory response to baroreceptor unloading. The present study further examined the sex differences in forebrain modulation of cardiovagal response at the onset of isometric exercise. Forebrain activity in healthy men (n = 8) and women (n = 9) was measured using functional magnetic resonance imaging during 5 and 35% maximal voluntary contraction handgrip exercise. Heart rate (HR), mean arterial pressure (MAP), and muscle sympathetic nerve activity (MSNA) were collected in a separate recording session. During the exercise, HR and MAP increased progressively, while MSNA was suppressed (P < 0.05). Relative to men, women demonstrated smaller HR (8 +/- 2 vs. 18 +/- 3 beats/min) and MAP (3 +/- 2 vs. 11 +/- 2 mmHg) responses to the 35% maximal voluntary contraction trials (P < 0.05). Although a similar forebrain network was activated in both groups, the smaller cardiovascular response in women was reflected in a weaker insular cortex activation. Nevertheless, men did not show a stronger deactivation at the ventral medial prefrontal cortex, which has been associated with modulating cardiovagal activity. In contrast, the smaller cardiovascular response in women related to their stronger suppression of the dorsal anterior cingulate cortex activity, which has been associated with sympathetic control of the heart. Our findings revealed sex differences in both the physiological and forebrain responses to isometric exercise.     

Pyruvate potentiates inotropic effects of isoproterenol and Ca(2+) in rabbit cardiac muscle preparations

Catecholamines and elevated extracellular Ca(2+) concentration ([Ca(2+)](o)) augment contractile force by increased Ca(2+) influx and subsequent increased sarcoplasmic reticulum (SR) Ca(2+) release. We tested the hypothesis that pyruvate potentiates Ca(2+) release and inotropic response to isoproterenol and elevated [Ca(2+)](o), since this might be of potential importance in a clinical setting to circumvent deleterious effects on energy demand during application of catecholamines. Therefore, we investigated isometrically contracting myocardial preparations from rabbit hearts at 37 degrees C, pH 7.4, and a stimulation frequency of 1 Hz. At a [Ca(2+)](o) of 1.25 mM, pyruvate (10 mM) alone increased developed force (F(dev)) from 1.89 +/- 0.42 to 3.62 +/- 0.62 (SE) mN/mm(2) (n = 8, P < 0.05) and isoproterenol (10(-6) M) alone increased F(dev) from 2.06 +/- 0. 55 to 25.11 +/- 2.1 mN/mm(2) (P < 0.05), whereas the combination of isoproterenol and pyruvate increased F(dev) overproportionally from 1.89 +/- 0.42 to 33.31 +/- 3.18 mN/mm(2) (P < 0.05). In a separate series of experiments, we assessed SR Ca(2+) content by means of rapid cooling contractures and observed that, despite no further increase in F(dev) by increasing [Ca(2+)](o) from 8 to 16 mM, 10 mM pyruvate could still increase F(dev) from 26.4 +/- 6.8 to 29.7 +/- 7. 1 mN/mm(2) (P < 0.05, n = 9) as well as the Ca(2+) load of the SR. The results show that the positive inotropic effects of pyruvate potentiate the inotropic effects of isoproterenol or Ca(2+), because in the presence of pyruvate, Ca(2+) and isoproterenol induced larger increases in inotropy than can be calculated by mere addition of the individual effects.     

Bimodal effects of chronically administered neurokinin B (NKB) on in vivo and in vitro cardiovascular responses in female rats

The in vivo cardiovascular effects of acutely administered neurokinin B (NKB) have been attributed both to direct effects on vascular tone and to indirect effects on central neuroendocrine control of the circulation. We proposed: 1) that a modest long-term increase in plasma NKB levels would decrease mean arterial pressure (MAP) due to attenuated peripheral vascular tone, and 2) that chronic high-dose NKB would increase MAP, due to increased sympathetic outflow which would override the peripheral vasodilation. We examined the in vivo and in vitro cardiovascular effects of chronic peripheral NKB. Low- (1.8 nmol/h) or high- (20 nmol/h) dose NKB was infused into conscious female rats bearing telemetric pressure transducers. MAP, heart rate (HR) and the pressor responses to I.V. phenylephrine (PE, 8 microg) and angiotensin II (Ang II, 150 ng) were measured. Concentration-response curves of small mesenteric arteries were constructed to PE using wire myography. Low-dose NKB reduced basal MAP (88+/-2 mm Hg to 83+/-2 mm Hg), did not affect resting HR, reduced the pressor responses to PE, and attenuated the maximal constriction of mesenteric arteries to PE and KCl. By contrast, high-dose NKB increased basal MAP (86+/-1 mm Hg to 89+/-1 mm Hg), increased HR (350+/-3 beats/min to 371+/-3 beats/min), increased the pressor responses to Ang II and, contrary to our hypothesis, increased the maximum contractile responses of mesenteric arteries to PE and KCl. The cardiovascular effects of NKB are thus dose-dependent: whereas chronic low-dose NKB directly modulates vascular tone to reduce blood pressure, chronic high-dose NKB induces an increase in blood pressure through both central (indirect) and peripheral (direct) pathways.