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PubMed1990

Cardiac chemical reflex control of preload in conscious dogs.

The purpose of our study was to determine the effects of cardiac chemical reflexes on left ventricular (LV) preload in conscious dogs. Adult mongrel dogs were instrumented to measure LV pressure and, with ultrasonic dimension crystals, to measure LV internal diameter. A catheter was inserted in the left circumflex coronary artery for the administration of increasing doses of veratridine, arachidonic acid (AA), and prostacyclin (PGI2). LV end-diastolic diameter (EDD) and end-diastolic pressure (EDP) were used as indexes of preload. Veratridine (0.4 micrograms/kg) reduced EDD 3.0 +/- 0.5% from 36.6 +/- 1.7 mm and EDP 24 +/- 5.0% from 6.1 +/- 0.5 mmHg (P less than 0.05). AA (100 micrograms/kg) reduced EDD by 3.7 +/- 0.5% from 37 +/- 1.1 mm and EDP by 25 +/- 4.4% from 7.0 +/- 0.6 mmHg (P less than 0.05). PGI2 (0.5 micrograms/kg) also reduced EDD by 3.3 +/- 0.5% from 37 +/- 0.5 mm and EDP by 25 +/- 6.0% from 7.8 +/- 0.3 mmHg (P less than 0.05). Although holding heart rate constant by pacing or combined beta-adrenergic and muscarinic receptor blockades did not reduce the preload responses to veratridine, AA, or PGI2, alpha 1-adrenergic blockade or vagotomy abolished them. Systemic arterial barodenervation markedly potentiated the reduction in myocardial size after stimulation of cardiac chemical receptors. Stimulation of inhibitory cardiac receptors, therefore, reduces preload via a vagal reflex by withdrawing peripheral alpha-adrenergic tone to capacitance vessels in the conscious dog.

Animals↗

PubMed1991

Assessment of elastin and collagen contribution to aortic elasticity in conscious dogs.

The elastic behavior of total elastin (EE) and collagen (EC) and the recruitment of collagen fibers (FC) supporting wall stress at a given transmural pressure level were assessed in seven conscious dogs using descending thoracic aortic pressure (microtransducer) and diameter (sonomicrometer) measurements. Stress-strain relationships values calculated at control and during bolus administration of angiotensin and nitroglycerin enabled quantification of angiotensin and nitroglycerin enabled quantification of elastic moduli of elastin (EE = 4.868 +/- 1.753 x 10(6) dyn/cm2; means +/- SD) and collagen (EC = 1,306 +/- 637 x 10(6) dyn/cm2) according to a biphasic model of elastin and collagen parallel arrangement. The FC was found to be 6.1 +/- 2.6% at a pressure level of 118 +/- 16 mmHg. Values for EE and EC were similar to those reported in in vitro studies and showed scarce variability. This approach provides a quantitative evaluation of elastin and collagen moduli in conscious animals and also permits the evaluation of FC, which may be of interest in studies of connective tissue diseases involving the aortic wall.

Angiotensin II↗

PubMed1991

Effects of atrial natriuretic factor on blood flow distribution and vascular resistance in conscious dogs.

Systemic and regional hemodynamic responses to atrial natriuretic factor (ANF) administered by either bolus or infusion were examined in conscious dogs in the presence and absence of ganglionic blockade. In intact dogs, bolus injection of ANF (9 micrograms/kg), which increased plasma ANF by 100,913 +/- 12,330 pg/ml, initially reduced mean arterial pressure (7 +/- 1%) and total peripheral (-31 +/- 2%), coronary (-28 +/- 3%), mesenteric (-19 +/- 2%), renal (-36 +/- 2%), and iliac (-24 +/- 2%) vascular resistances. During the recovery period, resistance rose in the total peripheral (+13 +/- 3%), coronary (+19 +/- 5%), mesenteric (+7 +/- 2%), and iliac (+42 +/- 8%) beds but did not rise in the renal bed. At 15 min after infusion of ANF (0.3 micrograms.kg-1.min-1 x 30 min), which increased plasma ANF by 4,296 +/- 869 pg/ml, resistance rose in the total peripheral (+19 +/- 3%), coronary (+17 +/- 2%), mesenteric (+23 +/- 7%), and iliac (+40 +/- 11%) beds but remained slightly depressed in the renal bed (-8 +/- 5%). Ganglionic blockade with hexamethonium did not modify substantially the pattern of change of regional vascular resistances to ANF. Thus in conscious dogs, ANF under steady-state conditions was found to elicit direct vasoconstriction in most regional vascular beds and minor vasodilation in the renal vascular bed. However, after bolus administration of ANF, which results in extremely high plasma ANF levels, transient vasodilation occurs in all regional vascular beds. These data suggest that the distribution of ANF receptors, which elicit vasodilation, differs in regional vascular beds, and that in most vascular beds, except those of the kidney, these receptors require extremely high levels of ANF to be activated.

Animals↗

PubMed1991

Alterations in myocardial contractility in conscious dogs with dilated cardiomyopathy.

We investigated the changes in left ventricular (LV) geometry and myocardial contractility in eight conscious chronically instrumented dogs studied before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. Significant increases (P less than 0.01) were observed in cardiac dimensions in both the LV long and short axes and in end-diastolic volume (control: 53 +/- 1 ml; cardiomyopathy: 76 +/- 2 ml) and end-systolic volume (control: 27 +/- 2 ml; cardiomyopathy: 56 +/- 7 ml). This was associated with the left ventricle assuming a more spherical shape with LV long-to-short axis ratio falling from 1.59 +/- 0.05 to 1.47 +/- 0.04 (P less than 0.05). Both isovolumic (LV dP/dt) and ejection phase indexes (LV mean velocity of circumferential fiber shortening, corrected LV short-axis diameter at point of maximum shortening, and LV ejection fraction) were depressed by 50%. The end-systolic elastance was also depressed significantly (control: 16.6 +/- 0.7 g.cm-2.ml-1; cardiomyopathy: 10.1 +/- 1.7 g.cm-2.ml-1, P less than 0.02). However, cardiac output was maintained at 3 wk due to a compensatory tachycardia (+31 +/- 3 beats/min), plasma volume expansion (+295 +/- 68 ml, P less than 0.05), and greater reliance on the Frank-Starling mechanism. However, in an additional four dogs studied at 4-5 wk, cardiac output fell significantly (P less than 0.05). Thus rapid ventricular pacing results in dilated congestive cardiomyopathy in conscious dogs characterized by globally depressed myocardial systolic function and changes in LV shape.

Animals↗

PubMed1997

Role of spinal NMDA and AMPA receptors in episodic hypertension in conscious spinal rats.

The neurotransmitters mediating the spinal sympathetic reflexes that initiate episodic hypertension after spinal cord injury are unknown. We examined the role of glutamatergic transmission in these reflexes by testing effects of the N-methyl-D-aspartate (NMDA)-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) and of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinone (NBQX) on the reflex hypertension caused by colon distension. Antagonists were administered intrathecally in conscious rats 1-2 days (acute, n = 10) or 15-16 days (chronic, n = 14) after cord transection at the fifth thoracic segment under barbiturate anesthesia. AP-5 blocked pressor responses to intrathecal NMDA but had no effect on responses to AMPA; similarly, NBQX blocked responses to AMPA but had no effect on responses to NMDA. Before antagonist injection, colon distension increased mean arterial pressure by 24 +/- 1 mmHg (from 100 +/- 3 mmHg) and by 37 +/- 2 mmHg (from 116 +/- 3 mmHg) in the acute and chronic groups, respectively. Pretreatment with AP-5 attenuated the pressor responses by 36 and 37% in these respective groups; pretreatment with NBQX attenuated them by 34 and 31%. These data suggest that both NMDA and AMPA receptors contribute to spinal viscerosympathetic transmission and initiation of episodic hypertension in conscious spinal rats.

2-Amino-5-phosphonovalerate↗

PubMed1997

Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits.

We tested the hypothesis that late preconditioning (PC) against myocardial infarction is triggered by the formation of nitric oxide (NO). Conscious rabbits underwent a 30-min coronary occlusion followed by 3 days of reperfusion. In group I (control group, n = 10), rabbits were not preconditioned, whereas in group II (n = 10), they were preconditioned 24 h earlier with a sequence of six 4-min occlusion/4-min reperfusion cycles. Myocardial infarct size (tetrazolium staining) was reduced by 50% by PC (28.6 +/- 3.2% of the risk region in group II vs. 56.9 +/- 5.9% in controls, P < 0.05). This reduction in cell death was associated with improved recovery of myocardial function [systolic thickening fraction (by sonomicrometry) at 3 days: 2.0 +/- 11.0% of baseline in group II vs. -20.0 +/- 2.8% in group I, P < 0.05]. Group III rabbits (n = 11) underwent the same protocol as group II except that the rabbits received the NO synthase inhibitor N omega-nitro-L-arginine (L-NNA, 13 mg/kg) before the PC ischemia. In these animals, infarct size did not differ significantly from that observed in control rabbits, indicating that L-NNA completely blocked the development of late PC against myocardial infarction. In group IV (n = 9), rabbits received L-NNA as in group III, but without the six occlusion-reperfusion cycles, and were subjected to the 30-min occlusion 24 h later. In this group, infarct size did not differ from that observed in controls, demonstrating that pretreatment with L-NNA, in itself, did not affect the extent of cell death. Taken together, these results indicate that, in the conscious rabbit, the development of late PC against myocardial infarction is triggered by the generation of NO during the PC ischemia. It is proposed that NO plays a key role in the delayed myocardial adaptation to ischemic stress.

Animals↗

PubMed1999

PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits.

Using conscious rabbits, we examined the effect of ischemic preconditioning (PC) on p44 and p42 mitogen-activated protein kinases (MAPKs). We found that both isoforms contribute significantly to total MAPK activity in the heart (in-gel kinase assay: p44, 59 +/- 1%; p42, 41 +/- 1%). Ischemic PC (6 cycles of 4-min occlusion/4-min reperfusion) elicited a pronounced increase in total cellular MAPK activity (+89%). This increase, which occurred exclusively in the nuclear fraction, was contributed by both isoforms (in-gel kinase assay: p44, +97%; p42, +210%) and was accompanied by migration of the two proteins from the cytosolic to the nuclear compartment. In control rabbits, MAPK kinase (MEK)1 and MEK2, direct activators of p44 and p42 MAPKs, were located almost exclusively in the cytosolic fraction. Ischemic PC induced a marked increase in cytosolic MEK activity (+164%), whereas nuclear MEK activity did not change, indicating that MEK-induced activation of MAPKs occurred in the cytosolic compartment. Activation of MAPKs after ischemic PC was completely blocked by the protein kinase C (PKC) inhibitor chelerythrine. Selective overexpression of PKC-epsilon in adult rabbit cardiomyocytes induced activation of both p44 and p42 MAPKs and reduced lactate dehydrogenase release during simulated ischemia-reperfusion, which was abolished by the MEK inhibitor PD-98059. The results demonstrate that 1) ischemic PC induces a rapid activation of p44 and p42 MAPKs in hearts of conscious rabbits; 2) the mechanism of this phenomenon involves activation of p44 and p42 MAPKs in the cytosol and their subsequent translocation to the nucleus; and 3) it occurs via a PKC-mediated signaling pathway. The in vitro data implicate PKC-epsilon as the specific isoform responsible for PKC-induced MAPK activation and suggest that p44/p42 MAPKs contribute to PKC-epsilon-mediated protection against simulated ischemia. The results are compatible with the hypothesis that p44 and p42 MAPKs may play a role in myocardial adaptations to ischemic stress.

Alkaloids↗

PubMed1999

Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure.

The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/dt), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 micrograms . kg-1. min-1 iv) increased LV dP/dt by 1,854 +/- 157 from 2,701 +/- 105 mmHg/s (P < 0.05) before HF. After HF the increase in LV dP/dt in response to milrinone was attenuated significantly (P < 0.05); it increased by 615 +/- 67 from 1,550 +/- 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/dt (+445 +/- 65 mmHg/s) in response to milrinone were markedly less (P < 0.01), and milrinone increased LV dP/dt even less in HF (+240 +/- 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly (P < 0.05) in LV endocardium (-26%) but not significantly in LV epicardium (-14%). PDE activity was also decreased significantly (P < 0.05) in LV endocardium (-18%) but not in LV epicardium (-4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.

Animals↗

PubMed1999

Nitric oxide donors attenuate myocardial stunning in conscious rabbits.

Although previous studies suggested that the protection of late preconditioning (PC) against myocardial stunning is mediated by nitric oxide (NO), direct evidence that exogenous administration of NO attenuates myocardial stunning is lacking. Furthermore, although exogenous NO administration was shown to elicit a late PC phase, it is unknown whether NO donors also induce an early PC phase. Therefore, conscious rabbits underwent two experimental stages (3 days of six 4-min occlusion/4-min reperfusion cycles each) 2 wk apart. In study I, both stages were control stages (n = 7). In studies II and III, stage I was the control stage. On day 1 of stage II, seven rabbits received infusion of nitroglycerin (NTG; 2 microg. kg(-1). min(-1) iv) during the ischemia-reperfusion sequence, starting 30 min before the 1st occlusion and ending 10 min after the 6th reperfusion (study II). Another seven rabbits received infusion of NTG (2 microg. kg(-1). min(-1) iv) for 1 h followed by a 30-min washout interval and then underwent six 4-min occlusion/4-min reperfusion cycles (study III). In the control stage of all three studies, recovery of wall thickening (WTh) after occlusion/reperfusion cycles was markedly enhanced on days 2 and 3 compared with day 1, indicating late PC. In study II, infusion of NTG during the occlusion/reperfusion cycles on day 1 resulted in significant and sustained enhancement in WTh recovery. A similar attenuation of stunning was observed in study IV in six rabbits given intravenous infusion of S-nitroso-N-acetylpenicillamine (SNAP) during occlusion/reperfusion cycles. The magnitude of the protection afforded by NTG and SNAP was comparable to that afforded by the late ischemic PC phase. In contrast, in study III infusion of NTG before occlusion/reperfusion cycles did not enhance WTh recovery, indicating that NTG failed to induce an early PC effect against stunning. This study demonstrates that administration of hemodynamically inactive doses of two unrelated NO donors alleviates myocardial stunning in conscious rabbits, providing direct evidence for a protective action of NO in this setting.

Analysis of Variance↗

PubMed2000

Biphasic response of cardiac NO synthase isoforms to ischemic preconditioning in conscious rabbits.

In conscious rabbits, a sequence of six 4-min coronary occlusion/4-min reperfusion cycles, which elicits late preconditioning (PC), caused rapid activation of calcium-dependent nitric oxide (NO) synthase (NOS) [cNOS; endothelial NOS (eNOS) and/or neuronal NOS (nNOS)], whereas calcium-independent NOS [inducible NOS (iNOS)] activity remained unchanged. The enhanced cNOS activity was associated with increased myocardial levels of NO(2) and/or NO(3) (NO(x)). Twenty-four hours after ischemic PC was induced, the opposite pattern was observed, i.e., there was a pronounced increase in cytosolic iNOS activity but no change in cNOS activity. The initial burst of ischemia-induced cNOS activity was not affected by pretreatment with the antioxidant N-2-mercaptopropionyl glycine (MPG), the protein kinase C (PKC) inhibitor chelerythrine, or the tyrosine kinase inhibitor lavendustin A, indicating that it is independent of the generation of oxidant species and the activation of PKC and tyrosine kinases. In contrast, the delayed upregulation of iNOS 24 h after PC was prevented by pretreatment with N(omega)-nitro-L-arginine, MPG, or chelerythrine before the PC ischemia, indicating that it is triggered by a signaling mechanism that involves the generation of NO, the formation of oxidant species, and the activation of PKC. Taken together, these results demonstrate that, in conscious animals, ischemic PC elicits a biphasic response in cardiac NOS activity, i. e., an immediate activation of cNOS (most likely eNOS) followed 24 h later by a delayed upregulation of iNOS. To our knowledge, this is the first study to directly measure NOS activity after brief myocardial ischemia in vivo. In conjunction with previous functional studies, the data support a distinctive role of NOS isoforms in late PC, with eNOS serving as the trigger on day 1 and iNOS as the mediator on day 2.

Animals↗

PubMed2000

Late preconditioning enhances recovery of myocardial function after infarction in conscious rabbits.

It is unknown whether late preconditioning (PC) enhances the recovery of left ventricular (LV) function after a myocardial infarction. Thus 25 conscious rabbits were subjected to a 30-min coronary occlusion followed by 28 days of reperfusion after PC 24 h earlier with either ischemia or nitric oxide donor administration [S-nitroso-N-acetylpenicillamine (SNAP)]. The recovery of wall thickening (WTh) after reperfusion was significantly improved in the ischemic PC and SNAP PC groups compared with controls, both at rest and during dobutamine stress. Interestingly, neither ischemia- nor SNAP-induced late PC attenuated myocardial stunning from day 1 through day 14. Infarct size was smaller in the ischemic PC and SNAP PC groups compared with controls. In all groups, WTh at 28 days was positively and linearly related to the percentage of viable tissue in the region underlying the ultrasonic crystal (r = 0.90), indicating that the improvement in LV function after both ischemia-induced and NO donor-induced late PC can be fully explained by the reduction in infarct size; a separate effect of late PC on LV remodeling or LV contractility need not be invoked. In conclusion, in conscious rabbits late PC, induced either by ischemia or pharmacologically, not only limits infarct size but also enhances the recovery of LV function after myocardial infarction. This finding has important clinical implications and provides triphenyltetrazolium chloride-independent evidence that late PC limits myocellular death after sustained ischemia.

Animals↗

PubMed2002

Oxidant species trigger late preconditioning against myocardial stunning in conscious rabbits.

Conscious rabbits underwent six 4-min occlusion and 4-min reperfusion cycles for 3 consecutive days (day 1, 2, and 3); on day 1, rabbits received intravenous vehicle [preconditioning (PC)] (group I, n = 6), superoxide dismutase (SOD; group II, n = 5), catalase (group III, n = 6), or the hydroxyl radical (. OH) and peroxynitrite (ONOO-)) scavenger N-2-mercaptopropionyl glycine (MPG [group IV], n = 6). In the PC group, the recovery of systolic wall thickening (WTh) after the sixth reperfusion was markedly improved on days 2 and 3 compared with day 1 and the total deficit of WTh was correspondingly reduced, indicating a late PC effect against myocardial stunning. Neither SOD nor catalase had any significant effect on the severity of stunning on day 1 or on the development of late PC on days 2 and 3, despite high plasma levels. In contrast, MPG markedly attenuated the severity of stunning on day 1 and prevented the development of late PC on day 2. Two additional groups of rabbits received an intracoronary infusion of vehicle (group V, n = 4) or the reactive oxygen species (ROS) generating solution [cumene hydroperoxide (CuOOH, group VI, n = 7)] on day 0, and were then subjected to the six occlusion/reperfusion cycles on days 1, 2, and 3. In group VI, infusion of CuOOH elicited a late PC effect 24 h later (on day 1). Taken together, these results demonstrate that oxidant species play an essential role in triggering the development of late PC against stunning in conscious rabbits. The fact that late PC was blocked by MPG and mimicked by CuOOH implicate ONOO- and/or .OH as the oxygen species responsible for the initiation of this phenomenon. In addition, the finding that exogenous ROS (CuOOH) reproduced the phenotype of late PC indicates that ROS are not only necessary but also sufficient to trigger this defensive adaptation of the heart to stress.

Animals↗

PubMed2002

Continual recordings of cardiac sympathetic nerve activity in conscious sheep.

Cardiac sympathetic nerve activity (CSNA) is of major importance in the etiology of heart disease but is impossible to measure directly in humans. Ovine and human cardiovascular systems are similar; therefore, we have developed a method for the daily recording of CSNA in conscious sheep. After thoracotomy, electrodes were glued into the left thoracic cardiac nerve and CSNA, blood pressure (BP), and heart rate were recorded daily. Satisfactory recordings > or =7 days of CSNA were obtained in 11 of 28 sheep (40%), mean recording time 10.6 days, range 7-47. During the first week, CSNA decreased gradually from 78 +/- 8 at baseline to 60 +/- 7 bursts/min on day 5 (P = 0.02) or from 76 +/- 9 to 57 +/- 7 bursts/100 beats on day 7 (P = 0.04). Similarly, BP decreased from 103 +/- 4 to 94 +/- 4 mmHg (P = 0.03). Low-frequency heart rate variability decreased from 0.12 +/- 0.02 to 0.06 +/- 0.02 ms(2) on day 6 (P = 0.004) but was not correlated to CSNA. In conclusion, CSNA that can be continually recorded in conscious sheep decreases during the first week postsurgery and, thereafter, stabilizes. This model should provide valuable insights in future investigations of cardiac disease.

Animals↗

PubMed2006

Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep.

After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml x kg(-1) x min(-1)) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 microg/min but not 20 or 2.0 microg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 +/- 3.2 vs. 13.9 +/- 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 microg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 +/- 1.5 vs. 13.9 +/- 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 microg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated mu-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase.

Acute Disease↗

PubMed2007

Hemodynamic responses and c-Fos changes associated with hypotensive hemorrhage: standardizing a protocol for severe hemorrhage in conscious rats.

The central mechanisms underlying the transition from compensation to decompensation during severe hemorrhage (HEM) are poorly understood. Furthermore, a lack of consistency in HEM protocols exists in the current literature. This study assessed the cardiovascular response and Fos-like immunoreactivity (FLI) in specific brain regions following severe HEM at three rates (2, 1, or 0.5 ml.kg(-1).min(-1)) in conscious rats. Heart rate (HR) and arterial pressure were recorded during the withdrawal of 30% of total blood volume (TBV). Data from animals hemorrhaged at the fast (F-HEM, n = 6), intermediate (I-HEM, n = 7), or slow (S-HEM, n = 7) rates were compared with saline (SAL, n = 5) and hypotensive (hydrazaline-induced, HYDRAZ, n = 5) controls. All HEM rates produced similar degrees of hypotension at the time of 30% TBV withdrawal. All HEM rates also produced bradycardia, but the change in HR was only significant in the F-HEM and I-HEM groups. Associated with I-HEM and F-HEM, but not HYDRAZ treatment were significant increases in FLI in the caudal ventrolateral periaqueductal gray (PAG), the central lateral nucleus of the rostral parabrachial nucleus, and locus coeruleus compared with SAL treatment. I-HEM also induced significant increases in FLI in the dorsomedial PAG, A7 region, and the cuneiform nucleus compared with SAL. S-HEM did not induce any significant change in FLI. Our results suggest that HEM at a rate of 1 ml.kg(-1).min(-1) may be most useful for investigating the potential role of the rostral brainstem regions in mediating hemorrhagic decompensation in conscious rats.

Animals↗

PubMed2002

Glutamate receptors in RVLM modulate sympathetic baroreflex in conscious rabbits.

In this study, we examined the effect of excitatory amino acid (EAA) receptor blockade in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex in conscious rabbits. Rabbits were implanted with guide cannulas for bilateral microinjections into the RVLM (+2 to +3 mm from the obex, n = 8) or into the intermediate ventrolateral medulla (IVLM; 0 to +1 mm from the obex, n = 5) and with an electrode for measuring renal sympathetic nerve activity (RSNA). After 7 days of recovery, microinjection of the EAA receptor antagonist kynurenate (10 nmol) into the RVLM did not affect resting RSNA or arterial pressure. Kynurenate decreased the gain of the RSNA baroreflex by 53% but did not change the reflex range. By contrast, injection of kynurenate into the IVLM increased resting arterial pressure and RSNA by 27 mmHg and 88%, respectively, but did not alter the RSNA baroreflex gain or range. Pentobarbital sodium anesthesia attenuated the gain and range of the RSNA baroreflex by 78 and 40%, respectively. Under these conditions, microinjection of kynurenate into the RVLM did not cause any further change in the gain of this reflex. These results suggest that endogenous EAA neurotransmitters in the RVLM are important in modulating the sympathetic baroreflex in conscious rabbits. Anesthesia can mask the functional significance of EAAs in the RVLM in modulating the baroreflexes, which may explain why previous studies in anesthetized animals found no effect of blocking EAA receptors in the RVLM on sympathetic baroreflexes.

Animals↗

PubMed2005

Neuronal activity within the ventrolateral periaqueductal gray during simulated hemorrhage in conscious rabbits.

The ventrolateral (vl) periaqueductal gray (PAG) has been proposed as a site responsible for the active process triggering the onset of hypotension (i.e., phase 2) during blood loss in conscious animals (Cavun S and Millington WR. Am J Physiol Regul Integr Comp Physiol 281: R747-R752, 2001). We recorded the extracellular activity of PAG neurons in conscious rabbits to test the hypothesis that vlPAG neurons change their firing frequency before the onset of hypotension during simulated hemorrhage. Arterial and venous catheters, an intrathoracic vena caval occluder, and midbrain microelectrodes on a microdrive were implanted in 10 rabbits. During simulated hemorrhage, the occluder was inflated until arterial pressure < or = 40 mmHg. We compared changes in neuronal activity during simulated hemorrhage with those during a similar length control period for 64 vlPAG and 29 dorsolateral (dl) PAG neurons. Arterial pressure pulse modulation of neuronal activity was present in 45 and 76% of vlPAG and dlPAG neurons, respectively. When we evaluated the absolute change in activity, thus accounting for both increases and decreases, simulated hemorrhage had a significant effect on activity of vlPAG but not dlPAG neurons. The majority (56%) of vlPAG neurons did not appear to respond to simulated hemorrhage. Of the 28 responsive vlPAG neurons, 11 showed an abrupt change in firing frequency during the time interval preceding the onset of hypotension; 13 responded after the onset of hypotension; and 4 showed a consistent direction of change across the entire simulated hemorrhage. Thus 24 (38%) of the vlPAG neurons recorded responded at a time consistent with a contribution to the hypotension associated with simulated hemorrhage.

Action Potentials↗

PubMed2002

Baroreflex stabilization of the double (pressure-rate) product at 0.05 Hz in conscious rabbits.

The product of heart rate (HR) and systolic blood pressure (SBP), the double product (DP), is an indirect index of cardiac oxygen consumption. We used spectral analysis to test the hypothesis that baroreflex adjustments of HR stabilize the DP during spontaneous variations in SBP. SBP and HR were recorded by telemetry in five male conscious rabbits. HR and SBP power spectra each exhibited a low frequency peak at approximately 0.05 Hz that was associated with high (>0.5) spectral coherence and a positive phase relationship between SBP and HR (SBP leading). A prominent peak was absent in the spectra of their product, suggesting that SBP and HR interacted to reduce DP variability in this frequency region. In contrast, a prominent 0.05-Hz peak was present in the power spectrum of calculated surrogates of the DP in which reflex interactions between HR and SBP had been removed. Our results suggest that baroreflex adjustments of HR stabilize the DP during spontaneous low-frequency variations in SBP in conscious rabbits.

Animals↗