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PubMed1998

Functional interaction of human immunodeficiency virus type 1 Vpu and Gag with a novel member of the tetratricopeptide repeat protein family.

Viral protein U (Vpu) is a protein encoded by human immunodeficiency virus type 1 (HIV-1) that promotes the degradation of the virus receptor, CD4, and enhances the release of virus particles from cells. We isolated a cDNA that encodes a novel cellular protein that interacts with Vpu in vitro, in vivo, and in yeast cells. This Vpu-binding protein (UBP) has a molecular mass of 41 kDa and is expressed ubiquitously in human tissues at the RNA level. UBP is a novel member of the tetratricopeptide repeat (TPR) protein family containing four copies of the 34-amino-acid TPR motif. Other proteins that contain TPR motifs include members of the immunophilin superfamily, organelle-targeting proteins, and a protein phosphatase. UBP also interacts directly with HIV-1 Gag protein, the principal structural component of the viral capsid. However, when Vpu and Gag are coexpressed, stable interaction between UBP and Gag is diminished. Furthermore, overexpression of UBP in virus-producing cells resulted in a significant reduction in HIV-1 virion release. Taken together, these data indicate that UBP plays a role in Vpu-mediated enhancement of particle release.

Amino Acid Sequence↗

PubMed2006

Interactions of Brf1 peptides with the tetratricopeptide repeat-containing subunit of TFIIIC inhibit and promote preinitiation complex assembly.

The binding of Brf1 to the tetratricopeptide repeat (TPR)-containing transcription factor IIIC (TFIIIC) subunit (Tfc4) represents a rate-limiting step in the ordered assembly of the RNA polymerase III initiation factor TFIIIB. Tfc4 contains multiple binding sites for Brf1 within its amino terminus and adjacent TPR arrays, but the access of Brf1 to these sites is limited by autoinhibition. Moreover, the Brf1 binding sites in Tfc4 overlap with sites important for the subsequent recruitment of another TFIIIB subunit, Bdp1, implying that repositioning of Brf1 is required after its initial interaction with Tfc4. As a starting point for dissecting the steps in TFIIIC-directed assembly of TFIIIB, we conducted yeast two-hybrid screens of Brf1 peptide libraries against different TPR-containing Tfc4 fragments. Short, biochemically active peptides were identified in three distinct regions of Brf1. Two peptides defined conserved but distal regions of Brf1 that participate in stable binding of Brf1 to TFIIIC-DNA. Remarkably, a third peptide that binds specifically to TPR6-9 of Tfc4 was found to promote the formation of both TFIIIC-DNA and Brf1-TFIIIC-DNA complexes and to reduce the mobility of these complexes in native gels. The data are consistent with this peptide causing a conformational change in TFIIIC that overcomes Tfc4 autoinhibition of Brf1 binding and suggest a structural model for the Brf1-Tfc4 interaction.

Amino Acid Sequence↗

PubMed1996

Mutational analysis of the hsp70-interacting protein Hip.

The hsp70-interacting protein Hip participates in the assembly pathway for progesterone receptor complexes. During assembly, Hip appears at early assembly stages in a transient manner that parallels hsp70 interactions. In this study, a cDNA for human Hip was used to develop various mutant Hip forms in the initial mapping of functions to particular Hip structural elements. Hip regions targeted for deletion and/or truncation included the C-terminal region (which has some limited homology with Saccharomyces cerevisiae Sti1 and its vertebrate homolog p60), a glycine-glycine-methionine-proline (GGMP) tandem repeat, and a tetratricopeptide repeat (TPR). Binding of Hip to hsp70's ATPase domain was lost with deletions from the TPR and from an adjoining highly charged region; correspondingly, these Hip mutant forms were not recovered in receptor complexes. Truncation of Hip's Sti1-related C terminus resulted in Hip binding to hsp70 in a manner suggestive of a misfolded peptide substrate; this hsp70 binding was localized to the GGMP tandem repeat. Mutants lacking either the C terminus or the GGMP tandem repeat were still recovered in receptor complexes. Truncations from Hip's N terminus resulted in an apparent loss of Hip homo-oligomerization, but these mutants retained association with hsp70 and were recovered in receptor complexes. This mutational analysis indicates that Hip's TPR is required for binding of Hip with hsp70's ATPase domain. In addition, some data suggest that hsp70's peptide-binding domain may alternately or concomitantly bind to Hip's GGMP repeat in a manner regulated by Sti1-related sequences.

Amino Acid Sequence↗

PubMed1996

Interaction of the interferon-induced PKR protein kinase with inhibitory proteins P58IPK and vaccinia virus K3L is mediated by unique domains: implications for kinase regulation.

Expression of the double-stranded RNA-activated protein kinase (PKR) is induced by interferons, with PKR activity playing a pivotal role in establishing the interferon-induced antiviral and antiproliferative states. PKR is directly regulated by physical association with the specific inhibitor, P58IPK, a cellular protein of the tetratricopeptide repeat (TPR) family, and K3L, the product of the corresponding vaccinia virus gene. P58IPK and K3L repress PKR activation and activity. To investigate the mechanism of P58IPK- and K3L-mediated PKR inhibition, we have used a combination of in vitro and in vivo binding assays to identify the interactive regions of these proteins. The P58IPK-interacting site of PKR was mapped to a 52-amino-acid aa segment (aa 244 to 296) spanning the ATP-binding region of the protein kinase catalytic domain. The interaction with PKR did not require the C-terminal DNA-J homology region of P58IPK but was dependent on the presence of the eukaryotic initiation factor 2-alpha homology region, mapping to the 34 aa within the sixth P58IPK TPR motif. Consistent with other TPR proteins, P58IPK formed multimers in vivo: the N-terminal 166 aa were both necessary and sufficient for complex formation. A parallel in vivo analysis to map the K3L-binding region of PKR revealed that like P58IPK , K3L interacted exclusively with the PKR protein kinase catalytic domain. In contrast, however, the K3L-binding region of PKR was localized to within aa 367 to 551, demonstrating that each inhibitor bound PKR in unique, nonoverlapping domains. These data, taken together, suggest that P58IPK and K3L may mediate PKR inhibition by distinct mechanisms. Finally, we will propose a model of PKR inhibition in which P58IPK or a P58IPK complex binds PKR and interferes with nucleotide binding and autoregulation, while formation of a PKR-K3L complex interferes with active-site function and/or substrate association.

Base Sequence↗

PubMed1997

A tetratricopeptide repeat mutation in yeast transcription factor IIIC131 (TFIIIC131) facilitates recruitment of TFIIB-related factor TFIIIB70.

Transcription factor IIIC (TFIIIC) plays an important role in assembling the initiation factor TFIIIB on genes transcribed by RNA polymerase III (Pol III). In Saccharomyces cerevisiae, assembly of the TFIIIB complex by promoter-bound TFIIIC is thought to be initiated by its tetratricopeptide repeat (TPR)-containing subunit, TFIIIC131, which interacts directly with the TFIIB-related factor, TFIIIB70/Brf1. In this work, we have identified 10 dominant mutations in TFIIIC131 that increase Pol III gene transcription. All of these mutations are found within a discrete 53-amino-acid region of the protein encompassing TPR2. Biochemical studies of one of the mutations (PCF1-2) show that the increase in transcription is due to an increase in the recruitment of TFIIIB70 to TFIIC-DNA. The PCF1-2 mutation does not affect the affinity of TFIIIC for DNA, and the differential in both transcription and TFIIIB complex assembly is observed at saturating levels of TFIIIB70. This indicates that mutant and wild-type TFIIIC-DNA complexes have the same affinity for TFIIIB70 and suggests that the increased recruitment of this factor is achieved by a nonequilibrium binding mechanism. A novel mechanism of activation in which the TPR mutations facilitate a conformational change in TFIIIC that is required for TFIIIB70 binding is proposed. The implications of this model for the regulation of processes involving TPR proteins are discussed.

Amino Acid Sequence↗

PubMed1997

Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.

The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.

Anaplastic Lymphoma Kinase↗

PubMed2001

Hsp104 interacts with Hsp90 cochaperones in respiring yeast.

The highly abundant molecular chaperone Hsp90 functions with assistance from auxiliary factors, collectively referred to as Hsp90 cochaperones, and the Hsp70 system. Hsp104, a molecular chaperone required for stress tolerance and for maintenance of [psi(+)] prions in the budding yeast Saccharomyces cerevisiae, appears to collaborate only with the Hsp70 system. We now report that several cochaperones previously thought to be dedicated to Hsp90 are shared with Hsp104. We show that the Hsp90 cochaperones Sti1, Cpr7, and Cns1, which utilize tetratricopeptide repeat (TPR) domains to interact with a common surface on Hsp90, form complexes with Hsp104 in vivo and that Sti1 and Cpr7 interact with Hsp104 directly in vitro. The interaction is Hsp90 independent, as further emphasized by the fact that two distinct TPR domains of Sti1 are required for binding Hsp90 and Hsp104. In a striking parallel to the sequence requirements of Hsp90 for binding TPR proteins, binding of Sti1 to Hsp104 requires a related acidic sequence at the C-terminal tail of Hsp104. While Hsp90 efficiently sequesters the cochaperones during fermentative growth, respiratory conditions induce the interaction of a fraction of Hsp90 cochaperones with Hsp104. This suggests that cochaperone sharing may favor adaptation to altered metabolic conditions.

Amino Acid Sequence↗

PubMed2002

A gain-of-function mutation in the second tetratricopeptide repeat of TFIIIC131 relieves autoinhibition of Brf1 binding.

The interaction between the tetratricopeptide repeat (TPR)-containing subunit of TFIIIC, TFIIIC131, and the TFIIB-related factor Brf1 represents a limiting step in the assembly of the RNA polymerase III (pol III) initiation factor TFIIIB. This assembly reaction is facilitated by dominant mutations that map in and around TPR2. Structural modeling of TPR1 to TPR3 from TFIIIC131 shows that one such mutation, PCF1-2, alters a residue in the ligand-binding groove of the TPR superhelix whereas another mutation, PCF1-1, changes a surface-accessible residue on the back side of the TPR superhelix. In this work, we show that the PCF1-1 mutation (H190Y) increases the binding affinity for Brf1, but does not affect the binding affinity for Bdp1, in the TFIIIC-dependent assembly of TFIIIB. Interestingly, binding studies with TFIIIC131 fragments indicate that Brf1 does not interact directly at the site of the PCF1-1 mutation. Rather, the data suggest that the mutation overcomes the previously documented autoinhibition of Brf1 binding. These findings together with the results from site-directed mutagenesis support the hypothesis that gain-of-function mutations at amino acid 190 in TPR2 stabilize an alternative conformation of TFIIIC131 that promotes its interaction with Brf1.

Amino Acid Substitution↗

PubMed2004

Propagation of Saccharomyces cerevisiae [PSI+] prion is impaired by factors that regulate Hsp70 substrate binding.

The Saccharomyces cerevisiae [PSI(+)] prion is believed to be a self-propagating cytoplasmic amyloid. Earlier characterization of HSP70 (SSA1) mutations suggested that [PSI(+)] propagation is impaired by alterations that enhance Ssa1p's substrate binding. This impairment is overcome by second-site mutations in Ssa1p's conserved C-terminal motif (GPTVEEVD), which mediates interactions with tetratricopeptide repeat (TPR) cochaperones. Sti1p, a TPR cochaperone homolog of mammalian Hop1 (Hsp70/90 organizing protein), activates Ssa1p ATPase, which promotes substrate binding by Ssa1p. Here we find that in SSA1-21 cells depletion of Sti1p improved [PSI(+)] propagation, while excess Sti1p weakened it. In contrast, depletion of Fes1p, a nucleotide exchange factor for Ssa1p that facilitates substrate release, weakened [PSI(+)] propagation, while overproducing Fes1p improved it. Therefore, alterations of Hsp70 cochaperones that promote or prolong Hsp70 substrate binding impair [PSI(+)] propagation. We also find that the GPTVEEVD motif is important for physical interaction with Hsp40 (Ydj1p), another Hsp70 cochaperone that promotes substrate binding but is dispensable for viability. We further find that depleting Cpr7p, an Hsp90 TPR cochaperone and CyP-40 cyclophilin homolog, improved [PSI(+)] propagation in SSA1 mutants. Although Cpr7p and Sti1p are Hsp90 cochaperones, we provide evidence that Hsp90 is not involved in [PSI(+)] propagation, suggesting that Sti1p and Cpr7p functionally interact with Hsp70 independently of Hsp90.

Adenosine Triphosphatases↗

PubMed1982

Vascular reactivity during the development of two-kidney, one-clip Goldblatt hypertension in conscious dogs.

This study evaluates the sequential changes in vascular reactivity in conscious dogs during the early and late phases of two-kidney, one-clip Goldblatt hypertension (2-KGH) produced by unilateral renal artery constriction (URAC). The in vivo responses to serotonin (5-HT), norepinephrine (NE), angiotensin II (Ang II), prostacyclin (PGI2), acetylcholine (ACH), and nitroglycerin (GTN) were reproducible and stable throughout the 32-day period of study in dogs subjected to sham URAC. The vascular responses to 5-HT, Ang II, and PGI2 were enhanced day 1 post-URAC, before mean arterial pressure (MAP), cardiac output (CO), or total peripheral resistance (TPR) increased. The magnitude of the enhanced reactivity progressed on days 4 and 32 post-URAC, as hypertension developed. The pressor responses to NE did not change from pre-URAC values until CO and MAP were elevated. The vasodepressor responses to ACH and GTN diminished over a 12-day period post-URAC, in parallel with the change in CO, but prior to any increase in TPR. These data suggest that in dogs with 2-KGH changes in vascular reactivity precede the development of the increased MAP and TPR of hypertension. The lack of uniformity of the onset of the reactivity changes to the different agonists suggests that both intrinsic factors and pressure changes modify the vascular wall in the early and later stages of 2-KGH.

Angiotensin II↗

PubMed1987

Comparative effects of rauwolscine, prazosin, and phentolamine on blood pressure and cardiac output in anesthetized rats.

The endogenous role of the alpha-adrenergic system in the maintenance of mean arterial pressure (MAP), total peripheral resistance (TPR), cardiac output (CO) and its distribution, and plasma norepinephrine and epinephrine release was investigated by the administration of selective alpha-adrenoceptor antagonists to halothane-anesthetized rats. The blockade of alpha 1-, alpha 2-, and both alpha 1- and alpha 2-receptors was accomplished by i.v. infusions of prazosin, rauwolscine, and phentolamine, respectively. The microsphere technique was used for the determination of CO and its distribution. Since the infusions of the three antagonists caused similar decreases of MAP and heart rate, the results suggest that postjunctional alpha 1- and alpha 2-receptors are both important in the control of MAP. During the infusion of prazosin, TPR was decreased but CO was not changed. In contrast, CO was decreased but TPR was not changed during the infusions of rauwolscine and phentolamine. Thus, CO was reduced after the blockade of alpha 2- but not alpha 1-receptors. All three antagonists caused an increase in percent distribution of CO to the lungs and muscle, suggesting that the sympathetic nervous system plays the greatest vasoconstrictor influence in the lungs and muscle via stimulations of both subtypes of alpha-adrenoceptors. The administration of either prazosin or rauwolscine caused little change in plasma catecholamine levels. In contrast, phentolamine caused large increases in both epinephrine and norepinephrine levels. Therefore catecholamine release was only increased after concurrent blockade of both alpha 1- and alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1980

Comparison of sodium salicylate, morphine sulfate, and acupuncture at Jen-Chung (Go-26) on the cardiovascular system of dogs.

The cardiovascular effects of the administration of sodium salicylate (100 mg/kg), the administration of morphine sulfate (0.5 mg/kg) and acupuncture by electrocautery at Jen-Chung (Go-26) were compared in groups of dogs under 0.75% halothane anesthesia. Cardiac output (CO), stroke volume (SV), heart rate (HR), mean arterial pressure (MAP), pulse pressure (PP), central venous pressure (CVP), total peripheral resistance (TPR), pH, PaCO2, PaO2 and base deficit were measured over a two hour period. A significant increase in CO, SV, PP, and CVP in addition to a significant decrease in TPR were observed following the administration of sodium salicylate. Morphine sulfate decreased the CO, HR, and MAP significantly while the SV and PP were significantly increased. Acupuncture by electrocautery at Jen-Chung (Go-26) produced a significant increase in CO, SV, HR, MAP, and PP and a significant decrease in TPR. This model was satisfactory in comparing cardiovascular changes evoked by a mild analgesic, sodium salicylate, a potent opiate, morphine sulfate, and acupuncture by electrocautery at Jen-Chung (Go-26).

Acupuncture Therapy↗

PubMed2004

What is the ultimate goal in neural regulation of cardiovascular function?

We used the following multiple-choice question after a series of lectures in cardiovascular physiology in the first year of an undergraduate medical curriculum (n = 66) to assess whether students had understood the neural regulation of cardiovascular function. In health, neural cardiovascular mechanisms are geared toward maintaining A) cardiac output, B) total peripheral resistance (TPR), C) arterial blood pressure (BP), D) tissue blood flow. The same question was administered to 275 graduates preparing for postgraduate exams (but not following the same series of lectures as the undergraduates). In both groups, we found a large proportion of incorrect answers (70% in undergraduates and 85% in graduates) and sorted this out by offering a step-by-step explanation and two examples and found it successful: 1) What happens to BP and heart rate (HR) when a person loses 500 ml of blood ( approximately 10% of blood volume) in one minute? 2) What happens to your BP and HR as you get out of bed after a night's sleep? Flow = perfusion pressure/resistance to flow; cardiac output = BP/TPR; BP = cardiac output x TPR = [stroke volume (SV) x HR] x TPR. In both examples, BP decreases and is rapidly brought into the normal range by the arterial baroreflex mechanism. TBF is regulated chiefly by varying local vascular resistance (autoregulation). In summary, the ultimate goal of all neural cardiovascular reflex mechanisms is to maintain arterial BP within a range in which tissues can regulate their own blood flows. Cardiovascular control during exercise was used as an example to emphasize these facts. A discussion of this kind triggered interest in the minds of students and graduates, helping them get rid of a major misconception in about 20-40 minutes.

Education, Medical, Undergraduate↗

PubMed2004

Regional blood volume and peripheral blood flow in postural tachycardia syndrome.

Variants of postural tachycardia syndrome (POTS) are associated with increased ["high-flow" POTS (HFP)], decreased ["low-flow" POTS (LFP)], and normal ["normal-flow" POTS (NFP)] blood flow measured in the lower extremities while subjects were in the supine position. We propose that postural tachycardia is related to thoracic hypovolemia during orthostasis but that the patterns of peripheral blood flow relate to different mechanisms for thoracic hypovolemia. We studied 37 POTS patients aged 14-21 yr: 14 LFP, 15 NFP, and 8 HFP patients and 12 healthy control subjects. Peripheral blood flow was measured in the supine position by venous occlusion strain-gauge plethysmography of the forearm and calf to subgroup patients. Using indocyanine green techniques, we showed decreased cardiac index (CI) and increased total peripheral resistance (TPR) in LFP, increased CI and decreased TPR in HFP, and unchanged CI and TPR in NFP while subjects were supine compared with control subjects. Blood volume tended to be decreased in LFP compared with control subjects. We used impedance plethysmography to assess regional blood volume redistribution during upright tilt. Thoracic blood volume decreased, whereas splanchnic, pelvic, and leg blood volumes increased, for all subjects during orthostasis but were markedly lower than control for all POTS groups. Splanchnic volume was increased in NFP and LFP. Pelvic blood volume was increased in HFP only. Calf volume was increased above control in HFP and LFP. The results support the hypothesis of (at least) three pathophysiologic variants of POTS distinguished by peripheral blood flow related to characteristic changes in regional circulations. The data demonstrate enhanced thoracic hypovolemia during upright tilt and confirm that POTS is related to inadequate cardiac venous return during orthostasis.

Adolescent↗

PubMed2004

Theoretical considerations in the dynamic closed-loop baroreflex and autoregulatory control of total peripheral resistance.

The most important goal of this study is to enhance our understanding of the crucial functional relationships that determine the behavior of the systemic circulation and its underlying physiological regulatory mechanisms with minimal modeling. To the present day, much has been said about the indirect hydraulic effects of right atrial pressure (PRA) via cardiac output (CO) on arterial pressure (Pa) through the heart and pulmonary circulation or the direct regulatory effects of PRA on Pa through the cardiopulmonary baroreflex; however, very little attention has been given to the hydraulic influence that PRA exerts directly through the systemic circulation. The experimental data reported by Guyton et al. in 1957 demonstrated that steady-state PRA and the rate at which blood passes through the systemic circulation are locked in a functional relationship independent of any consequence of altered PRA on cardiac function. With this in mind, we emphasize the analytic algebraic analysis of the systemic circulation composed of arteries, veins, and its underlying physiological regulatory mechanisms of baroreflex and autoregulatory modulation of total peripheral resistance (TPR), where the behavior of the system can be analytically synthesized from an understanding of its minimal elements. As a result of this analysis, we present a novel mathematical method to determine short-term TPR fluctuations, which accounts for the entirety of observed Pa fluctuations, and propose a new cardiovascular system identification method to delineate the actual actions of the physiological mechanisms responsible for the dynamic couplings between CO, Pa, PRA, and TPR in an individual subject.

Atrial Function, Right↗

PubMed2002

Noninvasive identification of the total peripheral resistance baroreflex.

We propose two identification algorithms for quantitating the total peripheral resistance (TPR) baroreflex, an important contributor to short-term arterial blood pressure (ABP) regulation. Each algorithm analyzes beat-to-beat fluctuations in ABP and cardiac output, which may both be obtained noninvasively in humans. For a theoretical evaluation, we applied both algorithms to a realistic cardiovascular model. The results contrasted with only one of the algorithms proving to be reliable. This algorithm was able to track changes in the static gains of both the arterial and cardiopulmonary TPR baroreflex. We then applied both algorithms to a preliminary set of human data and obtained contrasting results much like those obtained from the cardiovascular model, thereby making the theoretical evaluation results more meaningful. This study suggests that, with experimental testing, the reliable identification algorithm may provide a powerful, noninvasive means for quantitating the TPR baroreflex. This study also provides an example of the role that models can play in the development and initial evaluation of algorithms aimed at quantitating important physiological mechanisms.

Adult↗

PubMed2002

Pregnancy alters hemodynamic responses to hemorrhage in conscious rabbits.

Pregnant animals are less able to maintain mean arterial pressure (MAP) during hemorrhage compared with nonpregnant animals, but the hemodynamic basis of this difference is unknown. The hypothesis that pregnancy attenuates responses of cardiac output, as well as total peripheral resistance (TPR) and femoral conductance, to hemorrhage was tested in conscious rabbits in both the pregnant and nonpregnant state (n = 10). During continuous slow blood loss (2% of the initial blood volume per minute), MAP was maintained initially in both groups. However, MAP then abruptly decreased to <45 mmHg in all animals after a smaller percentage of the initial blood volume was removed in pregnant compared with nonpregnant rabbits (43.6 +/- 1.7%, nonpregnant; 29.6 +/- 2.2%, pregnant; P < 0.005). The more rapid transition to hypotension exhibited by pregnant rabbits was associated with greater initial falls in cardiac output (-56 +/- 10 ml/min, nonpregnant; -216 +/- 33 ml/min, pregnant; P < 0.005) and stroke volume (0.8 +/- 0.1 ml/beat, nonpregnant; -1.3 +/- 0.1 ml/beat, pregnant; P < 0.05). In addition, the increase in TPR as a function of the decrease in cardiac output was markedly attenuated (P < 0.0001) during pregnancy. Whereas femoral conductance decreased in nonpregnant rabbits, it did not change significantly in pregnant animals. In conclusion, the lesser ability of conscious pregnant rabbits to maintain MAP during hemorrhage is due largely to a greater decrease in cardiac output but also to inadequate reflex increases in TPR, possibly in part in the femoral vascular bed.

Animals↗

PubMed2003

Nitric oxide synthase inhibition does not affect regulation of muscle sympathetic nerve activity during head-up tilt.

To test the hypothesis that systemic inhibition of nitric oxide (NO) synthase does not alter the regulation of sympathetic outflow during head-up tilt in humans, in eight healthy subjects NO synthase was blocked by intravenous infusion of NG-monomethyl-L-arginine (L-NMMA). Blood pressure, heart rate, cardiac output, total peripheral resistance (TPR), and muscle sympathetic nerve activity (MSNA) were recorded in the supine position and during 60 degrees head-up tilt. In the supine position, infusion of L-NMMA increased blood pressure, via increased TPR, and inhibited MSNA. However, the increase in MSNA evoked by head-up tilt during L-NMMA infusion (change in burst rate: 24 +/- 4 bursts/min; change in total activity: 209 +/- 36 U/min) was similar to that during head-up tilt without L-NMMA (change in burst rate: 23 +/- 4 bursts/min; change in total activity: 251 +/- 52 U/min, n = 6, all P > 0.05). Moreover, changes in TPR and heart rate during head-up tilt were virtually identical between the two conditions. These results suggest that systemic inhibition of NO synthase with L-NMMA does not affect the regulation of sympathetic outflow and vascular resistance during head-up tilt in humans.

Adult↗