Maintenance Of Arterial Blood Pressure Research Articles

Abstract 37: Targeted Deletion of NKCC1 in Vascular Smooth Muscle Cells Lowers Blood Pressure in Normotensive and Hypertensive Mice

Background: Salt plays a major role in blood pressure homeostasis and the pathogenesis of arterial hypertension. While numerous mechanisms have been described by which Na + can influence arterial blood pressure, the role of Cl - in blood pressure regulation is still largely unexplored. The Na + -K + -2Cl - cotransporter NKCC1 is an important Cl - import pathway in vascular smooth muscle cells (VSMC). To investigate the role of NKCC1 in blood pressure regulation, we generated mice with an inducible VSMC-specific disruption of Slc12a2 . Methods: Mean arterial blood pressure and heart rate were measured by radiotelemetry in unrestrained mice lacking vascular NKCC1 (KO) and wildtype littermates (WT). Cardiac function was assessed by echocardiography. Plasma renin activity and aldosterone concentrations were quantified by radioimmunoassay. Protein expression of renal sodium transporters and channels was analyzed by Western blotting. Results: Mean arterial blood pressure was markedly decreased in Nkcc1 -deficient mice 6 weeks after induction of gene disruption (from 116±2 mm Hg to 103±4 mm Hg, n=18, p<0.001, 2-way ANOVA and Bonferroni post-test), while it did not change in WT control animals (n=17). Heart rate, stroke volume, fractional shortening, and ejection fraction remained unchanged compared to non-induced controls. We did not observe a compensatory increase in plasma renin activity or aldosterone levels, and the blood pressure response to ANG II receptor 1 antagonism by losartan treatment for 7 days was similar in both groups (ΔMAP KO -8.8±3.0 mm Hg, n=8, ΔMAP WT -12.4±1.9 mm Hg, n=7; p>0.05, 2-way ANOVA). In the kidney, the relative expression of total NCC (1.5- fold , n=7-8; p=<0.05, Student’s t-test) and pNCCThr53 (1.9- fold , n=7-8; p=<0.05, Student’s t-test) were modestly increased. The hypotensive effect of Nkcc1 disruption was maintained after induction of hypertension by either infusion of ANG II for 10 days (ΔMAP KO 43.8±6.5 mm Hg, n=6, ΔMAP WT 50.2±7.2 mm Hg, n=4; p>0.05, 2-way ANOVA) or a high salt diet for 10 days (ΔMAP KO 21.7±7.0 mm Hg, n=8, ΔMAP WT 34.0±7.3 mm Hg, n=5; p>0.05, 2-way ANOVA). Conclusions: Our findings indicate that NKCC1 in vascular smooth muscle contributes significantly to the maintenance of arterial blood pressure. Inhibition of NKCC1 in VSMC may provide additional blood pressure reduction in resistant hypertension.

Comparison of intravenous bolus phenylephrine, ephedrine and mephentermine for maintenance of arterial blood pressure during spinal anaesthesia in caesarean section

Background: Subarachnoid block, although being highly efficient, often has limitation such as hypotension which can result in adverse maternal and fetal outcome, continues to be a matter of concern to the Anesthesiologist. The study was to compare the effect of phenylephrine, ephedrine and mephentermine, for maintenance of arterial pressure during spinal anaesthesia for caesarean section. Methodology: A prospective randomized double blinded study involving 90 patients with hypotension after subarachnoid block under spinal anesthesia was conducted, dividing them into three groups: P (Phenylephrine) 100 mcg, E (Ephedrine) 6 mg, and M (Mephentermine) 6 mg. Patients were compared based on age, weight, height, hemodynamic parameters, complications, and neonatal APGAR scores. Results: On inter-group comparison rise in systolic, diastolic and mean arterial blood pressure at 1,2,4 and 6min after drug administration were significantly high in phenylephrine group (p <0.01) compared to ephedrine and mephentermine group. Thereafter the differences narrowed off. Heart rate was raised during episodes of hypotension. The mean heart rate was decreased significantly (p<0.05) in phenylephrine group compared to other two groups. The neonatal APGAR score were >/= 7 in the three groups at the 1st and 5th min. Conclusion: The study found that phenylephrine, ephedrine, and mephentermine effectively maintained arterial blood pressure in intravenous bolus form during subarachnoid block for caesarean section. Phenylephrine, a fast-acting, short-lived normotensive drug, significantly reduced heart rate compared to ephedrine and mephentermine, but did not cause significant adverse effects on mother and fetus. Keywords: hypotension; ephedrine; mephentermine; phenylephrine; subarachnoid block

English

BACKGROUND Subarachnoid block has been widely used for caesarean sections and is found to be safe. Hypotension being the most common complication may adversely affect both the mother and foetus. Different measures used to treat this hypotension include preloading with crystalloids/colloids and treatment with vasopressors. The standard choice of vasopressor agents such as ephedrine and phenylephrine is still a controversial issue. It is therefore important to compare the efficacy of the two drugs in the prevention and treatment of maternal hypotension after subarachnoid block and particularly assess their effect on the foetus. The purpose of this study was to assess and compare the foetal acid-base status and APGAR score following administration of bolus dose of ephedrine or phenylephrine that was given intravenously for maintenance of arterial blood pressure during lower segment caesarean section (LSCS) under a subarachnoid block. METHODS 100 parturients (18 to 35 years) scheduled for elective caesarean section under subarachnoid block were selected and divided into two groups of 50 each. Group P received 50 mcg i.v bolus of phenylephrine and Group E received 6 mg of ephedrine IV bolus whenever the blood pressure dropped 20 % from baseline or systolic blood pressure ˂ 90 mmHg. Haemodynamic parameters were measured in all patients. APGAR scores at 1 and 5 minutes following delivery of baby were assessed and cord blood was obtained for acid-base status analysis immediately following delivery. RESULTS Hemodynamic parameters including heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure did not show any significant difference between the two groups, however, Group E showed higher heart rates. The difference in umbilical artery pH (P-value < 0.001) and base excess (P-value = 0.004) was statistically significant with Group E showing lower pH and higher base excess values than Group P. There was no statistically significant difference in neonatal APGAR scores between the two groups. CONCLUSIONS Phenylephrine and ephedrine are equally efficient in managing hypotension during subarachnoid block for caesarean delivery. Thus, either vasopressor can be used although phenylephrine may be a better choice. KEY WORDS Caesarean Section, Phenylephrine, Ephedrine.

Low-dose ketamine affects blood pressure, but not muscle sympathetic nerve activity, during progressive central hypovolemia without altering tolerance.

Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage]×drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360mmHg‧min, p=0.77). Increases in MSNA burst frequency (time: P<0.01, trial: p=0.27, interaction: p=0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P<0.01, trial: P<0.01, interaction: p=0.01) and heart rate (time: P<0.01, trial: P<0.01, interaction: P<0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P<0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.

Effect of Acute Leg Heating On Circulating Endothelin‐1 in Aged Humans

There is a sustained reduction in arterial blood pressure that occurs in aged adults following exposure to acute leg heating. However, the neurovascular and humoral mechanisms mediating this hypotensive response remain unknown. The purpose of this study was to test the hypothesis that circulating concentrations of the potent vasoconstrictor substance endothelin‐1 would be attenuated concurrently with arterial blood pressure in aged adults following exposure to acute leg heating. Thirteen young adults (6 female; age 25 ± 4; height 172 ± 9 cm; weight 74 ± 15 kg; mean ± SD) and 10 aged adults (6 female; age 69 ± 5; height 166 ± 4 cm; weight 71 ± 11 kg; mean ± SD) were exposed to 45 minutes of acute leg heating. Subjects wore a tube‐lined water‐circulating garment that allowed leg skin temperature to be clamped at ~40°C during heating. Intestinal temperature was measured throughout via a telemetric pill. Systemic vascular conductance was calculated as cardiac output divided by mean arterial pressure and measured prior to heating (pre‐heat) and 30 min after (recovery). Plasma endothelin‐1 concentrations were quantified at pre‐heat and recovery time points via an enzyme‐linked immunosorbent assay. Leg heating increased body core temperature in young adults by 0.4 ± 0.1 °C and by 0.8 ± 0.2 °C in aged adults (both P &lt; 0.05 vs. 0 change). Body core temperature remained modestly elevated for both groups in recovery (both P &lt; 0.05 vs. pre‐heat). Mean arterial blood pressure was well maintained in young adults following leg heating (pre‐heat, 86 ± 6 mmHg vs. recovery, 88 ± 7 mmHg; P = 0.4), but was markedly reduced in aged adults (pre‐heat, 101 ± 7 mmHg vs. recovery, 94 ± 6 mmHg; P &lt; 0.05). Systemic vascular conductance in young adults did not differ from pre‐heat (69 ± 3 ml min−1 mmHg−1) to recovery (70 ± 3 ml min−1 mmHg−1; P = 0.7), whereas conductance was increased in aged adults (pre‐heat, 55 ± 6 ml min−1 mmHg−1 vs. recovery, 62 ± 5 ml min−1 mmHg−1; P = 0.07). Plasma endothelin‐1 concentrations did not differ between groups at the pre‐heat time point (young adults, 1.13 ± 0.13 pg ml−1 vs. aged adults, 1.44 ± 0.11 pg ml−1; P = 0.4). Plasma endothelin‐1 increased in recovery by 0.23 ± 0.42 pg ml−1 for young adults and by 0.20 ± 0.43 pg ml−1 for aged adults (both P &lt; 0.05 vs. 0 change). These data suggest that increased circulating endothelin‐1 may contribute to the maintenance of arterial blood pressure in young adults following exposure to acute leg heating by limiting systemic vascular conductance. Despite an increase in plasma endothelin‐1 in aged adults, arterial blood pressure was reduced in parallel with an increase in systemic vascular conductance which suggests that endothelin‐1‐mediated vasoconstriction may be altered following leg heating. Alternatively, increased endothelin‐1 may be preventing a further deleterious reduction in arterial blood pressure in aged adults by restraining the increase in systemic vascular conductance.Support or Funding InformationNational Institutes of Health (R01AG059314) and laboratory startup funds from the University of North Texas Health Science Center.

Water drinking enhances the gain of arterial baroreflex control of muscle sympathetic nerve activity in healthy young humans.

What is the central question of this study? Water drinking increases muscle sympathetic nerve activity (MSNA), and it increases arterial blood pressure (ABP) in older populations but not in young healthy subjects. Does an increase in gain of arterial baroreflex control of MSNA contribute to maintenance of ABP after water drinking in healthy young subjects? What is the main finding and its importance? The gain of arterial baroreflex control of MSNA was increased and remained elevated 60min after water drinking (500ml) but remained unchanged after saline intake. An enhancement in gain of arterial baroreflex control of MSNA contributes to the maintenance of ABP after water drinking in young healthy subjects, probably via osmosensitive mechanisms. Water drinking increases muscle sympathetic nerve activity (MSNA), which is accompanied by a profound pressor response in patients with impaired arterial baroreflex function and in older populations, but not in healthy young subjects. We tested the hypothesis that an enhancement in the gain of arterial baroreflex control of MSNA contributes to the maintenance of arterial blood pressure after water drinking in healthy young subjects. The MSNA, arterial blood pressure and heart rate were measured in 10 healthy men (24± 2 years old; mean ± SD) before and for 60min after ingestion of 500ml of bottled water or saline solution. Weighted linear regression analysis between MSNA and diastolic blood pressure was used to determine the gain (i.e. sensitivity) of arterial baroreflex control of MSNA. After water drinking, MSNA was significantly elevated within 15min and remained above baseline for up to 60min [e.g. 21± 10bursts (100heart beats)-1 mmHg-1 at baseline versus 35± 14 bursts (100heart beats)-1 mmHg-1 at 30min; P< 0.01], whereas mean arterial blood pressure (e.g. 87± 7mmHg at baseline versus 89± 7mmHg at 30min; P= 0.34) and heart rate were unchanged. The arterial baroreflex-MSNA gain for bursts incidence was increased and remained elevated throughout the protocol [e.g. -2.25± 0.99bursts (100heart beats)-1 mmHg-1 at baseline versus -4.32± 1.53 bursts (100heart beats)-1 mmHg-1 at 30min; P< 0.01]. Importantly, saline intake had no effect on arterial baroreflex-MSNA gain or any neurocardiovascular variables. These findings demonstrate that water drinking enhances the gain of arterial baroreflex control of MSNA in healthy young men, which may contribute to buffering the pressor response after water drinking, probably via osmosensitive mechanisms.

Comparative Study of Intravenous Phenylephrine with Mephenteramine for Maintenance of Arterial Blood Pressure in Caesarean Section

Comparative Study of Intravenous Phenylephrine with Mephenteramine for Maintenance of Arterial Blood Pressure in Caesarean Section

(-)-Terpinen-4-ol changes intracellular Ca2+ handling and induces pacing disturbance in rat hearts

(-)-Terpinen-4-ol is a naturally occurring plant monoterpene and has been shown to have a plethora of biological activities. The objective of this study was to investigate the effects of (-)-terpinen-4-ol on the rat heart, a key player in the control and maintenance of arterial blood pressure. The effects of (-)-terpinen-4-ol on the rat heart were investigated using isolated left atrium isometric force measurements, in vivo electrocardiogram (ECG) recordings, patch clamp technique, and confocal microscopy. It was observed that (-)-terpinen-4-ol reduced contraction force in an isolated left atrium at millimolar concentrations. Conversely, it induced a positive inotropic effect and extrasystoles at micromolar concentrations, suggesting that (-)-terpinen-4-ol may have arrhythmogenic activity on cardiac tissue. In anaesthetized animals, (-)-terpinen-4-ol also elicited rhythm disturbance, such as supraventricular tachycardia and atrioventricular block. To investigate the cellular mechanism underlying the dual effect of (-)-terpinen-4-ol on heart muscle, experiments were performed on isolated ventricular cardiomyocytes to determine the effect of (-)-terpinen-4-ol on L-type Ca2+ currents, Ca2+ sparks, and Ca2+ transients. The arrhythmogenic activity of (-)-terpinen-4-ol in vitro and in vivo may be explained by its effect on intracellular Ca2+ handling. Taken together, our data suggest that (-)-terpinen-4-ol has cardiac arrhythmogenic activity.

Methodological Considerations for Assessing Measures of Spontaneous Cardiac Baroreflex Sensitivity in Humans

The arterial baroreflex is a negative feedback control system that plays an important role in short‐term maintenance of arterial blood pressure (BP). Analyses assessing spontaneous beat‐to‐beat fluctuations in BP and heart rate (HR) are increasingly being used to estimate cardiac baroreflex sensitivity. Published results have commonly used 10 min recording durations for these analyses; however, some research protocols require shorter recording durations. Since the validity of using shorter compared to longer recording durations has not been established, we tested the hypothesis that reduced baseline durations diminish the reliability of spontaneous cardiac baroreflex sensitivity measures. Beat‐to‐beat HR and BP were measured continuously during supine rest in 10 healthy individuals for 10 min, and spontaneous cardiac baroreflex sensitivity was estimated using the sequence technique and low frequency transfer function analysis (0.04–0.15 Hz). The 10 min baseline for each subject was divided into two 5‐min segments and two 3‐min segments, and each analysis was repeated. Statistical analysis revealed similar spontaneous baroreflex sensitivity among the various baseline durations for both analyses (P&gt;0.05). For example, spontaneous cardiac baroreflex sensitivity for the sequence technique was 18±3 ms/mmHg for 10 min, 18±2 ms/mmHg for 5 min and 18±3 ms/mmHg for 3 min durations (P&gt;0.05). However, the reliability over the various recording durations as assessed by intra‐class correlation was acceptable only for the sequence technique. These preliminary findings suggest that shorter baseline durations appear adequate to assess spontaneous cardiac baroreflex sensitivity when using the sequence technique.

Adrenergic and non-adrenergic control of active skeletal muscle blood flow: implications for blood pressure regulation during exercise.

Blood flow to active skeletal muscle increases markedly during dynamic exercise. However, despite the massive capacity of skeletal muscle vasculature to dilate, arterial blood pressure is well maintained. Sympathetic nerve activity is elevated with increased intensity of dynamic exercise, and is essential for redistribution of cardiac output to active skeletal muscle and maintenance of arterial blood pressure. In addition, aside from the sympathetic nervous system, evidence from human studies is now emerging that supports roles for non-adrenergic vasoconstrictor pathways that become active during exercise and contribute to vasoconstriction in active skeletal muscle. Neuropeptide Y and adenosine triphosphate are neurotransmitters that are co-released with norepinephrine from sympathetic nerve terminals capable of producing vasoconstriction. Likewise, plasma concentrations of arginine vasopressin, angiotensin II (Ang II) and endothelin-1 (ET-1) increase during dynamic exercise, particularly at higher intensities. Ang II and ET-1 have both been shown to be important vasoconstrictor pathways for restraint of blood flow in active skeletal muscle and the maintenance of arterial blood pressure during exercise. Indeed, although both adrenergic and non-adrenergic vasoconstriction can be attenuated in exercising muscle with greater intensity of exercise, with the higher volume of blood flow, the active skeletal muscle vasculature remains capable of contributing importantly to the maintenance of blood pressure. In this brief review we provide an update on skeletal muscle blood flow regulation during exercise with an emphasis on adrenergic and non-adrenergic vasoconstrictor pathways and their potential capacity to offset vasodilation and aid in the regulation of blood pressure.

Endothelin-A-mediated vasoconstriction during exercise with advancing age.

The endothelin-1 vasoconstrictor pathway contributes to age-related elevations in resting peripheral vascular tone primarily through activation of the endothelin subtype A (ET(A)) receptor. However, the regulatory influence of ET(A)-mediated vasoconstriction during exercise in the elderly is unknown. Thus, in 17 healthy volunteers (n = 8 young, 24±2 years; n = 9 old, 70±2 years), we examined leg blood flow, mean arterial pressure, leg arterial-venous oxygen (O2) difference, and leg O2 consumption (VO2) at rest and during knee-extensor exercise before and after intra-arterial administration of the ET(A) antagonist BQ-123. During exercise, BQ-123 administration increased leg blood flow to a greater degree in the old (+29±5 mL/min/W) compared with the young (+16±3 mL/min/W). The increase in leg blood flow with BQ-123 was accompanied by an increase in leg VO2 in both groups, suggesting a reduced efficiency following ET(A) receptor blockade. Together, these findings have identified an age-related increase in ET(A)-mediated vasoconstrictor activity that persists during exercise, suggesting an important role of this pathway in the regulation of exercising skeletal muscle blood flow and maintenance of arterial blood pressure in the elderly.

Elevated local skin temperature impairs cutaneous vasoconstrictor responses to a simulated haemorrhagic challenge while heat stressed

During a simulated haemorrhagic challenge, syncopal symptoms develop sooner when individuals are hyperthermic relative to normothermic. This is due, in part, to a large displacement of blood to the cutaneous circulation during hyperthermia, coupled with inadequate cutaneous vasoconstriction during the hypotensive challenge. The influence of local skin temperature on these cutaneous vasoconstrictor responses is unclear. This project tested the hypothesis that local skin temperature modulates cutaneous vasoconstriction during simulated haemorrhage in hyperthermic humans. Eight healthy participants (four men and four women; 32 ± 7 years old; 75.2 ± 10.8 kg) underwent lower-body negative pressure to presyncope while heat stressed via a water-perfused suit sufficiently to increase core temperature by 1.2 ± 0.2 °C. At forearm skin sites distal to the water-perfused suit, local skin temperature was either 35.2 ± 0.6 (mild heating) or 38.2 ± 0.2 °C (moderate heating) throughout heat stress and lower-body negative pressure, and remained at these temperatures until presyncope. The reduction in cutaneous vascular conductance during the final 90 s of lower-body negative pressure, relative to heat-stress baseline, was greatest at the mildly heated site (-10 ± 15% reduction) relative to the moderately heated site (-2 ± 12%; P = 0.05 for the magnitude of the reduction in cutaneous vascular conductance between sites), because vasoconstriction at the moderately heated site was either absent or negligible. In hyperthermic individuals, the extent of cutaneous vasoconstriction during a simulated haemorrhage can be modulated by local skin temperature. In situations where skin temperature is at least 38 °C, as is the case in soldiers operating in warm climatic conditions, a haemorrhagic insult is unlikely to be accompanied by cutaneous vasoconstriction.

Endothelial actions of atrial and B‐type natriuretic peptides

The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro- and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the actions of NPs on endothelial permeability and regeneration.

Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway

AimsCardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP.Methods and resultsIntravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1−/− mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains.ConclusionANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume.

Cardiac output at pre‐syncope in the heat‐stressed human

Maintenance of arterial blood pressure is governed by a combination of vascular resistance and cardiac output. Although heat stress compromises the control of arterial blood pressure during simulated hemorrhage, it remains unknown whether this response is due to inadequate vascular resistance and/or cardiac output responses. This study evaluated cardiac output responses at the onset of syncopal symptoms in heat-stressed individuals. Simulated hemorrhage was imposed via lower body negative pressure (LBNP) to pre-syncope in 11 subjects during passive heating (increase core temperature 1.2 ± 0.2 °C). Cardiac output was measured via thermodilution while subjects were normothermic, heat stressed, and throughout subsequent LBNP. Heat stress increased cardiac output from 7.1 ± 1.1 L/min to 11.9 ± 2.0 L/min (P < 0.001). Although cardiac output at the onset of syncopal symptoms was 37 ± 13% lower relative to pre-LBNP, absolute cardiac output was not different than normothermic values (7.5 ± 1.8 L/min; P = 0.46). These data indicate that, in the setting of profound cutaneous vasodilation associated with heat stress combined with a simulated hemorrhagic challenge sufficient to cause syncopal symptoms, a cardiac output that is adequate to maintain blood pressure while normothermic is no longer adequate while heat stressed. Supported by NIH Grants HL61388 & HL84072

Resting arterial blood pressure (ABP), sympathetic control of resting ABP, and hypertensive responses to 7‐days of intermittent hypoxia are similar in rats bred for low and high aerobic capacity running

Rats bred (generation 23) for low aerobic capacity running (LCR) and high aerobic capacity running (HCR) were studied. Body mass was significantly (P&lt;0.001) greater in age‐matched male LCR (658 ± 35 g) than HCR (442 ± 43 g) rats. Telemetric recording of baseline ABP and HR in conscious rats revealed no statistical differences between stains. To test for differences in the contribution of sympathetic nerve activity (SNA) in the maintenance of ABP, ganglionic transmission was blocked in conscious rats with hexamethonium (20 mg/kg, iv). Within 5–10 minutes, mean ABP (MAP) fell to a similar level in LCR (n=4) and HCR (n=5) rats. Next, rats were exposed to intermittent hypoxia (IH; 3 min 21% O2 ‐ 3 min 10% O2, 8am–4pm) for 7 days to mimic the bouts of hypoxemia that occur in humans with sleep apnea. IH increased MAP from 101 ± 1 to 106 ± 1 mmHg in LCR rats (n=5) and from 104 ± 1 to 108 ± 1 mmHg in HCR rats (n=4). These findings indicated that resting ABP and its maintenance by ongoing SNA do not differ as a function of aerobic running capacity, in spite of clear differences in body mass between LCR and HCR rats. Similarly, differences in aerobic running capacity and body mass are not associated with different hypertensive responses to IH exposure. Support: HL088052, HL076312 (GMT), and RR 17718 (SLB and LGK).

No Evidence for an Enhanced Role of Endothelial Nitric Oxide in the Maintenance of Arterial Blood Pressure in the IUGR Sheep Fetus

The fetus makes a number of physiological adaptations to a restriction of placental substrate supply, including a decrease in body growth and an increase in peripheral vasoconstriction which maintains mean arterial pressure (MAP) and supports a redistribution of cardiac output to key fetal organs. It is not known, however, whether chronic restriction of placental substrate supply results in an enhanced or diminished role for vasodilators such as endothelial nitric oxide in the regulation of MAP. We hypothesised that there is an increased contribution of NO to blood pressure regulation in growth restricted fetuses and that a 2 h infusion of a nitric oxide synthase inhibitor, N(omega)-nitro- l-arginine methyl ester ( l-NAME) would result in an augmented rise in MAP in chronically hypoxemic, placentally restricted (PR, n = 8) fetuses compared to controls (n = 6) in late gestation. There was no difference in the increase in fetal MAP and decrease in HR during l-NAME infusion between Control and PR fetuses. In the PR group, fetuses with lower mean gestational PaO 2 had a lower increase in MAP during l-NAME infusion. Thus we have found no evidence for an enhanced role of NO in the maintenance of MAP in the chronically hypoxemic IUGR fetus.

A Comparative Study of Bolus Phenylephrine and Mephentermine for Treatment of Hypotension during Spinal Anesthesia for Cesarean Section

Background: Cesarean section under spinal anesthesia is commonly associated with hypotension which can be detrimental to mother and fetus. It is the responsibility of the anaesthesiologist to ensure stable arterial blood pressure throughout surgery to avoid any decrease in maternal organ blood flow and placental insufficiency. Methods: Vasopressors are the cornerstone in treatment of hypotension during spinal anesthesia. Phenylephrine, α1 agonist and mephentermine, a direct and indirect acting sympathomimetic can be used to increase the arterial blood pressure. The current study aims to compare phenylephrine and mephentermine for maintenance of arterial blood pressure. Results: This study shows that both vasopressors can be used for the indication. The clinical outcomes like neonatal Apgar score, incidence of nausea and vomiting and other adverse events were comparable with both the vasopressors. Phenylephrine however has the advantage of decreased heart rate and requirement of lesser amount and more efficacy at maintaining the arterial blood pressure. The systolic blood pressure was significantly higher with phenylephrine 6 minutes after administration as compared to mephentermine.Conclusions: Mephentermine should be avoided in patients in whom increased heart rate may be undesired. Phenylephrine seems to be a better choice for the treatment of hypotension during spinal anesthesia for cesarean section. Note: The study was conducted by the academic support of the institute.The study has no direct or indirect support/funding/sponsorship of any kind and there is no conflict of interest whatsoever.

Arterial Baroreflex Control of the Peripheral Vasculature in Humans

Arterial baroreceptors originating in the carotid arteries and aorta play a pivotal role in the rapid reflex adjustments that accompany acute cardiovascular stressors. There is now ample evidence to indicate that the arterial baroreflex remains functional during exercise by resetting in direct relation to the intensity of exercise from rest to maximum. Moreover, there is convincing evidence that a properly functioning arterial baroreflex is requisite for an appropriate neural cardiovascular response to exercise. Importantly, an understanding of the underlying means by which the baroreflex responds to changes in blood pressure has been elucidated. In this regard, both at rest and during exercise, alterations in stroke volume do not appear to contribute to the maintenance of arterial blood pressure (ABP) by the carotid baroreceptors (CBR), and therefore, any reflex-induced changes in cardiac output are the result of CBR-mediated changes in heart rate (HR). More importantly, it appears that CBR-induced changes in ABP are primarily mediated by alterations in vascular conductance with only minimal contributions from cardiac output. Therefore, the capacity of the CBR to regulate ABP depends critically on its ability to alter vascular tone both at rest and during exercise. Indeed, studies have clearly indicated that active and inactive skeletal muscle vascular beds contribute to mediating CBR-induced changes in ABP. The purpose of this review is to describe the mechanisms by which the CBR responds to alterations in ABP both at rest and during exercise in humans with a particular emphasis on the importance of baroreflex-mediated vascular responses.

Developmental Origins of Adult Health and Disease: The Role of Periconceptional and Foetal Nutrition

The 'developmental origins of adult health and disease' hypothesis stated that environmental factors, particularly maternal undernutrition, act in early life to programme the risks for adverse health outcomes, such as cardiovascular disease, obesity and the metabolic syndrome in adult life. Early physiological tradeoffs, including activation of the foetal hypothalamo-pituitary-adrenal (HPA) axis, confer an early fitness advantage such as foetal survival, while incurring delayed health costs. We review the evidence that such tradeoffs are anticipated from conception and that the periconceptional nutritional environment can programme the developmental trajectory of the stress axis and the systems that maintain and regulate arterial blood pressure. There is also evidence that restriction of placental growth and function, results in an increased dependence of the maintenance of arterial blood pressure on the sequential recruitment of the sympathetic nervous system and HPA axis. While the 'early origins of adult disease' hypothesis has focussed on the impact of maternal undernutrition, an increase in maternal nutritional intake and in maternal body mass intake has become more prevalent in developed countries. Exposure to overnutrition in foetal life results in a series of central and peripheral neuroendocrine responses that in turn programme development of the fat cell and of the central appetite regulatory system. While the physiological responses to foetal undernutrition result in the physiological trade off between foetal survival and poor health outcomes that emerge after reproductive senescence, exposure to early overnutrition results in poor health outcomes that emerge in childhood and adolescence. Thus, the effects of early overnutrition can directly impact on reproductive fitness and on the health of the next generation. In this context, the physiological responses to relative overnutrition in early life may directly contribute to an intergenerational cycle of obesity.