Systemic Vascular Resistance Responses Research Articles

Metaboreflex Dysregulation In Type 2 Diabetes Mellitus

In healthy subjects, when the muscle metaboreflex (MM) is activated, mean blood pressure (MBP) increases because of a sympathetic-induced increase in both systemic vascular resistance (SVR) and cardiac output (CO)1. It has been reported that this reflex is dys-regulated in patients suffering some metabolic diseases. In detail, patients with type 1 diabetes mellitus (DM) have a blunted MBP response during the MM due to sympathetic deficit2; moreover, patients suffering from metabolic syndrome show an exaggerated SVR during the MM because of their sympathetic hyperactivation. PURPOSE: to discover whether the MM is dys-regulated is patients with type 2 DM. METHODS: 14 MS patients with type 2 DM obesity (4 females, 62.7±8.3 yrs) together with 13 control subjects (CTL, 5 females 61.2±10.5 yrs) participated in this study. They underwent randomly assigned the following protocol: 1) post-exercise muscle ischemia (PEMI) session, to study the MM, and 2) control exercise recovery (CER) session. Response to the metaboreflex for each cardiovascular parameter was assessed as PEMI minus CER level. Hemodynamic parameters were evaluated by impedance cardiography. RESULTS: patients with type 2 DM showed an exaggerated SVR response as compared to the CTL group (392.5±549.6, vs -68±248.5 dynes•s-1•cm-5 respectively, p<0.05), whereas MBP response was not different between groups (8.9±5.7 vs. 6.8±8.7 mmHg respectively, p>0.05). CONCLUSIONS: This investigation indicates that patients with type 2 DM have an exaggerated vasoconstriction in response to the MM activation. This phenomenon is different to what observed in type 1 DM2 and similar to what reported for metabolic syndrome3. 1 Crisafulli A et al. Muscle metaboreflex-induced increases in stroke volume. Med Sci Sports Exerc 2003; 35: 221-228. 2 Roberto S et al. Altered hemodynamics during muscle metaboreflex in young, type 1 diabetes patients. J Appl Physiol 2012; 113: 1323-1331. 3 Milia R et al. Differences in hemodynamic response to metaboreflex activation between obese patients with metabolic syndrome and healthy subjects with obese phenotype. Am J Physiol (Heart Circ Physiol) 2015; 309: H779-789.

The influences of nitric oxide, epinephrine, and dopamine on vascular tone: dose-response modeling and simulations.

Sodium Nitroprusside has successfully been an excellent choice when considering a decrease in systemic vascular resistance in the critical care setting. However, reflex tachycardia and ventilation-perfusion mismatch are possible side effects of this agent. To maintaining cardiac output, cerebral perfusion pressure, and concurrently drop SVR, low-dose epinephrine or dopamine are viable options. The aim of this paper is to conduct dose-response simulations to identify the equivalent dopamine, epinephrine, and nitroprusside infusion doses to decrease the systemic vascular resistance by 20% and by 40% from baseline resting values. Three studies were identified in the literature with reported epinephrine, dopamine, and sodium nitroprusside infusion doses with corresponding systemic vascular resistance responses. Infusion doses were normalized to mcg/kg/min and SVR values were normalized and scaled to the percent decrease (%SVR) in SVR from baseline resting values. The original published studies were mathematically modeled and the Hill equation parameters used for further dose-response simulations of a virtual population. One-hundred patients were simulated various doses resulting in corresponding %SVR responses for each of the three drugs. Equivalent infusion doses achieving in an approximate 20-25% decrease in SVR, from baseline, were identified for epinephrine, dopamine, and sodium nitroprusside. Moreover, equivalent infusion doses were identified for epinephrine and nitroprusside to decrease the SVR by 40% from baseline. Even though sodium nitroprusside is traditionally used in decreasing SVR, low doses of dopamine or epinephrine are viable alternatives to patients with contraindications to nitroprusside infusions or who will require prolonged infusions to avoid toxicity. The multiple comparisons procedure-modeling approach is an excellent methodology for dose-finding exercises and has enabled identification of equivalent pharmacodynamic responses for epinephrine, dopamine, and sodium nitroprusside through mathematic simulations.

The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias.

Without an active regulatory feedback loop, increased blood viscosity could lead to a vicious cycle of ischemia, increased erythropoiesis, further increases of blood viscosity, decreased tissue perfusion with worsened ischemia, further increases in red cell mass, etc. We suggest that an increase in blood viscosity is detected by mechanoreceptors in the left ventricle which upregulate expression of cardiac natriuretic peptides and soluble erythropoietin receptor. This response normalizes systemic vascular resistance and blood viscosity at the cost of producing 'anemia of chronic disease or inflammation' or 'hemolytic anemia' both of which are better described as states of compensated hyperviscosity. Besides its role in disease, this response is also active in the physiologic adaptation to chronic exercise. Malfunction of this response may cause primary hypertension.

Altered Metaboreflex Activity In Patients With Metabolic Syndrome

In healthy individuals, activation of the muscle metaboreflex leads to increase in mean blood pressure (MBP) due to increase in both systemic vascular resistance (SVR) and cardiac output (CO)1. It has been reported that patients suffering from metabolic syndrome (MS) have a dysregulation of this reflex with an exaggerated SVR increase with respect to normal controls2. However, it is not clear whether this is the consequence of MS per se or this is due to concomitant obesity (OB). PURPOSE: to discover whether MS and OB had different hemodynamic response during the metaboreflex. METHODS: 13 MS patients with obesity (5 females, 50.3±16.3 yrs, body mass index 32.1±4.4), 11 patients with OB without MS (6 females, 38.4±10.1 yrs, body mass index 34.6±5.7) together with 12 control subjects (CTL, 6 females 41±10.5 yrs, body mass index 21.5±2.5) took part in this study. Each individual underwent randomly assigned the following protocol: 1) post-exercise muscle ischemia (PEMI) session, to study the metaboreflex, and 2) control exercise recovery (CER) session. Response to the metaboreflex for each cardiovascular parameter was assessed as PEMI-CER level. Central hemodynamics were evaluated by means of impedance cardiography. RESULTS: the main result was that patients with MS had an exaggerated SVR response with respect to the OB and the CTL group (481.6±595.3, -0.52±376.6, and 130.4±373.7 dynes•s-1•cm-5 for the MS, the OB, and the CTL group respectively, p<0.05), whereas MBP response was not different between groups (10.2±5.6, 8.3±8.6, and 6.05±8.6 mmHg for the MS, the OB, and the CTL group respectively, p>0.05). CONCLUSIONS: This investigation demonstrates that patients with obesity and metabolic syndrome show an exaggerated vasoconstriction in response to metaboreflex activation. This fact was not present in OB without MS. Thus, it is not obesity per se to dysregulate hemodynamics during the metaboreflex. REFERENCES 1 Crisafulli A et al. Muscle metaboreflex-induced increases in stroke volume. Med Sci Sports Exerc 2003; 35: 221-228. 2 Limberg J et al. Mechanical and metabolic reflex activation of the sympathetic nervous system in younger adults with metabolic syndrome. Aut Neurosci 2014 (at press).

Molecular-based mechanisms of Mendelian forms of salt-dependent hypertension: questioning the prevailing theory.

This critical review directly challenges the prevailing theory that a transient increase in cardiac output caused by genetically mediated increases in activity of the ENaC in the aldosterone sensitive distal nephron, or of the NCC in the distal convoluted tubule, accounts entirely for the hemodynamic initiation of all Mendelian forms of salt-dependent hypertension (Figure 1). The prevailing theory of how genetic mutations enable salt to hemodynamically initiate Mendelian forms of salt-dependent hypertension in humans (Figure 1) depends on the results of salt-loading studies of cardiac output and systemic vascular resistance in nongenetic models of hypertension that lack appropriate normal controls. The theory is inconsistent with the results of studies that include measurements of the initial hemodynamic changes induced by salt loading in normal, salt-resistant controls. The present analysis, which takes into account the results of salt-loading studies that include the requisite normal controls, indicates that mutation-induced increases in the renal tubular activity of ENaC or NCC that lead to transient increases in cardiac output will generally not be sufficient to enable increases in salt intake to initiate the increased BP that characterizes Mendelian forms of salt-dependent hypertension (Table). The present analysis also raises questions about whether mutation-dependent increases in renal tubular activity of ENaC or NCC are even necessary to account for increased risk for salt-dependent hypertension in most patients with such mutations. We propose that for the genetic alterations underlying Mendelian forms of salt-dependent hypertension to enable increases in salt intake to initiate the increased BP, they must often cause vasodysfunction, ie, an inability to normally vasodilate and decrease systemic vascular resistance in response to increases in salt intake within dietary ranges typically observed in most modern societies. A subnormal ability to vasodilate in response to salt loading could be caused by mutation-related disturbances originating in the vasculature itself or in sites outside the vasculature (eg, brain or adrenal glands) that have the capacity to affect vascular function.

A cholinergic contribution to the circulatory responses evoked at the onset of handgrip exercise in humans

A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular resistance (SVR) in young healthy males, while performing either 20 s of isometric handgrip contraction at 40% maximum voluntary contraction (protocol 1; n = 9) or 20 s of low-intensity leg cycling exercise (protocol 2; n = 8, 42 ± 8 W). Exercise trials were conducted under control (no drug) conditions and following cholinergic blockade (glycopyrrolate). Under control conditions, isometric handgrip elicited an initial increase in BP (+5 ± 2 mmHg at 3 s and +3 ± 1 mmHg at 10 s, P < 0.05), while SVR dropped after 3 s (-27 ± 6% at 20 s; P < 0.05). Cholinergic blockade abolished the isometric handgrip-induced fall in SVR and, thereby, augmented the pressor response (+13 ± 3 mmHg at 10 s; P < 0.05 vs. control). In contrast, cholinergic blockade had a nonsignificant effect on changes in BP and SVR at the onset of leg cycling exercise. These findings suggest that a cholinergic mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans.

Abnormal Systemic Vascular Resistance Response to Submaximal Exercise in Young Unfit Adult Females

Abnormal Systemic Vascular Resistance Response to Submaximal Exercise in Young Unfit Adult Females

Blood pressure regulation IV: adaptive responses to weightlessness

During weightlessness, blood and fluids are immediately shifted from the lower to the upper body segments, and within the initial 2 weeks of spaceflight, brachial diastolic arterial pressure is reduced by 5 mmHg and even more so by some 10 mmHg from the first to the sixth month of flight. Blood pressure thus adapts in space to a level very similar to that of being supine on the ground. At the same time, stroke volume and cardiac output are increased and systemic vascular resistance decreased, whereas sympathetic nerve activity is kept surprisingly high and similar to when ground-based upright seated. This was not predicted from simulation models and indicates that dilatation of the arteriolar resistance vessels is caused by mechanisms other than a baroreflex-induced decrease in sympathetic nervous activity. Results of baroreflex studies in space indicate that compared to being ground-based supine, the carotid (vagal)-cardiac interaction is reduced and sympathetic nerve activity, heart rate and systemic vascular resistance response more pronounced during baroreflex inhibition by lower body negative pressure. The future challenge is to identify which spaceflight mechanism induces peripheral arteriolar dilatation, which could explain the decrease in blood pressure, the high sympathetic nerve activity and associated cardiovascular changes. It is also a challenge to determine the cardiovascular risk profile of astronauts during future long-duration deep space missions.

Neuropeptide Y (NPY): Genetic Variation in the Human Promoter Alters Glucocorticoid Signaling, Yielding Increased NPY Secretion and Stress Responses

This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells.The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15.Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population.Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇-880Δ (2-bp TG/-, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h(2)) stress traits: higher NPY secretion (h(2) = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇-880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele -880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter -880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes.We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇-880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

A comparison of the changes in cardiac output and systemic vascular resistance during exercise following high-fat meals containing DHA or EPA

Long-chain n-3 PUFA can lower blood pressure (BP) but their acute effects on cardiac output, BP and systemic vascular resistance (SVR) in response to dynamic exercise are uncertain. We compared the effects of high-fat meals rich in EPA (20:5n-3), DHA (22:6n-3) or oleic acid (control) on cardiac output, BP and SVR in response to exercise stress testing. High-fat meals (50g fat) containing high-oleic sunflower oil enriched with 4·7g of either EPA or DHA v. control (high-oleic sunflower oil only) were fed to twenty-two healthy males using a randomised cross-over design. Resting measurements of cardiac output, heart rate and BP were made before and hourly over 5h following the meal. A standardised 12min exercise test was then conducted with further measurements made during and post-exercise. Blood samples were collected at fasting, 5h postprandially and immediately post-exercise for the analysis of lipid, glucose and 8-isoprostane-F2α (8-iso-PGF2α). Plasma concentrations of EPA and DHA increased by 0·22mmol/l 5h following the EPA and DHA meals, respectively, compared with the control (P<0·001). Resting cardiac output and 8-iso-PGF2α increased similarly following all meals and there were no significant differences in cardiac output during exercise between the meals. SVR was lower at 5h and during exercise following the DHA but not EPA meal, compared with the control meal, by 4·9% (95% CI 1·3, 8·4; P<0·01). Meals containing DHA appear to differ from EPA with regard to their effects on cardiovascular haemodynamics during exercise.

β2‐Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade

Regional infusions of beta(2)-adrenoceptor (ADRB2) agonist have generally shown that individuals homozygous for Gly16 produces greater vasodilatation than those homozygous for Arg16. Systemic infusions have shown an opposite effect on systemic vascular resistance (SVR), possibly confounded by baroreflexes or interactions between single nucleotide polymorphism (SNP) positions 16 and 27. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (Terb) during ganglionic blockade. Forty healthy young adults were recruited according to the double homozygous haplotypes: Arg16 + Gln27 (n = 13), the rare Gly16 + Gln27 (n = 6), and Gly16 + Glu27 (n = 21). Arterial pressure was measured by brachial arterial catheter, and cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3-7 mg min(1)), continuous phenylephrine was titrated to restore blood pressure to baseline. Terb was infused i.v. at 33 and 67 ng kg(1) min(1) for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR (P = 0.06). For SNP position 16, the highest dose of Terb produced lower SVR in Gly16 (mean +/- s.e.m.: 7.5 +/- 0.4) vs. Arg16 (8.9 +/- 0.7 units; P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs. Arg16 (P = 0.05). We conclude that during ganglionic blockade, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16 + Glu27 homozygotes, with greater influence from Gly16, providing further evidence that ADRB2 gene variation influences vasodilatation.

High sodium intake alters the hemodynamic response to mental stress in normotensive subjects after systemic beta adrenergic blockade

We tested the hypothesis that dietary Na+ intake alters the hemodynamic response to mental stress (MS) in normotensive subjects, which could be mediated by β‐adrenergic receptors (ADRB). As part of an ongoing ADRB2 phenotyping protocol, 12 subjects (age 23±5 year) completed 5 days of low (10 mmol day−1), normal (150) and high (400) dietary Na+ intake. We measured heart rate (ECG), mean arterial pressure (MAP, Finometer), and calculated stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) responses to arithmetic MS, before and after administration of propranolol. The high Na+ diet decreased CO (6.3±0.3 vs. 5.7±0.3 l min−1, p&lt;0.01) and increased SVR (1187±47 vs. 1311±68 dynes s−1 cm−1, p&lt;0.01) at rest, but MAP was unchanged (92±2 vs. 93±3 mmHg, p=0.37). During MS, the increase in HR, CO, and MAP was not affected by diet, nor was the decrease in SVR. However, on the high Na+ diet β‐blockade increased resting MAP (93±3 vs. 97±2 mmHg, p&lt;0.01), while the absolute MAP response to MS was unchanged, the ΔMAP was blunted (7.3 vs. 4.3 %, p=0.03) and ΔSV was decreased (1.7±3.5 vs. −5.3±2.0 %, p=0.03). In conclusion, reactivity to MS was not influenced by dietary Na+, but systemic β‐blockade after high Na+ blunted the SV response during MS. This may be suggestive of augmented ADRB function or blunted non‐ADRB mechanisms of ventricular function during MS after high Na+. Support: R‐01 HL‐089331 and CTSA RR‐024150.

Role of the central nucleus of the amygdala in hemodynamic responses to cocaine in conscious rats.

The central nucleus of the amygdala (CeA) has been shown to play an important role in sympathetic and behavioral responses to stress. We observed a greater vasoconstrictor response to cocaine in some rats (vascular responders or VR) compared to other rats (mixed responders or MR). We hypothesized that the CeA was responsible for greater increases in systemic vascular resistance (SVR) in response to cocaine and that angiotensin II (Ang) and corticotropin‐releasing factor (CRF) receptors were involved. Rats were instrumented for arterial pressure and cardiac output determination and for drug microinjection into the CeA. Rats were given cocaine (5 mg/kg, iv, twice daily, 4X) to determine their response pattern (VR or MR). Subsequently, rats were pretreated with bilateral microinjections (100 nl) of saline, muscimol (80 pmol), losartan (20 ng), or á‐helical‐CRF9‐41 (60 ng) followed by cocaine. Pretreatment with muscimol or losartan attenuated the increase in systemic vascular resistance (SVR) evoked by cocaine. Pretreatment with CRF antagonist prevented the difference in responsiveness between MR and VR by increasing the increase in SVR in MR. Our data suggests that the greater increases in SVR in vascular responders depend on neuronal transmission in the CeA and that Ang receptors facilitate and CRF receptors inhibit SVR responses to cocaine administration. Supported by USPHS RO1 DA13256 and DA0017371.

Abstract 2407: Increased Arteriolar Resistance Of Heart Failure Is Associated With Rho-Independent Inhibition Of MLCP.

Background: The clinical syndrome of heart failure (HF) is caused by decreased cardiac output, and is both compensated for and exacerbated by increased systemic vascular resistance (SVR). We posit that a mechanistic understanding of the vasomotor abnormalities that accompany HF may enable new diagnostic and therapeutic tools. Objective: To determine the molecular mechanisms underlying increased resistance of mesenteric arteries (MAs) in a mouse model of HF. Methods &amp; Results: In a mouse left anterior descending (LAD)-ligation model of myocardial infarction (MI)-induced HF, echocardiography and hemodynamics documented markedly increased SVR. Isolated perfused MAs manifested dramatic, early (1 wk), and sustained (12 wk) increases in myogenic responses (MR). Vasoconstrictor responses to S1P and ET-1 were also increased in MAs of HF but not SHAM mice. At wk 6, aorta and MA were analyzed for levels and or activity of Rho/GTP-Rho, a key mediator of enhanced vasoconstrictor responses. We also measured total and phosphorylated levels of: MYPT1 (Thr850), the myosin targeting subunit of myosin light chain phosphatase (MLCP), an end-regulatory molecule of smooth muscle contraction; CPI-17 (Thr38), an inhibitor of MLCP; and (iv) myosin light chain itself (MLC; Ser19). When phosphorylated, MYPT1 inhibits MLCP, limiting its dephosphorylation of MLC, and thus prevents relaxation. Given our results with respect to ET-1 and S1P, we were surprised to find significantly decreased levels of total and GTP-Rho in MAs and aorta of HF as compared to SHAM mice. By contrast, increased levels of phosphorylated-MYPT1, CPI-17 and MLC were found in HF. Conclusion: These data implicate a heretofore unrecognized mechanism of ‘Rho-independent’ inhibition of MLCP in the increased SVR, MR, and vasoconstrictor responses observed in the MI model of HF in mice.

Angiotensin and NMDA receptors in the median preoptic nucleus mediate hemodynamic response patterns to stress.

The brain renin-angiotensin system plays an important role in the regulation of arterial pressure in response to stress, in part due to activation of AT1 receptors in the hypothalamic median preoptic nucleus (MnPO) by endogenous angiotensin II (ANG II). N-methyl-d-aspartate (NMDA) receptors are also involved in the angiotensinergic signaling pathway through the MnPO. We investigated whether AT1 and NMDA receptors in the MnPO are responsible for variable hemodynamic response patterns to stress. Cocaine or startle with cold water evoked a pressor response in Sprague-Dawley rats due, in some rats [vascular responders (VR)], to a large increase in systemic vascular resistance (SVR) and, in other rats [mixed responders (MR)], to small increases in SVR and cardiac output (CO). Microinjection of the GABAA agonist muscimol into the MnPO to block synaptic transmission attenuated the cocaine- or stress-induced increase in SVR and the decrease in CO seen in VR without altering either response in MR. Likewise, administration of either an AT1 receptor antagonist, losartan, or an NMDA receptor antagonist, MK-801, attenuated the increase in SVR and the decrease in CO in VR in response to either cocaine (losartan and MK-801) or startle with cold water (losartan) without altering either response in MR. We propose that the MnPO is responsible for greater SVR responses in VR and that AT1 and NMDA receptors play an important role in greater SVR responses in VR. These data provide additional support for the critical role of the MnPO in cardiovascular responses to stress.

Insulin Resistant Women Exhibit Abnormal Vascular Reactivity To Mental Challenge

Insulin resistant women have reduced blood flow to working muscles. Whether other autonomic responses are different from women possessing normal insulin levels is undetermined. PURPOSE: To examine the hemodynamic implications of insulin resistance (IR). METHODS: Seven normotensive, insulin-resistant women and 11 age-matched healthy women with normal fasting insulin with respect to mental challenge response were compared. During 10 min of the Stroop task heart rate, blood pressure, cardiac output, systemic vascular resistance, vascular resistance, and vascular conductance were assessed using impedance cardiography and venous occlusion. Peak oxygen uptake was measured using open-circuit spirometry. RESULTS: The IR and control groups were of similar weight (64 versus 69 kg), BMI (24 versus 26 kg/m2), age (21.9 versus 22.8 years), blood pressure (115/69 versus 117/67 mmHg), and peak aerobic power (32.1 versus 28.2 ml·kg-1·min-1). The IR group possessed significantly higher fasting insulin (49.8 versus 11.7 μU/ml) and HOMA-IR (9.8 versus 2.5). During Stroop forearm vascular resistance significantly increased for the IR compared to controls (+12.5 versus −11.7 ml·100 ml tissue-1·min-1), whereas forearm vascular conductance change was significantly decreased (−0.4 versus +0.7 ml·100 ml tissue-1·min-1). Controls demonstrated increased cardiac output (.8 L/min) and a small increase in vascular resistance (+13 dyne.s.cm-5), whereas IR subjects demonstrated a smaller increase in cardiac output (.2 L/min) and a significantly larger increase in systemic vascular resistance (+197 dyne.s.cm-5). CONCLUSIONS: IR women showed a blunted cardiac output and an exaggerated systemic vascular resistance response to mental challenge. This pattern of cardiac output and vascular resistance response may be a marker for future hypertension in young normotensive, hyperinsulinemic women.

Enhanced Vasoreactivity and Its Response to Antihypertensive Therapy in Hypertensive Elderly Women

Several previous studies have demonstrated sex differences in cardiovascular autonomic control in healthy young women, but little is known about the regulation of blood pressure in hypertensive elderly women, who have the greatest risk of adverse cardiovascular events. Therefore, we examined sex differences in physiological responses to upright tilt in 21 healthy (13 men and 8 women), 22 controlled hypertensive (10 men and 12 women), and 18 uncontrolled hypertensive (9 men and 9 women) elderly men and women. Of these, 19 normotensives, 18 controlled hypertensives, and 14 uncontrolled hypertensives completed 6 months of observation or pharmacological therapy for uncontrolled hypertension. All of the subjects underwent continuous monitoring of cardiac (RR) interval (ECG), finger arterial pressure (photoplethysmography), and stroke volume (transthoracic impedance) and periodic measurements of forearm blood flow (venous occlusion plethysmography) while resting supine and during a graded head-up tilt. Blood pressure and RR-interval power spectra were computed. Baroreflex gain was estimated by the cross-spectral and sequence methods. In contrast to other groups, elderly hypertensive women increased systemic vascular resistance during tilt. This response was associated with greater low-frequency systolic pressure variability, a presumed marker of sympathetic vascular control. After 6 months of successful antihypertensive therapy, women showed attenuation of the systemic vascular resistance response and a reduction in low-frequency systolic blood pressure variability to levels similar to men and normotensive controls. These results highlight the beneficial effects of antihypertensive therapy on the systemic vasculature, particularly for elderly women in whom enhanced vasoreactivity may contribute to excessive cardiovascular morbidity and mortality.

Continuous cardiac output monitoring with pulse contour analysis: A comparison with lithium indicator dilution cardiac output measurement

Pulse contour analysis can be used to provide beat-to-beat cardiac output (CO) measurement. The current study sought to evaluate this technique by comparing its results with lithium dilution CO (LiCO) measurements. Prospective, observational study. Surgical intensive care unit. Twenty-two patients after cardiac or major noncardiac surgery. After initial calibration of the pulse contour CO (PCO) method, CO was measured by PCO and by LiCO methods at 4, 8, 16, and 24 hrs. Recalibration of PCO was performed every 8 hrs. The systemic vascular resistance and dynamic response characteristics of the arterial catheter-transducer system were measured at each time point to determine whether these influenced the agreement between PCO and LiCO methods. There was an excellent correlation between methods (r = .94). Bias was small (-0.005 L/min), and clinically acceptable limits of agreement were demonstrated between techniques. Although many catheter-transducer systems had poor dynamic response characteristics, this did not influence the level of agreement between the two techniques. An increase in systemic vascular resistance between two time points did tend to cause overestimation of LiCO by the PCO. PCO measurement compared well with the lithium dilution method and can be considered an accurate technique for measuring beat-to-beat CO with limited risk to the patient.

Central β-adrenoceptors mediate phasic and sustained components of hemodynamic responses to acute behavioral stress

Startle elicits a pattern of cardiovascular responses that is consistent within individual rats but varies between rats. We examined the hypothesis that central β-adrenoceptors mediate differences in the hemodynamic responses to stress. Conscious rats exposed to cold water (1 cm deep, 1 min) had an initial phasic (startle) response (first 5 s) that varied considerably between rats. We designated those rats with an initial increase in cardiac output (CO) and systemic vascular resistance (SVR) as mixed responders while those with only an increase in SVR were vascular responders. Propranolol pretreatment (3 μg, icv) made the phasic changes in CO more negative, whereas isoproterenol (3 μg) made the CO response more positive in mixed responders and attenuated the increases in arterial pressure and SVR in vascular responders. Metoprolol (30 μg, icv) depressed the change in CO due to startle in mixed responders by decreasing heart rate. ICI 188,551 (25 μg, icv) did not alter the responses to startle but depressed the heart rate and CO responses and enhanced the pressor and SVR responses to sustained stress (1 min exposure to cold water). The results suggest that startle elicits hemodynamic responses that are primarily dependent on β 1-adrenoceptors but responses to sustained stress are dependent on β 2-adrenoceptors in the CNS.

Muscarinic cholinergic and beta-adrenergic contribution to hindquarters vasodilation and cardiac responses to cocaine.

Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats. Propranolol pretreatment prevented the vasodilation and enhanced the pressor response, whereas atropine methylbromide pretreatment reduced the increase in systemic vascular resistance. We studied the role of selective muscarinic and beta-adrenoceptor antagonists on responses to cocaine in rats with an increase in systemic vascular resistance to cocaine (vascular responders). Arterial blood pressure and ascending aortic and distal descending aortic blood flow using pulsed Doppler flowmetry were measured. In conscious rats, cocaine (5 mg/kg i.v.) elicited consistent pressor responses but variable systemic and hindquarters vascular resistance responses that were directly correlated, suggesting that skeletal muscle resistance responses comprise an important component of systemic vascular resistance. ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)-amino]-2-butanol] (0.5 mg/kg i.v.) pretreatment prevented the hindquarters vasodilation, enhancing the increase in systemic vascular resistance and the pressor response while further depressing the cardiac output response, similar to the effects of propranolol. Atenolol (1 mg/kg) pretreatment attenuated the stroke volume and cardiac output responses while enhancing the increase in systemic vascular resistance without affecting the hindquarters responses. In contrast, M2 antagonist methoctramine (0.3 mg/kg) pretreatment had similar effects as atropine in reducing the decrease in cardiac output by reducing the increase in systemic vascular resistance, whereas the M1 antagonist pirenzipine (0.02 mg/kg) did not alter responses. Therefore, the cocaine-induced pressor response is ameliorated by beta2-adrenoceptor mediated skeletal muscle vasodilation, whereas the decrease in cardiac output and the increase in systemic vascular resistance are dependent on M2-cholinoceptor activation.