Fall In Total Peripheral Resistance Research Articles

5-HT7 receptors mediate dilation of rat cremaster muscle arterioles in vivo.

Serotonin (5-HT) infusion in vivo causes hypotension and a fall in total peripheral resistance. However, the vascular segment and the receptors that mediate this response remain in question. We hypothesized that 5-HT7 receptors mediate arteriolar dilation to 5-HT in skeletal muscle microcirculation. Cremaster muscles of isoflurane-anesthetized male Sprague-Dawley rats were prepared for in vivo microscopy of third- and fourth-order arterioles and superfused with physiological salt solution at 34°C. Quantitative real-time PCR (RT-PCR) was applied to pooled samples of first- to third-order cremaster arterioles (2-4 rats/sample) to evaluate 5-HT7 receptor expression. Topical 5-HT (1-10 nmols) or the 5-HT1/7 receptor agonist, 5-carboxamidotryptamine (10-30 nM), dilated third- and fourth-order arterioles, responses that were abolished by 1 μM SB269970, a selective 5-HT7 receptor antagonist. In contrast, dilation induced by the muscarinic agonist, methacholine (100 nmols) was not inhibited by SB269970. Serotonin (10 nmols) failed to dilate cremaster arterioles in 5-HT7 receptor knockout rats whereas arterioles in wild-type litter mates dilated to 1 nmol 5-HT, a response blocked by 1 μM SB269970. Quantitative RT-PCR revealed that cremaster arterioles expressed mRNA for 5-HT7 receptors. 5-HT7 receptors mediate dilation of small arterioles in skeletal muscle and likely contribute to 5-HT-induced hypotension, in vivo.

Skin Vascular Resistance Decreases during 5-HT-Induced Hypotension in the Rat.

A recognized vasodilator, the infusion of 5-hydroxytryptamine (5-HT, serotonin) decreases blood pressure through the reduction of total peripheral resistance in the rat. It is not clear which vascular beds/tissues are responsible for this fall. We hypothesized that an increase in blood flow within the skin, measured as an elevated temperature (T) in the thermoregulatory tail and paws, enables at least part of 5-HT-induced reduction in blood pressure through active vasodilation. The temperature of thermoregulatory regions of the skin of an anesthetized male, Sprague Dawley rats were measured using a Optris PI640 thermal camera. The blood pressure of the animal and the temperature of each paw and four locations along the tail (TL1-4) were recorded before, during, and after the infusion of 5-HT at a rate of 25 mg/min into a femoral vein. Contrary to our hypothesis, the temperature of the paws and tail was stable before and during 5-HT infusion and actually increased during the 15-min recovery period. This finding suggests that hyperemia of the skin circulation is not necessary for the fall in blood pressure observed with infused 5-HT, but that a reduction in cutaneous vascular resistance plays a part in the fall in total peripheral resistance.

5‐HT7 Receptors Mediate Dilation of Rat Cremaster Muscle Arterioles in vivo

Serotonin (5‐HT) infusion in vivo causes hypotension and a fall in total peripheral resistance (TPR) that is mediated by 5‐HT7 receptors. 5‐HT dilates small arterioles in skeletal muscle, a microcirculation that importantly contributes to TPR. However, the receptors that mediate this dilation have not been established. Therefore, we tested the hypothesis that 5‐HT7 receptors mediate the arteriolar dilation in the skeletal muscle microcirculation. Cremaster muscles of isoflurane‐anesthetized male Sprague‐Dawley rats were prepared for digital in vivo microscopy and superfused with physiological salt solution (PSS) at 34 °C. Bolus (1‐10 nmols) application of 5‐HT into the superfusate caused substantial dilation of 3rd to 5th order arterioles from 10 ± 1 to 27 ± 1 μm (n = 10 arterioles from 4 rats, p <0.0001) that recovered within 2‐3 min. Dilation to bolus application of 5‐HT was inhibited by superfusion with 1 μM SB269970, a selective 5‐HT7 receptor antagonist (diameter in SB = 9 ± 1 μm; diameter in SB + 5‐HT = 10 ± 1 μm; n = 10 arterioles from 4 rats; p = 0.8763). Similarly, steady‐state superfusion with 10‐30 nM of the 5‐HT1/7 receptor agonist 5‐carboxamidotryptamine (5‐CT) dilated 3rd‐5th‐order arterioles from 16 ± 3 to 37 ± 5 μm (n = 7 arterioles from 3 rats, p = 0.0004). This dilation was reversed (diameter in 1 μM SB269970 = 13 ± 2 μm, n = 7, p = 0.1479 vs. baseline) or blocked (diameter in 1 μM SB269970 + 10‐30 nM 5‐CT = 10 ± 2 μm, n = 7, p = 0.0005 vs. 5‐CT alone) by 1 μM SB269970. Dilation of arterioles to the muscarinic agonist, methacholine (MCH) was not inhibited by SB269970 verifying the specificity of the antagonist; arterioles dilated from 13 ± 2 μm to 25 ± 2 μm to 100 nmols MCH and dilated from 9 ± 2 μm to 32 ± 2 μm in response to MCH in the presence of 1 μM SB269970; n = 10 arterioles from 4 rats; p = 0.7232 vs. dilation in the absence of SB269970. Consistent with these data, pooled samples (4‐5 rats) of 1st and 2nd – order cremaster arterioles expressed message for 5‐HT7 receptors by quantitative real‐time PCR (CT = 36.4 ± 0.74, n = 3 pooled samples, p = 0.039 vs CT = 40). These data support our hypothesis that 5‐HT7 receptors mediate dilation of small arterioles in skeletal muscle and likely contribute to the observed hypotension when these receptors are engaged in vivo.

Abstract MP19: Endogenous 5-hydroxytryptamine May Regulate Skeletal Muscle Vascular Resistance In Normal Healthy Rats

Infusing low doses of 5-hydroxytryptamine (5-HT) into normal rats causes chronic (weeks to months) hypotension and a fall in total peripheral resistance. These effects are mediated by activation of 5-HT 7 receptors. Therefore, we generated 5-HT 7 receptor knockout rats (5-HT 7 KO) to explore possible cardiovascular effects of 5-HT 7 receptors under normal and pathophysiological conditions. We previously reported that healthy 5-HT 7 KO rats have normal blood pressure and total peripheral resistance at rest. This suggested that 5-HT 7 receptors plays no role in cardiovascular regulation under normal conditions. But total peripheral resistance is determined by multiple vascular beds that differ in their sensitivity to 5-HT. Others have indicated that 5-HT 7 receptors in the skeletal muscle vasculature are particularly sensitive to the effects of 5-HT. Therefore, we hypothesized that 5-HT 7 KO rats would show both reduced responsiveness to exogenous 5-HT and increased resting skeletal muscle vascular resistance. Experiments were performed in isoflurane-anesthetized, male Sprague-Dawley (SD) (n=6), 5-HT 7 wild-type (5-HT 7 WT) (n=5) and 5-HT 7 KO (n=6) rats at 7-8 months of age. Arterial pressure was measured with an aortic catheter. Blood flow to the hindquarters (mostly skeletal muscle) was measured with transit-time, ultrasound flowmetry. After 10 minutes of baseline hemodynamic measurements were obtained, 5-HT was infused iv at a rate of 25 μg/kg/min for 15 minutes, followed by a 15-minute recovery period. As expected, 5-HT 7 KO rats did not show a significant fall in hindquarter vascular resistance (HQVR) during 5-HT infusion, while SD and 5-HT 7 WT did. More importantly, HQVR at baseline was significantly (p < 0.05) higher in 5-HT 7 KO rats (16.0 ± 2.0 mmHg/ml/min) than in 5-HT 7 WT rats (10.9 ± 0.06 mmHg/ml/min) or SD rats (7.0 ± 0.03 mmHg/ml/min). These results support our hypothesis that in healthy (albeit anesthetized) rats, 5-HT 7 receptors reduce skeletal muscle vascular resistance.

Abstract P158: Preeminent Role of the Cardiorenal Axis in the Antihypertensive Response to an Arteriovenous Fistula: An In Silico Analysis

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to: 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After simulating a small fistula there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 weeks BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Further, when chronic resetting of atrial mechanoreceptors was prevented during the fistula RSNA decreased 7% and, along with the same 3-fold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared to the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.

Safety, hemodynamic effects, and detection of acute xenon inhalation: rationale for banning xenon from sport.

This study aimed to quantify the sedative effects, detection rates, and cardiovascular responses to xenon. On 3 occasions, participants breathed xenon (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) in a nonblinded design. Sedation was monitored by a board-certified anesthesiologist. During 70% xenon, participants were also verbally instructed to operate a manual value with time-to-task failure being recorded. Beat-by-beat hemodynamics were measured continuously by ECG, photoplethysmography, and transcranial Doppler. Over 48 h postadministration, xenon was measured in blood and urine by gas chromatography-mass spectrometry. Xenon caused variable levels of sedation and restlessness. Task failure of the self-operating value occurred at 60-90 s in most individuals. Over the first minute, 50% and 70% xenon caused a substantial reduction in total peripheral resistance (P < 0.05). All dosages caused an increase in cardiac output (P < 0.05). By the end of xenon inhalation, slight hypertension was observed after all three doses (P < 0.05), with an increase in middle cerebral artery velocity (P < 0.05). Xenon was consistently detected, albeit in trace amounts, up to 3 h after all three doses of xenon inhalation in blood and urine with variable results thereafter. Xenon inhalation caused sedation incompatible with self-operation of a breathing apparatus, thus causing a potential life-threatening condition in the absence of an anesthesiologist. Yet, xenon can only be reliably detected in blood and urine up to 3 h postacute dosing.NEW & NOTEWORTHY Breathing xenon in dosages conceivable for doping purposes (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) causes an initial rapid fall in total peripheral resistance with tachycardia and thereafter a mild hypertension with elevated middle cerebral artery velocity. These dose duration intervals cause sedation that is incompatible with operating a breathing apparatus and can only be detected in blood and urine samples with a high probability for up to ~3 h.

Early blood pressure response to isometric exercise is attenuated in obese individuals who have undergone bariatric surgery

ObjectiveBlood pressure (BP) reactivity to stress is predictive of the development of cardiovascular disease. Cardiovascular reactivity is attenuated in individuals after bariatric surgery; however, the underlying mechanisms are not completely understood. We hypothesized the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery when compared to obese adults and the reliance on total peripheral resistance (TPR) would be attenuated.MethodsTwenty‐six individuals [7 non‐obese (28±3 yrs, 23±1 kg/m2), 11 obese (33±2 yrs, 39±1 kg/m2), 8 post‐bariatric surgery (35±2 yrs, 29±1 kg/m2)] completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30‐s of exercise.ResultsCompared to non‐obese controls, obese adults exhibited a slower initial rise in BP (9.3± 3.9 vs 21.7±2.5 s) and higher peak BP change (Δ6.7±2.1 vs Δ11.9±2.1 mmHg) at the onset of isometric handgrip exercise (p&lt;0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery (14.0±4.1 s, Δ5.6±1.3 mmHg) and non‐obese controls (p&gt;0.05). Non‐obese controls exhibited an exercise‐mediated increase in CO whereas obese adults increased TPR (p&lt;0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery (p&gt;0.05). Low cardiac baroreflex sensitivity (BRS) and heart rate variability (HRV: SDNN, standard deviation of normal to normal R‐R intervals) at rest were related to smaller increases in CO (BRS: R=0.47, p&lt;0.01; SDNN: R=0.57, p&lt;0.01) and greater increases in TPR (BRS: R=−0.49, p=0.01; SDNN: R=−0.60, p&lt;0.01) during exercise.ConclusionsIn contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at the onset of isometric handgrip exercise. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest bariatric surgery attenuates BP reactivity to physical stress via improvements in the time‐course of hemodynamic responses and reflex autonomic adjustments.Support or Funding InformationNIH HL130339, NIH HL083947, NIH DK82424, NIH UL1 RR024150, Mayo Clinic Department of Anesthesiology, Mayo Foundation for Medical Education and ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Early blood pressure response to isometric exercise is attenuated in obese individuals who have undergone bariatric surgery.

Blood pressure (BP) reactivity is predictive of the development of cardiovascular disease. We hypothesized that the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery compared with obese adults and that the reliance on total peripheral resistance (TPR) would be attenuated. Twenty-six individuals (7 nonobese, 11 obese, 8 postbariatric surgery) completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform, and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30 s of exercise. Obese adults exhibited a slower rise in BP and higher peak BP at exercise onset compared with nonobese controls ( P < 0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery and nonobese controls ( P > 0.05). Nonobese controls exhibited an exercise-mediated increase in CO, whereas obese adults increased TPR ( P < 0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery ( P > 0.05). In contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at exercise onset. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest that bariatric surgery improves BP reactivity via changes in the time course of hemodynamic responses. NEW & NOTEWORTHY Bariatric surgery has been shown to reduce the blood pressure (BP) response to isometric handgrip exercise. By examining the time course of the BP response to exercise, we found, in contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at exercise onset, which is associated with a fall in total peripheral resistance and results in lower peak BP at the onset of isometric exercise. These data suggest that bariatric surgery improves BP reactivity via reflex autonomic adjustments.

Methylprednisolone Stiffens Aortas in Lipopolysaccharide-Induced Chronic Inflammation in Rats

IntroductionGlucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and auto-immune diseases. The current study investigated the effects of methylprednisolone (a synthetic glucocorticoid) on aortic distensibility and vascular resistance in lipopolysaccharide-induced chronic inflammation in male Wistar rats.MethodsChronic inflammation was induced by implanting a subcutaneous slow-release ALZET osmotic pump (1 mg kg−1 day−1 lipopolysaccharide) for either 2 or 4 weeks. Arterial wave transit time (τ) was derived to describe the elastic properties of aortas using the impulse response function of the filtered aortic input impedance spectra.ResultsLong-term lipopolysaccharide challenge enhanced the expression of advanced glycation end products (AGEs) in the aortas. Lipopolysaccharide also upregulated the inducible form of nitric oxide synthase to produce high levels of nitric oxide (NO), which resulted in vasodilation, as evidenced by the fall in total peripheral resistance (Rp). However, lipopolysaccharide challenge did not influence the elastic properties of aortas, as shown by the unaltered τ. The NO-mediated vascular relaxation may counterbalance the AGEs-induced arterial stiffening so that the aortic distensibility remained unaltered. Treating lipopolysaccharide-challenged rats with methylprednisolone prevented peripheral vasodilation because of its ability to increase Rp. However, methylprednisolone produced an increase in aorta stiffness, as manifested by the significant decline in τ. The diminished aortic distensibility by methylprednisolone paralleled a significant reduction in NO plasma levels, in the absence of any significant changes in AGEs content.ConclusionMethylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs.

5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved

Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10–9 M to 10–5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP.

Regional blood flow changes underlying the hypotensive action of 5‐HT:Studies using Doppler and Microsphere technologies

Serotonin (5‐hydroxytryptamine, 5‐HT) causes a sustained decrease in mean arterial pressure (MAP) and elicits a fall in total peripheral resistance (TPR) in normal conscious rats. We hypothesized that the decrease in TPR induced by 5‐HT is caused by relaxation (direct or indirect) of arteries serving one or more major regional vascular beds. Alzet pumps containing vehicle or 5‐HT (25 ug/kg/min) were implanted in male Sprague‐Dawley rats and 24 hours later the rats were anesthetized and underwent: 1) ear and tail blood flow measurements using Doppler to determine cutaneous vascular contribution; or 2) left ventricular injection of fluorescent microspheres (300,000 yellow green microspheres) to determine global organ blood flow. Infusion of 5‐HT increased ear (69.1±20.5% time‐controlled vehicle) and tail (23.5±2.5%) blood flow (Doppler) while elevating small intestinal (50% increase) flow (microsphere) over vehicle‐infused rats. In the microsphere experiments there was no alteration in blood flow by 5‐HT infusion (vs vehicle) in spleen, liver, lung, right or left kidney, leg muscle, abdominal skin, visceral fat or brain, and right and left kidney flows were statistically similar (R; 3.78±0.69 vs L: 4.00±0.74 ml/min/g tissue, p&gt; 0.05). These findings define the cutaneous and splanchnic vasculature as regions of interest to study the mechanism of 5‐HT ability to lower MAP and TPR. NIH HL081115.

Dissection of carotid sinus hypersensitivity: the timing of vagal and vasodepressor effects and the effect of body position

We assessed the timing of vagal and sympathetic factors that mediate hypotension during CSM (carotid sinus massage) in patients with carotid sinus hypersensitivity. We hypothesized that a fall in cardiac output would precede vasodepression, and that vasodepression would be exaggerated by head-up tilt. We performed pulse contour analyses on blood pressure recordings during CSM in syncope patients during supine rest and head-up tilt. In a subset we simultaneously recorded muscle sympathetic nerve activity supine. During supine rest, systolic blood pressure decreased from 150±7 to 107±7 mmHg (P<0.001) and heart rate from 64±2 to 39±3 beats/min (P<0.01). Cardiac output decreased with heart rate to nadir (66±6% of baseline), 3.1±0.4s after onset of bradycardia. In contrast, total peripheral resistance reached nadir (77±3% of baseline) after 11±1s. During head-up-tilt, systolic blood pressure fell from 149±10 to 90±11 mmHg and heart rate decreased from 73±4 to 60±7 beats/min. Compared with supine rest, cardiac output nadir was lower (60±8 compared with 83±4%, P<0.05), whereas total peripheral resistance nadir was similar (81±6 compared with 80±3%). The time to nadir from the onset of bradycardia did not differ from supine rest. At the onset of bradycardia there was an immediate withdrawal of muscle-sympathetic nerve activity while total peripheral resistance decay occurred much later (6-8s). The haemodynamic changes following CSM have a distinct temporal pattern that is characterized by an initial fall in cardiac output (driven by heart rate), followed by a later fall in total peripheral resistance, even though sympathetic withdrawal is immediate. This pattern is independent of body position.

Myogenic activity in autoregulation during low frequency oscillations

Lower body negative pressure (LBNP) was applied in eight human subjects to trigger low frequency oscillations in order to study the nature of functional coupling between the hemodynamic and autonomic nervous systems, with particular focus on how the myogenic response fits within this coupling. To this end muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were measured at baseline and during LBNP and were then examined in both the time and frequency domains. At the height of low frequency oscillations (~ 0.1 Hz) there was a strong coupling between all the five indices, marked by perfect alignment of their oscillatory frequencies. Results in the time domain show that a fall in MAP is followed by a fall in TPR at 1.58 s SD 0.69), a rise in heart rate at 2.64 s (SD 0.98), a rise in cardiac output at 3.72 s (SD 0.60), a peak in MSNA at 5.71 s (SD 1.27) and, finally, a rise in TPR at 7.13 s (SD 1.02). A possible interpretation of the latter is that a drop in MAP first triggers a drop in TPR via a myogenic response before the expected rise in TPR via a rise in MSNA. In other words, following a drop in arterial pressure, myogenic response controls vessel diameter before this control is taken over by MSNA. These findings provide a possible resolution of a longstanding conceptual argument against attributing a significant role for the myogenic response in blood flow autoregulation.

Decreases in splanchnic vascular resistance contribute to hypotensive effects ofl-serine in hypertensive rats

l-Serine administration reduces mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats rendered hypertensive by chronic oral treatment with the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). To determine if the fall in MAP was due to decreases in vascular resistance or cardiac output (CO), and to record regional hemodynamic effects, we measured the distribution of fluorescent microspheres to single bolus intravenous injections of l-serine (1 mmol/kg) in 14-wk-old male WKY, SHR, and l-NAME-treated WKY rats. MAP and total peripheral resistance (TPR) were significantly higher (P < 0.01), whereas CO was lower in l-NAME-treated WKY (P < 0.01) and SHR (P < 0.05). l-Serine administration led to a rapid fall in MAP (WKY 22%, l-NAME-WKY 46%, SHR 34%,) and TPR (WKY 24%, l-NAME-WKY 68%, SHR 53%), whereas CO was elevated. In WKY rats, l-serine induced an increase in blood flow only in the small intestine (53%) while it was more profound in several vascular beds of hypertensive rats [l-NAME-WKY: small intestine (238%), spleen (184%), diaphragm (85%), and liver (65%); SHR: small intestine (217%), spleen (202%), diaphragm (116%), large intestine (105%), pancreas (96%), and liver (93%)]. Pretreatment with a combination of apamin (a small calcium-activated potassium channel inhibitor) and charybdotoxin (an intermediate calcium-activated potassium channel inhibitor) abolished the l-serine-induced changes in blood flow and TPR. l-Serine acts predominantly on apamin- and charybdotoxin-sensitive potassium channels in the splanchnic circulation to increase blood flow, thereby contributing to the fall in TPR and the pronounced blood pressure-lowering effect of l-serine in hypertensive rats.

Automated Peritoneal Dialysis Has Significant Effects on Systemic Hemodynamics

Maintenance of residual renal function (RRF) is an important determinant of outcome in peritoneal dialysis patients. It remains contentious as to whether automated peritoneal dialysis (APD) leads to an increased rate of decline of RRF compared with continuous ambulatory peritoneal dialysis (CAPD). We studied whether APD was associated with significant systemic hemodynamic changes that may play a role in the accelerated loss of RRF. As a follow-on from a previous study, 8 well-established CAPD patients underwent a 4-hour APD treatment consisting of 3 drain/fill cycles using 2 x 2.5 L 1.36% glucose and 1 x 3.86% glucose dialysate. Each dwell phase lasted 76 minutes. Blood pressure (BP) and a full range of hemodynamic variables, including pulse (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR), were measured noninvasively using continuous arterial pulse wave analysis. BP fell during 2 of the 3 drain/fill periods when dialysate was drained from the peritoneal cavity, but then rose upon instillation of dialysate fluid. The fall in BP was associated with a fall in TPR, matched by an inadequate rise in SV and CO. Over the entire study period, TPR progressively rose to +53.4% above baseline (p = 0.032). Both SV and CO fell over the same period, to -21.1% (p = 0.060) and -22.4% from baseline (p = 0.037) respectively. This did not result in any significant difference between start and end BP. This study demonstrates that APD is associated with significant systemic hemodynamic effects. The increased number of drain/fill cycles compared to CAPD, or the progressive rise in TPR and reduction in CO (possibly due to a cooling effect), may potentially be factors that adversely affect RRF in APD patients.

In vivo interaction of endotoxin and recombinant bactericidal/permeability-increasing protein (rBPI23): Hemodynamic effects in a human endotoxemia model

The cardiovascular derangement that results from the administration of endotoxin in healthy subjects is qualitatively similar to what is observed in patients in septic shock. The biological response to endotoxin is attributed in part to cytokine release. In experimental endotoxemia, recombinant bactericidal/permeability increasing protein (rBPI23) has shown a protective effect by binding endotoxin with the subsequent inhibition of the endotoxin-induced cytokine release and of neutrophil activation. In a controlled, blinded crossover study the early cardiovascular effects of rBPI23 were investigated in an experimental endotoxemia model in humans. The beat-to-beat changes in arterial pressure and cardiac output following infusion of endotoxin (40 EU/kg body weight) and rBPI23 (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg) were studied for 2 hours in 8 healthy male adults. Endotoxin or rBPI23 alone did not induce significant cardiovascular changes. Endotoxin following rBPI23 infusion elicited a fall in total peripheral resistance with its nadir after 4 minutes to 40% (range 16-53; P <.001) of control level. Mean arterial pressure showed little change, and the fall in total peripheral resistance was associated with a reflex increase in heart rate and cardiac output (32%; range 43-106). Changes in cardiovascular variables in the subsequent 2 hours were not significant. In vitro activation of the contact system by, respectively, rBPI23, LPS, and LPS-rBPI23 complexes was assessed. Following incubation with rBPI23, LPS, and LPS-rBPI23 complexes, complex levels were generated at levels comparable to those observed in the buffer control. The rapid vasodilatation by endotoxin administered concomitantly with rBPI23 is not mediated by complement or contact system activation. The early vasodilatation is compensated by an increase in cardiac output, which therefore does not result in arterial hypotension. The monitoring of continuous cardiac output allows for the detection of rapid effects on systemic flow and conductance that go unnoticed in a recording of arterial pressure. (J Lab Clin Med 2002;140:228-35)

Hemodynamic responses to hypoxia and hypercapnia during acute normovolemic hemodilution in anesthetized cats.

The present study was undertaken to evaluate the effects of hypoxia and hypercapnia on circulatory parameters during acute normovolemic hemodilution. Cats anesthetized with a mixture of alpha-chloralose and urethane were maintained by positive pressure ventilation. Muscles were paralysed by intramuscular vecuronium (0.1 mg/kg) to eliminate reflex respiratory movements. Cats were exposed to hypoxia (12% O(2) and 7% O(2)) and hypercapnia (4% CO(2) and 7% CO(2)) at normal hematocrit (Ht 40.1 +/- 2.8%) and then at graded levels of normovolemic hemodilution (Ht 24.0 +/- 2.0% and Ht 13.0 +/- 1.5%, respectively). Left ventricular pressure (LVP), LV dP/dt(max), arterial blood pressure (ABP), heart rate (HR), and right atrial pressure (RAP) were recorded on a polygraph. Cardiac output (CO) was measured using a cardiac output computer. Hemodilution per se did not produce any significant change in ABP, RAP or LV dP/dt(max), however, it produced a significant rise in HR and a significant fall in total peripheral resistance (TPR). Exposure to hypoxic gas mixtures caused significant increases in HR and CO at control Ht; but after hemodilution it caused the reverse effects. Hypercapnia did not produce any significant effect on ABP, LV dP/dt(max) or RAP either at control Ht or after hemodilution. Hypercapnia produced a fall in HR, CO and stroke volume (SV) at normal Ht and percent fall in HR response was enhanced following hemodilution. The reversal of chronotropic response to hypoxia and enhanced bradycardia response to hypercapnia, under conditions of acute normovolemic hemodilution would be deleterious as the tissues would become more hypoxic. Such a response may be attributed to altered control mechanisms under such conditions of severe stress.

Effects of Calcium Entry Blockers on Distribution of Blood Volume

To evaluate the effects on hemodynamics and the distribution of blood volume of various calcium entry blocker (CEB) agents, we invasively studied 24 hypertensive patients before and after treatment with isradipine, diltiazem, and verapamil. All three agents reduced arterial pressure through a significant fall in total peripheral resistance without causing reflex tachycardia, while preserving stroke volume and cardiac output. Verapamil reduced the central blood volume (CBV) and the ratio of CBV to total blood volume (TBV) in the supine position ( P < .05), suggesting peripheral venodilatation. Isradipine and verapamil modified the responses to head-up tilt. The orthostatic decrease in stroke volume was accentuated following treatment, and it was associated with a greater fall in the ratio of CBV to TBV, suggesting that these two agents attenuate the reflex venoconstriction induced by postural change. In contrast to verapamil and isradipine, diltiazem did not affect volume distribution in the supine or head-up positions. These results suggest that the effect of CEBs varies in order of venodilatory effect from verapamil to isradipine to diltiazem, with verapamil having the greatest effect. Am J Hypertens 1996;9:628–632

Production by R-alpha-methylhistamine of a histamine H3 receptor-mediated decrease in basal vascular resistance in guinea-pigs.

1. The effect of the selective histamine H3 receptor agonist, R-alpha-methylhistamine given intravenously (10-100 micrograms kg-1) was examined on baseline total peripheral resistance (TPR), and cardiovascular haemodynamics in bilaterally vagotomized, anaesthetized guinea-pigs. 2. R-alpha-methylhistamine produced a dose-dependent hypotension and fall in TPR at 30 and 100 micrograms kg-1. A decrease in heart rate (HR) was observed at a dose of 100 micrograms kg-1. R-alpha-methylhistamine (10-100 micrograms kg-1) also produced a dose-dependent fall in rate pressure product (RPP). There was no effect on cardiac output (CO) or stroke volume (SV) at these doses. 3. Histamine H1 and H2 blockade in animals pretreated with a combination of chlorpheniramine (0.3 mg kg-1) and cimetidine (3.0 mg kg-1) did not alter the haemodynamic actions of R-alpha-methyl-histamine (100 micrograms kg-1, i.v.). Pretreatment with the selective H3 antagonist, thioperamide (1 mg kg-1), completely blocked the action of R-alpha-methylhistamine on haemodynamic parameters. 4. To study the mechanism of action of R-alpha-methylhistamine, the vasodilator hydralazine (1 mg kg-1, i.v.) was used. Hydralazine lowered BP, TRP and RPP in guinea-pigs pretreated with ipratropium (50 micrograms kg-1, i.v.). Hydralazine had no effect on HR, SV or CO. 5. R-alpha-methylhistamine (100 micrograms kg-1) did not affect the vasopressor action and increases in TPR produced by adrenaline (1 and 3 micrograms kg-1). On the other hand, the vasodilator hydralazine (1 mg kg-1, i.v.) inhibited the effects of adrenaline (3 micrograms kg-1) on TPR and RPP. The effect of both doses of adrenaline on BP were attenuated by hydralazine. Therefore, the inhibitory effects of R-alpha-methylhistamine are not mediated through a direct action on vascular smooth muscle.6. In adrenalectomized guinea-pigs, R-alpha-methylhistamine (100 microg kg-1) produced a drop in BP and HR.There was no difference between the effects of R-alpha-methylhistamine on blood pressure and heart rate in adrenalectomized and non-adrenalectomized guinea-pigs.7. These results show that activation of peripheral H3 receptors lowers basal BP, HR and TPR, most likely by a peripheral prejunctional mechanism. The fall in BP and TPR is probably due to a decrease in noradrenaline release from sympathetic effector nerves innervating the resistance blood vessels.