Mean Intra-arterial Blood Pressure Research Articles

Continuous Blood Pressure Monitoring Using Nonpulsatile Photoplethysmographic Components for Low-Frequency Vascular Unloading

<italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Objective</i> : Continuous blood pressure (BP) monitoring gives a better understanding of a person’s cardiovascular health status than single BP measurements. The existing measurement techniques are often highly complex and expensive, or suffer from inaccuracies. We propose a simple yet effective technique for continuous blood pressure monitoring. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Methods</i> : Our method is based on the finding that the non-pulsatile (DC) component of the photoplethysmograph (PPG) correlates with blood pressure. By keeping the infrared PPG DC component constant by altering the applied external pressure using a feedback mechanism the BP can be measured continuously. This way the pressure read from the pressure sensor follows the mean intra-arterial BP. We call this low-frequency vascular unloading. We propose a method for assessing the measurement error introduced by changes in vasomotor tone. Green PPG was used for the vasomotor compensation method. We packaged the technology to a wearable finger-worn device similar to a pulse oximeter probe. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Results</i> : We measured over 90 minutes of continuous BP data from total of 7 subjects. The subjects were asked to perform different BP altering maneuvers during the measurement. The ability to track BP changes was verified by continuous mean arterial pressure (MAP) readings measured with the reference device (CNSystems CNAP 500) and our device, resulting in correlation of <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">r</i> = 0.894 and (( <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">mean</i> ± <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SD</i> ) mmHg) of (0.3±4.3) mmHg for mean arterial pressure. Without vasomotor tone compensation the results were with slightly less accurate: <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">r</i> = 0.83, (-1.4±5.1) mmHg. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Conclusion</i> : The proposed technology performed well compared to traditional vascular unloading technique while requiring significantly less complex control logic and no fast-switching pneumatics. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Significance</i> : The proposed technique is simple, yet effective, low-cost solution and it can be constructed from off-the-shelf components and miniaturized into a wearable form factor. The technique has potential in the field of health wearables and remote continuous BP monitoring for personalized health applications.

Comparing oscillometric noninvasive and invasive intra-arterial blood pressure monitoring in term neonates under general anesthesia: A retrospective study.

Oscillometric noninvasive blood pressure and/or invasive intra-arterial blood pressure are commonly used to measure the systolic, diastolic, and mean components of blood pressure. Agreement between the two methods has been reported in adults, children, and infants, but rarely in neonates, especially under general anesthesia. This retrospective study compared the agreement of each measured blood pressure value (oscillometric noninvasive or invasive intra-arterial blood pressure monitoring) in term neonates under general anesthesia. Data were collected from neonates born at ≥36weeks of gestation whose body weight was ≥2500g and who underwent abdominal or noncardiac thoracic surgery with both oscillometric noninvasive and invasive intra-arterial blood pressure measurements from January 2015 to March 2020. The primary outcome was the agreement of systolic, diastolic, and mean blood pressure values between the two methods using Bland-Altman analysis. Paired blood pressure measurements (n=1193) from 67 cases were compared. In Bland-Altman analysis, bias (standard deviation), 95% limits of agreement, and percentage error were -9.3 (8.4), -26.1-7.6, and 26.9% for systolic; 1.6 (6.5), -11.3-14.6, and 38.7% for diastolic; and -1.3 (5.8), -13.0-10.3, and 26.9% for mean blood pressure, respectively. During low blood pressure (intra-arterial mean blood pressure ≤30mmHg), the biases (standard deviation) of systolic, diastolic, and mean blood pressure were -11.4 (5.7), -0.7 (3.7), and -5.1 (4.2), whereas during high blood pressure (intra-arterial mean blood pressure ≥60mmHg), the values were 0.1 (9.7), 5.6 (9.4), and 6.4 (7.4), respectively. Based on the bias and percentage error, the mean blood pressure exhibited the most acceptable agreement between oscillometric noninvasive and invasive intra-arterial blood pressure monitoring in term neonates under general anesthesia. However, during hypertension or hypotension, there was a large discrepancy between the two methods.

Noninvasive measurement of arterial blood pressure in patients with continuous-flow left ventricular assist devices: a systematic review.

Accurate mean blood pressure determination is essential to prevent adverse events in patients with continuous-flow left ventricular assist devices (CFLVAD). We sought to evaluate the accuracy of noninvasive methods of blood pressure measurement compared with invasive intra-arterial recordings in patients with CFLVAD. Systematic electronic search was performed on four online databases (PubMed, Scopus, Embase, and Web of Knowledge) for the terms "Blood Pressure" AND ("Heart-Assist Devices" OR "Left ventricular Assist Devices"). Only studies that compared an intra-arterial and noninvasive blood pressure measurement were included. Electronic search of scientific literature identified 5968 articles. After deduplication, screening of titles and abstracts, full-text review, and excluding incorrect populations and comparator, a total of 12 studies with 502 participants were included, of those 402 participants who had intra-arterial blood pressure measurement. Doppler mean arterial blood pressure showed a very high correlation with mean intra-arterial blood pressure (r = 0.97, r = 0.87) in low pulsatility situations. When the pulsatility was not evaluated, the correlation was high moderate (r = 0.63, r = 0.741). In low pulsatility situations, the correlation was moderate to high moderate (r = 0.42 to r = 0.65). Oscillometer automatic blood pressure cuff showed a moderate to very high correlation with intra-arterial mean arterial blood pressure (r = 0.42, r = 0.86) but also could be low in the context of low pulsatility associated with inconsistent success in noninvasive measurement (r = 0.25). Studies correlating intra-arterial with noninvasive techniques were performed in the context of routine clinical care using fluid-filled catheters. The degree of correlation between both methods is at least moderate.

HP-01-004 The effects of antifibrotic agent-pirfenidone on penile cavernous function in experimental ischaemic priapism-induced rat model

Aim of the study was to assess the impact of an antifibrotic and anti inflammatory agent-pirfenidone in an experimental ischemic rat priapism model. 0Forty-eight male Albino-Wistar rats were randomized into four groups (n=12 in each group): Group-1 (non-priapism, no-medication), Group-2 (one-hour priapism, no-medication), Group-3 (one-hour priapism, six-weeks followup, no-medication), and Group-4 (one-hour priapism, six-weeks pirfenidone). Erection model was created by electrical stimulation of the cavernous nerve. The intracavernosal pressure (ICP) and the blood pressure were recorded (Fig. 1a). Degree of the fibrosis were evaluated as (+), (++), (+++), and (++++) using Masson's trichrome strain. Malondialdehyde (MDA) and reducted glutathione (GSH) levels were measured by spectrophotometric method. Statistical analyses were performed with SPSS program for windows. Group-2 and 3 showed marked cavernosal fibrosis following the formation of an ischemic priapism model. In contrast, Group-4 showed significant decrease in fibrosis compared to Group-3 (Fig. 1b). The mean basal ICP (BICP), maximum ICP (MICP), mean ICP (MeICP), the difference between MICP and BICP (DICP), area under curve (AUC), and the ratio of MeICP/ mean intraarterial blood pressure (MIBP) were recorded. In Group-2, all these parameters showed significant decrease compared to Group-1 (p<0.05). The mean MICP, MeICP and the MeICP/MIBP ratios significantly decreased in Group-3 compared to Group-1 (p<0.05). The mean BICP, MICP, MeICP, DICP, AUC, and MeICP/MIBP values were similar in Group-1 and 4 (p>0.05) (Fig. 1c). Group-4 showed a statistically significant decrease in cavernosal mean MDA levels compared to Group-3, (p<0.05). Group 4 showed a statistically significant increase in the mean GSH levels compared to Group-3 (p<0.05) (Fig. 1d).

Evidence in hypertensive rats of hypotensive effect after mandibular extension.

Previous studies in anesthetized normotensive rats demonstrated that a single mouth opening for 10 min obtained by an ad hoc dilator (mandibular extension [ME]) produced a blood pressure reduction by about 20 mmHg lasting for about 2 h and that once‐repeated ME prolonged this effect. We here describe these effects in hypertensive rats. Mean (intra) arterial blood pressure (MABP) and heart rate (HR) was followed for up to a maximum of 470 min after single or repeated 10 min‐lasting ME in two groups of anesthetized, male, 6–9 months old hypertensive rats. In one group, hypertension was induced by dexamethasone (20 μg/kg/day, subcutaneously for 7 days; Dex‐HT); the other group was spontaneously hypertensive rats (SHR). Studies were done, in Dex‐HT rats, after only surgical procedures (no ME, sham‐operated rats), single ME, early repeated (after 10 min) ME (ER‐ME) and late repeated (after 160 min) ME (LR‐ME) and, in SHR, after only surgical procedures and ER‐ME. One‐way ANOVA for repeated measures revealed no significant effect on MABP and HR in sham‐operated groups. In Dex‐HT rats, single ME was followed by a significant MABP decline by 25 mmHg, lasting for 100 min; ER‐ME and LR‐ME were followed by an even greater significant MABP decline by 40 mmHg, which outlasted the experimental observation period. In SHR, ER‐ME gave similar results as in Dex‐HT rats. HR significantly declined in all, except sham‐operated groups. In conclusions, ME is followed by a prolonged MABP decline also in hypertensive rats. This effect is even more pronounced, in length and magnitude, after repeated ME.

The CNAP™ Finger Cuff for Noninvasive Beat-To-Beat Monitoring of Arterial Blood Pressure: An Evaluation in Intensive Care Unit Patients and a Comparison with 2 Intermittent Devices

Continuous and intermittent noninvasive measurements of arterial blood pressure (BP) have not been compared in the same population. In a large panel of intensive care unit patients, we assessed the agreement between CNAP™ (Continuous Noninvasive Arterial Pressure) finger cuff beat-to-beat monitoring of BP and reference intraarterial measurements. Two automated oscillometric brachial cuff devices were also tested: CNAP brachial cuff (used for CNAP finger cuff calibration) and an alternative device. The performance for detecting hypotension (intraarterial mean BP <65 mm Hg or systolic BP <90 mm Hg), response to therapy (therapy-induced increase in mean BP >10%), and hypertension (intraarterial systolic BP >140 mm Hg) was evaluated. We also assessed the between-calibration drift of CNAP finger cuff BP in specific situations: cardiovascular intervention or no intervention. With each device, 3 pairs of noninvasive and intraarterial measurements were prospectively collected and analyzed according to current guidelines, the International Organization for Standardization (ISO) standard. The trending ability and drift of the CNAP finger cuff BP were assessed over a 15-minute observation period. In 182 patients, CNAP finger cuff and CNAP brachial cuff readings did not conform to ISO standard requirements (mean bias ± SD exceeding the maximum tolerated 5 ± 8 mm Hg), whereas the alternative automated brachial cuff succeeded for mean and diastolic BP. CNAP finger cuff trending ability was poor (concordance rate <70% over a 15-minute period) owing to a significant drift since calibration, especially if a cardiovascular intervention was performed (n = 75, -7.5 ± 10.2 mm Hg at the 14th minute, ie, before recalibration, versus -2.9 ± 7.9 mm Hg if no cardiovascular intervention occurred, n = 103, P = 0.0008). However, a similar and reliable performance was observed for the detection of hypotension with the CNAP finger cuff (within 4 minutes after calibration) and with the 2 automated brachial cuffs (area under the receiver operating characteristic curve ≥0.91, positive and negative likelihood ratios ≥5 and ≤0.20, respectively). The performance for the detection of response to therapy or of hypertension was slightly lower. In a large population of intensive care unit patients, CNAP did not fulfill the ISO criteria and exhibited a relevant between-calibration drift. However, CNAP measurements collected within 4 minutes after calibration were reliable for detecting hypotension, as were oscillometric devices, while providing beat-to-beat measurements. Interestingly, an alternative automated brachial cuff was more reliable than the native one, used for calibration. This information is important to clinicians using those devices and for further development of the CNAP technology.

Role of the Na+/H+exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines

The role of Na+/H+ exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3−/−) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3+/+) and tgNhe3−/− mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3−/− mice (P < 0.01). Basal glomerular filtration rate, 24 h urine excretion, urinary Na+ excretion, urinary K+ excretion, and urinary Cl− excretion were significantly lower in tgNhe3−/− mice (P < 0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na+/HCO3 cotransporter, the α1 subunit isoform of Na+/K+-ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex of tgNhe3−/− mice (P < 0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3+/+, as expected, but all of these responses to ANG II were attenuated in tgNhe3−/− mice (P < 0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension.

Flow-Mediated Dilation of the Radial Artery Is Offset by Flow-Induced Reduction in Transmural Pressure

Flow-mediated dilation of the brachial or radial artery in response to transient hyperaemic flow, the most widely used test of endothelial function, is only manifest after flow decays back to baseline. We examined whether this dissociation of flow and diameter might be explained by a reduction in transmural pressure generated by high flow. Studies were performed in healthy subjects 20 to 55 years of age. Flow-mediated dilation was measured in the radial artery using a standard protocol and after flow interruption at peak hyperemia during brachial artery infusion of saline and the NO synthase inhibitor N(G)-monomethyl-L-arginine (8 μmol/min). Flow interruption 20 seconds after cuff release (during high flow but no dilatation) produced an immediate increase in radial artery diameter of 5.36±2.12%, inhibited by N(G)-monomethyl-L-arginine to 1.09±0.67% (n=8; P<0.001). Mean intra-arterial radial blood pressure and, hence, transmural pressure fell after cuff release by a mean of 26±1.8 mm Hg (n=6; P<0.0001) at the time of peak hyperemic flow. Modulation of transmural pressure within the brachial artery by cuff inflation around the artery demonstrated that this fall is sufficient to reduce arterial diameter by an amount similar to flow-mediated dilation. These results suggest that flow-dependent, NO-dependent dilation is offset by a flow-induced fall in local arterial pressure and, hence, in transmural pressure. Shear related NO release is likely to play a greater role in the short-term regulation of arterial tone than that suggested by flow-mediated dilation.

Remodelling of mesenteric arteries in genetically hypertensive rats cross‐fostered from birth to normotensive Wistar rats

1. The effects of cross-fostering genetically hypertensive (GH) with normotensive (N) Wistar rats on the structure of mesenteric resistance arteries (MRA) in young (6 week old) and adult (18 week old) rats were investigated to see whether the abnormal remodelling known to exist in GH rats could be prevented by changing the maternal environment. 2. Genetically hypertensive and normotensive rat pups were reared either by their natural mothers or a foster mother of the opposite strain (NX and GHX) with fostering done within 24 h of birth. 3. Blood pressure (BP) was measured from age 6-18 weeks; at 6 and 18 weeks MRA structure was assessed. 4. At the time of death, intra-arterial mean BP was measured (via the femoral artery), after which MRA were fixed by perfusion (at the systolic BP of the rat) via the abdominal aorta, first with 75% Tyrode's solution containing heparin and papaverine, followed by 2% glutaraldehyde in 75% Tyrode's solution. Arteries were dissected out, processed and embedded in Technovit (Heraeus Kulzer, Werheim, Germany) and serial sections were cut and stained with Giemsa. 5. Stereological techniques were used to determine media width, lumen diameter and medial cross-sectional area (CSA); in addition, the ratio of media width to lumen diameter was calculated. Smooth muscle cell density was also calculated. 6. In MRA from 6-week-old rats, GH rats compared with N rats had increased media width and CSA and an increased ratio of media width to lumen diameter. 7. There were no significant changes in structure in the GHX group compared with GH rats. The NX group compared with N rats had increased media width and CSA and lumen diameter, but no change in the ratio of media width to lumen diameter. Smooth muscle cell density, reduced in GH compared with N rats, was increased (P < 0.001) in the NX group, but not changed in the GHX group compared with GH rats. 8. In 18-week-old GH rats compared with N rats, the MRA had a decreased media width and medial CSA and smaller lumen diameter, but there was no change in the ratio of media width to lumen diameter. 9. In the GHX group compared with GH rats, media width and CSA were reduced; in the NX group compared with N rats, media width was increased, lumen decreased and the ratio of media width to lumen diameter increased. Smooth muscle cell density was increased (P < 0.001) in the GHX group, but not in the NX group. 10. Changing the maternal environment significantly affected BP in GHX and NX groups up to 9-10 weeks of age but, in adult rats, the BP differences were no longer present. Thus, structural changes were seen at 6 weeks of age in MRA from NX rats and also at 18 weeks in GHX and NX rats (even though the BP differences were no longer significant); structural remodelling occurred independently of BP.

Perinatal salt restriction: a new pathway to programming insulin resistance and dyslipidemia in adult wistar rats.

Several studies support the hypothesis that chronic diseases in adulthood might be triggered by events that occur during fetal development. This study examined the consequences of perinatal salt intake on blood pressure (BP) and carbohydrate and lipid metabolism in adult offspring of dams on high-salt [HSD; 8% (HSD2) or 4% (HSD1)], normal-salt (NSD; 1.3%), or low-salt (LSD; 0.15% NaCl) diet during pregnancy and lactation. At 12 wk of age, female Wistar rats were matched with adult male rats that were fed NSD. Weekly tail-cuff BP measurements were performed before, during, and after pregnancy. After weaning, the offspring received only NSD and were housed in metabolic cages for 24-h urine collection for sodium and potassium and nitrate and nitrite excretion measurements. At 12 wk of age, intra-arterial mean BP was measured, a euglycemic-hyperinsulinemic clamp was performed, and plasma lipids and nitrate and nitrite concentrations were determined. Tail-cuff BP was higher during pregnancy in HSD2 and HSD1 than in NSD and LSD dams. Mean BP (mm Hg) was also higher in the offspring of HSD2 (110 +/- 5) and HSD1 (107 +/- 5) compared with NSD (100 +/- 2) and LSD (92 +/- 2). Lower glucose uptake and higher plasma cholesterol and triacylglycerols were observed in male offspring from LSD dams (glucose uptake: HSD2 17 +/- 4, HSD1 15 +/- 3, NSD 11 +/- 3, LSD 4 +/- 1 mg . kg(-1) . min(-1); cholesterol: HSD2 62 +/- 6, HSD1 82 +/- 11, NSD 68 +/- 10, LSD 98 +/- 17 mg/dL; triacylglycerols: HSD2 47 +/- 15, HSD1 49 +/- 12, NSD 56 +/- 19, LSD 83 +/- 11 mg/dL). In conclusion, maternal salt intake during pregnancy and lactation has long-term influences on arterial pressure, insulin sensitivity, and plasma lipids of the adult offspring.

Ramipril improves hemodynamic recovery but not microvascular response to ischemia in spontaneously hypertensive rats

Background Angiotensin converting enzyme (ACE) inhibition exerts positive effects on the microvasculature of normotensive animals, although this concept is not universally accepted. Recently, ACE inhibitors have been suggested to be useful for rescue in peripheral ischemia. Methods We investigated whether chronic treatment with the ACE inhibitor ramipril may have a positive impact on the defective healing response to ischemia that is typical of spontaneously hypertensive rats (SHR). Unilateral limb ischemia was induced in 20-week-old SHR by surgically removing the left femoral artery. Rats were allowed to regain consciousness and then were randomly allocated to treatment with ramipril (1 mg/kg body weight in drinking water) or vehicle for 28 days. Results The SHR failed to develop reparative angiogenesis in response to ischemia, thus having inadequate perfusion recovery. Ramipril reduced both tail-cuff systolic blood pressure (180 ± 7 v 207 ± 2 mm Hg in the vehicle group at 28 days, P < .05) and intra-arterial mean blood pressure (115 ± 6 v 135 ± 5 mm Hg in the vehicle group, P < .05). These effects were associated with increased responsiveness to endothelium-dependent vasodilatation by acetylcholine. Treatment with ramipril did not influence muscular capillary and arteriole density but accelerated the rate of perfusion recovery, leading to complete healing within 28 days after surgery. Conclusions These results indicate that ACE inhibition by ramipril may be useful for the treatment of peripheral vascular complications in hypertension.

Chronic hypertension alters the expression of Cx43 in cardiovascular muscle cells.

Connexin43 (Cx43), the predominant gap junction protein of muscle cells in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension on the expression of Cx43 in aorta and heart in three different models of experimental hypertension. Rats were made hypertensive either by clipping one renal artery (two kidney, one-clip renal (2K,1C) model) by administration of deoxycorticosterone and salt (DOCA-salt model) or by inhibiting nitric oxide synthase with N G-nitro-L-arginine methyl ester (L-NAME model). After 4 weeks, rats of the three models showed a similar increase in intra-arterial mean blood pressure and in the thickness of the walls of both aorta and heart. Analysis of heart mRNA demonstrated no change in Cx43 expression in the three models compared to their respective controls. The same 2K,1C and DOCA-salt hypertensive animals expressed twice more Cx43 in aorta, and the 2K, 1C rats showed an increase in arterial distensibility. In contrast, the aortae of L-NAME hypertensive rats were characterized by a 50% decrease in Cx43 and the carotid arteries did not show increased distensibility. Western blot analysis indicated that Cx43 was more phosphorylated in the aortae of 2K,1C rats than in those of L-NAME or control rats, indicating a differential regulation of aortic Cx43 in different models of hypertension. The data suggest that localized mechanical forces induced by hypertension affect Cx43 expression and that the cell-to-cell communication mediated by Cx43 channels may contribute to regulating the elasticity of the vascular wall.

Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo

We have investigated the role of cytochrome P450 (CYP-450) metabolites of arachidonic acid in the modulation of vascular reactivity to angiotensin II in vivo using an in situ blood-perfused mesenteric preparation in anaesthetized spontaneously hypertensive rats (SHR). Miconazole, a non-selective inhibitor of CYP-450 that inhibits both hydroxylation and epoxidation, substantially suppressed mesenteric vasoconstrictor responses to angiotensin II in SHR, but had no effect on responses to noradrenaline or sympathetic nerve stimulation. In normotensive Wistar–Kyoto (WKY) rats, miconazole caused only a modest suppression of vasoconstrictor responses to angiotensin II. N-Methylsulphonyl-12,12-dibromododec-11-enamide (DDMS), a new selective inhibitor of CYP-450 ω-hydroxylase activity, decreased mean intra-arterial blood pressure and significantly attenuated mesenteric angiotensin II-induced vasoconstrictor responses in SHR. Isolated mesenteric vessels were able to metabolize 14C-labelled arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) in vitro, and this was substantially inhibited by DDMS. The results from the present studies combined with the existing evidence that angiotensin II stimulates the release of 20-HETE, a CYP-450 metabolite of arachidonic acid, suggest that CYP-450-derived HETEs may be important mediators in angiotensin II-induced vasoconstriction. However, the development of more sensitive assays for the detection in vivo of 20-HETE in mesenteric vessels would be required to confirm these findings.

Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo

We have investigated the role of cytochrome P450 (CYP-450) metabolites of arachidonic acid in the modulation of vascular reactivity to angiotensin II in vivo using an in situ blood-perfused mesenteric preparation in anaesthetized spontaneously hypertensive rats (SHR). Miconazole, a non-selective inhibitor of CYP-450 that inhibits both hydroxylation and epoxidation, substantially suppressed mesenteric vasoconstrictor responses to angiotensin II in SHR, but had no effect on responses to noradrenaline or sympathetic nerve stimulation. In normotensive Wistar-Kyoto (WKY) rats, miconazole caused only a modest suppression of vasoconstrictor responses to angiotensin II. N-Methylsulphonyl-12, 12-dibromododec-11-enamide (DDMS), a new selective inhibitor of CYP-450 omega-hydroxylase activity, decreased mean intra-arterial blood pressure and significantly attenuated mesenteric angiotensin II-induced vasoconstrictor responses in SHR. Isolated mesenteric vessels were able to metabolize (14)C-labelled arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) in vitro, and this was substantially inhibited by DDMS. The results from the present studies combined with the existing evidence that angiotensin II stimulates the release of 20-HETE, a CYP-450 metabolite of arachidonic acid, suggest that CYP-450-derived HETEs may be important mediators in angiotensin II-induced vasoconstriction. However, the development of more sensitive assays for the detection in vivo of 20-HETE in mesenteric vessels would be required to confirm these findings.

Aortic connexin43 is decreased during hypertension induced by inhibition of nitric oxide synthase.

Connexin43 (Cx43), the predominant gap junction protein in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension induced by inhibition of nitric oxide synthase on the expression of Cx43 in aorta and heart as well as on the distensibility of the carotid artery. Administration of 0.4 g/L NG-nitro-L-arginine methyl ester (L-NAME) to rats in their drinking water for 4 weeks increased intra-arterial mean blood pressure, wall thickness of aorta and carotid artery (25%), and heart weight (17%). Analysis of heart mRNA demonstrated increased expression of the fetal skeletal alpha-actin and of atrial natriuretic peptide but not of Cx43. In contrast, Cx43 mRNA and protein were decreased by 50% in the aortas of L-NAME-treated rats that did not show increased carotid distensibility. Because these data contrasted with those obtained in the 2-kidney, 1 clip model of rat hypertension, which is characterized by increased arterial distensibility and Cx43 expression in aorta, we investigated by Western blot analysis the posttranslational modifications of Cx43. We found that Cx43 was more phosphorylated in the aorta of 2-kidney, 1 clip rats than in that of L-NAME or control rats, which indicated a differential regulation of Cx43 in different models of hypertension. The data suggest that the cell-to-cell communication mediated by Cx43 channels may help regulate the elasticity of the vascular wall.

Acute and chronic blood pressure response to recurrent acoustic arousal in rats

Repetitive episodic hypoxia every 30 sec administered chronically to Sprague-Dawley (SD) rats has been shown by previous studies to cause a sustained increase in daytime blood pressure (BP). Acoustic arousal in humans during wake or sleep produces an acute BP rise. The question then arises as to whether chronic episodic acoustic arousal applied with the same frequency and duration as episodic hypoxia induces elevated BP. We exposed 14-week-old (N = 10) SD rats in individual cages to recurrent buzzer noise (500 Hz, 100 dB) 6 out of every 30 sec, 7 h/day for 35 days. Ten other rats were placed in similar cages daily but not exposed to noise, to provide a sham condition. An infrared beam with a detector was positioned at the end of each cage. This allowed us to quantify motion by registering the number of times the rat broke the beam per 7 h period. Mean intraarterial BP was measured in unrestrained conscious animals at baseline and at the end of 35 days of their respective conditions. Acute episodic acoustic stimulation caused an immediate response in BP and heart rate. Habituation occurred in that the movement response to 120 noises per hour was 75% in hour one and 20% in hours two through seven on day one. The movement response was further reduced by day 35 but remained significantly higher than in animals not stimulated by noise. The cardiovascular response to noise also showed signs of habituation. Chronic noise stimulation produced no sustained increases in BP after 35 days of exposure.

Hypertension increases connexin43 in a tissue-specific manner.

Connexin43 (Cx43), a membrane protein involved in the control of cell-to-cell communication, is thought to play a role in the contractility of the vascular wall and in the electrical coupling of cardiac myocytes. The aim of this study was to investigate the effects of experimental hypertension on Cx43 expression in rat aorta and heart. Rats were made hypertensive after one renal artery was clipped (two kidney, one-clip renal model) or after the administration of deoxycorticosterone and salt (DOCA-salt model). After 4 weeks, all rats showed a similar increase in intra-arterial mean blood pressure and in the thickness of both the aortic wall and the heart. Northern blot analysis of aorta mRNA and immunolabeling for Cx43 showed that hypertensive rats expressed twice as much Cx43 in aorta as the control animals. In contrast, no difference in Cx43 mRNA or in the immunolabeled protein was observed in heart. The results show that rats exhibiting a similar degree of blood pressure elevation, as the result of different mechanisms, feature a comparable increase in Cx43 gene expression, which was observed in the aortic but not in the cardiac muscle. These data suggest that localized mechanical forces induced by hypertension are major tissue-specific regulators of Cx43 expression.

Hypertension differentially affects the expression of the gap junction protein connexin43 in cardiac myocytes and aortic smooth muscle cells.

Electrical and mechanical coupling of myocytes in heart and of smooth muscle cells in the aortic wall is thought to be mediated by intercellular channels aggregated at gap junctions. Connexin43 (Cx43) is one of the predominant membrane proteins forming junctional channels in the cardiovascular system. This study was undertaken to assess its expression during experimental hypertension. Rats were made hypertensive by clipping one renal artery (two-kidney, one-clip renal hypertension) or by administering deoxycorticosterone and salt (DOCA-salt hypertension). After four weeks, rats from both models showed a similar increase in intra-arterial mean blood pressure, as well as in the thickness of both aorta and heart walls. Northern blot analysis showed that, compared to controls, hypertensive rats expressed twice more Cx43 in aorta, but not in heart. These results suggest that localized mechanical forces induced by hypertension are major tissue-specific regulators of Cx43 expression.

Sleep and blood pressure: spontaneous baroreflex sensitivity in dippers and non-dippers.

Baroreflex sensitivity (BRS) increases during sleep, whereas arterial blood pressure falls. Some hypertensive patients do not have a nocturnal fall in blood pressure (non-dippers). The objective was to ascertain whether there is a difference between 24 h BRS values in dippers and non-dippers that might account for the difference in nocturnal blood pressure behaviour. In a group of consecutive untreated hypertensive patients undergoing 24 h ambulatory intra-arterial blood pressure (IABP) monitoring, 18 were non-dippers i.e., their mean IABP during sleep failed to drop by 10% of their waking IABP. Each non-dipper was matched for age and waking IABP with two dippers. The BRS had previously been assessed with the "Oxford' bolus phenylephrine technique; spontaneous BRS was assessed throughout the 24 h period by off-line computer analysis of spontaneous variations in IABP and R-R interval. In both groups there was a significant increase in spontaneous BRS during sleep (P < 0.0001 for dippers, P < 0.0001 for non-dippers). There was no significant difference between spontaneous BRS in dippers and non-dippers, when they were either awake or asleep. BRS did not differ significantly between dippers and non-dippers, when they were either awake or asleep. Changes in BRS during sleep are not likely to account for the abnormal dipping pattern in a minority of hypertensives and are not likely to contribute to the normally observed nocturnal fall in blood pressure.

Ambulatory intraarterial blood pressure in essential hypertension: Effects of age, sex, race, and body mass—the northwick park hospital database study

Twenty-four-hour recordings of intraarterial blood pressure (IABP) from 723 untreated hypertensive patients were analyzed for the effects of age, sex, race, and body mass index on the level of IABP and its circadian variation. Age had a highly significant positive relationship (P < .001) with the cuff systolic and diastolic blood pressures, with regression coefficients (SE) of +0.83 (0.07) and -0.24 (0.04) mm Hg/year, respectively. There was a similar (P < .001) positive relationship between age and 24-h mean systolic IABP, measuring +0.71 (0.07) mm Hg/year, but 24-h mean diastolic IABP did not increase significantly with age. There was a significant (P < .001) inverse relationship between age and 24-h mean heart rate (HR), at -0.17 (0.03) beats/min/year. Nocturnal fall in systolic and diastolic IABP, calculated as the difference between daytime and nighttime mean IABP, had a significant (P < .001) negative relationship with age. Nocturnal fall in HR, calculated similarly, also significantly (P < .001) decreased with age. Age did not affect long-term systolic and diastolic IABP variability but did decrease long-term HR variability significantly (P < .001). Hypertensive men and women of similar age, had comparable daytime mean systolic and diastolic IABP (P = .15 and P = .03 respectively), but women had significantly (P < .001) lower nighttime mean systolic and diastolic IABP than men. The nocturnal fall in systolic and diastolic IABP was significantly (P < .002) greater in women as compared to men. Women also had significantly (P < .01) greater long-term systolic and diastolic IABP variability than men. Women had significantly (P < .001) greater 24-h, daytime mean and nighttime mean HR than men. Twenty-four-hour, daytime and nighttime mean IABP were all significantly higher (P < .01) in Afro-Caribbeans as compared to whites and Asians. No significant differences were observed in the magnitude of nocturnal IABP fall or long-term IABP variability between the three races. Asians and Afro-Caribbeans had significantly (P < .001) lower nocturnal HR falls and long-term HR variability (P < .01) than whites. Body mass index (BMI) did not relate directly to the level of daytime blood pressure, clinic cuff, or daytime mean IABP, in either men or women. BMI did have a highly significant (P < .001) positive relationship with nighttime mean IABP in men, but not in women. The degree of nocturnal fall of IABP had a significant (P < .001) inverse relationship with BMI in hypertensive men.