Decrease In Total Peripheral Resistance Research Articles

Impact of calcium antagonists on the cardiovascular system: experience with lacidipine.

The evaluation of haemodynamic patterns in hypertensive patients by radionuclide techniques and a tomographic gamma camera has revealed differences between older and younger patients. In younger hypertensive patients, the hyperkinetic state is reflected in an increase in heart rate and, consequently, an increased cardiac index and left ventricular ejection fraction (LVEF) in comparison with normotensive controls. Older hypertensive patients, however, show a different haemodynamic pattern, with reduced systolic and diastolic function at rest compared with normotensive elderly people, and marked depression of cardiac reserve during exercise. Elderly hypertensive patients also show strikingly higher hyperresistance and reduced peripheral perfusion in comparison with younger hypertensive patients. These haemodynamic differences need to be taken into account when considering antihypertensive treatment. In a study in elderly hypertensive patients, lacidipine treatment (4 mg/day for 90 days) produced a significant decrease in total peripheral resistance and blood pressure, together with a reduction in left ventricular (LV) afterload and an increase in cardiac output and LVEF (tending towards normal values). The LV peak filling rate was also increased, and evaluation of systolic and diastolic cardiac reserve during exercise showed positive changes in cardiac performance. The haemodynamic changes with lacidipine were similar to those produced by other long-acting dihydropyridines [nifedipine gastrointestinal therapeutic system (GITS) and nitrendipine], but changes occurring with nisoldipine were less significant. The reduction in left ventricular hypertrophy (LVH) is an obvious goal of antihypertensive therapy, and several studies have demonstrated the effectiveness of lacidipine treatment in decreasing LVH in hypertensive patients. In hypertensive patients with associated LV dysfunction, favourable effects on global parameters of LV function similar to those with amlodipine have been noted with lacidipine. Myocardial blood flow was strikingly increased during lacidipine treatment and coronary resistance was significantly decreased, both at baseline and after maximal vasodilatation with dipyridamole. Thus, lacidipine's vasodilatory and anti-ischaemic profile makes it an appropriate choice for the treatment of hypertension.

Effect of Kampo formulations (traditional Chinese medicine) on circulatory parameters.

The pharmacological action of 6 main Kampo formulations (1.Mao -to: [Japanese pictograph see text] MA HUANG TANG; 2. Shimbu -to: [Japanese pictograph see text]: ZHEN WU TANG; 3. Ninjin -to: [Japanese pictograph see text] : REN SHEN TANG; 4.Shigyaku-san: [Japanese pictograph see text] : SI NI SAN; 5.Keishi-to: Japanese pictograph see text] : GUI ZHI TANG; 6. Shimotsu - to: [Japanese pictograph see text] : SI WU TANG) on circulatory and autonomic nervous system were studied. 7 healthy adult males( age, 22.3 +/- 1.8 years old ) had 6 basic Kampo formulations, followed by noninvasive measurement of systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP), heart rate (HR), stroke volume (SV), cardiac output (CO ), cardiacindex (CI), total peripheral resistance (TPR) by means of systolic area method of brachialsphygmography, every 30 minutes for 2 hours. As results, Mao - to induced an increase of BP,HR,SV,CO and CI, but a decrease of TPR. Keishi - to induced an increase of SBP and SV, and Shimotsu-to induced an increase of DBP and MBP, HR was slowed during former period after oral administration of Shigyaku - san, and later period after oral administration of Shimbu-to and Shimotsu-to. Regarding autonomic activity, Mao-to(former period of experiment ), Shimbu - to and Shimotsu-to induced supression of sympathetic activity, on the other hand, Mao-to (later period of experiment ) and Shiyaku - san showed a tendency of parasympathomimetic action. Mao -to induced the strongest activation of circulatory system of 6 main farmulations, and showed change of autonomic nervous activity, however, the change of circulatory and automonic nervous activity were not coincident each other. It was speculated that comprehensive mechanism of Mao-to were not only dependent of ephedrin, main active constituent of Mao, but also dependent on Keishi's vasodilatory action in it. Ninjin -to showed no actions on circulatory or autonomic system. This is indicated that there are difference of actions on circulatory and autonomic nervous system among 6 main Kampo fromulations.

Postexercise decrease in arterial blood pressure, total peripheral resistance and in circulatory responses to brief hyperoxia in subjects with mild essential hypertension.

The objective of our study was: (1) to compare the influence of moderate exercise on circulatory after-response in mildly hypertensive (n = 8) and normotensive male subjects (n = 9); (2) to examine the circulatory response to 3-min hyperoxic inactivation of arterial chemoreceptors at rest and during postexercise period in both groups. Hypertensive men (HTS) with a systolic blood pressure (SBP) 148 +/- 5 mm Hg, diastolic blood pressure (DBP) 92.4 +/- 4 mm Hg; and normotensive men (NTS), with a SBP 126 +/- 3 mm Hg, DBP 75.6 +/- 1.3 mm Hg, were submitted to 20-min of moderate exercise on a cycloergometer (up to the level of 55% of each subject's resting heart rate reserve). Finger arterial BP was recorded continuously with Finapres, impedance reography was used for recording stroke volume, cardiac output and arm blood flow. In HTS a significant decrease in SBP by 14.5 +/- 3.4 mm Hg, DBP by 8.9 +/- 1.9 mm Hg, total peripheral resistance (TPR) by 0.45 +/- 0.05 TPR u. (33.7 +/- 2.7%), and in arm vascular resistance (AVR) by 11.0 +/- 2.7 PRU u. (35.6 +/- 7%), was observed over a 60-min postexercise period. NTS exhibited insignificant changes in SBP, DBP, AVR except a significant decrease in TPR limited only to 20-min postexercise period. Hyperoxia decreased SBP, DBP and TPR in HTS. This effect was significantly attenuated during the postexercise period. Long-lasting antihypertensive effect of a single dynamic exercise in HTS suggests that moderate exercise may be applied as an effective physiological procedure to reduce elevated arterial BP in mild hypertension. We suggest also that the attenuation of the sympathoexcitatory arterial chemoreceptor reflex may contribute to a postexercise decrease in arterial BP and in TPR in mildly hypertensive subjects.

Chronic regulation of arterial blood pressure by ANP: role of endogenous vasoactive endothelial factors.

Atrial natriuretic peptide (ANP) exerts a chronic hypotensive effect due to a decrease in total peripheral resistance (TPR). This study examines if chronic ANP-dependent vasodilation is attributable to differences in the cardiovascular regulatory activity of vascular endothelium (VE), based on evidence that ANP affects synthesis/release and target cardiovascular effects of endothelin-1 (ET-1), C-type natriuretic peptide (CNP), and nitric oxide (NO). To determine if the synthetic activity of resistance vasculature VE is chronically altered by plasma ANP activity, we measured ET-1, CNP, and endothelial constitutive NO synthase (ecNOS) concentration and total NOS enzyme activity in homogenates of kidney, heart, lung, hindquarter skeletal muscle, and brain from hypotensive transgenic mice with elevated plasma ANP, hypertensive knockout mice (-/-) characterized by the absence of ANP, and the corresponding normotensive wild-type (NT, +/+) mice. Tissue distribution and abundance patterns of ET-1, CNP, ecNOS, and NOS enzyme activity were comparable between the different genotypes and did not differ significantly between mutant and control mice. Antagonism of ETA/B receptors in -/- and +/+ mice in vivo with SB-209670 reduced arterial blood pressure (ABP) significantly and comparably in both genotypes (-27 +/- 4 and -25 +/- 2% change for -/- and +/+ mice, respectively) independent of any significant changes in heart rate (HR) (-6 +/- 8 and -4 +/- 4% change for -/- and +/+ mice, respectively). Immunoneutralization of CNP-specific guanylate cyclase-linked receptors (GC-B) with monoclonal antibodies (3G12) increased ABP slightly, but not significantly, by similar relative amounts in both -/- (10 +/- 6% change) and +/+ mice (8 +/- 3% change), without changing HR significantly (4 +/- 1% change for both +/+ and -/- mice). Inhibition of NOS activity (by NG-nitro-L-arginine methyl ester) significantly increased ABP, but the changes were comparable between -/- (53 +/- 5% change) and +/+ mice (50 +/- 6% change) and occurred in the absence of significant changes in HR (-1 +/- 5 and 7 +/- 5% change for -/- and +/+ mice, respectively). We conclude that the differences in ABP associated with chronic variations in endogenous ANP activity are not due to alterations in synthesis or responsiveness of the cardiovascular system to the effects of ET-1, CNP, or NO.

Effect of benidipine on microvascular remodeling and coronary flow reserve in two-kidney, one clip Goldblatt hypertension.

To determine whether chronic treatment with benidipine, a calcium antagonist, leads not only to regression of left ventricular hypertrophy, but also to an improvement in coronary flow reserve and microvascular remodeling. Two-kidney, one clip Goldblatt hypertensive rats were assigned either to a benidipine-treatment group or to a group without treatment after their kidneys had been clipped for 4 weeks. Benidipine was administered to rats in the treatment group for 6 weeks. At the end of the treatment, the systemic hemodynamics and coronary blood flow were determined in conscious unrestrained rats by using nonradioactive colored microspheres injected through the left atrium. The coronary blood flow was determined in rats of both groups with the rats at rest and after near-maximal vasodilatation induced by carbochrome. For evaluation of the microvascular remodeling capillary density, the wall : lumen ratio of arterioles and perivascular fibrosis were quantified by using an image analyzer after fixation of heart tissue. Benidipine treatment lowered the blood pressure significantly with a decrease in total peripheral resistance, and the left ventricular mass decreased markedly compared with that of untreated hypertensive rats. The coronary flow reserve of the untreated hypertensive rats was lower than that of the controls, but benidipine treatment improved the coronary flow reserve. We found a significant decrease in capillary density, and significant increases in wall : lumen ratio and perivascular fibrosis in untreated hypertensive rats. These changes in microvasculature were improved by benidipine treatment. Taken together, these results suggest that benidipine exerts favorable effects as an antihypertensive drug by reversing cardiac hypertrophy and improving the coronary flow reserve and microvascular remodeling.

Effects of polymerization on the hypertensive action of diaspirin cross-linked hemoglobin in rats

It is believed that the hypertensive effect of diaspirin crosslinked hemoglobin, a viable blood substitute, can be resolved by polymerization, which reduces the diffusion of this derivative into the interstitial space between nitric oxide-producing endothelium and the target vascular smooth muscle. We studied the systemic and renal responses to infusion of three cell-free human hemoglobins in anesthetized isovolemic rats: unmodified (HbAO), crosslinked (α-DBBF), and polymerized crosslinked (poly α-DBBF). HbAO produced a significant increase in mean arterial blood pressure (MAP) throughout the 60-minute infusion. α-DBBF, on the other hand, produced a more marked and prolonged increase in MAP over 120 minutes. Only a moderate increase in MAP was observed in rats after a 30-minute infusion with poly α-DBBF. The extent of renal insufficiency produced by these proteins, as determined by the glomerular filtration rate, was in the following order: HbAO > poly α-DBBF > α-DBBF. Infusion of poly α-DBBF, under hypovolemic but not isovolemic conditions in rats, produced an increase in heart rate, cardiac output, and stroke volume and a decrease in total peripheral resistance after 60 minutes. Chemical polymerization to increase the size of α-DBBF does not appear to improve its hemodynamic properties in rats, especially under partial exchange transfusion, a more clinically relevant indication for a hemoglobin-based blood substitute.

Changes in hemodynamics, ventricular remodeling, and ventricular contractility during normal pregnancy: A longitudinal study

To investigate the hemodynamic changes occurring in normal pregnancy and to see if these changes were associated with an increase in myocardial contractility. In a longitudinal study, primigravidas were studied with echocardiography in early (15 +/- 1.8 weeks), mid (26 +/- 1.2 weeks), and late (36 +/- 1.0 weeks) gestation, as well as at 6 weeks postpartum. Cardiac dimensions were measured with two-dimensional and M-mode echocardiography and hemodynamic indices were calculated. All measurements were made with subjects in the left lateral decubitus position. Statistical analysis was performed with repeated measures analysis of variance. Seventy-six women with normal pregnancy outcomes completed all four studies. From the baseline study to late gestation, an increase in cardiac output of 27% (from [mean +/- standard error] 4.2 +/- 0.1 to 5.8 +/- 0.2 L/min, P = .001), and a decrease in total peripheral resistance of 33% (from 1356 +/- 69 to 941 +/- 37 dynes/second cm-5, P = .001) occurred. Over this same time period, left ventricular function, while demonstrating a small and non-significant increase in velocity of circumferential fiber shortening (from 1.25 +/- 0.02 to 1.27 +/- 0.02 cm/second), revealed a 12% decrease in wall stress (from 36.3 +/- 1.0 to 31.9 +/- 1.0 g/cm2, P = .001) and a 13% decrease in the load-independent wall stress to velocity of circumferential fiber shortening ratio (from 30.0 +/- 1.2 to 26.1 +/- 1.0, P = .01), implying enhanced intrinsic myocardial contractility. Normal pregnancy is characterized by enhanced myocardial performance.

Stroke volume response to cycle ergometry in trained and untrained older men.

The aims of this study were threefold: (1) to investigate the stroke volume (SV) response of trained older male cyclists [Cyclists: 65 (2.1) years, n = 10] during incremental cycle ergometry (20 W.min-1); (2) to determine the SV dynamics and total peripheral resistance response of untrained, but healthy and active older male controls [ 66 (1.1) years; n = 10]; (3) to compare the maximum oxygen consumption (VO2max) and SV response of trained older male runners [Runners: 65 (3.4) years; n = 11] with that of age-matched Cyclists. Impedance cardiography was used to assess the response of cardiac output (CO), SV and total peripheral resistance to exercise involving cycle ergometry. The mean VO2max of the trained Cyclists [54 (1.6) ml.kg-1.min-1] was significantly higher (P < 0.05) than that of the Runner [48 (3.9) ml.kg-1.min-1], whereas both groups possessed a significantly higher VO2max than the CONTROLS [28 (1.3) ml.kg-1.min-1]. During exercise, at a heart rate of 90 beats.min-1, the SV of the Cyclists increased by 41%, that of the Runners increased by 47%, and that of the CONTROLS increased by 31%. However, the Cyclists' and Runners' SV response was significantly greater than that of the CONTROLS. The SV for cyclists and controls peaked at 30% of VO2max. This early increase in SV was a major factor underlying the increase in CO during exercise in both the trained and the untrained subjects. In addition, all three groups showed a significant decrease in total peripheral resistance throughout exercise. The finding that older male runners possessed a large exercise SV and high VO2max suggests that run training results in enhanced cardiovascular performance during cycle ergometry.

In vivo evidence of positive inotropism of EMD 57033 through calcium sensitization.

The previous separation of the racemic cardiotonic thiadiazinone derivative EMD 53998 yielded two enantiomers with different pharmacologic properties: EMD 57,033, a potent Ca2+ sensitizer with some residual phosphodiesterase III (PDE III) inhibition, and EMD 57,439, a pure PDE III inhibitor. Although numerous in vitro studies demonstrated the ability of EMD 57,033 to increase the responsiveness of cardiac contractile proteins to Ca2+, in vivo evidence for such an action is lacking. Because there is no possibility of directly proving Ca2+ sensitization in vivo, we attempted to exclude PDE III inhibition as a major contributing component of the positive inotropic action of EMD 57,033. In anesthetized rats, EMD 57,033 increased left ventricular (LV) first derivative of change in systolic pressure over time (dP/dt max) without affecting blood pressure. In contrast, the PDE III-inhibitory enantiomer EMD 57,439 decreased blood pressure. The pattern of hemodynamic effects in anesthetized dogs revealed similar differences between EMD 57,033 and PDE inhibitors. Thus the increase in LV dP/dt max in response to EMD 57,033 was not accompanied by changes of heart rate and blood pressure. As expected for PDE inhibitors, pimobendan and milrinone increased cardiac contractile force in dogs, concomitant, however, with tachycardia, hypotension, and a decrease in total peripheral resistance. When regional contractility was measured separately in two different areas of the dog myocardium, the positive inotropic action of the PDE inhibitors pimobendan and milrinone was antagonized by local coronary infusion of acetylcholine. The cardiotonic effect of the Ca2+ sensitizer EMD 57,033 was entirely resistant to inhibition by acetylcholine. In conscious dogs, beta-blockade markedly attenuated the increase in LV dP/dt max produced by two different doses of the PDE III inhibitor EMD 57,439. In contrast, a dose of EMD 57,033 equieffective in positive inotropic action with the lower dose of EMD 57,439 remained unaffected by < b tau-blockade. We concluded (a) that EMD 57,033 increases cardiac contractile force in two species in vivo, (b) that this action is independent of the cardiac cyclic adenosine monophosphate (AMP) system, (c) that EMD 57,033 does not reduce blood pressure and increase heart rate, an action indicative of PDE inhibition, and (d) that, on the basis of numerous previous in vitro findings, the mechanism of action of EMD 57,033, also in vivo, is consistent with sensitization of the cardiac myofibrils to Ca2+. Of special importance is the finding that this Ca2+ sensitizer at appropriate doses may be able to improve systolic function without adverse effects on diastolic function, as indicated by a slight decrease in left ventricular end-diastolic pressure.

Cardiovascular Effects of a Trandolapril/Verapamil Combination in Patients With Mild to Moderate Essential Hypertension

The cardiovascular effects of a combination of trandolapril and verapamil were evaluated in 14 patients with mild to moderate essential hypertension. This combination therapy decreased arterial pressure mainly through a decrease in total peripheral resistance without causing an increase in heart rate or cardiac output: left ventricular mass was significantly reduced, cardiac systolic function improved, and plasma volume and renal blood flow remained unchanged.

Physiological characteristics and hormonal profile of young normotensive men with exaggerated blood pressure response to exercise.

Exaggerated blood pressure (BP) response to exercise in normotensive subjects is considered as a predictor of future hypertension. The aim of the study was to find out whether elevated BP response to exercise is associated with any other haemodynamic, metabolic or hormonal abnormalities. Abnormal BP response to exercise, i.e. systolic BP (SBP) > 200 mmHg at 150 W or lower workload, was found in 37 out of 180 normotensive, male students, aged 20-24 years. Fifteen students with elevated exercise BP (group E) volunteered for further examinations. Their resting and ambulatory BP showed high normal values. Eight of them had a family history of hypertension. Four subjects met the criteria of cardiac hypertrophy. Significant correlations were found between exercise SBP and left ventricular mass index, average 24 h and daytime SBP recordings. In comparison with normal subjects of the same age (group N, n = 13), those from group E did not differ in body mass index, plasma lipid profile, fasting glucose, insulin and catecholamine (CA) concentrations, but had increased erythrocyte sodium content, slightly elevated plasma renin activity and cortisol level. During exercise, E subjects showed greater cardiac output (CO) increases with normal heart rate, total peripheral resistance (TPR) and plasma CA. There were no significant differences between groups in haemodynamic and plasma CA responses to posture change from supine to standing. Glucose ingestion (75 g) caused smaller increases in CO and smaller decreases in TPR in E than in N subjects without differences in BP, blood glucose plasma insulin and CA. It is concluded that young normotensive men with exaggerated BP response to exercise show some other characteristics that may be considered as markers of predisposition to hypertension or factors promoting the development of hypertension.

Hemodynamic profile of activation of histamine H 3 receptors by R-α-methylhistamine in the guinea pig

1. 1. The effect of R-α-methylhistamine, a histamine H 3 receptor agonist, was studied on cardiovascular hemodynamics in bilateral vagotomized, anesthetized guinea pigs. 2. 2. R-α-methylhistamine (100 μg/kg, IV) a dose that selectively activates histamine H 3 receptors, produced hypotension and bradycardia. Total peripheral resistance (TPR) and rate pressure product (RPP) were also decreased at this dose. 3. 3. Pretreatment with the ganglionic blocker hexamethonium (20 mg/kg, IV) blocked the blood pressure (BP), heart rate (HR), TPR, and RPP effects of R-α-methylhistamine (100 μg/kg, IV). Hexamethonium did not block the hypotensive and TPR lowering actions of the muscarinic agonist methacholine (1 and 3 μg/kg, IV). 4. 4. Pretreatment with the α 1-adrenoceptor antagonist prazosin (0.5 mg/kg IV), blocked R-α-methylhistamine's (100 μg/kg, IV) effects on BP, TPR, and RPP. Prazosin did not antagonize the bradycardia effect of R-α-methylhistamine. 5. 5. Pretreatment with the β-adrenoceptor antagonist atenolol (1 mg/kg, IV) did not alter the BP, TPR, or RPP actions of R-α-methylhistamine. The HR effects of R-α-methylhistamine were blocked by atenolol. 6. 6. The hemodynamic effects of R-α-methylhistamine were compared to the hemodynamic profile of the calcium channel blocker, verapamil (0.5 mg/kg, IV). Verapamil had little effect on TRP and had a greater cardiac depressant effect as evidenced by a significant reduction in HR and cardiac output (CO). 7. 7. In summary, these results show that activation of prejunctional H 3 receptors with R-α-methylhistamine decreases basal, BP, HR, TPR, and RPP in anesthetized guinea pigs. The fall in BP is mediated by a decrease in TPR. Furthermore, the inhibitory effects of R-α-methylhistamine on sympathetic control of the vasculature appears to impart a greater physiologic effect on the H 3-histamine mediated hypotension than its inhibitory effects on sympathetic agents to the heart.

Does Spinal Anesthesia Result in a More Complete Sympathetic Block Than That from Epidural Anesthesia?

Background Spinal and epidural injection of local anesthetics are used to produce sympathetic block to diagnose and treat certain chronic pain syndromes. It is not clear whether either form of regional anesthesia produces a complete sympathetic block. Spinal anesthesia using tetracaine has been reported to produce a decrease in plasma catecholamine concentrations. This has not been demonstrated for epidural anesthesia in humans with level of anesthesia below C8. One possible explanation is that spinal anesthesia results in a more complete sympathetic block than epidural anesthesia. To examine this question, a cross-over study was performed in young, healthy volunteers. Methods Ten subjects underwent both spinal and epidural anesthesia with lidocaine (plain) on the same day with complete recovery between blocks. By random assignment, spinal anesthesia and epidural anesthesia were induced via lumbar injection. Before and 30 min after local anesthetic injection, a cold pressor test (CPT) was performed. Blood was obtained to determine epinephrine and norepinephrine plasma concentrations at four stages: (1) 20 min after placing peripheral catheters, (2) at the end of a 2-min CPT (before conduction block), (3) 30 min after injection of epidural or spinal lidocaine, and (4) at the end of a second CPT (during anesthesia). Mean arterial pressure, heart rate, noninvasive cardiac index, and analgesia to pin-prick were monitored. Results Neither spinal nor epidural anesthesia changed baseline resting values of catecholamines or any hemodynamic variable, except heart rate, which was slightly decreased during spinal anesthesia. Median level of analgesia was T4 during spinal and T3 during epidural anesthesia. CPT before conduction block reliably increased heart rate, mean arterial pressure, cardiac index, epinephrine, and norepinephrine. Conduction block attenuated the increase in response to CPT only in mean arterial pressure (spinal and epidural) and cardiac index (spinal only). Neither technique blocked the increase in heart rate, norepinephrine, or epinephrine to CPT. Conclusions Spinal anesthesia did not result in a more complete attenuation of the sympathetic response to a CPT than did epidural anesthesia. In response to the CPT, spinal anesthesia blocked the increase in cardiac index, and epidural anesthesia resulted in a decrease in total peripheral resistance compared to the pre-anesthesia state. The differences between the techniques are not significant and are of uncertain clinical implications.

Adenosine does not mediate renal sodium retention and peripheral vasodilation elicited by partial portal vein ligation in rats

This study was conducted to assess the role of adenosine in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) in the rat. The experiment was performed on day 1 after surgery when transient maximal sodium retention developed and day 7 when rats returned to sodium balance. Hemodynamic studies were conducted under anesthesia in portal hypertensive rats with sodium retention and in sham-operated controls. Measurements were obtained before and after administration of a nonselective A1 and A2 adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (10 mg/kg intravenously followed by 150 micrograms/min). Under baseline conditions, portal hypertensive rats with sodium retention were hypotensive, with decreases in total peripheral resistance and filtration fraction on day 1 in comparison with the control group. Although hyperdynamic circulation was still maintained by day 7, there was a return to sodium balance. The adenosine receptor antagonist had a modest vasoconstrictor effect on systemic and renal vasculature in both groups, but less in portal hypertensive rats. However, no change in glomerular filtration rate was observed. DPSPX induced a natriuresis in control rats (from 0.40 +/- 0.11 to 5.97 +/- 0.61 mEq/min on day 1, from 0.48 +/- 0.20 to 6.34 +/- 0.45 mEq/min on day 7). This response was attenuated in portal hypertensive rats on day 1 (from 0.14 +/- 0.04 to 1.67 +/- 0.57 mEq/min). but not on day 7 (from 0.20 +/- 0.06 to 5.11 +/- 0.55 mEq/min). These results suggest that in portal hypertensive rats (1) adenosine is not responsible for vasodilation and sodium retention, (2) a sodium-retaining factor acting directly on the renal tubule is responsible for sodium retention. (Hepatology 1996 Feb;23(2):346-52)

Adenosine does not mediate renal sodium retention and peripheral vasodilation elicited by partial portal vein ligation in rats

This study was conducted to assess the role of adenosine in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) in the rat. The experiment was performed on day 1 after surgery when transient maximal sodium retention developed and day 7 when rats returned to sodium balance. Hemodynamic studies were conducted under anesthesia in portal hypertensive rats with sodium retention and in sham-operated controls. Measurements were obtained before and after administration of a nonselective A1 and A2 adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (10 mg/kg intravenously followed by 150 micrograms/min). Under baseline conditions, portal hypertensive rats with sodium retention were hypotensive, with decreases in total peripheral resistance and filtration fraction on day 1 in comparison with the control group. Although hyperdynamic circulation was still maintained by day 7, there was a return to sodium balance. The adenosine receptor antagonist had a modest vasoconstrictor effect on systemic and renal vasculature in both groups, but less in portal hypertensive rats. However, no change in glomerular filtration rate was observed. DPSPX induced a natriuresis in control rats (from 0.40 +/- 0.11 to 5.97 +/- 0.61 mEq/min on day 1, from 0.48 +/- 0.20 to 6.34 +/- 0.45 mEq/min on day 7). This response was attenuated in portal hypertensive rats on day 1 (from 0.14 +/- 0.04 to 1.67 +/- 0.57 mEq/min). but not on day 7 (from 0.20 +/- 0.06 to 5.11 +/- 0.55 mEq/min). These results suggest that in portal hypertensive rats (1) adenosine is not responsible for vasodilation and sodium retention, (2) a sodium-retaining factor acting directly on the renal tubule is responsible for sodium retention.

Effects of CPAP on cardiac output in pigs with pacing-induced congestive heart failure.

Continuous positive airway pressure (CPAP) may improve left ventricular (LV) function in patients with congestive heart failure (CHF). To understand mechanisms involved, in nine sedated, unanesthetized pigs with pacing-induced CHF we measured cardiac index (CI), heart rate (HR), LV pressures and volumes, ejection fraction (LVEF), and maximal rate of LV pressure rise (dp/dtmax). LV end-systolic transmural pressure (afterload) was estimated as LV end-systolic pressure (LVESP)-CPAP. Measurements were taken at CPAP 0, 5, 10, and 15 cm H2O and during recovery. At CPAP 5 cm H2O, CI increased from 4.23 +/- 1.00 to 4.99 +/- 0.88 L/min/m2 (p < 0.005), LV end-systolic volume decreased from 82.3 +/- 32.1 to 72.7 +/- 30.3 ml (p < 0.04) and LVEF increased from 0.30 +/- 0.09 to 0.36 +/- 0.12 (p < 0.02), and dp/dtmax increased. LVESP-CPAP was unchanged. After CPAP was discontinued, there was a rise in CI (p < 0.03), HR (p < 0.03), LVESP (p < 0.02), dp/dtmax (p < 0.02) and a decrease in total peripheral resistance (p < 0.03). We conclude that in CHF, low levels of CPAP improved CI, at least partly by improving contractility. Increased CI after discontinuing CPAP may be due to sympathoadrenal stimulation or withdrawal of alpha-adrenergic tone.

Factors associated with hyperdynamic or hypodynamic circulation and role of platelet-activating factor in hemodynamic alterations in bacterial peritonitis in conscious rats.

Male Wistar rats injected intraperitoneally (i.p.) with 10(9) U Escherichia coli ATCC 25922 developed acute bacterial peritonitis. Hemodynamic studies, with microspheres labeled with 103Ru 57Co, and 113Sn, were performed before, 30 min after bacterial injection, and 30 min after administration of either the platelet-activating factor (PAF) antagonist BN-52021 (5 mg/kg body weight) or isotonic saline. A blood sample of 0.3 ml was obtained for bacterial culture and endotoxemia measurements. Plasma PAF levels were measured in a different group of 10 control rats and 20 animals with experimental peritonitis. One group of rats injected with E. coli (n = 13) displayed hyperdynamic circulation, with an increase in cardiac output (CO) from 15.1 +/- 1.2 to 19.4 +/- 1.1 ml/min/100 g body weight and a decrease in total peripheral resistance (TPR) from 19.5 +/- 2.4 to 14.9 +/- 1.1 dynes.s.cm-5 10(-4). Furthermore, these rats showed high endotoxin blood concentrations and low hemoculture levels. The remaining 7 peritonitic rats showed a significant decrease in CO from 16.3 +/- 1.6 to 12.7 +/- 1.2 ml/min/100 g body weight and an increase in TPR from 17.3 +/- 1.8 to 22.6 +/- 2.8 dynes.s.cm-5 10(-4). In addition, these rats showed low endotoxin blood concentrations and high hemoculture levels. Endotoxin blood concentrations were positively correlated with the change in CO (r = 0.87, p < 0.05), and cell hemocultures were positively correlated with CO (r = 0.89, p < 0.05). Rats with high endotoxin blood levels showed higher PAF plasma levels than control rats or peritonitic rats with low endotoxin blood levels. When peritonitic rats were injected with the specific PAF-receptor blocker BN-52021 (5 mg/kg body weight) as a bolus, CO and TPR returned to baseline values in both groups of animals. These data suggest that the hemodynamic changes induced by bacterial peritonitis depend on endotoxemia and bacteremia in opposite ways. In addition, PAF appears to be involved in both the hyperdynamic and hypodynamic hemodynamic changes shown by peritonitic rats.

Mechanism of systemic vasodilation during normovolemic hemodilution.

In the nonfailing heart, normovolemic hemodilution increases cardiac output and decreases total peripheral resistance (TPR). Putative mechanisms mediating the decrease in TPR include reflex vasodilation and changes in the local regulation of blood flow. Our objectives were to determine whether ablation of reflex neural mechanisms or the inhibition of nitric oxide (NO) synthase, the enzyme responsible for the synthesis of the endothelium-derived relaxing factor (EDRF-NO), modulates the systemic vasodilator response to normovolemic hemodilution. Three groups of male Sprague-Dawley rats were subjected to acute normovolemic hemodilution, which was achieved by exchanging a volume of blood equivalent to 3.8% of body weight with hydroxyethyl starch. Hemodilution increased cardiac output and decreased TPR. Subsequent administration of the NO synthase inhibitor, L-nitroarginine (LNA), returned both cardiac output and TPR to control values. Pretreatment with LNA prior to hemodilution increased TPR, an effect that was partially reversed by the NO donor, sodium nitroprusside. In this setting, hemodilution failed to decrease TPR. After spinal cord destruction by "pithing," hemodilution decreased TPR to the same extent as that observed in intact rats. This hemodilution-induced decrease in TPR was abolished by the subsequent administration of LNA. These results indicate that neural reflexes do not modulate the systemic vascular response to hemodilution. Moreover, the systemic vasodilator response to hemodilution is abolished after inhibition of endogenous NO synthesis.

Circadian Profile of Systemic Hemodynamics

We determined the continuous 24-hour profile of mean arterial pressure, heart rate, stroke volume, cardiac output, and total peripheral resistance in eight healthy ambulatory volunteers. Beat-to-beat intra-arterial blood pressure was recorded with the Oxford system; subjects were ambulant during daytime and slept at night. Beat-to-beat stroke volume was determined by the pulse contour method from the arterial pulse wave. During the nighttime, compared with the daytime average, there was a decrease in blood pressure (9 mm Hg), heart rate (18 beats per minute), and cardiac output (29%); stroke volume showed a small decrease (7%), and total peripheral resistance increased unexpectedly by 22%. When subjects arose in the morning a steep increase in cardiac output and decrease in total peripheral resistance were found. Comparable changes were seen during a period of supine resting in the afternoon, whereas physical exercise caused opposite changes in hemodynamics. This pattern was observed in all subjects. We conclude that the circadian pattern of cardiac output and total peripheral resistance originates from the day-night pattern in physical activity: during the nighttime, blood flow to the skeletal muscles is decreased through local autoregulation, which increases total peripheral resistance and decreases cardiac output compared with the daytime.

Denopamine as an α1H-adrenoceptor antagonist in isolated blood vessels

The effects of denopamine, clinically used as a cardiotonic β 1-adrenoceptor agonist, were investigated on α-adrenoceptor-mediated contraction in vascular preparations of rats, guinea-pigs and rabbits. Norepinephrine, phenylephrine ( α 1-adrenoceptor agonist) and clonidine [and 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14,304, α 2-adrenoceptor agonists)] concentration dependently contracted the vascular preparations. Phenylephrine was more potent than the α 2-adrenoceptor agonists in the rat aorta and carotid artery. The reverse was true in the rabbit ear vein. pA 2 values for prazosin (rat tissues, 9.7–10; guinea-pig aorta, 9.1–9.3) and for yohimbine (rat tissues, 6.6–6.9; guinea-pig aorta, 6.2–6.3; rabbit ear vein, 7.9) suggested that α 1H (high affinity for prazosin)-, α 1L (lower affinity for prazosin)-, and α 2-adrenoceptors were predominantly distributed in the rat tissues, the guinea-pig aorta, and in the rabbit ear vein, respectively. Vasoconstrictions mediated by α 1H-adrenoceptor subtypes were more susceptible to inhibition by denopamine than those mediated by α 1L and α 2 subtypes. These results suggested that in addition to activity as a β 1-adrenoceptor agonist, denopamine also possessed activity as an α 1H-adrenoceptor-selective antagonist. These actions may contribute to the denopamine-induced decrease in total peripheral resistance in vivo.