Decrease In Peripheral Resistance Research Articles

Ontogeny of Cardiovascular Control in Amphibians

SYNOPSIS. Cardiovascular variables in developing amphibians are affected by both allometry and organogenesis. Blood pressure, cardiac output, and stroke volume increase during development, whereas peripheral resistance decreases. Invariably, resting heart rate changes as development proceeds from embryo through larva to adult. The pattern of change, however, varies between species and does not even correlate with family. The mechanisms underlying these varying patterns of developmental changes in heart rate of anuran amphibians larvae awaits complete description. Cardiovascular variables in adult vertebrates are influenced by nerves and hormones as well as intrinsic factors. However, information on the development of cardiovascular control systems is scarce, but receptor sensitivity apparently develops before functional innervation becomes apparent. The amphibian heart responds to acetylcholine and adrenaline several stages before functional innervation becomes evident, and in some species the cholinergic and adrenergic sensitivity of the cardiac pacemaker changes with development. As in mammals, acute hypoxia results in different cardiovascular responses depending on the developmental stage of the animal. The different responses reflect the relative maturity of neurohormonal mechanisms operating within the cardiovascular system.

High Blood Pressure and Calcium Antagonism

Calcium ions are intimately involved in many aspects of cardiovascular function. Modification of calcium homeostasis therefore represents a key target for pharmacological intervention to achieve therapeutic control of hypertension. The calcium channel blockers (CCBs) act by blocking calcium influx through voltage-dependent L (long-acting) channels without affecting calcium release from the sarcoplasmic reticulum. The effect of blocking these channels is a decrease in the intracellular calcium concentration, which reduces vascular smooth muscle tone. The subsequent decrease in peripheral resistance causes a decrease in systemic blood pressure. The CCBs also decrease myocardial contractility, which decreases myocardial oxygen consumption. Overall, the CCBs at therapeutic doses improve the efficiency of ventricular function. They also have a number of other beneficial effects, including an antiproliferative effect. The CCBs in clinical use vary according to their relative selectivities for vascular and cardiac tissue and their applicability to the treatment of hypertension or ischaemic heart disease. The first-generation CCBs (verapamil, nifedipine and diltiazem) are associated with a relatively short duration of action and unwanted cardiovascular effects that were related to poor vascular selectivity. In addition, nifedipine was associated with a very rapid onset of action that caused a sudden vasodilation and reflex tachycardia in some patients. The newer second-generation CCBs, for example the dihydropyridines, amlodipine, felodipine and nisoldipine, show greatly improved vascular selectivity and longer durations of action, achieved in part by novel controlled-release dosage forms. They bind to target receptors in a slow and sustained fashion, producing a smooth onset of action and 24-hour control of blood pressure. Once-daily dosing of these longer-acting agents improves patient compliance and is associated with a good side-effect profile. The second-generation CCBs are suitable antihypertensive agents for a wide range of patients, including the elderly and black patients, and those with concomitant diseases that preclude the use of other antihypertensives.

Propofol Alters Left Ventricular Afterload as Evaluated by Aortic Input Impedance in Dogs

Systemic vascular resistance incompletely describes left ventricular afterload because of the phasic nature of arterial pressure and blood flow. Aortic input impedance is an experimental description of left ventricular afterload that incorporates the frequency- dependent characteristics and viscoelastic properties of the arterial system. The effects of propofol on aortic input impedance were examined using three variables derived from the three-element Windkessel model: characteristic aortic impedance, total arterial compliance, and total arterial resistance. Eight dogs were chronically instrumented for measurement of aortic pressure, left ventricular pressure, +dP/dt, subendocardial segment length, and aortic blood flow. Systemic hemodynamics and aortic blood pressure and flow waveforms were recorded in the conscious state and after a bolus of 5 mg x kg(-1) propofol and infusion for 15 min at 25, 50 and 100 mg x kg(-1) x h(-1). Aortic input impedance spectra were generated using power spectral analysis of aortic pressure and flow waveforms corrected for the phase responses of the pressure and flow transducers. Characteristic aortic impedance, total arterial resistance, and total arterial compliance were calculated from the aortic input impedance spectrum and the aortic pressure waveform. Parameters describing the net site and magnitude or arterial wave reflection were determined from aortic impedance. Propofol decreased total arterial resistance (3.05 +/- 0.20 during control to 2.29 +/- 0.18 dynes x s x cm(-5) x 10(3) at the high dose) and increased total arterial compliance (0.53 +/- 0.04 during control to 1.15 +/- 0.17 ml x mmHg(-1) at the high dose) in a dose- related manner. Propofol increased characteristic aortic impedance (1.49 +/- 0.15 during control to 2.20 +/- 0.20 dynes x s x cm(-5) x 10(2) at the high dose). The net site and the magnitude of arterial wave reflection were unchanged by the propofol. In chronically instrumented dogs, propofol decreased total arterial resistance, a property of arteriolar resistance vessels, consistent with the known actions of this drug on systemic vascular resistance. Propofol also increased total arterial compliance and characteristic aortic impedance, indicating that this anesthetic affects the mechanical properties of the aorta. Propofol had no effect on arterial wave reflection patterns. The results indicate that propofol reduces left ventricular afterload via decreases in peripheral resistance and increases in arterial compliance.

The influence of aging on skin temperature and hemodynamic changes during spinal anesthesia.

We investigated the influence of aging on the relationship between arterial pressure and skin temperature as a simple and indirect indicator of cutaneous blood flow. Sole and palm skin temperatures, sublingual temperature, heart rate, mean arterial blood pressure (MAP), and the anesthetic level as determined by cold discrimination, were measured before and during minor surgery under spinal anesthesia in patients under 65 years (young group) and above 65 years (elderly group). The sole skin temperature (Tsole) started to increase in the young group whose anesthesia level reached above L1-L2, and approached the sublingual temperature in those whose anesthesia level reached above T8-T10 after spinal injection. There was, however, no relationship between the anesthesia level and Tsole in the young group. The change in Tsole was less in elderly patients than that in young patients with the same decrease in MAP. These findings suggest that a decrease in peripheral resistance may not be the main cause of hypotension during spinal anesthesia in elderly patients.

Squatting revisited: comparison of haemodynamic responses in normal individuals and heart transplantation recipients.

Squatting produces a prompt increase in cardiac output and arterial blood pressure which is accompanied by an immediate decrease in heart rate and forearm vascular resistance. The rise in cardiac output and blood pressure has been attributed to augmented venous return from compression of leg veins, while the decreases in heart rate and forearm vascular resistance are probably due to activation of cardiopulmonary and arterial baroreflexes. Haemodynamic patterns in nine normal men and six heart transplant recipients during 2 min of squatting were examined to determine the role of cardiac innervation in the mediation of these responses. Stroke volume was monitored by ensemble averaged thoracic impedance cardiography and blood pressure was determined with an Ohmeda fingertip plethysmograph. These techniques provided continuous measurements which were capable of detecting transient and non-steady state changes. Forearm blood flow was measured with venous occlusion plethysmography. Measurements were obtained after 3 min of quiet standing, immediately after squatting, and at 20, 60, and 120 s of sustained squatting. Both groups exhibited similar increases in stroke volume index (normal individuals 10.5 ml/m2; heart transplant recipients 10.3 ml/m2) and mean arterial pressure (normal individuals 8.5 mm Hg; heart transplant recipients 5.0 mm Hg) which were sustained throughout squatting. Each group also showed an initial decrease in peripheral resistance (normal individuals 3.6 units; heart transplant recipients 7.7 units) followed by a return to baseline values after 20 s. Heart rate decreased in normal individuals (10 beats/min) but was unchanged or minimally increased (2 beats/min) in heart transplant recipients. Forearm vascular resistance was conspicuously decreased in normal individuals (47.8 units) but only minimally (20.9 units) and not significantly in heart transplant recipients. The major haemodynamic responses to squatting (increased cardiac output and blood pressure) are similar in normal individuals and heart transplant recipients. These responses are primarily due to augmented venous return and are not altered by cardiac denervation. Both groups also exhibited a transient decline in peripheral vascular resistance which is most likely mediated by arterial baroreflexes activated by the acute rise in arterial blood pressure. The absence of a significant decrease in forearm vascular resistance in heart transplant recipients suggests that this response is partially mediated by cardiopulmonary or ventricular baroreflexes or that local forearm flow mediated vasodilatation remains impaired after heart transplantation.

Effects of blood pressure reduction on the elastic profile of the aortic tree in patients with coronary heart disease

Decreased arterial compliance of large arteries in coronary heart disease has been reported. Using intravascular ultrasound it was demonstrated that arterial compliance decreases with increasing distance from the heart. Until now changes in the elastic profile have not been investigated after a stepwise blood pressure (BP) reduction induced by antihypertensive agents. The local viscoelastic properties of the aortic tree were analyzed before and after a mean arterial BP reduction of about 5 and 15 mm Hg below baseline by the steady-state infusion of increasing doses of nisoldipine in 15 patients with coronary artery disease. Intravascular ultrasound imaging combined with arterial pressure measurements were performed at five sites along the aortic tree to determine the viscoelastic profile before nisoldipine administration and again after the 5 and 15 mm Hg nisoldipine-induced blood pressure reductions. The elasticity parameters varied depending on the distance from the heart and on the BP level. At both BP reduction levels nisoldipine infusion led to an increase in arterial compliance at the abdominal aorta and at the aortic bifurcation. A dissociation between the 5 and the 15 mm Hg BP reduction was found at the common iliac artery and at the external iliac artery. Our results provide direct quantitative evidence that stepwise BP reductions exhibit different and, in part, contrary effects on the elastic profile, depending on the aortic tree location. The results also suggest that nisoldipine infusion can significantly ameliorate local viscoelastic properties at the abdominal aorta and at the aortic bifurcation, an effect that was associated or caused by a change in BP attributable to a decrease in peripheral resistance.

Effect of chronic dihydropyridine (isradipine) on the large arterial walls of spontaneously hypertensive rats.

The effect of genetic hypertension and of chronic therapy by calcium entry blocker (CEB, isradipine) on the function and structure of large arteries has been studied in adult spontaneously hypertensive rats (SHR, n = 30) and in their normotensive control Wistar-Kyoto (WKY) rats (n = 30). Fifteen-week-old rats were randomly allocated to treatment with isradipine (3 mg/kg subcutaneously once a day) or to placebo and followed for 12 weeks. Hemodynamic parameters, including instantaneous pressure and aortic velocity, were recorded under anesthesia at the end of the treatment period. Passive mechanical properties of carotid arteries were measured in situ in the presence or the absence of smooth muscle cell activity (potassium cyanide poisoning). Histomorphometric parameters of the carotid and aortic media, including cross-sectional area, medial thickness, nucleus density and size, and medial contents of proteins of interstitial matrix, were measured by an automated morphometric system. Untreated SHRs had greater peripheral resistance, stiffer and thicker arterial walls because of smooth muscle cell hyperplasia (thoracic aorta and carotid artery) and/or hypertrophy (thoracic aorta), and increased collagen content than did normotensive control rats. SHRs showed a significant left ventricular hypertrophy. For the whole duration of treatment, treatment with CEB normalized the arterial pressure in SHRs. We observed a significant decrease in peripheral resistance, increased cardiac output, and left ventricular contractility without significant reduction in left ventricular hypertrophy. Increases in diuresis and natriuresis were associated during the last week of treatment in both treated strains with marked increase in plasma renin activity; in contrast, urinary aldosterone was increased by treatment in WKY rats but not in SHRs. Arterial compliance was significantly increased by CEB under control and passive conditions. CEB induced a significant reduction in the medial hypertrophy of the aortic walls of SHRs and WKY rats associated with a reduction in medial hyperplasia. In the carotid artery, CEB reduced smooth muscle cell hypertrophy but did not affect the smooth muscle cell hyperplasia. Isradipine significantly reduced the arterial wall collagen contents in both strains, with marked increases in the elastin content in the carotid but not in the aortic wall. These results suggest that (1) despite normalization of arterial pressure, chronic treatment with CEB in SHRs does not significantly reduce left ventricular hypertrophy, probably because of increase in myocardial contractility and/or increase in plasma renin activity; (2) mechanical properties of the arterial wall are normalized by treatment; and (3) remodeling of the arterial wall by CEB is not uniform according to the studied vessel.

Characterization of binding sites and effects of calcitonin gene-related peptide (CGRP) and CGRP 8–37 on regional blood flow in rabbit salivary glands

Calcitonin gene-related peptide (CGRP) is a neuropeptide present in nerve fibres of salivary glands in several species, including man. One of the major targets of these nerve fibres are blood vessels of the glands. The presence and distribution of specific binding sites for CGRP in the rabbit major salivary glands was here investigated autoradiographically. In order to determine the physiological role of CGRP, regional blood flow was measured after intravenous (i.v.) or intra-arterial (i.a.) administration of CGRP or the antagonist CGRP 8–37, using a microsphere technique. Specific binding sites for CGRP were found in the parotid, submandibular and sublingual glands, distributed mainly in the muscular and endothelial layers of the blood vessel walls. CGRP injected i.a. (10 pmol/kg) caused a significant increase in regional blood flow in all major salivary glands. However, i.v. infusion of CGRP (120 pmol/kg) decreased regional blood flow in the parotid and sublingual glands, due to a general decrease in peripheral resistance and redistribution of peripheral blood flow. CGRP 8–37 given i.a. together with CGRP significantly inhibited the blood-flow increase by CGRP alone. It is concluded that most of the CGRP receptors in the rabbit salivary glands are localized in vascular elements. The physiological data show that CGRP acts as a vasodilator in the major salivary glands of the rabbit in vivo, and that the effect of CGRP is inhibited by the CGRP antagonist CGRP 8–37.

Takayasu's disease: Ultrasonic evaluation of extracranial and intracranial hemodynamics

In Takayasu's disease, inflammatory vessel wall changes occur in the large extracranial arteries and may consequently influence cerebral hemodynamics. This study describes the extra- and intracranial hemodynamic states in three young patients, aged 32, 29, and 22 years, without permanent neurological deficit. Extracranial vessels were investigated primarily by duplex scanner and intracranial vessels by three-dimensional transcranial Doppler before and after intravenous administration of 1 g acetazolamide. The ultrasonic findings were confirmed by aortocervical angiography. Two patients were treated by corticosteroids. In spite of extracranial vessel narrowing, all three patients had normal MCA velocities in the resting condition. Impaired vasomotor reactivity was found in the middle cerebral artery corresponding to the high degree stenosis of the brachiocephalic trunk in one patient and in the anterior and posterior cerebral arteries unilaterally in two patients and bilaterally in one. Decrease in the pulsatility index after acetazolamide administration probably depends on the vasodilation and decrease in peripheral resistance. Extra- and intracranial Doppler ultrasound is valuable to follow the progress of arteritis and to adjust treatment.

Adjuvant Prostanoid Treatment During Femorodistal Reconstruction

A prospective randomized placebo-controlled trial was conducted to determine the effects of the stable prostacyclin analogue iloprost on early graft patency and hemodynamic parameters during femorodistal reconstruction for critical leg ischemia. Peripheral resistance and graft blood flow were measured using an operative Doppler flowmeter and graft pressure transducer. Postoperative graft surveillance was continued at 1-month and then at 3-month intervals by duplex Doppler ultrasonography, measurement of ankle-brachial pressure indices, and intravenous digital subtraction angiography when indicated. In patients receiving 3000 ng of iloprost (n = 45) infused into the graft on completion there was an immediate mean decrease in peripheral resistance of 44% that persisted to skin closure in comparison with controls (n = 38) in whom no such decrease in resistance occurred (p < 0.001, Wilcoxon test). During the same period, mean graft blood flow increased in iloprost-treated patients by 74.5% compared with controls in whom there was a 6% increase in flow (p < 0.001). Primary cumulative patencies at 1 month were significantly higher in iloprost-treated grafts, 98% compared to 83% for controls (p < 0.05, log-rank test). Cumulative primary patencies at 1 year and secondary patencies at 1 month and 1 year were also greater in the iloprost-treated group (67%, 98%, and 87.6%, respectively) compared to controls (65%, 86%, and 79.3%, respectively), but these did not achieve statistical significance. A single bolus infusion of iloprost has prolonged beneficial effects on graft blood flow and peripheral resistance during femorodistal reconstruction. This is reflected by improved early primary graft patencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Iloprost reduces peripheral resistance during femoro-distal reconstruction

A randomised placebo-controlled trial was conducted to investigate the effect of iloprost, a stable prostacyclin mimetic, on peripheral resistance during femoro-distal bypass. Patients undergoing femoro-distal long saphenous vein bypass for critical ischaemia received 3000 ng of iloprost or placebo infused into the graft via an unligated side branch over 2 min. Graft blood flow and peripheral resistance were measured for 20 min, using an operative Doppler flowmeter (OpDop 130, SciMed, U.K.) and a pressure transducer to record graft pressure. Postoperatively, graft blood flow was assessed by daily duplex ultrasound for 7 days. Iloprost produced an immediate drop in peripheral resistance in all cases (n = 18) by a mean (range) of 40% (4-80%) compared with controls (n = 15) in whom there was a 5.3% (-8 to +36%) increase in resistance (p less than 0.01, Wilcoxon test). Decreased peripheral resistance in iloprost-treated patients persisted to 20 min. The largest decreases in peripheral resistance occurred in patients with the highest initial resistances (r = 0.56, p less than 0.02). Graft flow during the same period increased by 52% (-7 to 294%) compared with controls in whom there was a 6% (-17 to 26%) increase in flow, (p less than 0.01). Flow remained elevated by 53% over baseline values at 1 week post-infusion in the iloprost-treated group but this did not achieve statistical significance compared to controls in whom flow also increased by 13%. Iloprost produces an immediate decrease in peripheral resistance associated with a prolonged increase in graft blood flow. This may reduce graft failure in the early postoperative period.

Hemodynamic effects of Ro 23-6152 in patients with essential hypertension

In a double blind study 8 patients with uncomplicated essential hypertension received in random order single oral doses of placebo and 10, 30 and 80 mg Ro 23-6152, a novel calcium entry blocker, on 4 different days. Patients were assessed 15 min before dosing and at several time intervals over the following 6 h. Ro 23-6152 30 and 80 mg induced a significant decrease (mean maximum 7 mmHg.1-1.min-1) in total peripheral resistance, while cardiac output, stroke volume and heart rate were slightly increased (mean maximum 0.51.min-1, 10 ml, 5 beats.min-1, respectively) but not significantly so. Systolic blood pressure decreased significantly (5 to 10 mmHg) from 0.5 to 6 h after the 80 mg dose. After the 10 and 30 mg doses the decreases in systolic pressure were not significant. Diastolic blood pressure and mean arterial blood pressure were non-significantly decreased (mean maximum 7 mmHg) after all doses. The PQ interval was also non-significantly increased by no more than 20 ms. It appears that the main hemodynamic effect of Ro 23-6152 in hypertensive patients is a decrease in peripheral resistance. The antihypertensive effect, at least in this short term study, was only modest, probably because the fall in peripheral resistance was partly compensated by an increase in cardiac output.

Hypotension during vasopressin receptor blockade: role of V2 receptors and sympathetic nervous system

This study investigated possible mechanisms for the hypotension produced by nitroprusside infusion in conscious dogs pretreated with a V1 vasopressin antagonist. The hypothesis that an action of vasopressin at V2-like receptors contributes to the hypotension was tested by comparing the effects of a V1 antagonist to the effects of a combined V1/V2 antagonist. Nitroprusside infusion produced dose-dependent decreases in arterial and atrial pressures. Larger decreases in pressures were produced in animals pretreated with either antagonist; however, the decreases in V1/V2-blocked dogs were not less than the decreases in V1-blocked dogs. These data suggest that V2-like actions of vasopressin do not contribute to the hypotensive effects of V1 blockade. A second hypothesis was that the greater hypotension was due to activation of a cardiac reflex to cause withdrawal of sympathetic tone, a decrease in peripheral resistance, and adrenal activation. Measurement of cardiac output revealed that the larger decreases in arterial pressure were due to larger decreases in total peripheral resistance. The hypotension was also associated with decreases in heart rate, unchanging plasma norepinephrine concentration, and increases in epinephrine concentration. These data are consistent with the hypothesis that the fall in pressure observed in dogs pretreated with a V1 antagonist is secondary to a decrease in peripheral resistance that is due at least in part to withdrawal of sympathetic tone.

Renal Hemodynamics in Normal and Hypertensive Pregnancy: Lessons From Micropuncture

Rats are an excellent animal model in which to study the changes in renal hemodynamics associated with normal pregnancy. Midterm pregnant rats exhibit a maximal renal vasodilation leading to increases in glomerular filtration rate (GFR) and renal plasma flow (RPF). Micropuncture studies in midterm pregnant Munich-Wistar rats have shown that single-nephron GFR (SNGFR) increases, due entirely to increases in plasma flow and, importantly, glomerular capillary blood pressure (PGC) remains unchanged in normotensive pregnancy, due to parallel and proportionally similar reductions in preglomerular (RA) and efferent (RE) arteriolar resistance. Despite the chronic gestational renal vasodilation, pregnancy in normotensive rats with either normal kidneys or a variety of underlying diseases, causes no adverse changes in renal function, perhaps because the glomeruli are protected from damaging high PGC. In the presence of systemic hypertension, the renal vasodilation of pregnancy could put the maternal kidney at risk of injury due to increases in PGC. There are few renal functional studies in preexisting, essential hypertension, but micropuncture studies in spontaneously hypertensive rats (SHRs) have shown that repetitive pregnancies in SHRs cause no functional impairment. Surprisingly, SHRs demonstrated no gestational renal vasodilation, although gestational decreases in peripheral resistance certainly occur in the SHR. This absence of gestational renal vasodilation may be a protective mechanism; it remains to be determined whether hypertensive states in which renal vasodilation does occur are associated with increased risk to the maternal kidney.

CHARACTERISTICS OF CARDIOVASCULAR REFLEXES ORIGINATING FROM 5‐HT3 RECEPTORS IN THE HEART AND LUNGS OF UNANAESTHETIZED RABBITS

1. When phenylbiguanide (1-PBG) (6.25-400 micrograms) was injected into the left atrium, right atrium or pulmonary artery of unanesthetized rabbits it caused dose-dependent falls of heart rate and arterial pressure, and short-lived hypopnoea or apnoea. The threshold dose was 50-100 micrograms. Maximal falls of heart rate (86-108 beats/min) and arterial pressure (33-35 mmHg) occurred at a dose of 200 micrograms. The latency between injection and onset of the bradycardia was 2.2-2.6 s and did not depend on the route. Cardiac output fell transiently with heart rate, but at the time of the maximal fall of arterial pressure it had returned to normal. All effects were abolished by intrapericardial procaine. The haemodynamic effects were exaggerated by sino-aortic barodenervation. Intrapericardial 1-PBG (200-400 micrograms) was without effect. Injection of 1-PBG (greater than 50-100 micrograms) into the aortic arch caused a variable increase in heart rate and arterial pressure. 2. When both cervical vagus nerves were crushed the depressor effects of atrial 1-PBG were reduced by only 76-84%. 3. The dose-response curves for left atrial and pulmonary artery injection of 1-PBG were shifted successively to the right by intravenous infusion of the 5-HT3 antagonist MDL72222 (0.1 and 1.0 mg/kg). 4. We conclude that in unanesthetized rabbits left atrial 1-PBG selectively excites myocardial afferents, whereas right atrial or pulmonary artery 1-PBG excites afferents that originate close to the pulmonary vasculature. In each case 1-PBG acts through pharmacologically specific 5-HT3 receptors. The afferents run mainly, but not exclusively, in the vagus nerves. The reflex fall of arterial pressure is accounted for almost entirely by a decrease in peripheral resistance.

Diuretics and the treatment of systemic hypertension

Diuretics are still among the most frequently used antihypertensive drugs in the treatment of hypertension. Their pharmacologic and hemodynamic properties are based on the water and salt metabolism in the pathophysiology of high blood pressure. Initially, there is a reduction of plasma and extracellular fluid volume; cardiac output also decreases. After this early phase, cardiac output returns to normal with an accompanying decrease in peripheral resistance so as to correct the underlying hemodynamic fault of the hypertensive state. Diuretics have a high therapeutic efficacy either as monotherapy or in combination with β blockers, angiotensin-converting enzyme inhibitors or calcium antagonists. The main problem with the use of diuretics is related to their metabolic side effects, which are dose-related. Currently, there is a tendency to administer low-dose diuretics, which result in fewer clinical and metabolic side effects, but with a continued antihypertensive efficacy. Therefore, low doses of diuretics can be recommended as initial therapy in the stepped-care approach of hypertension.

Effect of celiprolol on large and small arteries of the forearm circulation in hypertensive patients

Celiprolol, a new highly cardioselective beta blocker, also has direct vasodilating properties. Since the noninvasive echo Doppler technique applied to the forearm circulation (brachial artery) allows the differentiation of arteriolar vasodilation (revealed by the increasing arterial blood flow velocity) from vasodilation of large arteries (shown by an increase in arterial diameter), it seems important to study the site of celiprolol's vasodilating effect. Thirty-five hypertensive patients, (21 male, 14 female; mean age, 59 +/- 11, range 42-79 years) were treated with increasing doses of celiprolol, 200 and 400 mg, over 15 days. The duplex echo Doppler technique (Aloka 7.5 M Hz probe) was used before and during each celiprolol dose period. Statistical analysis was performed by Student's paired t test. It was observed that celiprolol significantly increases the brachial artery diameter in a dose-dependent manner, and also increases the blood flow velocity (not being direct dose-related). Since the increase in diameter was clear with a higher dose, a dose-dependent increase in blood volume, a decrease in peripheral resistance, and an increase in compliance followed. Since the higher dose of celiprolol did not further reduce blood pressure (BP) in comparison to the lower dose, and a dose-dependent increase in arterial diameter and compliance occurred and a vasodilating effect of celiprolol on arterial wall ensued that was not related to BP. In conclusion, in the doses used, celiprolol dilates both arterioles and large arteries, but the mechanism of action needs to be clarified.

Part II: Radionuclide evaluation of aortic regurgitation

The timing for valve replacement in patients with aortic regurgitation remains a complex clinical problem. Rest radionuclide angiography measurement of ejection fraction is a simple informative study to help evaluate the appropriate timing for valve replacement in the asymptomatic patients or those with mild symptoms. In patients with normal ejection fractions the disease probably has not yet evolved to the phase in which valve replacement is essential. If the ejection fraction is mildly depressed (0.40 to 0.49) the time is right for intervention. By the time the ejection fraction falls to < 0.40 the left ventricle is likely damaged and unlikely to regain normal function. If the patient has severe symptoms with maximal medical therapy, surgery is indicated no matter what the ejection fraction. The latter situation can arise especially when aortic regurgitation evolves over a short period, as might be the case in patients with bacterial endocarditis. A single ejection fraction measurement is not as reliable as serial studies. If, for example, the ejection fraction (under similar circumstances) falls from the ≥0.50 range to the 0.40 to 0.49 range, the physician should be alerted to the possibility that the left ventricle is deteriorating, and surgery should be considered. It should be understood that multiple hemodynamic factors in aortic regurgitation can alter the ejection fraction and could limit its use as the sole measure of left ventricular performance. Other systolic or diastolic parameters cannot be relied on in isolation as an indication or contraindication for aortic valve replacement. The exercise ejection fraction response reflects the total stroke volume and does not distinguish between regurgitant flow and forward flow. It is therefore possible to observe a decrease in ejection fraction in association with an increase in forward stroke volume during exercise as a result of an increase in heart rate and a decrease in peripheral resistance. Accordingly, it is not appropriate to compare the ejection fraction during exercise in aortic insufficiency with the expected response of the normal ventricle. Exercise position (sitting vs. supine) affects loading conditions and ejection fraction response. 44Because of the complexity of the exercise ejection fraction response, it is not clear that there is a role for exercise ejection fraction measurements in determining the appropriate time for aortic valve replacement. Criteria based on supine exercise may not be applicable to studies in the upright position. Other markers of left ventricular performance, including end-systolic volumes and pressure-volume relationships, also have been examined. These parameters are preload independent and incorporate the effects of afterload. End-ejection pressure-volume ratios appear to be reasonable predictors of left ventricular contractile performance in chronic aortic regurgitation. 45 The continued problem of the timing of aortic valve replacement inspires the hope that serial measurement left ventricular function with exercise may have some predictive power. Parameters other than ejection fraction, such as regurgitant fraction and end-systolic and end-diastolic volume response, also may be useful. Careful consideration of aortic valve replacement should be given to patients with deterioration of these other radionuclide angiographic parameters, particularly when associated with a decrease in functional performance and worsening of symptoms. Nevertheless, only the resting LVEF has been shown to correlate with survival after valve replacement. Radionuclide studies provide a means to assess the change in left ventricular function after valve replacement. It has been observed that soon after valve replacement LVEF decreases, likely due to acute reduction in preload and increase in heart rate. This reduction should not be misconstrued as reduction in left ventricular performance, and under these circumstances end-systolic volume-endsystolic pressure may be a more useful test of left ventricular function. However, over the ensuing weeks to months ejection fraction tends to normalize in those patients in whom surgery was appropriately timed. The frequent occurrence of late postoperative deaths due to chronic congestive heart failure (78% in the National Institutes of Health study 46) underscores the importance of continued serial radionuclide evaluation of left ventricular performance in the improved methods to better time when aortic valve replacement should be performed. Operated and unoperated patients receiving chronic vasodilator therapy also benefit from serial evaluation of ventricular function to assess the response to therapy and define prognosis.

本態生高血圧におけるＡＣＥ阻害薬ｌｉｓｉｎｏｐｒｉｌおよびβ１選択性β遮断薬ｂｅｔａｘｏｌｏｌの循環動態上の効果

Hemodynamic effects of lisinopril, a new angiotensin converting enzyme inhibitor, and betaxolol, a new β1-selective β-blocking agent, were evaluated in 21 outpatients with essential hypertension (WHO I / II stage) introducing them orally for six wks. Lisinopril (mean dose, 13.5 ±2.2 (SEM) mg/day) and betaxolol (8.4 ± 1.9 mg/day) reduced blood pressure (lisinopril, 176/103 ± 7/2 to 154/88±6/3 mmHg, P<0. 01; betaxolol, 171/107 ± 5/2 to 152/92±5/2 5/2 mmHg, P< 0.005) with different effects on heart rate ; betaxolol reduced heart rate significantly (66 ± 2 to 61 ± 3 bpm, P< 0.01) but lisinopril did not (71 ± 3 to 71 ± 3 bpm). These two drugs did not induce any significant change in circulating blood volume (measured using 131I-labeled human serum albumin) (lisinopril, 2. 95 ± 0. 17 to 2. 93 ± 0.15 l/m2 ; betaxolol, 2.80± 0.08 to 2.77± 0.09 l/m2) and cardiac output (measured using 99mTc in vivo labeled red cells) (lisinopril, 3.19 ± 0.20 to 3. 19 ±0.19 l/min/m2 ; betaxolol, 3.23 ± 0.09 to 3.19 ±0.16 l/min/m2). Both of them induced a slight and insignificant increase in left ventricular ejection fraction (LVEF) and reduced total peripheral resistance index (lisinopril, 3, 302 ± 196 to 2, 828 ± 150 dyn·sec·cm-5·m2, P<0.01; betaxolol, 3, 179 ± 75 to 2, 856 ± 167 dyn·sec·cm-5·m2), though the decrease in the betaxolol group was not significant.These effects in the lisinopril-treated group may be attributable to angiotensin converting enzyme inhibiting activity mainly in vascular beds. As β1-selective β-blocking agents without vasodilating properties, such as atenolol and metoprolol, were reported to reduce cardiac pump function without decrease in peripheral resistance, and celiprolol, one with vasodilating properties, was reported to reduce peripheral resistance in essential hypertension, these results obtained in the betaxolol-treated group warrant a further investigation on its vasodilating properties.

8 Volume homeostasis and osmoregulation in human pregnancy

This chapter reviews alterations in volume and sodium homeostasis and osmoregulation during human pregnancy. Pregnant women undergo extracellular and plasma volume increases of 50-70%, and these changes accompany marked cumulative sodium retention shared by both mother and fetus. Pregnancy alters several factors with opposing effects on renal salt handling; however, mechanisms by which gestational sodium accumulation and volume expansion are achieved remain obscure. Furthermore, despite substantial increases in absolute blood volume, considerable uncertainty exists as to how this volume is sensed, particularly in late pregnancy when a rapid increase in volume is associated with decreases in peripheral resistance and blood pressure. Attempts to assess 'effective' intravascular volume suggest that pregnant women sense their volume as normal. Osmoregulation is also changed. Body tonicity and the osmotic thresholds for AVP release and thirst decrease by about 10 mosm/kg. The mechanisms responsible for the osmoregulatory changes are obscure. Haemodynamic stimuli such as decrements in blood pressure and of 'effective circulating volume' do not seem to account for them. Of the many increments in hormone levels known to accompany gestation, only hCG has so far been implicated in these changes. Pregnant women experience three- to fourfold increments in AVP disposal rates between early and mid pregnancy; this may be caused by the striking rise in circulating cystine-aminopeptidase (vasopressinase) which also occurs during this period. The increments in MCR may be one reason why the hormonal response to a given osmotic stimulus appears to decrease in late pregnancy. All these alterations permit speculation on the manner in which the decrease in Posm occurs and is maintained within narrow limits. Lowering the osmotic threshold to drink stimulates a rise in water intake and dilution of body fluids. Since AVP release is not suppressed at the usual level of hypotonicity, AVP continues to circulate at levels sufficient to permit water retention. Posm continues to decline until it decreases below the new osmotic thirst threshold, when a new steady state is established. At this point water turnover, too, resembles that in the non-pregnant state. The change in MCR and the marked increment in plasma vasopressinase may explain certain observations regarding disordered water metabolism during late pregnancy. These are the transient DI syndromes due either to subclinical hypothalamic disease or to a disorder peculiar to pregnancy which is AVP-resistant but dDAVP-responsive; the latter analogue resists degradation by vasopressinase.