Decrease In Total Peripheral Resistance Research Articles

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

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. 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. 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. 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.

Effects of pregnancy and progesterone metabolites on regulation of sympathetic outflow.

1. Pregnancy is characterized by a 40% increase in blood volume and cardiac output, a decrease in arterial blood pressure and thus a substantial decrease in total peripheral resistance. The aims of the experiments described in this manuscript were: (i) to determine if pregnancy resulted in alterations in baroreflex control of sympathetic outflow; and (ii) to evaluate possible mechanisms for pregnancy-induced changes in control of sympathetic outflow. 2. Arterial baroreflex control of efferent renal sympathetic nerve activity was examined in female pregnant and non-pregnant normotensive Sprague-Dawley and Wistar-Kyoto rats. In both rat strains, pregnancy was associated with a decrease in baseline arterial pressure, a shift in the baroreflex function curve to a lower operating pressure range and an attenuated ability to reflexly increase sympathetic outflow above baseline levels during a hypotensive challenge. Pregnant Sprague-Dawley rats retained their ability to respond to a hypertensive challenge, whereas pregnant Wistar-Kyoto rats exhibited a decreased sensitivity to hypertensive as well as hypotensive challenges. 3. The inhibitory amino acid transmitter, GABA, mediates baroreflex sympatho-inhibition within the rostral ventral lateral medulla (RVLM) of the brainstem. Since 3 alpha-OH dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, is elevated in pregnancy and has been reported to potentiate central nervous system GABAA inhibitory responses, experiments were performed to determine if effects of this metabolite of progesterone could contribute to the pregnancy associated changes in control of sympathetic outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic response to head-up tilt in elderly hypertensives and diabetics.

To examine the haemodynamic mechanism associated with postural hypotension (PH) in elderly people, haemodynamic response to head-up tilt was studied in 14 elderly hypertensives and 13 elderly diabetics. Hypertensives and diabetics were divided into those with or without PH, defined as > or = 10 mmHg decline in mean blood pressure in response to head-up tilt. There was no significant change in cardiac output in hypertensives or diabetics with PH, whereas there was a significant increase during tilt in hypertensives without PH (p < 0.0001) and diabetics without PH (p = 0.0054). Hypertensives without PH showed a significant decrease in total peripheral resistance in response to head-up tilt (p = 0.0043). In hypertensives with PH and in both diabetic groups, there was no change in total peripheral resistance in response to head-up tilt. There was no difference in ejection fractions or heart rate responses between subjects with and without PH in either disease group. The difference in cardiac output change was not explained by myocardial changes observed at echocardiography nor by heart rate response nor by differences in total peripheral resistance. The results suggest that an increase in cardiac output in response to changing posture may be more important than vasoconstriction in protecting elderly subjects from PH.

Response of the rat heart to catecholamines and thyroid hormones.

Catecholamines and thyroid hormones have a similar influence on heart function and metabolism, but this may occur in a differential manner and to a different extent. In this study, the effects of norepinephrine (NE) and of triiodothyronine (T3) were studied in regard to the function of the left (LV) and right ventricle (RV) and to the oxidative pentose phosphate pathway (PPP). NE was applied in rats as continuous i.v. infusion (0.2 mg/kg/h) for three days. T3 was given as daily s.c. injections (0.2 mg/kg) for the same period of time. LV and RV function was measured in the closed-chest trapanal-anesthetized animals using special Millar ultraminature catheter pressure transducers. NE induced an increase in heart rate, in mean arterial pressure, and in total peripheral resistance (TPR). The cardiac RNA/DNA and the left ventricular weight/body weight ratios were increased by about 40%. These effects were prevented by simultaneous alpha- and beta-receptor blockade with prazosin and metoprolol, respectively, but not by verapamil which abolished the hemodynamic effects. RVSP was significantly elevated by NE in a dose-dependent manner. The functional effects of T3 on the LV were not as pronounced as those induced by NE. Heart rate and LV dp/dtmax were increased by T3, and this increase was prevented by concomitant beta-receptor blockade with metoprolol. In contrast to NE, T3 induced an increase in cardiac output and a concomitant decrease in TPR. The RNA/DNA ratio was elevated and cardiac hypertrophy had developed after treatment for three days with T3. These changes were not affected by beta-receptor blockade with metoprolol. RVSP was increased by T3 to a lesser extent than with NE. In metabolic terms it turned out that only NE, but not T3 had a stimulating effect on the cardiac PPP. NE increased the mRNA and activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of this pathway. However, there was no effect of T3 on G-6-PD activity nor on 6-phosphogluconate dehydrogenase activity, one of the following enzymes in the pathway within the first 5 days of T3 treatment. These results demonstrate that the functional effects of T3 were not as pronounced as or even different from those of NE, and that T3 lacked a stimulating effect on the cardiac PPP.

BQ-123, a selective endothelin subtype A-receptor antagonist, lowers blood pressure in different rat models of hypertension

To investigate the role of endothelin-1 in the pathogenesis of hypertension directly by using the selective endothelin subtype A-receptor antagonist BQ-123. The antihypertensive and hemodynamic effects of sustained BQ-123 administration were examined in conscious, unrestrained spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) rats and renin hypertensive rats. Sustained infusions of BQ-123 (0.16-164 nmol/kg per min, intravenously, for 6 h) produced dose-dependent reductions in mean arterial pressure in SHR, the maximal reduction being obtained with a dose of 16 nmol/kg per min. This reversible response was evident up to 14 h after the cessation of antagonist infusion. The antihypertensive response to a maximal dose of BQ-123 was associated with bradycardia, but only a minimal reduction in cardiac output (since the stroke volume was elevated) in the SHR. Therefore, the antihypertensive effect of BQ-123 resulted from a decrease in total peripheral resistance. In contrast, in WKY rats the infusion of the high dose (164 nmol/kg per min, intravenously for 6 h) produced a small but significant reduction in mean arterial pressure. BQ-123 did not alter the pressor response or tachycardia observed in pithed SHR following stimulation of the thoracolumbar sympathetic outflow. BQ-123 was also antihypertensive in renin hypertensive rats, lowering the blood pressure to an extent similar to that observed in SHR. The data presented indicate a role for endothelin in the pathophysiology of hypertension.

Calcitonin gene-related peptide (human α-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage

Calcitonin gene-related peptide (CGRP) is a neuropeptide co-stored with tachykinins (substance P, neurokinin A) in cerebrovascular sensory fibers in the trigeminal ganglion. Preceding studies on subarachnoid hemorrhage (SAH) revealed that an enhanced release of CGRP resulted in the selective loss of perivascular CGRP. Therefore, the present study was designed to evaluate the effects of intravenous administration of human α-CGRP on cerebral vasoconstriction in the postoperative course after SAH in 5 patients (8 infusions). Cerebral vasoconstriction was evaluated with transcranial Doppler sonography. The increase in the relationship between middle cerebral artery (MCA) velocity and internal carotid artery (ICA) velocity (the hemodynamic index) was used as an indicator of vasoconstriction and compared to the contralateral side. A significant reduction was found in the hemodynamic index during the CGRP infusion (4.3 ± 0.5, P < 0.05) as to compared to before infusion (6.2 ± 0.5). There was no measurable change in the hemodynamic index on the contralateral side. No significant change was observed in pulsatility index, blood pressure or consciousness during the peptide infusion. A significant increase in heart rate was observed during the infusion as compared to before and after infusion (90 ± 4 vs. 76 ± 5). Cardiac ultrasound data indicated a mean cardiac output increase of 1.9 liter/min, and a mean decrease in total peripheral resistance of 538 dynes s/cm 5. The results obtained show that infusion of human α-CGRP may induce normalisation of cerebrovascular tone in SAH.

Postexertional hypotension: A brief review

A statistically and clinically significant reduction in arterial pressure occurs following a single bout of low intensity, short duration aerobic exercise in individuals with hypertension. The reduction in arterial pressure is most often associated with a decrease in total peripheral resistance, peripheral sympathetic nerve activity, and plasma norepinephrine concentration; however, cardiac output is often elevated without a change in heart rate. The purpose of this article is to review the literature and propose a model that analyzes the components contributing to the postexercise reduction in arterial pressure. The model implicates an attenuated vascular response to catecholamine stimulation and an enhanced inhibitory cardiopulmonary reflex response. Recent evidence has shown that a single bout of dynamic exercise significantly attenuated the vasoconstrictor response to phenylephrine in an isolated aortic ring preparation and in the intact conscious rabbit and rat. This suggests that the ability of the ...

Effects of slow-release nifedipine on hemodynamics and pharmacokinetics in elderly hypertensives

Ten elderly hypertensives (4 men, 6 women) were studied before and after 8-week administration of 20 mg/day slow-release nifedipine. Systemic and regional hemodynamic data were measured using a pulsed Doppler technique. Slow-release nifedipine reduced mean arterial pressure, while cardiac output remained unchanged, resulting in a decrease in total peripheral resistance. None of common carotid, vertebral, celiac, superior mesenteric, renal, or terminal aortic flow changed significantly before or after administration of slow-release nifedipine. Pharmacokinetic parameters were as follows: Cmax, 59.1 ng/ml; AUC, 288.2 ng hr/ml; Tmax, 3.4 hr; t1/2, 5.5 hr. There was a direct relationship between the concentration of slow-release nifedipine and its depressor effect. Slow-release nifedipine had no influence on humoral factors such as plasma renin activity, angiotensin II, aldosterone, atrial natriuretic peptide, noradrenaline or adrenaline. Slow-release nifedipine may provide desirable hemodynamic effects in elderly hypertensives.

Effect of the platelet‐activating factor antagonist, TCV‐309, and the cyclo‐oxygenase inhibitor, ibuprofen, on the haemodynamic changes in canine experimental endotoxic shock

1. The present study was conducted in order to examine the effects of the platelet-activating factor (PAF) antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the acute haemodynamic responses to endotoxin in anaesthetized dogs. 2. Endotoxin (2 mg kg-1, i.v.) induced a severe hypotension by decreasing both total peripheral resistance (TPR) and cardiac output. Endotoxin also decreased central venous pressure and increased effective vascular compliance (EVC), indicating a blood pooling in the capacitance vessels. 3. The endotoxin-induced hypotension but not the fall in cardiac output, was markedly attenuated by ibuprofen. Ibuprofen abolished the decrease in TPR and even caused a systemic vasoconstriction. Ibuprofen abolished the increase in EVC. 4. The hypotension caused by endotoxin was attenuated by TCV-309 to a lesser extent than ibuprofen. However, the reduction in cardiac output produced by endotoxin was markedly attenuated by the PAF antagonist. TCV-309 also abolished the increase in EVC. In contrast to ibuprofen, TCV-309 did not affect the decrease in TPR caused by endotoxin. 5. Combined treatment with ibuprofen and TCV-309 markedly attenuated the endotoxin-induced hypotension, but not the fall in cardiac output. Nevertheless, when compared with animals treated with ibuprofen alone, treatment with ibuprofen and TCV-309 partly attenuated the endotoxin-induced reduction in cardiac output and systemic vasoconstriction. 6. These data indicate that dilatation of both resistance vessels and capacitance vessels contributes to the endotoxin-induced hypotension. It is suggested that (i) both prostanoids and PAF are involved in dilatation of capacitance vessels, (ii) prostanoids, but not PAF cause dilatation of resistance vessels and(iii) PAF may partly contribute to prostanoid-independent reduction in cardiac output in acute canine experimental endotoxin shock.

Cardiac performance enhancement from dobutamine in patients refractory to hypervolemic therapy for cerebral vasospasm.

The use of the beta-agonist dobutamine in combination with hypervolemic preload enhancement of cardiac performance was analyzed in 23 patients who failed to respond to traditional preload enhancement following aneurysmal subarachnoid hemorrhage. The patients ranged in age from 13 to 82 years, and three had a history of cardiac disease. Each patient underwent placement of a flow-directed balloon-tipped catheter and the following measurements were obtained during hyperdynamic therapy: pulmonary artery wedge pressure, central venous pressure, cardiac index, stroke volume index, total peripheral resistance, and left ventricular stroke work index (LVSWI). Mean baseline cardiac function was found to be within normal limits (LVSWI = 47.6 +/- 4.2 gm/min/sq m and cardiac index = 3.30 +/- 0.22 liter/min/sq m). After baseline measurements were recorded, 5% albumin was infused at 300 cc/hr and dobutamine was initiated at a rate of 5 to 10 micrograms/kg/hr. This hyperdynamic therapy with dobutamine in the presence of volume loading resulted in a 52% increase in cardiac index, a 15% increase in LVSWI, and a 21% decrease in total peripheral resistance. The clinical reversal of ischemic symptoms due to subarachnoid hemorrhage was evident in 18 (78%) of the 23 patients.

Hemodynamic effects of a novel hypotensive peptide, human adrenomedullin, in rats

The hemodynamic effects of human adrenomedullin were investigated in anesthetized Wistar rats. Intravenous administration of adrenomedullin (1.0 nmol/kg) caused a rapid and marked reduction in mean blood pressure associated with a decrease in total peripheral resistance. This reduction in mean blood pressure was closely correlated with the decrease in total peripheral resistance. These findings indicate that human adrenomedullin is a potent vasodilator and may have some role in the regulation of blood pressure.

Systemic and coronary effects of the angiotensin II receptor antagonist EXP3174 in dogs.

The effects of EXP3174 (0.03-0.3 mg/kg), the active metabolite of the angiotensin II (AII) receptor antagonist losartan, on systemic and coronary hemodynamics as well as on regional myocardial blood flow (radioactive microspheres) were evaluated in anesthetized, open-chest dogs with or without preactivated renin-angiotensin system (RAS) (furosemide treatment). These effects were compared with those of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat (0.1-1 mg/kg). In dogs without preactivated RAS, EXP3174 or enalaprilat did not exert marked hemodynamic effects other did not exert marked hemodynamic effects other than a significant decrease in mean arterial blood pressure (MAP) at the highest doses. In dogs with preactivated RAS, EXP3174 induced a marked, dose-dependent decrease in MAP (maximum decrease -23 +/- 7%), associated with a significant decrease in total peripheral resistance (TPR), whereas cardiac output (CO), heart rate (HR), and left ventricular dP/dt remained unchanged. At the coronary level, EXP3174 induced a decrease in mean coronary resistance that paralleled that of AP. Similar systemic and coronary hemodynamic effects were obtained with enalaprilat administered at doses three times higher. However, regional myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural) or its transmural distribution (endo/epi ratios) was not affected by EXP3174 or enalaprilat. Thus, these results indicate that blockade of the AT1 receptor of AII by EXP3174 induces hemodynamic modifications similar to those evoked by the ACE inhibitor enalaprilat. The lack of effect of EXP3174 or enalaprilat on regional myocardial blood flow (RMBF) suggests, however, that the RAS does not play a role in regulation of myocardial tissue perfusion.

Arterial hemodynamics and cardiac effects of enoximone, dobutamine, and their combination in severe heart failure

The acute systemic and regional hemodynamic effects of dobutamine (5, 10, and 15 μg/kg/min intravenously), of enoximone (1, 1.5, and 2 mg/kg intravenously), and of the dobutamine-enoximone combination were compared in eight patients with severe congestive heart failure. Dobutamine and enoximone similarly and dose-dependently increased cardiac index and decreased systemic vascular resistance, right atrial pressure, and mean capillary wedge pressure. Dobutamine, but not enoximone, increased heart rate after 10 and 15 μg/kg/min. The combination of the two drugs caused a greater increase in cardiac index and a greater decrease in total peripheral resistance than did each drug alone. In the forearm vascular bed, brachial blood flow and brachial artery diameter were increased by enoximone significantly and dose-dependently and by dobutamine only at 5 μg/kg/min. Finally, the combination of the two drugs increased brachial blood flow but not brachial artery diameter to a larger extent than enoximone alone. Hepatosplanchnic and renal blood flows were not altered by any of the treatments. These results indicate that (1) enoximone exerts a significantly greater muscular vasodilator action than dobutamine; (2) the dobutamine-enoximone combination potentiates the systemic and brachial vasodilator effects of each drug; and (3) high doses of dobutamine (10 and 15 μg/kg/min) improve hemodynamics through their positive inotropic and chronotropic effects, whereas at low doses (5 μg/kg/min) a peripheral vasodilation also contributes.

The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog

15AU81, a tricyclic benzindene analog of prostacyclin, is currently under preclinical evaluation as a potential treatment for congestive heart failure. The cardiovascular effects of 15AU81 were evaluated in anesthetized beagle dogs given 4-h infusions at rates of either 0.1, 0.3, 1.0, or 3.0 μg/kg/min. Plasma samples taken from these dogs prior to, during, and after the infusion, were analyzed for 15AU81 by a radioimmunoassay (RIA). This report integrates the vasodilatory effects and plasma concentration data from the 15AU81 infusion study. Pharmacokinetic analysis of mean data indicated a biphasic decay of 15AU81 in plasma, with an initial half-life of approximately 2 min, and a terminal half-life of approximately 20 min. Visual inspection of plots of drug effect and drug concentration against time indicated a close relationship between plasma concentration of 15AU81 and the onset of decreases in total peripheral resistance (TPR) and pulmonary vascular resistance (PVR). In general, the decreases in TPR and PVR induced by 15AU81 were maintained during infusion. Concentration-effect plots indicated some hysteresis in TPR vs plasma concentrations of 15AU81 after termination of the infusion; possible explanations for this hysteresis include the presence of saturating concentrations of 15AU81 at the effect site, with a delay in the clearance of 15AU81 from the effect site compared to its clearance from plasma, and/or the presence of active metabolites at the effect site. A fit of the TPR and PVR data to the E max pharmacodynamic model predicted that the maximum decrease in TPR achievable with 15AU81 in anesthetized dogs was 66%, and that the concentration of 15AU81 producing 50% of the maximum effect (EC 50) was 8.6 ng/ml. Similarly, the predicted maximum reduction in PVR achievable with 15AU81 in dogs was estimated to be 22%, and the EC 50 value was estimated to be 11.3 ng/ml. Thus, while the magnitude of the effect of 15AU81 on TPR and PVR may be different, the similar EC 50 values suggested that there may be no selectivity of 15AU81 for the pulmonary or peripheral circulation in the normotensive, anesthetized dog.

Differential regional hemodynamic changes produced by L-glutamate stimulation of the locus coeruleus

The locus coeruleus (LC) exerts an inhibitory influence on the cardiovascular system. Microinjection of the excitatory amino acid, L-glutamate, into the LC elicits a decrease in arterial pressure as a result of a decrease in total peripheral resistance (TPR). The aim of the present study was to examine the role of the LC in the regulation of the regional hemodynamics. Employing anesthetized rats, the blood flow to the renal, mesenteric and hind-limb vascular beds was measured with an electromagnetic flowmeter. The changes in regional blood flow tnd vascular resistance evoked by chemical stimulation of the LC were examined separately in each region. During the depressor response elicited by LC stimulation, the hind-limb and renal vascular resistance was signfficantly decreased, while the mesenteric resistance was unchanged. The vasodilatation appeared to be more prominent in the hind-limb muscle than in the systemic circulation. Renal nerve denervation attenuated the decrease in renal vascular resistance elicited by LC stimulation. However, a small part of this response still remained in the denervated kidney. The present results suggest therefore that: (1) LC neurons exert differential hemodynamic effects on the hind-limb muscle, renal and mesenteric vascular beds; (2) the largest contribution to the decrease in TPR is related to vasodilatation in the hind-limb muscles; and (3) the renal vasodilatation elicited by LC stimulation is not mediated solely by the renal innervation.

Hemodynamic effects of antihypertensive agents: A comparison of diuretics, beta-blockers, calcium antagonists, and angiotensin converting enzyme inhibitors

A total of 121 patients with essential hypertension were treated with a diuretic, beta-blocker, calcium antagonist, or angiotensin converting enzyme (ACE) inhibitor. Hemodynamic assessments were made before and after 3 months of treatment. After 30 minutes of rest in the supine position, the patients' blood pressure, cardiac output, systolic time intervals, total peripheral resistance, and volume-elasticity index were measured. Plasma renin activity in most cases was measured with a furosemide-loading test (in an upright position) before treatment. Only patients who had a decrease in mean arterial pressure of >13 mmHg before and after treatment were included in the analysis. The principal hemodynamic change before and after treatment with diuretics and beta-blockers was a decrease in cardiac output; the main change with calcium antagonists and ACE inhibitors was a decrease in total peripheral resistance. Based on their hemodynamic characteristics, patients were placed in a high cardiac output group or high vascular resistance group. Each group was further divided into high-renin, normal renin, or low-renin groups. In the high cardiac output group: the high-renin group responded best to beta-blockers, the normal renin group to diuretics or beta-blockers, and the low-renin group to diuretics. The high vascular resistance group responded best to calcium antagonists or ACE inhibitors, regardless of the plasma renin activity. Our results indicate that an antihypertensive agent should be selected not only for its effects on blood pressure but also for its effects on hemodynamics and renin activity.

Hemodynamic effects of amosulalol (YM-09538) in patients with essential hypertension

Amosulalol 40 to 60 mg was orally administered for approximately 3 months to 14 patients with mild to moderate essential hypertension to investigate the drug's hemodynamic effects. Eight patients who responded well to the therapy showed an increase in cardiac output and stroke volume and a decrease in total peripheral resistance and volume elasticity, but no changes in heart rate. These hemodynamic effects of amosulalol noticeably differed from those of propranolol. The important hemodynamic features of amosulalol include decreased total peripheral resistance and suppression of reflex tachycardia; these effects result from the drug's selective alpha 1-blocking and beta-blocking activity. From a hemodynamic aspect, amosulalol is preferable to a beta-blocker in the treatment of hypertension.

Hemodynamic and metabolic effects of intravenous clentiazem in hypertensive patients

To determine the hemodynamic and certain metabolic effects of clentiazem, a diltiazem congener, 10 untreated essential hypertensive patients were given the calcium antagonist in 3 successive doses totaling 1.0 mg/kg intravenously. Mean arterial pressure and total peripheral resistance progressively declined from 121 ± 3 mm Hg and 47 ± 2 U (mean) to 110 ± 3 mm Hg and 33 ± 1 U, respectively (p <0.05); heart rate remained unchanged. Cardiac output increased as a result of augmented cardiopulmonary volume (p <0.05) produced by peripheral venoconstriction and norepinephrine release (from 258 ± 41 to 319 ± 42 pg/ml; p <0.01). Surprisingly, there was an immediate reduction in plasma aldosterone (10.4 ± 1.2 to 6.5 ± 1.0 ng/dl; p <0.01), serum potassium (4.3 ± 0.1 to 3.6 ± 0.1 mEq/dl; p <0.001) and calcium (9.5 ± 0.1 to 8.8 ± 0.1 mg/dl; p <0.001) concentrations, whereas epinephrine increased (21.2 ± 3.3 to 45.8 ± 5.9 pg/ml; p <0.002). Previous studies with diltiazem, conducted similarly, did not show these changes. Therefore, clentiazem reduced mean arterial pressure through a decrease in total peripheral resistance, and released epinephrine was associated with intracellular potassium influx (urinary potassium did not change). The inhibited aldosterone release was not compensated by altered renal blood flow, glomerular filtration or increased plasma renin activity. These findings underscore the concept that calcium antagonists are a remarkably heterogeneous antihypertensive group.

Chemical stimulation of the locus coeruleus: inhibitory effects on hemodynamics and renal sympathetic nerve activity

We examined the role of the locus coeruleus (LC) in the regulation of the hemodynamics and sympathetic nerve activity in anesthetized rats. Unilateral microinjection into the LC of the excitatory amino acid, l-glutamate (Glu), elicited dose-dependent decreases in arterial pressure (AP) and heart rate (HR). The bradycardic response was partially attenuated after intravenous injection of atropine sulfate, but the greater part of this response still remained. Interruption of the ascending projections of the LC by midbrain of transection did not affect the depressor and bradycardic responses elicited by chemical stimulation. The renal sympathetic nerve activity showed transient but strong inhibition with this stimulation. Cardiac output was measured using an electromagnetic flowmeter implanted in the ascending aorta. The stroke volume and total peripheral resistance (TPR) were calculated. Microinjection of Glu elicited a significant decrease in TPR and slight decreases in cardiac output and stroke volume. Microinjection of the inhibitory amino acid, γ-aminobutyric acid (GABA), or theα 2-adrenergic agonist, clonidine, exerted no effect on AP and HR. The present results therefore suggest that: (1) the LC neurons have an inhibitory influence on the sympathetic nervous system, and stimulation of these neurons can elicit depressor and bradycardic responses; (2) the depressor response was produced predominantly as a result of a decrease in vascular resistance, rather than a decrease in cardiac output; (3) these inhibitory responses may be provided not via the ascending projections of the LC; and (4) the LC neurons do not have a tonic influence on the cardiovascular system.

The effects of 15AU81, a chemically stable prostacyclin analog, on the cardiovascular and renin-angiotensis systems of anesthetized dogs

15AU81 is a chemically stable tricyclic benzindene analog of prostacyclin. Prostaglandins, PGI 2 and PGE 2, and their analogs have demonstrated acute hemodynamic benefit in congestive heart failure. The purpose of this study was to evaluate the cardiovascular effects of 15AU81 in anesthetized dogs in order to assess this agent's potential for clinical study in the treatment of congestive heart failure. Four hour intravenous infusions of 15AU81 at 0.1, 0.3, 1.0, or 3.0 μg/kg/min produced dose-dependent decreases in mean arterial blood pressure of 10%, 43%, 55% and 68% respectively with associated decreases in total peripheral resistance of 20%, 32%, 56% and 73%, respectively. 15AU81 dilated the pulmonary circulation; however, the effects of 15AU81 on the pulmonary vascular bed were not dose dependent and not stable over time. Maximal decreases in mean pulmonary artery blood pressure achieved were 9%, 23%, 22% and 18% with an associated decrease in pulmonary vascular resistance of 9%, 33%, 30% and 23%, at doses of 15AU81 of 0.1, 0.3, 1.0 and 3.0 μg/kg/min respectively. The onset of vasodilator effects were rapid, reaching a maximum within 5–10 min with an equally rapid recovery when the infusion was discontinued. Cardiac and hormonal effects associated with 15AU81 treatment included decreases in inotropy, and lusitropy and increases in heart rate and plasma angiotensin II concentration. The increase in plasma angiotensin II concentrated correlated significantly with the decrease mean arterial blood pressure. These effects are interpreted to be generally secondary to the potent and profound vasodilator activity of 15AU81 and not likely due to direct cardiac or neurohumoral effects. The hemodynamic profile of 15AU81 suggests that, through its rapid onset and ability to reduce loading conditions of the right and left ventricles and its chemical stability over natural prostacyclin, this prostacyclin analog may have utility in the management of chronic congestive heart failure.