Role of peripheral adrenoreceptors and vasopressin in the suppression of plasma renin activity by L-dopa in carbidopa-treated dogs.

When extracerebral dopa decarboxylase is inhibited by carbidopa, L-dopa lowers plasma renin activity (PRA). The present study was designed to determine whether this suppression of PRA is mediated by the sympathetic nerves, and to identify the peripheral adrenergic receptor types involved. All experiments were performed in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were minimized by means of a suprarenal aortic clamp. Neither alpha adrenoreceptor blockage with phenoxybenzamine nor beta adrenoreceptor blockade with propranolol was by itself sufficient to block the suppression of PRA by L-dopa with carbidopa. However, combined alpha and beta adrenoreceptor blockade lowered PRA and completely prevented any further suppression of PRA by L-dopa with carbidopa. It was also observed that phenoxybenzamine decreased PRA by 48% when administered to propranolol-treated animals. Taken together, these data indicate that L-dopa with carbidopa suppresses PRA by decreasing sympathetic nerve stimulation of both alpha and beta adrenoreceptors. Plasma vasopressin concnetration was significantly decreased by L-dopa with carbidopa both in the control group and in animals with combined alpha and beta adrenoreceptor blockade. Because plasma vasopressin levels decreased after L-dopa, vasopressin is unlikely to play a causative role in the suppression of PRA.     

Centrally mediated increased reflex vagal bradycardia after L-dopa in monoamine oxidase-inhibited anesthetized dogs.

In monoamine oxidase-inhibited dogs whose peripheral dopa decarboxylase was inhibited with MK-486, L-dopa (K mg/kg i.v.) caused significant hypotension and bradycardia. In addition, reflex bradycardia but not pressor responses to norepinephrine were markedly enhanced by the drug. Similar results were obtained after intracerebroventricular administration of L-dopa (0.5 mg/kg) in monoamine oxidase-inhibited dogs not receiving MK-486. Proparnolol prevented the bradycardia caused by L-dopa but was without effect on the reflex facilitation. Both atropine and phentolamine had no effect on L-dopa bradycardia but prevented the facilitatory effect on reflexes. Inhibition of both peripheral and central dopa decarboxylase with Ro 4-4602 prevented all the effects of L-dopa. Infusions of dopamine which had obvious cardiovascular effects had no effect on reflex responses to norepinephrine. It is concluded that L-dopa, after decarboxylation, causes a centrally mediated enhancement of reflex vagal bradycardia. Pharmacological analysis of this enhancement suggests that this effect appears to be a result of central alpha receptor stimulation.     

Bretylium tosylate and electrically induced cardiac arrhythmias during hypothermia in dogs.

The effect of bretylium tosylate on plasma catecholamines and on electrically induced arrhythmias was evaluated in anesthetized hypothermic dogs. Bretylium at a dose of 7.5 mg/kg was administered prior to cooling from 37 degrees C to 27 degrees C. During cooling, the ventricular arrhythmia threshold (VAT) in control animals decreased from 10.1 +/- 1.9 to 4.4 +/- 1.3 impulses, while the VAT in bretylium-treated animals increased from 9.8 +/- 2.9 to 23.2 +/- 2.7 impulses. Catecholamine levels increased during cooling in all animals. In control animals, the epinephrine/norepinephrine ratio was unchanged, but in animals treated with bretylium tosylate, the ratio increased more than 10-fold (from 0.48 +/- 0.1 to 5.49 +/- 0.32 at 29.9 degrees C). The demonstrated increase in catecholamine levels during hypothermia suggests that the protection offered by bretylium tosylate against cardiac arrhythmias is not explained by modification of catecholamine levels, and is more likely due to an alteration of the electrophysiologic properties of cardiac tissues.     

Characteristics of 100 consecutive patients presenting with orthostatic hypotension

OBJECTIVE: To elucidate the demographic and clinical characteristics of a consecutive series of patients who presented for evaluation of orthostatic hypotension. PATIENTS AND METHODS: From January 1, 1997, through September 30, 2001, we assessed retrospectively the demographic and clinical characteristics, antihypertensive medication use, and blood pressure variability in 100 consecutive patients with orthostatic hypotension who underwent 24-hour ambulatory blood pressure monitoring (OH group) and in a convenience sample of 100 age-matched patients who underwent 24-hour ambulatory blood pressure monitoring for evaluation of hypertension (HTN group). RESULTS: The OH group had a mean +/- SD age of 71.6 +/- 9.4 years, and 42% were women. The most common symptoms were light-headedness and weakness. Comorbid conditions included neurologic diseases (38%), preexisting hypertension (36%), hyperlipidemia (31%), cardiac arrhythmias and coronary artery disease (45%), and neoplasm (28%). During ambulatory blood pressure monitoring, postprandial decreases in blood pressure were noted in 83% of the OH group, supine or sleep hypertension in 84%, and noncompensatory heart rate variability in 75%. Findings on autonomic testing were abnormal in 99% of patients, serum creatinine value was increased in 30%, proteinuria was present in 27%, and left ventricular hypertrophy was present in 20%. CONCLUSIONS: Orthostatic hypotension is present in a heterogeneous group of disease states, is usually symptomatic, and is often associated with an abnormal blood pressure profile of reversal of circadian pattern, postprandial hypotension, and noncompensatory heart rate variability. Consequent target organ (kidney) damage can be as frequent as in patients who undergo 24-hour ambulatory blood pressure monitoring for evaluation of hypertension.     

久强脑立清对急性高血压大鼠重要器官的保护作用

目的探讨久强脑立清（JNQ）对急性高血压大鼠重要器官脑、肾、心的影响。方法采用左旋硝基精氨酸（L-NNA）制做急性高血压大鼠模型，然后给高、中、低剂量JNQ和阳性对照药硝苯地平，观察心功能指标及重要器官HE染色的变化。结果急性高血压大鼠血压两周后比对照升高36％，脑、肾、心均可见病理性改变，但各组大鼠的心率、心电图和血压未见明显差异。经JNQ治疗的大鼠心肌收缩力和心肌耗氧量明显下降，左室内压上升速度明显减慢；脑、心、肾病理改变有不同程度改善。结论尽管JNQ对急性高血压大鼠的心率、血压无明显影响，但可降低心肌耗氧，改善心功能指标，对重要器官脑、肾、心的病变有较明显的保护作用。     

The neurochemistry of Parkinson's disease: effect of L-dopa therapy.

Post-mortem brain material from control and Parkinson's disease patients was examined to elucidate further the neurochemistry of this disease and to determine the mechanism of action of L-dopa as a therapeutic agent. The activities of L-aromatic amino acid decarboxylase (dopa D), tyrosine hydroxylase, monoamine oxidase and catechol-O-methyl transferase were examined; in addition the tissue levels of dopa, 3-O-methyldopa, dopamine (DA) and homovanillic acid (HVA) were determined. In the non-dopa-treated Parkinsonian patients, the greatest decreases were detected for striatal DA and dopa D, with homovanillic acid and tyrosine hydroxylase levels showing a lesser change. The activities of monoamine oxidase and catechol-O-methyl transferase in the striatal nuclei were not different from the controls. The putamen was consistently the most severely affected region. Dopa and 3-O-methyldopa were detectable in all brain areas only in those patients treated with L-dopa shortly before death. The mean concentrations of DA in the striatum of these patients were 1) 9 to 15 times higher than those in non-dopa-treated patients, 2) related to the time before death of the last dose of L-dopa and 3) greater in the striatum of patients clinically classified as "good responders" as compared to "poor responders." Although L-dopa therapy increased homovanillic acid levels in all brain areas, a preferential increase was observed in the striatum. It was concluded that L-dopa's principal therapeutic effects in Parkinson's disease are consistent with its transformation to DA in the striatum.     

EFFECTS OF CALCIUM ENTRY BLOCKERS ON BLOOD PRESSURE AND HEART RATE IN NEUROGENIC HYPERTENSIVE DOGS

The hypotensive and negative chronotropic effects of 5 calcium entry blockers (verapamil 200 micrograms/kg IV; diltiazem 300 micrograms/kg IV; nifedipine 5 micrograms/kg IV; nicardipine 50 micrograms/kg IV; and bepridil 5 mg/kg IV) were compared in control normotensive and acute neurogenic hypertensive anaesthetized dogs. Acute neurogenic hypertension was induced by sino-aortic denervation (SAD). In control normotensive dogs, all drugs (except bepridil) induced a slight and transient decrease in blood pressure. Nifedipine and nicardipine increased heart rate whereas the three other drugs remained ineffective. SAD caused a 2-2.5-fold increase in the hypotensive properties of the 5 drugs in dogs. Moreover, the duration of this induced hypotension was longer than in control normotensive animals. In SAD dogs, all calcium entry blockers significantly decreased heart rate. This study indicates that the direct cardiac inhibitory action of calcium channel blockers is modulated by baroreceptor activity in intact animals. The mechanism of the selective action of calcium entry blockers in hypertensive SAD in contrast to normotensive dogs is discussed.     

Reciprocal renal effects of dopamine and 5-hydroxytryptamine formed within the rat kidney

1. Clearance of inulin and p-aminohippurate and excretion of water and sodium were measured for eight to 11 clearance periods of 20 min duration in anaesthetized, 3% volume-expanded rats, before and after intravenous infusions of the amino acids L-dopa (L-3,4-dihydroxyphenylalanine) and 5-hydroxytryptophan. During the final two clearance periods, the peripheral decarboxylase inhibitor, carbidopa (S-alpha-hydrazino-3,4-dihydroxy-alpha-methylbenzenepropanoic acid monohydrate), was infused additionally. 2. Renal formation of dopamine (3,4-dihydroxyphenethylamine) and 5-hydroxytryptamine was demonstrated during infusions of L-dopa and 5-hydroxytryptophan, respectively; carbidopa blocked the renal formation of these biogenic amines. 3. During infusion of dopa, a diuresis and a natriuresis were observed; during the infusion of 5-hydroxytryptophan, slight reductions in clearances of inulin and p-aminohippurate, but significant reductions in sodium and water excretion, were measured. 4. The addition of carbidopa diminished diuretic and natriuretic responses to dopa as renal dopamine excretion decreased; the infusion of carbidopa also ameliorated the antinatriuretic and antidiuretic effects of 5-hydroxytryptophan, as 5-hydroxytryptamine excretion decreased. 5. Although dopa and 5-hydroxytryptophan are substrates for the same enzyme, aromatic L-amino-acid decarboxylase, simultaneous infusions of both amino acids at comparable rates gave no evidence of competitive inhibition of amine synthesis. However, the infusion of dopa, after 5-hydroxytryptophan, decreased its antinatriuretic and antidiuretic effects. 6. These data raise the possibility that dopamine and 5-hydroxytryptamine are formed as reciprocal intrarenal hormones by the identical enzyme, aromatic L-amino-acid decarboxylase, which is located within cells of the renal tubule.     

Alterations in the Baroreceptor Reflex in Conscious Dogs with Heart Failure

The effectiveness of the baroreceptor reflex in conscious dogs with experimental cardiac hypertrophy and heart failure was compared with that in a group of normal conscious dogs. Cardiac hypertrophy and heart failure were produced by tricuspid avulsion and progressive pulmonary stenosis. The sensitivity of the baroreceptor reflex to transient hypertension was assessed by determining the slope of the regression line relating the prolongation of the R-R interval to the rise in systolic arterial pressure during the transient elevation of arterial pressure induced by an intravenous injection of 1-phenylephrine. The mean slope averaged 22.4+/-2.3 msec/nm Hg in 16 normal animals. 23.1 +/-1.5 in five sham-operated animals, and was significantly reduced to 8.3 +/-0.8 in 10 dogs with hypertrophy alone (P < 0.001), and to 3.3+/-0.5 in nine dogs with heart failure (P < 0.001). The response to baroreceptor hypotension was compared during bilateral carotid artery occlusion (BCO) in six normal and six heart failure dogs previously instrumented with Doppler flow transducers on the superior mesenteric and renal arteries. During BCO, in normal dogs arterial pressure increased 52+/-4 mm Hg, heart rate 33+/-2 beats/min, mesenteric resistance 0.17+/-0.03 mm Hg/ml per min, and renal resistance 0.37+/-0.10 mm Hg/ml per min. In the heart failure group all of these variables increased significantly less (P < 0.01); arterial pressure rose 25 +/-3 mm Hg, heart rate 13 +/-4 beats/min, mesenteric resistance 0.04+/-0.007 mm Hg/ml per min, and renal resistance 0.18+/-0.09 mm Hg/ml per min.Thus, in heart failure, all measured systemic and regional circulatory adjustments consequent to baroreceptor hypo- and hypertension are markedly attenuated. This study demonstrates a profound derangement of a major cardiovascular control mechanism in experimental heart failure.     

Simple gas chromatographic analysis of plasma dopa and dopamine

A method for gas Chromatographie analysis of plasma dopa and dopamine is described. Deproteinized plasma was shaken with acid washed aluminium oxide at pH 8.8. Dopa and dopamine were eluted from alumina with weak acids and evaporated to dryness. The pentafluoropropionic derivative of dopamine and the trifluoroacetic derivative of dopa were made and injected into a gas chromatograph equipped with a ⁶³Ni electron capture detector. Alpha-methyl derivatives of each substance were used as internal standards. Linearity of plasma working curves of each substance was good. This method was applied to the assay of plasma samples from Parkinsonian patients under treatment with L-dopa with or without peripheral dopa decarboxylase inhibitors. The method described is sensitive and simple enough to monitor the blood levels of dopa and dopamine of these patients.     

Hyperthermia-induced cardiac arrest in dogs and monkeys

The pattern of dying from immersion hyperthermia was documented in 8 dogs, 9 rhesus monkeys and 12 pigtail monkeys. Under light general anesthesia and spontaneous breathing, the animals were immersed into water of 45 degrees C, which was subsequently adjusted to control brain (parietal epidural) temperature at 42 +/- 0.5 degrees C. Transient initial hypertension, tachycardia, tachypnea and hypocarbia were followed by progressive hypotension with decreasing central venous pressure and pulmonary artery occlusion pressures (measured in three dogs only), bradycardia and bradypnea. Cardiac arrest occurred in the dogs after immersion of 288 +/- 66 min and more rapidly (P less than 0.02) in the rhesus monkeys (at 137 +/- 75 min) and pigtail monkeys (at 178 +/- 26 min). EEG silence occurred in the monkeys at MAP 40 mmHg and in the dogs at MAP 25 mmHg. Cardiac arrest occurred in form of sudden ventricular fibrillation (2/5 dogs, 2/9 rhesus monkeys, 3/12 pigtail monkeys), or later in electromechanical dissociation leading to electric asystole (3/5 dogs, 7/9 rhesus monkeys, 9/12 pigtail monkeys). The mean blood glucose levels decreased to less than 30 mg/dl (P less than 0.002), whereas hematocrit, serum osmolality, lactate and potassium levels increased. Necropsies revealed macroscopic petechial hemorrhages in all extracerebral organs, but not in the brain. There was no gross evidence of cerebral edema. Death seemed to be the result of primary cardiovascular failure leading to secondary (ischemic) cerebral failure (EEG silence) and apnea, which coincided with pulselessness.     

3H-delta9-tetrahydrocannabinol tissue and subcellular distribution in the central nervous system and tissue distribution in peripheral organs of tolerant and nontolerant dogs.

Tolerant and nontolerant dogs received one i.v. administration of 0.5 mg/kg of 3H-delta9-tetrahydrocannabinol 30 minutes before they were sacrificed. Plasma, peripheral and brain tissues, as well as subcellular fractions of brain tissues from both treatment groups, were analyzed for radioactivity. Throughout the time period before sacrifice, the plasma concentrations of radioactivity in the tolerant and nontolerant dogs were not significantly different. The percentage of radioactivity in brain and plasma that was due to either unchanged delta9-tetrahydrocannabinol or a major metabolite was the same in each group. Of the radioactivity in brain, 46% was identified as delta9-tetrahydrocannabinol. Regardless of treatment, there was a specific accumulation of radioactivity in adrenals, liver, kidney, heart and pancreas. The only significant differences in radioactivity between tolerant and nontolerant peripheral tissues were found in liver, kidney cortex, heart and lymph nodes. Although all brain areas from tolerant dogs contained less radioactivity than the comparable brain areas from nontolerant animals, only pituitary and putamen were significantly less. There was a specific accumulation of radioactivity in some brain areas that could be associated with behavioral effects. The concentration in cerebellar and cerebral gray was significantly greater than that in white, and there was a marked reduction in the concentration in gray after tolerance developed. The mean percentage of radioactivity in each subcellular fraction was as follows: 23% crude nuclei, 44% mitochondria, 8% cholinergic nerve endings, 7% noncholinergic nerve endings, 2% free mitochondria and 6% synaptic vesicles. The quantity of radioactivity in homogenates of brains from tolerant dogs was 17% less than brains of nontolerant animals, which was merely a reflection of the respective plasma concentrations. The distribution of radioactivity was similar in both groups, although most of the subcellular fractions from tolerant dogs contained a lesser amount of radioactivity. The most notable difference was observed in the synaptic vesicle fraction. The synaptic vesicle fraction of tolerant dogs contained 40% less radioactivity than did the same fraction from nontolerant dogs, which implied a possible mechanism of action. A comparison of the remaining subcellular fractions did not appear to explain the development of tolerance.     

Nesiritide: a new drug for the treatment of decompensated heart failure

Nesiritide, a recombinant human B-type natriuretic peptide, is the first in a new drug class for the treatment of decompensated heart failure. The drug binds to receptors in the vasculature, kidney, adrenal gland, and brain, and overcomes resistance to endogenous BNP present in patients with CHF. Nesiritide administration leads to a rapid and balanced vasodilatory effect, which results in a significant decrease in right and left ventricular filling pressures and systemic vascular resistance and at the same time in an increase in stroke volume and cardiac output without a change in heart rate. These early hemodynamic changes result in a rapid improvement in symptoms of heart failure. In addition, nesiritide lowers aldosterone, catecholamines, and endothelin-1 levels and its effect on the kidney leads to an increased natriuresis and diuresis without effect on serum potassium or renal function. Prior to its approval for clinical use, nesiritide was studied in 10 different clinical trials involving 941 patients with moderate and severe CHF, including elderly patients, patients with both systolic and diastolic dysfunction, and patients with arrhythmias, renal insufficiency, and acute ischemic syndrome. In comparative studies with available vasoactive therapies frequently used for treatment of patients with decompensated heart failure, nesiritide was proven comparable in efficacy to inotropic drugs such as dobutamine, but superior in safety. In a recent study, nesiritide was found to be more effective and better tolerated than the vasodilator, nitroglycerin. The most common side effects expected with the use of nesiritide are headaches and decrease in blood pressure. At the recommended dose of nesiritide, headache was reported during the first 24 hours of treatment in 8% of patients and symptomatic hypotension in 4% of patients, compared to 20% and 5% in nitroglycerin-treated patients.     

L-Dopa Treatment and Parkinson's Disease

Seventeen years after its introduction, L-dopa, now administeredin combination with a peripheral dopa decarboxylase inhibitorremains the most effective palliative remedy for Lewy body Parkinson'sdisease. A therapeutic effect to large doses is so consistentthat alternative diagnoses should be considered in any patientwith a Parkinsonian syndrome who fails completely to respond.Despite improving the quality of life, it probably does notinfluence appreciably the reduced life expectancy in Parkinson'sdisease and the long-term therapeutic response is frequentlymarred by drug-induced oscillations in motor performance, dyskinesiasand psychotoxicity. Experimental studies using continuous intravenousinfusions of L-dopa in order to obtain constant plasma levelssuggests that additional refinements in management may be achievedby the design of a practical controlled delivery system, andprototype pumps and sustained release formulations are alreadyunder evaluation.     

Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritic hypertension

BACKGROUND: A new beta 3-adrenoceptor (beta3-AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the beta3-AR agonist, SR58611 in normal and hypertensive dogs. MATERIALS AND METHODS: In protocol 1, SR58611 was infused in normal dogs after placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB. RESULTS: In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensive dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 +/- 32 to 125 +/- 35 mmHg; - 26%, P < 0.0001), that was greater than in normal dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0.0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an effect not observed in normal dogs. CONCLUSIONS: Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.     

Regional blood flow distribution in dog during induced hypotension and low cardiac output. Spontaneous breathing versus artificial ventilation.

Respiratory muscle blood flow and organ blood flow was studied in two groups of dogs with radioactively labeled microspheres to assess the influence of the working respiratory muscles on the regional distribution of blood flow when arterial pressure and cardiac output were lowered by pericardial tamponade. In one group (n = 6), the dogs were paralyzed and mechanically ventilated (Mv), while in the other (n = 6), they were left to breathe spontaneously (Sb). Cardiac output fell to 30% of control values during tamponade in both groups and was maintained constant. None of the dogs was hypoxic. Ventilation in the Sb group peaked after 50 min of hypotension, but remained unchanged in the Mv group. Duplicate measurements of blood flow were made during a control period and after 50 min of tamponade (corresponding to the peak ventilation in Sb). Blood flow to the respiratory muscles increased significantly (P less than 0.001) during tamponade in Sb (diaphragmatic flow increased to 361% of control values), while it decreased in Mv. Although the arterial blood pressure and cardiac output were comparable in the two groups, blood flow distribution during tamponade was different. In Sb, the respiratory muscles received 21% of the cardiac output, compared with only 3% in the Mv group. Thus, by muscle paralysis and Mv, a large fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during low cardiac output state: blood flows to the liver, brain, and quadriceps muscles were significantly higher during tamponade in the Mv group compared with the Sb group. Similarly, blood lactate at all times after the induction of low cardiac output and hypotension was significantly lower in the Mv animals (P less than 0.005).     

Prevalence of cardiovascular disorders among the elderly in primary care in Estonia

OBJECTIVE: To assess the prevalence of diagnoses of cardiovascular disorders among the elderly in family practice. DESIGN: Cross-sectional study. SETTING: Estonia, population aged 65 years or older (206,915 persons). SUBJECTS: 811 elderly persons selected randomly from the lists of family practitioners. MAIN OUTCOME MEASURES: Prevalence of hypertension, hypotension, coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF) and cardiac arrhythmias; differences between the genders and age groups. RESULTS: The prevalence of cardiovascular disorders was as follows: hypertension 63.2%, hypotension 11.1%, CHD 56.5%, MI 9.8%, HF 41.4% and arrhythmias 37.5%. Women had a significantly higher prevalence of hypertension and men of MI. The prevalence of CHD and hypotension was significantly higher in the oldest elderly persons. CONCLUSION: Among the older population in Estonia, cardiovascular disorders that have broader diagnostic criteria and need expensive methods for verifying (CHD, HF) have a high prevalence and are most likely over-diagnosed. The need for strict and simple diagnostic methods for these disorders in primary care practice continues to be serious.     

Contribution of peripheral blood pooling to central hemodynamic disturbances during endotoxin insult in intact dogs

The aim of the present study was to determine possible effects of Escherichia coli endotoxin on peripheral vascular compliance and relate them to concomitant central hemodynamic disturbances. Endotoxin was infused at 0.25 micrograms/kg.min during 2 h in six anesthetized dogs, while six additional animals served as controls. Vascular compliance of the systemic circulation was calculated in intact animals from the changes in CVP after known changes in systemic blood volume. In control dogs, vascular compliance averaged 2.3 ml/mm Hg.kg body weight. During slow endotoxin infusion, cardiovascular effects were measurable only after a certain period of time had elapsed from the start of endotoxin insult and consisted of hypotension associated with systemic vasodilation. Systemic BP decreased gradually from 124 to 68 mm Hg while vascular compliance was finally increased by 100%, when compared to control values. This latter rise was responsible for a reduction in the cardiac preloads. Pulmonary wedge pressure and CVP were decreased from 7.1 to 3.4 and from 4.5 to 2.6 mm Hg, respectively. However, parallel to the decrease in left ventricular preload, endotoxin induced a progressive decrease in left ventricular afterload. Because of the balance in ventricular loading, cardiac output remained almost unchanged. After volume loading (dextran 30 ml/kg), cardiac output was remarkably increased from 3.28 to 6.24 L/min.m2 while peripheral vasodilation was not affected by this maneuver. It is concluded that low dose endotoxin infusion induces in dogs a hemodynamic pattern similar to human sepsis. The left ventricular loading changes are related to an enhanced systemic vascular compliance from 2.3 to 4.5 ml/mm Hg.kg. High flow shock state is encountered provided peripheral blood pooling is compensated by adequate volume replacement.     

Effect of quinpirole, a specific dopamine DA2 receptor agonist on the sympathoadrenal system in dogs

The effects of quinpirole, a specific dopamine DA2 receptor agonist, were investigated on both cardiovascular responses in conscious dogs and catecholamine release from the adrenal medulla in anesthetized dogs. In conscious normal dogs, i.v. quinpirole (30 micrograms/kg) elicited a decrease in blood pressure and a marked increase in heart rate associated with a rise in plasma catecholamine levels. The increase in heart rate is due to both baroreflex and central mechanisms because a slight but significant positive chronotropic effect persists in sinoaortic denervated dogs (i.e., animals deprived of baroreflex pathways). The central origin of this excitatory effect was confirmed by two subsequent protocols: intracisterna magna injection of quinpirole (5 micrograms/kg) increased blood pressure, heart rate and plasma catecholamines; i.v. domperidone reversed the hypotensive effect of i.v. quinpirole into a pressor response. The rise in plasma catecholamines was associated with an increase in plasma vasopressin levels. In anesthetized dogs, i.v. quinpirole (10 micrograms/kg/min during 12 min), which also decreased blood pressure, failed to modify epinephrine (and norepinephrine) release from the adrenal medulla whatever the stimulation frequencies (1, 3 and 5 Hz) of the sectioned splanchnic nerve. Similar results were obtained with apomorphine (5 micrograms/kg/min during 12 min). These results show that two mechanisms are involved in the action of quinpirole: first, a peripheral depressor action (which elicits the decrease in blood pressure) and secondly, a central pressor component involving an increase in both sympathetic tone and vasopressin release. They also demonstrate clearly that peripheral DA2 receptors are not involved in the control of catecholamine release from the adrenal medulla under in vivo conditions.     

L-dopa treatment and Parkinson's disease

Seventeen years after its introduction, L-dopa, now administered in combination with a peripheral dopa decarboxylase inhibitor remains the most effective palliative remedy for Lewy body Parkinson's disease. A therapeutic effect to large doses is so consistent that alternative diagnoses should be considered in any patient with a Parkinsonian syndrome who fails completely to respond. Despite improving the quality of life, it probably does not influence appreciably the reduced life expectancy in Parkinson's disease and the long-term therapeutic response is frequently marred by drug-induced oscillations in motor performance, dyskinesias and psychotoxicity. Experimental studies using continuous intravenous infusions of L-dopa in order to obtain constant plasma levels suggests that additional refinements in management may be achieved by the design of a practical controlled delivery system, and prototype pumps and sustained release formulations are already under evaluation.