Comparison of effects of dopamine hydrochloride and dopexamine hydrochloride on abdominal and femoral hemodynamics in anesthetized dogs.

The effects of dopamine and dopexamine administered in graded intravenous bolus injections (0.1-51.2 micrograms.kg-1) were compared in the renal and femoral, and in a number of splanchnic vessels at the organ level simultaneously in anesthetized dogs. Hemodynamic data are presented for each artery as conductance, which was obtained by dividing mean flow by mean arterial pressure. The data were analyzed in two different ways: 1) by responses at intervals of 3 sec to 12.8 micrograms dopamine or dopexamine during 1 min, and 2) by dose-response curves. Additionally, urine volume was measured during dopamine and dopexamine administration. During a period of 1 min after an injection of dopamine, early and late effects could be distinguished, while heart rate was unaltered. In the superior mesenteric, inferior mesenteric, splenic, common hepatic, renal, and femoral arteries, an early (at 18-21 sec) reduction in conductance was seen. The early reduction was often followed by an increase above the preinjection level. After dopexamine, the early reduction in conductance was not seen, except in the left gastric artery. In contrast to the effect of dopamine, dopexamine induced a more pronounced increase during the late phase. Contrary to dopamine, dopexamine increased the conductance in the common hepatic artery bed. It remains questionable whether dopaminergic receptors are present in this vascular bed. Dopamine raised blood pressure and urine production dose-dependently. Dopexamine decreased aortic pressure. Low dosages of dopexamine increased urine production, without raising renal blood flow. An advantage of dopexamine over dopamine could be that dopexamine does not stimulate alpha-adrenergic receptors.

Influences of nifedipine on vascular conductance of portally drained viscera, liver and kidney.

Nifedipine is a potent vasodilator, which induces various dose-related hemodynamic responses in the gastrointestinal tract, liver and kidney. Blood flow was assessed in anesthetized dogs with non-cannulating electromagnetic flow sensors. Nifedipine was injected into a brachial vein at intervals of 2 min in graded doses from 1-16 micrograms.kg-1. The pulsatile flow and pressure signals were analog-digital converted and processed by a computer program to obtain mean flow (ml.min-1) and mean pressure (mm Hg) values for every 3 s. The vascular data are presented as conductance. The arterial pressure decreased 45% while vascular conductance in vessels of the stomach, duodenum, small and large bowel increased between 75 and 128%. No response was observed in the splenic and common hepatic artery. An increase of resistance in the hepatic artery proper, while portal flow increased suggests that there were changes in liver metabolism. Although the literature indicates a decrease in renal vascular resistance, we encountered a decrease in flow but no change in resistance. Neither did we find an increase in heart rate. We propose that small intravenous doses of nifedipine reduce the afterload of the left ventricle.

Effects of dopamine on intestinal vessels in anesthetized dogs.

The effects of dopamine administered in graded intravenous bolus injections (0.1 to 51.2 micrograms.kg-1) were studied simultaneously in a number of splanchnic vessels at organ level in anesthetized dogs with and without preceding administration of phenoxybenzamine. Hemodynamic data are presented for each artery as conductance, which were obtained by dividing mean flow by mean arterial pressure. The data were analyzed by two different means: 1) the response to 12.8 micrograms of dopamine during one minute, and 2) by dose-response curves. Early and late effects during the one minute post injection measurement time could be distinguished after the administration of dopamine. In the superior pancreaticoduodenal, the superior mesenteric, the inferior mesenteric, the left gastric, and the hepatic arteries an early reduction in conductance was seen, while in the femoral artery an increase in conductance was observed. Early reduction was often followed by an increase in conductance above the preinjection level. This early reduction in conductance was absent when dopamine was administered after phenoxybenzamine, while a more pronounced increase was observed during the late phase. There was a slight reduction in renal artery flow, probably caused by a slight reduction in arterial pressure. Because there was no increase in the conductance of the hepatic artery--both with and without phenoxybenzamine--it may be concluded that no specific dopamine receptors are present in this vascular bed in dogs.

Distinction between alpha-adrenergic receptors in eight vascular areas of the dog.

The study concerns the heterogeneity of the vascular alpha-adrenergic receptor population studied in anesthetized dogs. Two groups of animals were used: a control group that received only the agonists noradrenaline (1-1024 ng/kg i.v.) and phenylephrine (64-16384 ng/kg i.v.) and a group that additionally received the antagonist phenoxybenzamine (67-2250 micrograms/kg i.v.). Arterial pressure was measured and the vascular responses were simultaneously monitored in liver, stomach, duodenum, jejunum, ileum, colon, kidney and hindleg, simultaneously with electromagnetic blood flow sensors. Phenoxybenzamine with regard to noradrenaline only blocked the renal vasoconstriction. Effects of some dosages of noradrenaline were inhibited only by the highest dose of phenoxybenzamine. In contrast, phenoxybenzamine inhibited phenylephrine-induced vasoconstriction in all the investigated vascular beds, but not completely in the hindleg. The response in the stomach was even reversed to a vasodilation. It is concluded that (1) all vascular beds studied contain alpha 1-adrenergic receptors; (2) noradrenaline exerts its vasoconstrictive activity by interaction with alpha 1-adrenergic receptors but also with phenoxybenzamine-insensitive alpha-adrenergic receptors. This conclusion indicates a heterogeneity of alpha-adrenergic receptors in the vascular beds studied.

Magnesium and cardiac arrhythmias: nutrient or drug?

The antiarrhythmic potency of Mg has been described repeatedly since 1935, both as a factor in human disease and in animal experiments. Nevertheless, this therapeutic efficacy is rarely mentioned in textbooks. Both the pharmacological effect of Mg and the correction of Mg deficiency have been used in treatment of digitalis toxicity, variant angina, Torsades de Pointes, as well as in arrhythmia of unknown origin. Mg-deficiency can be caused by malabsorption or by excessive urinary loss. Both situations can occur on a congenital basis. The most frequent cause is probably alcoholism. Iatrogenic factors include digitalis, diuretics, gentamicin, as well as cisplatinum, which appreciably enhance urinary Mg loss. Correction of Mg-deficiency by parental and/or oral administration should lead to recovery. If the cause of the deficiency can be eliminated, once the deficit is repaired it may be acceptable to discontinue the supplement. However, the cause is often multifactorial, requiring further evaluation and treatment.

Control of O2 supply to the pancreas during a cholecystokinin-induced increase in metabolism.

In the anesthetized dog, the pancreatic excretion of enzymes and the pancreatic blood flow were stimulated by a cholecystokinin (CCK) shot of 1 U/kg iv. The question raised was: is this augmented blood flow a metabolically controlled hyperemia or is it independent of the metabolic performance. After the administration of CCK, blood flow as well as O2 consumption were increased, while O2 extraction initially remained unchanged but later it increased. Capillary density, mitochondrial O2 consumption, capillary PO2 and cellular PO2 were calculated, using the model of the metabolic control of tissue oxygenation. The changes mentioned above could be simulated rather exactly. These simulations revealed that during the CCK stimulation of the pancreas is able to control its O2 supply through a fast decrease of the arteriolar resistance and a slow capillary recruitment. Thus, by a metabolic control the oxygen is sufficiently supplied to the pancreatic tissue.

Control of O2 supply to the pancreas during a vasopressin-induced vasoconstriction.

In the anesthetized dog, the metabolic level of the pancreas was elevated by a secretin infusion (1.2 U/kg/hr iv), displaying a metabolic control of tissue oxygenation and blood flow. Question was raised how this system would response to a decrease in O2 supply, as induced by increasing doses of vasopressin (2-131 mU/kg, iv). These vasopressin administrations progressively diminished blood flow (down to 20%), as well as secretory rate (down to 7%) and O2 consumption (down to 33%). The O2 extraction was increased up to 227%. Capillary density, mitochondrial O2 consumption, capillary PO2 and cellular PO2 were calculated by simulating these data with the model of the metabolic control of tissue oxygenation. The changes mentioned above could be simulated adequately. These simulations revealed that a. in the pancreas vasopressin primarily increases arteriolar resistance; the inhibition of metabolism is secondary to the vasopressin-induced vasoconstriction. b. The pancreas responds with a small compensatory capillary recruitment (up to 29%), which in itself would increase tissue oxygenation. c. The main consequence of the lowering of blood flow is a dramatic decrease of mean capillary PO2 (down to 38%), as well as a lowering in mean cellular PO2 (down to 41%). This lowering of O2 supply to the tissue will slow down the metabolic rate, as evidenced by the decrease of the volume of the excretion.

On vasodilators, magnesium and second messengers.

Detailed hemodynamic studies of vasodilating compounds in anesthetized dogs were performed. Multichannel electromagnetic flowmetry at organ level showed for a number of peptide hormones and biogenic amines that each chemical entity had its own "map" of vascular responses. In contrast magnesium-ions appear to reduce vascular resistance in each vascular area, in a similar time-frame, similar dose-dependency and without changing left ventricular volume output or perfusion of any vascular bed. The restricted vascular activity of the hormones and amines is set against the homogeneity of the morphology of arteriolar walls throughout the body. The hypothesis is put forward that these compounds cause vasodilation through release of one or more metabolites from their target cells. Such a metabolite would then act as a second messenger. A number of requirements are set forth for reactions to be expected after intravenous administration of such a hypothetical metabolite. It is concluded that magnesium and may be potassium fulfill these requirements, and should therefore be considered as potential second messenger vasodilators.

Antidiuretic effect of ritodrine with and without beta-adrenergic blockade.

Dose-related effects of ritodrine and ritodrine combined with metoprolol on urinary excretion rate were studied in anesthetized dogs. Urine production was abruptly reduced after a total dose of 4 micrograms.kg-1 of ritodrine. This effect could not be antagonized by metoprolol, although the ritodrine-induced decrease of mean arterial pressure and renal arterial blood flow was significantly inhibited. The possible role of fluid retention during tocolytic treatment, even with beta-adrenergic blockade, in the etiology of pulmonary edema is discussed with a review on recent literature.

Cardiovascular effects of ritodrine are blocked by metoprolol in the anesthetized dog.

Inhibition of ritodrine-induced cardiac and peripheral vascular effects by the beta 1-adrenergic blocker metoprolol, was studied by electromagnetic flow measurements in anesthetized dogs. As expected, metoprolol inhibited the ritodrine-induced/increased cardiac workload and heart rate. Metoprolol also inhibited ritodrine-induced peripheral vasodilation. This leads to questions about the cardiac beta 1-adrenergic selectivity of metoprolol. Regarding earlier studies showing no interference in labor inhibition, the combination of ritodrine and metoprolol might be useful in treatment of preterm labor, while economizing cardiovascular performance centrally as well as peripherally.

Functional arterio-venous anastomoses between the testicular artery and the pampiniform plexus in the spermatic cord of rams.

Blood flow to the testis, haemoglobin oxygen saturation and testosterone concentration in arterial and venous testicular blood vessels were studied in Texel rams in the breeding and non-breeding season. Blood flow in the proximal and distal testicular artery was measured electromagnetically. The mean flow in the proximal testicular artery was 18.5 ml/min and in the distal testicular artery 7.5 ml/min, and there was no detectable seasonal influence. Haemoglobin oxygen saturation and testosterone concentration were measured in the saphenous artery and vein, the distal testicular artery and vein, and in the proximal testicular vein. The haemoglobin oxygen saturation in the proximal testicular vein was significantly higher than in the distal testicular vein in both seasons. The mean testosterone concentration was significantly lower in the proximal testicular vein than in the distal testicular vein in both seasons. Based on haemoglobin oxygen saturation and testosterone data, it was calculated that between 28 and 46% of the testicular arterial blood was bypassing the testis and was directly flowing through arterio-venous anastomoses towards the pampiniform plexus in the spermatic cord of conscious rams. In anaesthetized rams 55 and 64% of the blood was flowing directly from the testicular artery to the pampiniform plexus based on blood flow data. Transfer of testosterone and oxygen by passive diffusion from the testicular artery to the pampiniform plexus and vice versa in the spermatic cord was not detected.

Cholinergic and pancreatic actions of purified porcine and synthetic vasoactive intestinal peptide (VIP).

In this study the vascular effects of VIP were studied in connection with its secretory performances in the pancreas and the liver. In anesthetized dogs pancreatic blood flow was measured parallel with measurement of bile and pancreatic secretion. VIP was injected intravenously at intervals of 1 minute in amounts of 1-2048 ng.kg-1. Striking conductance increases were observed in the pancreatic vascular beds ranging from an increase of 400% (pancreatic branch of splenic a.) to an increase of 80% (inferior pancreatic duodenal a.). Pancreatic secretion increased from 0 to 408 microliters.min-1 and bile secretion from 95 to 145 microliters.min-1. VIP has powerful vasodilating effects on pancreatic vascular beds accompanying pancreatic secretion and bile secretion. Porcine VIP and 2 synthetic VIP analogues exhibited similar hemodynamic and metabolic actions. Although a correlation between vascular and metabolic effects possibly exists, the effects of VIP on gut vessels and pancreatic secretory cells are most probably separate events: at low VIP doses increase in conductance was observed without a concomitant increased secretion. A possible role of VIP maintaining an adequate blood supply to the pancreas is discussed.

Vasoactivity of adrenaline in regions covering the canine gastrointestinal tract.

Little is known about the action adrenaline has on vascular areas of functionally different parts of the stomach and intestine. Therefore the vasoactivity of adrenaline (1-1024 ng/kg i.v.) was studied by electromagnetic flow measurements in 8 vascular beds covering the gastrointestinal tract. Adrenaline induced 1) a vasodilation in the lesser curvature and antrum of the stomach; 2) a vasoconstriction in the greater curvature of the stomach; 3) a vasoconstriction followed by a vasodilation in the duodenum and jejunum; 4) a vasoconstriction in the ileum, caecum/colon and colon/rectum. Phenoxybenzamine (750 micrograms/kg i.v.) blocked systematically the vasoconstriction in the duodenum and jejunum but not in the ileum and colon. Vasodilation could be blocked by propranolol (100 micrograms/kg i.v.). It is concluded that 1) adrenaline-effects are mediated predominantly by beta-receptors in the antrum and lesser curvature of the stomach; predominantly by alpha-receptors in the greater curvature of the stomach; by alpha- and beta-receptors in the duodenum and jejunum; 2) receptors in the large intestine are of another alpha-adrenergic type than those in the small intestines. Evidence was provided for a gradient of diminishing vasodilating effects of adrenaline from cranial to caudal of the gut.

Pancreatic O2 consumption and CO2 output during secretin-induced, exocrine secretion from the pancreas in the anesthetized dog.

Secretin stimulates pancreatic water and CO2 excretion as well as pancreatic blood flow. It has been questioned whether the production (i.e. water and CO2 excretion) is reflected in the input-output difference of nutrients. In pentobarbital anesthetised dogs, pancreatic exocrine secretion was stimulated by secretin (Karolinska), 1 U/kg injected as an i.v. bolus. Secretion was maximally increased at 2 min after the secretin shot and returned to a basal value at between 16 and 32 min after secretin. Blood flow was also maximally increased at 2 min, but decreased to the basal value at between 8 and 16 min. O2 extraction first decreased (at 2 min) and then gradually increased until it was higher than the basal value (at 16 min) and then returned to the basal level (at 32 min). O2 consumption increased quickly, reached a plateau, lasting from 1 to 16 min, and then decreased to the basal level (32 min). CO2 transfer from blood to tissue reached a maximum at 4 min and then decreased to the basal value (at between 16 and 32 min). The curves for CO2 transfer from tissue to pancreatic secretion and for CO2 in the secretion had the same shape. It is concluded that the curve of production (of water and CO2 excretion) parallels the curve of O2 consumption fairly well. The O2 consumption curve did not correlate either with the blood flow curve or with the O2 extraction curve. About one quarter of the excreted CO2 originated from pancreatic metabolism and the remaining three quarters were transferred from blood, through the pancreatic tissue into the secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

A vasopressin-induced decrease in pancreatic blood flow and in pancreatic exocrine secretion in the anesthetized dog.

Vasopressin decreases blood flow as well as secretory flow in the pancreas. The question raised was whether the blood flow decrease is the determinant of the decrease in secretion or quite the reverse. In pentobarbital anesthetized dogs, secretory flow was first increased to a steady level by infusion of secretin. At this steady state, O2 consumption and O2 extraction were increased, while blood flow remained at the control level, indicating an increase in the area available for exchange i.e. an increase in capillary density. At increasing doses of vasopressin, secretory flow decreased, arterial flow decreased, and O2 extraction increased, while O2 consumption decreased and venous-arterial CO2 concentration difference was not changed. At the same time CO2 transport decreased, CO2 concentration in the secretion was unchanged and CO2 output in the secretion was decreased. The decrease in blood flow was always seen about 25 s before the decrease in secretory flow, strongly suggesting that the decrease in blood flow induced the decrease in secretory flow. A higher dose of vasopressin was required to decrease the O2 consumption (i.e. this effect was less sensitive) than to increase O2 extraction. The decrease in secretory flow and the decrease in blood flow showed an intermediate sensitivity. So O2 consumption seems to be preserved at a high level by the increase in O2 extraction. It is concluded that the vasopressin-induced decrease in blood flow is the determinant of the decrease in secretory flow. This phenomenon is discussed in terms of the model for metabolic control of tissue oxygenation.