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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.

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.

The effects of the beta-receptor blocking agent propranolol (100 microgram/kg i.v.) and of the alpha-receptor blocking agent dihydroergotamine (50 microgram/kg i.v.) on hemodynamic responses to isoproterenol and norepinephrine (both 1--1024 ng/kg) were investigated in anesthetized dogs. The effects studied were: (1) flow in the ascending aorta and the coronary, common hepatic, gastroduodenal, splenic, cranial mesenteric, renal and femoral arteries: (2) maximal flow acceleration in the splenic, cranial mesenteric and femoral arteries; (3) maximal rate of change of left ventricular pressure (LV dP/dt max). Propranolol shifted the dose-response curves for the isoproterenol-induced flow increases in the common hepatic, gastro-duodenal, and cranial mesenteric arteries to the right. It did not influence the flow responses to isoproterenol in the ascending aorta or the coronary, splenic, renal and femoral arteries. Propranolol prevented the decrease of arterial pressure evoked by isoproterenol. Propranolol shifted the isoproterenol-induced increase of LV dP/dt max and maximal blood flow to the same extent. Propranolol blocked the flow to the liver and gastrointestinal tract to a greater extent than the LV dP/dt max and maximal flow acceleration. Propranolol had no effect on the norepinephrine-induced increases in flow in the splenic, femoral and coronary arteries, but blocked the norepinephrine-evoked increases of flow accelerations and LV dP/dt max to the same extent. Dihydroergotamine inhibited the norepinephrine-induced increase in flow in the femoral artery and the decreases in flow in the hepatic, splenic, cranial mesenteric and renal arteries, and reversed the reduction of flow in the gastroduodenal artery. It is argued that dihydroergotamine may inhibit the increase in femoral flow through two mechanisms: (1) blocking the flow reduction to norepinephrine in the abdomen, and thereby passively shunting blood from the abdomen in preference to the femoral bed; (2) attenuating the norepinephrine-evoked reflexogenic femoral vasodilatation. It is concluded that: (1) propranolol is a beta-receptor blocking agent with a preference for blockade of isoproterenol-induced vascular effects; (2) norepinephrine-induced flow increases are not direct actions on vascular beta-receptors; (3) the increase of maximal blood flow accelerations after isoproterenol and norepinephrine is mediated by stimulation of cardiac beta-receptors; (4) dihydroergotamine is an alpha-receptor blocking agent particularly in the splanchnic vascular region.

The effects of furosemide on biliary secretion and on pancreatic hemodynamics and exocrine function were studied by quantitative flowmetry and timed collections of biliary and pancreatic exocrine secretion in the anesthetized dog. Biliary flow and the output of its components (Na+, K+, Ca, Mg, 3-OH bile salts, and bilirubin) increased significantly following a furosemide injection of 0.6 mg/kg and rose progressively to 75-150 per cent above basal levels as the furosemide dose was increased to 9.6 mg/kg. Pretreatment with secretin had no influence on furosemide-induced biliary secretion. Furosemide doses of 4.8 and 9.6 mg/kg increased blood flow in the superior pancreaticoduodenal arterial bed by 30-60 per cent but did not alter flow in the inferior pancreaticoduodenal arterial bed or the pancreatic branch of the splenic artery. However, small increases were seen in flow in the latter two arterial beds after furosemide when secretin administration preceded furosemide. Basal pancreatic secretion was not affected by furosemide, but pretreatment with a submaximal sustaining infusion of secretin uncovered a furosemide action to increase pancreatic exocrine flow and the outputs of Na+, K+, Ca, Mg, and enzymes by 25-35 per cent. These data extend previous studies of the gastrointestinal vasodilator effects of furosemide to the pancreatic circulation and previous data demonstrating furosemide-induced ionic transport in nonrenal systems to biliary, pancreatic acinar, and ductular transport in both organs. Whether the augmentation of pancreatic blood flow is secondary to enhanced ion transport in the exocrine pancreas or to an effect on ionic cotransport in vascular smooth muscle is unknown.

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.

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.

The ability of furosemide to induce vasodilation in the canine gastrointestinal system was studied by quantitative flowmetry. Blood flow and conductance increased maximally by 60 per cent in the stomach and duodenum and by 80 per cent in the small and large intestine. Vasodilation was evident at 2.4 mg/kg furosemide and higher. The onset of vasodilation occurred at 24 to 30 seconds and was maximal at 36 seconds in the stomach, at 66 seconds in the duodenum, at 78 to 84 seconds in the small intestine, and at 90 seconds in the large intestine. Hepatic arterial, splenic, and renal blood flows were unchanged. Simultaneous arteriovenous sampling from the small intestine indicated that the increased blood flow was not associated with increased O2 consumption. However, CO2 addition to the venous effluent decreased by 70 per cent. These data indicate that furosemide has a vasodilatory action on the gastrointestinal tract due either to a delayed effect on the vascular smooth muscle cell or on anaerobic bowel wall metabolism. The CO2 data are compatible with, but do not prove, stimulation of secretion of HCO3- by the intestinal mucosa.

In splenectomized dogs swimming causes a stronger vasoconstriction in the kidney than treadmill running. Renal blood flow measured by electromagnetic flow probes decreased by 10% during treadmill running and by 37% during swimming. The renal perfusion remained low during 30 min after both running and swimming. Arterial pressure increased during running and during swimming. Phenoxybenzamine, an alpha-adrenergic blocking agent, practically abolished the changes in renal perfusion induced by exercise, but not those in arterial pressure. The changes in renal blood flow and arterial pressure were stronger than those found in a previous study in non-splenectomized dogs. We conclude that in splenectomized dogs sympathetic and adrenomedullary response during exercise is increased resulting in a stronger renal vasoconstriction and a more pronounced increase in arterial pressure, than in intact dogs.

The contractile activity of the canine rectal wall exhibits a positive influence on the behaviour of fatty suppositories in vivo with respect to both spreading abilities and rate and extent of release of the readily water-soluble compound phenazone. This influence on bio-availability was marked when the drug was suspended in a large particle size (100-125 µm). When used in small particles (< 35µm), far less influence of contractile activity was found. Small particles were equivalent to coarse particles with respect to the bioavailability. The addition of colloidal silicium oxide has a marked influence on spreading and bioavailability. Enhanced rectal motility exhibits an influence on the absorption only when a coarse fraction of the drug is suspended. It was concluded that rectal motility might be a cause of variation in bioavailability of drugs from rectal suppositories. For this reason only well-trained animals should be used when bioavailability of drugs from suppositories is tested in an animal model.

Dose-response curves of the uterine relaxants fenoterol and ritodrine were established for vascular conductance in 10 peripheral arterial beds in anesthetized dogs. Vascular sensitivity was expressed as (E)D50 of conductance response. Fenoterol induced strong vasodilation in all arterial beds except in the kidneys. The gastrointestinal vessels are significantly more sensitive to fenoterol than are muscle and brain vessels. Ritodrine induced strong vasodilation in all arterial beds except in the kidneys and the liver. The vascular sensitivity spectrum of ritodrine differs from that of fenoterol. On a molecular basis fenoterol was 66 times as potent as ritodrine if arterial pressure reduction was used as criterion. When (E)D50 values of vascular conductances of both drugs were plotted against arterial pressure reduction as reference, the gastrointestinal vessels (left gastric, splenic, gastroduodenal, proper hepatic, and superior mesenteric arteries) appeared to be significantly more sensitive to fenoterol than to ritodrine. In contrast, vascular sensitivity in the myocardium, striated muscles, and brain (left coronary, common carotid, femoral, and vertebral arteries) was not statistically different for the two drugs.

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.

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.