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.

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.

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.

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.

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.

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.

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.

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.

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. The increase in O2 consumption was achieved by an increase in blood flow, followed by an increase in O2 extraction. The release of a vasodilator metabolite by the pancreatic cells upon arrival of the secretin molecules, may explain both the increase in blood flow and the successive increase in O2 extraction. Therefore these data can be interpreted according to the model for metabolic control of tissue oxygenation.

Vascoactive Intestinal Peptide [VIP] is a highly basic octacosapeptide (molecular weight 3809) originally extracted from porcine lung tissue by Said and Mutt (Said et al. 1968), but later isolated and purified from porcine upper intestine (Said and Mutt (1970). Immunhistochemical studies have revealed a widespread occurrence of VIP containing neurons and nerve fibers in the brain, the peripheral nerves, salivary glands, trachea, lung, upper and lower digestive tract, urogenital tract, and around peripheral blood vessels (Said et al. 1968; Said and Mutt 1970; Said and Rosenberg 1976; Lundberg et al. 1984; Polak and Bloom 1982; Larsson et al. 1976; Larsson 1977; Ottesen 1983; Hokfelt et al. 1978; Uddman et al. 1981). A broad spectrum of actions has been ascribed to VIP, of which the most important are vasodilation and hypotension (Said et al. 1968) relaxation of smooth muscle (Polak and Bloom 1982; Ottesen 1983), excretion of water and bicarbonate by the pancreas (Maklouf et al. 1978), intestinal secretion (Krejs et al. 1978) and release of insulin and glucagon (Schebalin et al. 1977). A recent study showed that VIP can stimulate renin relase and increase renal blood flow (Porter et al. 1982). The following experiments were conducted to investigate the effects of VIP on renal function in connection with hemodynamic responses.

The relationship of arginine-mediated release of endogenous glucagon and insulin to renal and splanchnic arterial blood flow, blood pressure, and heart rate was studied in dogs. Intravenous injection of argininehydrochloride (arg-HCl) in logarithmically increasing doses increased the concentration of glucagon (pGl) in the femoral artery from 143 ± 39 pg/ml (pre-injection) to 282 ± 49 pg/ml (following maximum dosage of arg-HCl) and insulin concentration from 23 ± 5 to 41 ± 11 µU/ml. Sodium chloride (NaCl) and urea, isovolemic and isosmolar to arg-HCl, failed to change pGl and insulin. Arg-HCl depressed arterial blood pressure from 93 ± 13 (preinjection) to 60 ± 14 mm Hg (maximum dose), NaCl increased it from 89 ± 13 to 99 ± 13 mm Hg. The blood flow increase due to arg-HCl was comparable with that due to NaCl in renal as well as in celiac and left gastric artery. The former was more pronounced in superior and inferior pancreaticoduodenal artery by 61 and 102%, and in gastroduodenal and superior mesenteric artery by 11 and 35%. Infusion of arg-HCl increased pGl from 294 ± 90 to 731 ± 200 pg/ml, and insulin from 23 ± 5 to 63 ± 18 µU/ml; the resulting blood flow increase, however, only differed in both pancreatic arteries by 10–20% from the rise during NaCl infusion where no change of pGl was observed and a decline occurred in insulin from 64 ± 21 to 27 ± 8 µU/ml. It is concluded that physiological levels of pGl have no systemic effect on arterial blood flow. A local flow increasing effect of glucagon and/or insulin on the arteries next to the pancreas is discussed.

Evidence for the presence of specific histamine H1- and H2-receptors in the gastrointestinal circulation was obtained using histamine, 2-methylhistamine (a specific H1-agonist), 4-methylhistamine (a specific H2-agonist), and selective H1- and H2-receptor antagonists in the anesthetized dog. Histamine and 2-methylhistamine increased conductance in the vascular beds of the superior mesenteric artery, the left gastric artery and the common hepatic artery, whereas 4-methylhistamine mainly enhanced conductance in the vascular beds of the left gastric artery and the common hepatic artery. All three agents depressed systemic arterial blood pressure. The vasodilatory effect of histamine and 2-methylhistamine on the superior mesenteric artery bed occurred earlier and was of shorter duration than their effect on the two other vessels. The H1-receptor antagonists mepyramine and clemastine blocked the response of the superior mesenteric artery bed to histamine, but had a lesser inhibitory effect on the histamine response of the common hepatic artery and the left gastric artery. The addition of the H2-receptor antagonist cimetidine to mepyramine blockade augmented the inhibiting effect of mepyramine on the common hepatic artery. Cimetidine bolus injections prevented enhancement of vascular conductance by 4-methylhistamine, but did not influence conductance enhancement by histamine or 2-methylhistamine. These data demonstrate there are separable histamine H1- and H2-receptors in the gastrointestinal circulation which are distinguished by anatomic location, temporal relationships of receptor response, and response to specific histamine H1- and H2-agonists and antagonists.

Seven strain gage force transducers were sutured in line to the stomach of an anesthetized dog. Quantification of tonic acitivity and of phasic activity (amplitude, frequency and propagation velocity) on 7 locations from fundus to pylorus resulted in an overall picture of gastric motor activity. Pentagastrin (dose-response curve, 1--8192 ng/kg, i.v.) did not change propagation velocity of the contractile waves, but increased the amplitude and frequency of phasic activity on corpus and antrum. Amplitude increased on the antrum more than on the corpus. Frequency increase was uniform over corpus and antrum. Moreover pentagastrin increased muscle tone (tonic activity) in a specific area on the corpus from 12--18 cm to pylorus. The distinct responses to pentagastrin of tonic activity and of amplitude and frequency of phasic activity indicate that pentagastrin acts on 3 different receptor-effector systems.

Gastrointestinal motor activity of the anesthetized dog was assessed by strain gage force transducers on longitudinal and transverse muscle of the gastric body and antrum, duodenum, jejunum, ileum, and colon. Dose-dependent effects of pentagastrin (1-8192 ng/kg, i.v.) were only seen on the stomach: increases in gastric body tone, antral contractile force and contractile frequency of the gastric phasic activity. Body tone and antral force were more sensitive to pentagastrin than was contractile frequency. Supra-maximal doses and repetition of the dose-response protocol gave smaller increments for body tone and antral force, while the increase in contractile frequency remained unaffected. The different responses to pentagastrin of force and frequency indicate that pentagastrin acts on 2 different receptor-effector systems.

Vasopressin (ADH) is known to reduce secretin-stimulated pancreatic exocrine secretion. The present study attempts to relate this inhibitory effect to the vasoconstrictive potency of ADH. Regional blood flow was measured electromagnetically in anesthetized dogs. ADH reduced blood flow inmmost of the vascular areas. The greatest reduction in blood flow was seen in the gastrointestinal area especially in the left gastric artery, cranial and caudal pancreaticoduodenal arteries, as well as the cranial and caudal mesenteric arteries. Renal blood flow was not altered by those concentrations of ADH that reduced gastrointestinal blood flow. ADH reduced pancreaticoduodenal blood flow in concentrations comparable to those concentrations that reduced pancreatic secretory flow. The reduction of gastrointestinal blood flow was due to increased impedance and not to diminished cardiac inotropy.

Responses to norepinephrine (NE) and isoprenaline (ISO) (1–1024 ng/kg i.v.) were assessed by electromagnetic flowmetry on 18 arteries of the splanchnic region in anesthetized dogs. Measurements were judged according to the 2 criteria: 1. direction of effect; 2. sensitivity of vascular areas to catecholamines, expressed as D50 (i.e. the calculated dose inducing 50% of the maximum effect). NE decreased flow in all arteries (40–80%), but caused additionally an increase in the celiac, splenic and splenic artery proper. Thus changes in the spleen are responsible for the increase with NE. Flow reduction in the pancreatic branch of the cranial mesenteric artery was small. All flow reductions induced by NE had a similar D50 (about 30 ng/kg), except that in the hepatic artery (100 ng/kg).

In anesthetized dogs the norepinephrine (NE) and isoprenaline (ISO) (1–1024 ng/kg i.v.)-induced increase of maximum peripheral flow acceleration (celiac artery, cranial mesenteric artery, renal artery, and femoral artery) and the changes of the maximum first derivative of arterial pressure were compared with the increases of maximum ascending aortic flow acceleration and maximum first derivative of left ventricle pressure (LV dP/dt max).