Effects of nifedipine on hepatic blood volume in cats: indirect venoconstriction and absence of inhibition of postsynaptic alpha 2-adrenoceptor responses

Intravenous administration of hypotensive doses (30-200 micrograms/kg) of nifedipine to cats anesthetized with pentobarbital caused an increase in cardiac output accompanied by hepatic venoconstriction. The hepatic venoconstriction and the increase in cardiac output were abolished in animals in which the hepatic sympathetic nerves were cut, the adrenal glands were excluded, and the kidneys were removed. This contrasts with the indirect hepatic venoconstrictor action of isoproterenol which was shown previously not to be abolished by these procedures. Further experiments showed that the hepatic venoconstrictor effect of nifedipine was blocked by removal of the kidneys, but not by removal of the hepatic sympathetic nerves and adrenals. These results support the hypothesis that venoconstriction plays an important role when drugs produce increased cardiac output. In nephrectomized animals, nifedipine had no direct effects on hepatic blood volume and it did not alter the effects of infusions of norepinephrine on hepatic blood volume, which have previously been shown to be mediated through alpha 2-adrenoceptors. However, it did reduce the hepatic venous responses to hepatic sympathetic nerve stimulation by 30%.     

Role of beta-adrenergic agonists in the control of vascular capacitance

The role of beta-adrenergic agonists, such as isoproterenol, on vascular capacitance is unclear. Some investigators have suggested that isoproterenol causes a net transfer of blood to the chest from the splanchnic bed. We tested this hypothesis in dogs by measuring liver thickness, cardiac output, cardiopulmonary blood volume, mean circulatory filling pressure, portal venous, central venous, pulmonary arterial, and systemic arterial pressures while infusing norepinephrine (2.6 micrograms.min-1.kg-1), or isoproterenol (2.0 micrograms.min-1.kg-1), or histamine (4 micrograms.min-1.kg-1), or a combination of histamine and isoproterenol. Norepinephrine (an alpha- and beta 1-adrenergic agonist) decreased hepatic thickness and increased mean circulatory filling pressure, cardiac output, cardiopulmonary blood volume, total peripheral resistance, and systemic arterial and portal pressures. Isoproterenol increased cardiac output and decreased total peripheral resistance, but it had little effect on liver thickness or mean circulatory filling pressure and did not increase the cardiopulmonary blood volume or central venous pressure. Histamine caused a marked increase in portal pressure and liver thickness and decreased cardiac output, but it had little effect on the estimated mean circulatory filling pressure. Isoproterenol during histamine infusions reduced histamine-induced portal hypertension, reduced liver size, and increased cardiac output. We conclude that the beta-adrenergic agonist, isoproterenol, has little influence on vascular capacitance or liver volume of dogs, unless the hepatic outflow resistance is elevated by agents such as histamine.     

Pharmacodynamics and pharmacokinetics of dihydroergotamine (DHE) in conscious beagle dogs

Dihydroergotamine (DHE) elicits selective and longlasting venoconstrictor activity though the drug disappears rapidly from the blood. Changes in the diameter of the saphenous vein were determined in conscious beagle dogs and compared to plasma level-time curves of DHE and its metabolites. After both intravenous and oral administration of DHE the venoconstrictor response is of markedly longer duration than would be expected on the basis of the half life for elimination of DHE from blood. Furthermore, 3 out of 5 of the main metabolites of DHE elicited considerable constrictor effects when infused locally into the vein. It is suggested that the long duration of the DHE-induced venoconstriction is due to an extremely slow dissociation of the drug from its receptor sites on the venous smooth muscle cell and to the formation of active metabolites.     

Maintenance of hepatic arterial blood flow during hemorrhage is mediated by adenosine

The effect of hemorrhage (1.91 mL/min, 10 mL/kg) on splanchnic blood flow was determined in cats anesthetized with pentobarbital. The hepatic artery (HA) is relatively protected during hemorrhage and does not constrict, whereas the superior mesenteric artery (SMA) undergoes significant vasoconstriction. Adenosine receptor antagonism with 8-phenyltheophylline blocks the dilator response to infused adenosine selectively (does not block responses to isoproterenol). The dilator response to reduced portal blood flow (the HA buffer response) is also antagonized and adenosine receptor blockade converts the HA response to hemorrhage to one similar to that of the SMA. Thus, the protective dilation of the HA during hemorrhage is mediated by adenosine. In contrast, the vasodilation of the HA seen with reinfusion of the shed blood is not altered by adenosine receptor antagonism.     

The use of 8-phenyltheophylline as a competitive antagonist of adenosine and an inhibitor of the intrinsic regulatory mechanism of the hepatic artery

Reduction of portal blood flow results in compensatory vasodilation of the hepatic artery, the hepatic arterial buffer response. The hypothesis tested is that the regulation of the buffer response is mediated by adenosine, where the local concentration of adenosine in the region of the hepatic arterial resistance vessels is regulated by washout of adenosine into portal venules that are in intimate contact with hepatic arterioles. In anesthetized cats, portal flow was reduced to zero by complete occlusion of all arterial supply to the guts. The resultant dilation of the hepatic artery compensated for 23.9 +/- 4.9% of the decrease in portal flow. Dose-response curves were obtained for the effect of intraportal adenosine infusion on hepatic arterial conductance in doses that did not lead to recirculation and secondary effects on the hepatic artery via altered portal blood flow. The dose to produce one-half maximal response for adenosine is 0.19 mg X kg-1 X min-1 (intraportal) and the estimated maximal dilation is equivalent to an increase in hepatic arterial conductance to 245% of the basal (100%) level. The adenosine antagonist, 8-phenyltheophylline, produced dose-related competitive antagonism of the dilator response to infused adenosine (but not to isoproterenol) and a similar, parallel antagonism of the hepatic arterial buffer response. If supramaximal blocking doses were used, the hepatic artery showed massive and prolonged constriction with blood flow decreasing to zero. The data strongly support the hypothesis that intrinsic hepatic arterial buffer response is mediated entirely by local adenosine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of respiratory response to isoproterenol in glomectomized cats

Effects of intravenous isoproterenol (2-3 micrograms) on arterial pressure, end-tidal CO2 partial pressure (PCO2), medullary extracellular fluid (ECF) pH, and phrenic activity were studied in 13 anesthetized paralyzed cats whose vagi and carotid sinus nerves were cut. The cats were servo-ventilated to keep PCO2 relatively constant. Injections of Ringer solution were without effect. Isoproterenol caused arterial pressure to fall, a transient small (1 Torr) increase of PCO2, increased venous CO2 return to the lungs, a medullary ECF acidosis, and a stimulation of respiration that continued to be elevated after arterial pressure, PCO2, and medullary ECF pH had returned to control. We show that the ECF acidosis is minimally due to the hypotension and to the small transient rise of PCO2. We also show that the respiratory response cannot be explained solely by the ECF acidosis. We conclude that, in addition to its known stimulation of peripheral chemoreceptors, isoproterenol causes medullary ECF to become acidic probably due to metabolic effects on neural tissue and has a separate direct stimulating effect on neurons in the brain.     

Effect of raised portal venous pressure and postocclusive hyperemia on superior mesenteric arterial resistance in control and adenosine receptor blocked state in cats

Superior mesenteric arterial (SMA) blood flow was measured in pentobarbital-anesthetized cats using a noncannulating electromagnetic flowprobe. The selective adenosine antagonist 8-phenyltheophylline (8-PT) antagonized the dilator effect of infused adenosine but not isoproterenol. The vasodilation in response to reduced arterial perfusion pressure (autoregulation) was blocked by the adenosine receptor blockade, which also reduced the degree of postocclusive (1 min) hyperemia by one-half to two-thirds. The remainder of the hyperemia may have been due partially to adenosine, since exogenous adenosine still produced a small vasodilation (26%), so effects of endogenous adenosine could also still be expected to exert a small effect. Myogenic effects appear unlikely to be the mechanism of the small remaining hyperemia, since venous pressure increments within physiologically relevant ranges did not cause altered SMA conductance, and arterial dilation in response to large decreases in arterial pressure could be blocked by adenosine antagonism. Portal pressure was increased using hepatic nerve stimulation (8 Hz) to raise pressure from 7.0 to 12.4 mmHg (1 mmHg = 133.3 Pa). The small vasoconstriction seen in the SMA was due to the rise in systemic blood pressure, since prevention of a rise in SMA pressure prevented the response and 8-PT blocked the response (previously shown to block arterial pressure-flow autoregulation). An equal rise in PVP imposed by partial occlusion of the portal vein did not lead to changes in SMA vascular conductance. Thus, we conclude that within physiologically relevant ranges of arterial and portal venous pressure, the SMA does not show myogenic responses of the resistance vessels.     

Hepatic venoconstriction is involved in anaphylactic hypotension in rats

We determined the roles of liver and splanchnic vascular bed in anaphylactic hypotension in anesthetized rats and the effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused rat livers. In anesthetized rats sensitized with ovalbumin (1 mg), an intravenous injection of 0.6 mg ovalbumin caused not only a decrease in systemic arterial pressure from 120 +/- 9 to 43 +/- 10 mmHg but also an increase in portal venous pressure that persisted for 20 min after the antigen injection (the portal hypertension phase). The elimination of the splanchnic vascular beds, by the occlusions of the celiac and mesenteric arteries, combined with total hepatectomy attenuated anaphylactic hypotension during the portal hypertension phase. For the isolated perfused rat liver experiment, the livers derived from sensitized rats were hemoperfused via the portal vein at a constant flow. Using the double-occlusion technique to estimate the hepatic sinusoidal pressure, presinusoidal (R(pre)) and postsinusoidal (R(post)) resistances were calculated. An injection of antigen (0.015 mg) caused venoconstriction characterized by an almost selective increase in R(pre) rather than R(post) and liver weight loss. Taken together, these results suggest that liver and splanchnic vascular beds are involved in anaphylactic hypotension presumably because of anaphylactic presinusoidal contraction-induced portal hypertension, which induced splanchnic congestion resulting in a decrease in circulating blood volume and thus systemic arterial hypotension.     

Effects of bromocryptine on hepatic blood volume responses to hepatic nerve stimulation in cats

Arterial pressures, portal pressures, and hepatic blood volumes were recorded after hepatic denervation in cats anesthetized with pentobarbital. Bromocryptine (50 micrograms/kg) lowered arterial pressure but did not significantly change portal pressure or hepatic blood volume. However, both portal pressure and hepatic blood volume responses to hepatic nerve stimulation were significantly depressed after bromocryptine especially at low frequencies of stimulation. Responses to intraportal infusions of norepinephrine were significantly impaired only at the highest dose. The inhibitory effect of bromocryptine on the neural responses may, therefore, involve a presynaptic inhibition of norepinephrine release, but the mechanism requires further study. These data provide further support for the hypothesis that drugs which impair hepatic venous responses to sympathetic stimuli cause significant impairment of postural reflexes and orthostatic hypotension during clinical use.     

Thromboxane A2 analogue contracts predominantly the hepatic veins in isolated canine liver

Thromboxane A₂ (TxA₂) is a potent vasoconstrictor and has been implicated as a mediator of liver diseases such as ischemic-reperfusion injury. We determined the effects of TxA₂ and the well-known hepatic venoconstrictor histamine, on the vascular resistance distribution and liver weight in isolated canine livers perfused with blood via the portal vein. The stable TxA₂ (STA₂; 20 μg, n=5) and histamine (5 μg, n=6) similarly increased the hepatic total vascular resistance, 2.5- and 2.4-fold, respectively. The increase in the hepatic venous resistance was significantly greater than that of the portal resistance (threefold vs. 1.9-fold for STA2; threefold vs. 1.8-fold for histamine). Predominant hepatic venoconstriction induced by both agents was confirmed in livers perfused in a reverse direction from the hepatic vein to the portal vein, as shown by marked precapillary vasoconstriction. STA2 transiently increased liver weight loss (−3.6 g/100g liver weight), followed by a gradual weight gain (9.0 g/100 g). Histamine caused a progressive weight gain (9.1 g/100 g). In conclusion, similar to histamine, TxA₂ constricts predominantly the hepatic vein in isolated canine livers.     

Effect of endothelin-1 and vasoactive intestinal contractor on blood flow and output of vasoactive intestinal polypeptide in the feline colon

Injection of the structurally related peptides, endothelin-1 and vasoactive intestinal contractor (VIC), into a branch of the superior mesenteric artery in anesthetized cats caused dose-dependent reductions in blood flow in the portal vein and inferior mesenteric artery. The maximum effect occurred after 1 minute and was more prolonged in the portal vein. The effects of the two peptides were not significantly different. The colonic output of vasoactive intestinal polypeptide (VIP) into portal venous blood was decreased significantly by endothelin-1 and VIC, returning to baseline more rapidly than blood flow. When norepinephrine was injected to produce comparable reductions in blood flow, the output of VIP into portal venous blood was not altered significantly. These results suggest that inhibition of output of the vasodilator VIP contributes to the vasoconstrictor effects of endothelin-1 and VIC in the feline colonic vascular bed.     

Vascular mechanisms involved in angiotensin II-induced venoconstriction in hypertensive rats

To investigate the venoconstrictor effect of angiotensin II (Ang II) in spontaneously hypertensive rats (SHR), we used preparations of mesenteric venular beds and the circular muscle of the portal veins. Vessels were tested with Ang II in the presence or absence of losartan, PD 123319, HOE 140, L-NAME, indomethacin, or celecoxib. In the mesenteric venular bed of SHR, the effect of Ang II (0.1 nmol) was nearly abolished by losartan and enhanced by HOE 140, indomethacin, and celecoxib, while PD123319 and L-NAME had no effect. In portal vein preparations, cumulative-concentration response curves (CCRC) to Ang II (0.1–100 nmol/L) exhibited a lower maximal response (E_max) in SHR compared to Wistar rats. AT₁ receptor expression was similar in the two strains, while AT₂ receptor levels were lower in SHR portal veins when compared to Wistar. In SHR portal veins, losartan shifted the CCRC to Ang II to the right, while indomethacin and HOE 140 increased the E_max to Ang II. PD 123319, celecoxib, and L-NAME had no effect. Taken together, our results suggest that Ang II-induced venoconstriction in SHR is mediated by activation of AT₁ receptors and this effect may be counterbalanced by kinin B₂ receptor and COX metabolites. Furthermore, our data indicate that there are different cellular and molecular mechanisms involved in the regulation of venous tonus of normotensive and hypertensive rats. These differences probably reflect distinct factors that influence arterial and venous bed in hypertension.     

The role of alpha-adrenergic receptors in carbon monoxide hypoxia

The importance of alpha-adrenergic receptors in the cardiac output and peripheral circulatory responses to carbon monoxide (CO) hypoxia was studied in anesthetized dogs. Phenoxybenzamine (3 mg/kg i.v.) was injected to block alpha-receptor activity and the data obtained were then compared with those from a previous study of CO hypoxia in unblocked animals. Values for cardiac output, hindlimb blood flow, vascular resistance, and oxygen uptake were obtained prior to and at 30 and 60 min of CO hypoxia which reduced arterial oxygen content by approximately 50%. alpha-Adrenergic blockade resulted in a lower (p less than 0.05) control value for cardiac output than observed in unblocked animals, but no differences were present between the two groups at 30 or 60 min of CO hypoxia. Similarly, limb blood flow was lower (p less than 0.05) during the control period in the alpha-blocked group but rose to the same level as that in the unblocked animals at 60 min of COH. No change in limb blood flow occurred during CO hypoxia in the unblocked group. These findings demonstrated that during CO hypoxia alpha-receptor mediated venoconstriction does not contribute to the cardiac output response and alpha-receptor mediated vasoconstriction probably does prevent a rise in hindlimb skeletal muscle blood flow.     

NO, but not CO, attenuates anaphylaxis-induced postsinusoidal contraction and congestion in guinea pig liver

The pathophysiology of the hepatic vascular response to anaphylaxis in guinea pig is not known. We studied effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused livers derived from guinea pigs sensitized with ovalbumin. We also determined whether nitric oxide (NO) or carbon monoxide (CO) modulates the hepatic anaphylaxis. The livers were perfused portally and recirculatingly at constant flow with diluted blood. With the use of the double-occlusion technique to estimate the hepatic sinusoidal pressure (Pdo), portal venous resistance (Rpv) and hepatic venous resistance (Rhv) were calculated. An antigen injection caused venoconstriction characterized by an increase in Rpv greater than Rhv and was accompanied by a large liver weight gain. Pretreatment with the NO synthase inhibitor NG-nitro-l-arginine methyl ester, but not the heme oxygenase inhibitor zinc protoporphyrin IX, potentiated the antigen-induced venoconstriction by increasing both Rpv and Rhv (2.2- and 1.2-fold increase, respectively). In conclusion, anaphylaxis causes both pre- and postsinusoidal constriction in isolated guinea pig livers. However, the increases in postsinusoidal resistance and Pdo cause hepatic congestion. Endogenously produced NO, but not CO, modulates these responses.     

Effects of dihydroergotamine on hemodynamic molsidomine actions in anesthetized dogs

In pentobarbital-anesthetized mongrel dogs the intravenous actions of 0.50 mg/kg molsidomine on pulmonary artery and left ventricular (LV) end-diastolic pressures and internal heart dimensions (preload), left ventricular systolic and peripheral blood pressures, and total peripheral resistance (afterload), as well as on heart rate, dP/dt, stroke volume, and cardiac output (heart performance) were studied for 2 h. Hemodynamic molsidomine effects were influenced by increasing amounts of intravenously infused dihydroergotamine solution (DHE, 1-64 micrograms X kg-1 X min-1). Molsidomine decreased preload, stroke volume, and cardiac output for over 2 h but decreased ventricular and peripheral pressures for 45 min. Systemic vascular resistance showed a tendency to decrease while heart rate and LV dP/dtmax were not altered. DHE infusion reversed molsidomine effects on the preload and afterload of the heart. The diminished stroke volume was elevated so that cardiac output also increased. Total peripheral resistance increased while heart rate fell in a dose-dependent fashion. The LV dP/dtmax remained unchanged until the highest dose of 64 micrograms X kg-1 X min-1 DHE elevated the isovolumic myocardial contractility. These experiments indicate that DHE can reverse the intravenous molsidomine effects on hemodynamics. Most likely, this is mediated through peripheral vasoconstriction of venous capacitance vessels, thereby affecting molsidomine's action on postcapillary beds of the circulation.     

Blood volume, the venous system, preload, and cardiac output

Cardiac output is determined by heart rate, by contractility (maximum systolic elastance, Emax) and afterload, and by diastolic ventricular compliance and preload. These relationships are illustrated using the pressure-volume loop. Diastolic compliance and Emax place limits determined by the heart within which the pressure-volume loop must lie. End-diastolic and end-systolic pressures and hence the exact position of the loop within these limits are determined by the peripheral circulation. In the presence of minimal sympathetic tone, some 60% of total blood volume is hemodynamically inactive and constitutes a blood volume reserve (the unstressed volume). The remainder of the blood volume (the stressed volume) and the compliance of the venous system determine the venous pressure. This venous pressure together with venous resistance determines venous return, right atrial pressure, cardiac preload, and hence cardiac output. Venoconstriction causes conversion of unstressed volume to the stressed volume, the blood volume reserve is converted into hemodynamically active blood volume. After hemorrhage this replaces the lost stressed volume, while in other situations where total blood volume is not reduced, it allows a sustained increase in cardiac output. The major blood volume reserve is in the splanchnic bed: the liver and intestine, and in animals but not man, the spleen. A major unsolved problem is how the conversion of unstressed volume to stressed volume by venoconstriction is reflexly controlled.     

Active and passive liver microvascular responses from angiotensin, endothelin, norepinephrine, and vasopressin

Vasoconstrictor agents may induce a decrease in hepatic vascular volume passively, by decreasing distending pressure, or actively, by stimulating contractile elements of capacitance vessels. Hepatic venular resistance was estimated in anesthetized rabbits from hepatic venular pressure (P(mu hv); by servo-null micropipette), inferior vena cava pressure, and total hepatic blood flow (F(hv); by ultrasound flow probe). Changes in liver volume were estimated from measures of liver lobe thickness. Angiotensin (ANG) II, endothelin (ET)-1, norepinephrine (NE), and vasopressin (VP) were infused into the portal vein at a constant rate for 5 min. We conclude that ANG II and NE induced active constriction of hepatic capacitance vessels, because the liver lobe thickness decreased significantly even though P(mu hv) and portal venous distending pressure (P(pv)) increased. All four agents increased splanchnic and hepatic venous resistances in similar proportions. With VP, P(mu hv) and P(pv) decreased, but with ET-1, P(mu hv) and P(pv) increased. However, lobe thickness was not significantly changed by either drug during the infusion compared with the 2-min control period. Thus VP and ET-1 have only minor effects on hepatic capacitance vessels. ET-1, at 0.04 microg. min(-1). kg body wt(-1), caused an increase in systemic arterial blood pressure, but erythrocyte movement through the sinusoids in some animals stopped.     

Hepatic potassium movements induced by sympathomimetic amines before and after adrenergic blockade.

The hepatic K+-mobilizing effects of phenylephrine and isoproterenol were studied in dogs equipped with chronic indwelling portal vein catheters. Animals anesthetized with sodium pentobarbital, received intraportal injections of these sympathomimetic amines, alone or in combination, before and after alpha, or beta, or combined adrenergic blockade. Hepatic K+ movements were assessed by measuring systemic arterial and hepatic venous K+ levels. It was concluded that adrenergic blockade exerted no significant influence on the ability of these agents to provoke the initial release and subsequent uptake of K+ by the liver.     

Impact of the hepatic arterial buffer response on splanchnic vascular responses to intravenous adenosine, isoproterenol, and glucagon

Hepatic arteries (HA) and superior mesenteric arteries (SMA) of cats anesthetized with pentobarbital responded to direct intra-arterial infusion of isoproterenol, adenosine, and glucagon with dose-related vasodilation. In response to intravenous infusion, however, the HA failed to dilate significantly, while the SMA dilated thus elevating portal blood flow. The lack of dilation of the HA was due to the HA buffer response to the elevated portal blood flow, that is, elevation of portal flow causes the HA to constrict. When a clamp was used to return SMA flow to control levels during infusion of the drugs, the HA showed significant dilation to all three agents. Thus, HA vascular responses to i.v. drugs can only be assessed if portal flow is known, since the net effect is dependent upon direct action of the drug on the HA as well as the indirect effect of any drug-induced change in portal flow. None of the agents tested altered the magnitude of the HA buffer response obtained during i.v. infusions, but the effects of other agents on the buffer response remain unknown and must be considered in any tests of i.v. administered drugs. Bolus i.v. injections produce results on the HA flow that are uninterpretable.     

Impact of portal glucose delivery on glucose metabolism in conscious, unrestrained mice

Previous studies in mice suggest that portal venous infusion of glucose at a low rate paradoxically causes hypoglycemia; this does not occur in dogs, rats, and humans. A possible explanation is that fasting status in the mouse studies may have altered the response. We sought to determine whether the response to portal glucose delivery in the mouse was similar to that seen in other species and whether it was dependent on fasting status. Studies were performed on chronically catheterized conscious mice. Catheters were placed into the portal and jugular veins and carotid artery 5 days before study. After a 5- or 16-h fast, glucose was infused into either the portal (PO) or the jugular vein (JU) for 6 h at 25 microg.g(-1).min(-1). [3-(3)H]glucose was infused into the JU to measure glucose turnover. In 5-h-fasted mice, PO and JU exhibited similar increases in arterial blood glucose from 155 +/- 11 to 173 +/- 19 and 147 +/- 8 to 173 +/- 10 mg/dl, respectively. Endogenous glucose production decreased and arterial insulin increased to the same extent in both PO and JU. A similar response was observed in 16-h-fasted mice; however, the proportion of hepatic glycogen synthesis occurring by the indirect pathway was increased by fasting. In summary, portal glucose delivery in the mouse did not cause hypoglycemia even when the duration of the fast was extended. The explanation of the differing response from previous reports in the mouse is unclear.