Effect of secretin and caerulein on the absorption of water, electrolytes and glucose from the jejunum of dogs

The effects of secretin and caerulein on the absorption of water, sodium, potassium and glucose from the jejunum of dogs were investigated. Intravenous infusion of 1 clinical unit (CU; 82 pmol/kg/h) of secretin inhibited jejunal absorption of water, sodium and glucose compared to control period. Adding an intravenous infusion of 0.4 micrograms (300 pmol)/kg/h of caerulein to the infusion of secretin, the jejunal absorption rates of water, sodium and glucose were restored to control values. Intravenous infusions of 0.2 and 0.4 micrograms/kg/h of caerulein induced no significant difference in the absorption compared to control. Thus it seems that secretin inhibits the absorption of water, sodium and glucose from the jejunum of dogs and caerulein, added to secretin, reverses the effect of secretin.     

Effects of caffeine and coffee on fluid transport in the small intestine

Although caffeine is known to stimulate small intestinal water secretion in man, no available studies have examined the effect of coffee on small intestinal fluid transport. We have studied the effect of both coffee and caffeine on jejunal sodium and water transport by the triple lumen intestinal perfusion technique. Both caffeine and coffee solutions had equivalent caffeine concentrations, approximating the caffeine concentration in one cup of coffee. Control and coffee perfusion resulted in net absorption of 0.9 +/- 0.2 and 1.1 +/- 0.3 ml per min per 30 cm, respectively, whereas caffeine perfusion resulted in net water secretion of 2.4 +/- 0.4 ml per min per 30 cm (P less than 0.02). Net sodium absorption was observed with control and coffee solutions with a mean absorption of 190 +/- 32 and 184 +/- 40 muEq per min per 30 cm, respectively. Net sodium secretion of 334 +/- 25 muEq er min per 30 cm was observed during caffeine perfusion (P less than 0.02). We conclude that coffee perfusion has no significant effect on sodium and water transport in the jejunum in spite of the marked secretory effects of caffeine solutions. The results of this study yield further support to the suggestion that the effects of caffeine may not be similar to the effects of caffeine-containing compounds such as coffee.     

Hypotensive effect of chronic intrarenal infusion of acetylcholine during angiotensin hypertension

We examined the role of the pressure natriuresis phenomenon in long-term arterial pressure control. Uninephrectomized dogs were housed in metabolic cages and made hypertensive with a continuous background intravenous infusion of angiotensin II (AngII, 12 ng/kg/min). To increase the ability of the kidney to excrete salt and water, we infused acetylcholine (ACH, 2.0 micrograms/kg/min), a potent natriuretic agen, directly into the renal artery. In four dogs, ACH decreased mean arterial pressure (MAP) from 144 +/- 5 mm Hg to 113 +/- 3 mm Hg. Sodium excretion increased by about 60% on the first day of infusion and then returned rapidly toward the control value. On cessation of the ACH infusion, there was a transient but marked sodium retention, and the hypertension returned. A control infusion of ACH intravenously rather than into the renal artery in the same four dogs did not affect MAP or sodium excretion during AngII hypertension.     

Effect of CGRP antagonist,alpha-CGRP 8-37, on acid secretion in the dog

The recently synthesized calcitonin gene-related peptide (CGRP) antagonist, human alpha-CGRP 8-37, was used to study its effects on gastric acid secretion. Four dogs with gastric fistula were used to measure the antagonist's physiologic effects in the stomach. All dogs received a bactopeptone dextrose meal (intragastric titration to pH 5.5) with either continuous CGRP 8-37 (1000 pmol/kg/hr) or saline (control). Additionally, intravenous bombesin (75–600 ng/kg/hr) and bethanecol (12.5–100 µg/kg/hr) was tested in the presence of the antagonist. Plasma gastrin levels also were measured via radioimmunoassay (RIA) in control and CGRP 8-37-stimulated animals. Gastric acid secretion increased by 100% with infusion of 1000 pmol/kg/hr CGRP 8-37 when compared to the control. Acid output increased 98% with both intravenous antagonist and 600 ng/kg/hr bombesin when compared to bombesin alone. However, no augmentation of acid secretion by CGRP 8-37 was shown with 25 µg/kg/hr bethanecol. RIA of plasma gastrin demonstrated no effect with the antagonist when given alone and did not increase bombesin-stimulated gastrin release. We conclude that CGRP 8-37 blocks native CGRP inhibitory effects on gastric acid secretion. Our findings of potentiation of acid secretion by bombesin as well as no change in gastrin levels in the presence of the antagonist is likely due to a blockage in a noncholinergic neuron to the somatostatin cell. Furthermore, CGRP 8-37 did not increase bethanecolstimulated acid secretion, most likely due to bethanecol's (acetylcholine) nearly ubiquitous positive effects on acid secretion.Funded by NIH Grant DK 40790.     

Somatostatin inhibits fluid secretion in the rat jejunum

We determined the effect of somatostatin on water, glucose, sodium, and urea transport by utilizing an in vivo perfusion technique in the rat jejunum. Somatostatin (2.5-37.5 micrograms/kg . min) infused intravenously had no effect on basal absorption of water, sodium, or urea. However, infusion of somatostatin at the rate of 10 micrograms/kg . min completely blocked prostaglandin E1-induced inhibition of water absorption (P less than 0.01) and partially blocked net water secretion induced by theophylline (P less than 0.001). This effect of somatostatin occurred despite unchanged basal or theophylline and prostaglandin E1-stimulated cyclic AMP levels. In contrast, somatostatin did not affect glucose absorption in the rat jejunum. These results demonstrate that somatostatin may affect water and electrolyte movement by blocking the action of cyclic AMP in the rat jejunum.     

Polyuria, polydypsia, and hypertension produced by a six-day intravenous infusion of prostaglandin E1 in the conscious dog

The effects of a continuous intravenous infusion of prostaglandin E1 (PGE1) on mean arterial pressure (MAP), sodium and water balance, and plasma renin activity (PRA) were examined in 10 conscious dogs maintained on a 70 to 75 mEq/day sodium intake. In a crossover pattern, each dog received 6 days of intravenous PGE1 (0.1 micrograms/kg/min) and 6 days of intravenous diluent. When compared to diluent, intravenous PGE1 resulted in a mild sustained rise in MAP. By Day 6 the intravenous PGE1, MAP had increased from 98 +/- 4 to 112 +/- 5 mm Hg (mean +/- SE) (p less than 0.04). Concurrent with the MAP increase, PRA increased from 0.6 +/- 0.2 to 3.1 +/- 0.7 ng angiotensin I (AI)/ml/hr (p less than 0.03). To assess the role of the renin-angiotensin system in the maintenance of the systemic hypertension. AI converting-enzyme inhibitor was given to four dogs on Day 6 of both intravenous PGE1 and diluent. Only when the dogs were receiving PGE1 did the administration of converting-enzyme inhibitor result in a significant decrease in MAP (-19 +/- 5 mm Hg). In addition to increasing arterial pressure, the chronic infusion of PGE1 also produced changes in salt and water balance. When compared to diluent, PGE1 resulted in a twofold increase in both water intake and urine output, an increase in urinary sodium excretion (from 72 +/- 3 to 84 +/- 6 mEq/day, p less than 0.05, on Day 1), and a decrease in urine osmolality (from 942 +/- 82 to 586 +/- 61 mOsmol/kg H2O/day, p less than 0.05, on Day 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Verapamil reversal of serotonin-induced jejunal secretion of water and electrolytes in awake dogs

Intestinal handling of water and electrolytes was monitored in 5 conscious dogs with chronic 25-cm Thiry-Vella loops of proximal jejunum using a neutral isosmotic perfusate containing [14C]polyethylene glycol as a recovery marker. Under basal conditions the animals absorbed water, Na+, and Cl-, and there was minimal nonsignificant secretion of K+. Intravenous serotonin infusion (30 micrograms/kg X min) increased circulating hormone levels to 937 +/- 131 ng/ml and induced significant secretion of water (-150 +/- 52 microliter/min), Na+ (-22.8 +/- 8.4 microEq/min), Cl- (-23.5 +/- 6.0 microEq/min), and K+ (-1.79 +/- 0.34 microEq/min). Simultaneous infusion of verapamil, a calcium channel blocker, at 8.3 micrograms/kg X min, reversed the intestinal secretion to absorption of all these parameters (144 +/- 32 microliter/min, 15.1 +/- 5.1 microEq/min, 10.3 +/- 3.0 microEq/min, and 0.12 +/- 0.23 microEq/min, respectively). This was accompanied by a significant improvement in the clinical appearance of the animals, decreased visible agitation, and cessation of defecation. Cessation of verapamil infusion (leaving the serotonin infusion unopposed) resulted in prompt return to the secretory state. Serum electrolytes did not change significantly, with the exception of potassium, which fell from 5.1 +/- 0.2 to 4.1 +/- 0.1 mg/dl. In control experiments (no serotonin), verapamil had an insignificant stimulatory effect on the absorption of water, Na+, and Cl- whereas the effect on K+ was significant (-0.2 +/- 0.2 to +0.4 +/- 0.1 microEq/min; p less than 0.05). These data support the role of calcium in modulating the effects of serotonin, and they suggest a new promising technology for the management of serotonin-induced intestinal secretion such as that seen in the carcinoid syndrome.     

Central regulation of intestinal basal and stimulated water and ion transport by endogenous opiates in dogs

The influence of intracerebroventricular (ICV) vs intravenous (IV) administration of (D-Ala2, Met5) enkephalinamide (Dalamide) on normal and stimulated (cholera toxin) jejunal fluxes of water, Na+, and K+ were investigated in dogs prepared with a Thiry-Vella (TV) loop. Intestinal transport in the TV loop and concomitant transit time were measured during an infusion (2 ml/min) of an isotonic electrolyte solution alone, or containing 0.4 micrograms/ml of cholera toxin (CT). Basal net water absorption was slightly, but significantly (P less than 0.05), increased during an ICV infusion of Dalamide at 0.5 ng/kg/min, while the secretory effects of cholera toxin were markedly reduced by nearly 75%. Similar effects were observed for Na+ and K+ movement. In contrast, Dalamide infused intravenously at a five times higher dose, ie, 2.5 ng/kg/min did not affect the control and CT-stimulated water and electrolyte movements. The jejunal loop transit times were halved during CT infusion. Similar values were observed under Dalamide ICV administration as well as during a five times higher dose of Dalamide administered intravenously. It was concluded that (1) Dalamide administered into the CNS, but not peripherally, increased the absorption of water, Na+, and K+, causing a net reduction in their secretion induced by cholera toxin; and (2) these effects did not result from changes in transit time. These results also suggest that Met-enkephalin can act in the brain to affect the intestinal transport of water and electrolytes in dogs.     

Chronic hypotensive effects of verapamil in angiotensin hypertension are steroid independent

This study was designed to examine the mechanisms that contribute to the chronic hypotensive effects of verapamil during angiotensin II-induced hypertension. Hypertension was induced in five dogs by continuous intravenous infusion of angiotensin II (5 ng/kg/min) for 17 days. On the sixth day of angiotensin II infusion when daily sodium balance was achieved, mean arterial pressure (control, 92 +/- 4 mm Hg), plasma aldosterone concentration (control, 5.2 +/- 0.9 ng/dl), and renal resistance (control, 0.28 +/- 0.01 mm Hg/ml/min) were increased 37 +/- 8 mm Hg, 13.6 +/- 5.0 ng/dl, and 0.20 +/- 0.05 mm Hg/ml/min, respectively. At this time there were no significant changes in glomerular filtration rate, effective renal plasma flow, net sodium and water balance, or extracellular fluid volume. Subsequently, when verapamil was infused (at 2 micrograms/kg/min) simultaneously with angiotensin II (days 7-13), there was a net loss of 55 +/- 10 meq sodium, a 7.0 +/- 0.7% fall in extracellular fluid volume, and approximately a 70% reduction in the chronic effects of angiotensin II on mean arterial pressure and renal resistance; in contrast, verapamil failed to attenuate the long-term aldosterone response to angiotensin II. Further, although glomerular filtration rate and effective renal plasma flow tended to increase during verapamil administration, there were no consistent chronic long-term changes in these renal indexes. In comparison with these responses in hypertensive dogs, when verapamil was infused for 7 days before the induction of angiotensin II hypertension, there were no significant changes in any measurements except mean arterial pressure, which fell 11 +/- 1 mm Hg. Thus, these data fail to support the hypothesis that the chronic stimulatory actions of angiotensin II on aldosterone secretion are dependent on a sustained increase in transmembranal calcium influx. Moreover, these data indicate that the pronounced long-term hypotensive effects of verapamil in angiotensin II hypertension are due to impairment of the direct renal actions of angiotensin II rather than the indirect sodium-retaining effects that are mediated via aldosterone secretion.     

Dipyridamole decreases glomerular filtration in the sodium-depleted dog. Evidence for mediation by intrarenal adenosine

To determine the renal effects of inhibiting the uptake and subsequent metabolism of endogenous adenosine, dipyridamole, a nucleoside transport inhibitor, was infused intrarenally into anesthetized dogs. Dipyridamole (24 micrograms/kg per min) inhibited the cellular extraction of [14C]adenosine (72 +/- 3% vs. 9 +/- 3%) and elevated the excretion of endogenous adenosine (0.60 +/- 0.08 to 1.70 +/- 0.21 nmol/min, P less than 0.05). The action of exogenous adenosine to decrease glomerular filtration rate is known to be enhanced by sodium depletion, and is minimal or absent in sodium-loaded animals. To ascertain whether dietary sodium intake alters the renal effects of elevated endogenous adenosine, dipyridamole was infused into sodium-depleted and sodium-loaded dogs. In the sodium-depleted dogs (n = 9), dipyridamole infusion decreased the glomerular filtration rate by 59 +/- 7% (20 +/- 1 to 8 +/- 2 ml/min, P less than 0.05) which returned to control levels within 30 minutes after stopping infusion of dipyridamole. Renal vascular resistance was unchanged during dipyridamole infusion. In the sodium-loaded dogs (n = 5), dipyridamole had no effect on glomerular filtration rate (22 +/- 4 vs. 25 +/- 3 ml/min) or renal vascular resistance. In a separate series of sodium-depleted dogs (n = 8), the dipyridamole-induced decrease in glomerular filtration rate was completely reversed or inhibited by theophylline, an adenosine receptor antagonist. These experiments demonstrate that inhibition of cellular uptake of adenosine elevates adenosine levels, that dipyridamole decreases glomerular filtration rate in sodium-depleted but not sodium-loaded dogs, and that the decrease in glomerular filtration rate is inhibited by theophylline. We conclude that the decrease in glomerular filtration rate during dipyridamole administration is mediated by increased endogenous adenosine.     

Failure of superoxide dismutase and catalase to alter size of infarction in conscious dogs after 3 hours of occlusion followed by reperfusion

Superoxide dismutase (SOD) and catalase (CAT), enzymes that degrade superoxide anion and hydrogen peroxide, respectively, reduce size of infarction in anesthetized, open-chest dogs subjected to coronary occlusion followed by reperfusion. To evaluate potential protective effects of these enzymes in conscious animals, three groups of dogs were instrumented at sterile surgery with a hydraulic occluder on the left circumflex (LCX) coronary artery, sonomicrometers to measure regional wall thickness, and catheters to monitor arterial and left ventricular pressures. Ten to 14 days after surgery, the animals were sedated with morphine sulfate (0.5 mg/kg). The LCX artery was occluded for 3 hr by inflation of the hydraulic cuff. Infusions of SOD (n = 7), CAT (n = 6), or saline (control group, n = 7) were begun 15 min before reperfusion and lasted for 45 min of reperfusion. The doses of SOD and CAT were 5 mg/kg, dissolved in 60 ml of saline, and infused at a rate of 1 ml/min. Myocardial blood flow was measured with tracer-labeled microspheres (15 micron diameter) before occlusion, after 5 to 10 min of occlusion, after 150 min of occlusion, and 5 to 10 min after reperfusion. Size of infarction was measured 24 hr later by dual-perfusion staining with Evans blue and triphenyl tetrazolium. Size of infarction (expressed as a percentage of area at risk) did not differ significantly among the three groups: control, 32 +/- 17% (mean +/- SD); SOD, 38 +/- 17%; CAT, 27 +/- 17%. Hemodynamic parameters and myocardial blood flows (measured before infusion of any agents) were not significantly different among the three groups. Serum SOD levels in SOD-treated dogs were 19 +/- 2 micrograms/ml at the onset of reperfusion and 29 +/- 3 micrograms/ml at the end of the infusion. Blood assays collected after infusion showed a monoexponential decay of SOD levels with a half-life of 22 +/- 6 min. We conclude that myocardial protection by SOD or CAT is model dependent. In conscious dogs subjected to 3 hr of coronary occlusion followed by reperfusion, SOD and CAT failed to alter size of infarction.     

Beta-adrenergic drug therapy in newborn canine endotoxic shock

The mortality of septic shock remains high in newborns. Although the effectiveness of adrenergic drug therapy continues to be controversial, adrenergic drugs have been used for the treatment of newborn endotoxic shock. To elucidate the effects of beta-adrenergic drugs on the fulminant hemodynamic deterioration of newborn endotoxic shock, newborn dogs (2-10-day-old, 264-800 g) were given Escherichia coli lipopolysaccharide (LPS; 10 mg/kg iv) and treated with isoproterenol (0.1 micrograms/kg/min) or dopamine (5 micrograms/kg/min) infusion from 5 to 120 min after LPS injection. Isoproterenol attenuated the effects of LPS by increasing the mean arterial pressure (32 +/- 2 vs. 13 +/- 1 mmHg at 120 min), cardiac output (183 +/- 29 vs. 118 +/- 23 ml/min/kg at 120 min), and the survival time (5.3 vs 2.9 hr). However, dopamine did not improve the hemodynamic deterioration. As dopamine-beta-hydroxylase activity in the blood was significantly lower in newborn dogs than in adult dogs, inadequate response of newborn dogs to dopamine was thought to be in part due to enzymatic immaturity.     

Renal effects of atrial natriuretic factor during control of the renin-angiotensin system in anesthetized dogs

The contribution of the renin-angiotensin system to the natriuretic responses to intrarenal infusions of 1, 5, 25, and 125 pmol/kg/min synthetic rat atrial natriuretic peptide 101-126 was determined in one-kidney anesthetized dogs. In vehicle-treated dogs, atrial natriuretic peptide 101-126 increased fractional sodium excretion from 1.8 +/- 0.6% to a peak response of 5.1 +/- 0.9% during infusion of 25 pmol/kg/min. The peptide progressively decreased mean arterial pressure from 110 +/- 5 to 94 +/- 4 mm Hg, renal vascular resistance from 0.40 +/- 0.02 to 0.30 +/- 0.02 mm Hg/ml/min, and arterial plasma renin activity from 4.3 +/- 1.6 to 3.1 +/- 0.8 ng/ml/hr. When the renin-angiotensin system was blocked by 3 mg/kg i.v. enalaprilat, baseline pressure fell to 86 +/- 4 mm Hg, and subsequent infusions of atrial natriuretic peptide 101-126 did not affect fractional sodium excretion. The decreases in blood pressure (from 86 +/- 4 to 76 +/- 4 mm Hg) and in renal vascular resistance (from 0.27 +/- 0.03 to 0.23 +/- 0.02 mm Hg/ml/min) were also ameliorated compared with the control responses. Intravenous infusion of 2.5 ng/kg/min angiotensin II restored mean arterial pressure and potentiated the natriuretic and renal vascular responses to atrial natriuretic peptide 101-126. In two additional groups of anesthetized dogs, enalaprilat did not produce the profound hypotension and did not affect the natriuretic responses to atrial natriuretic peptide 101-126. When renal vascular resistance was elevated by intrarenal infusion of angiotensin II in enalaprilat-treated dogs, the natriuretic response was improved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of atrial natriuretic factor in anesthetized and conscious dogs

Atrial natriuretic factor lowers blood pressure in normotensive and hypertensive animal models. The present study examined the mechanism of the blood pressure-lowering effect in 10 normotensive dogs. Four awake dogs previously instrumented with electromagnetic flow probes for measurement of cardiac output and catheters for systemic hemodynamic and cardiac dynamic measurements were studied. After a 30-minute control period, a 3 micrograms/kg bolus followed by 0.3 micrograms/min/kg of a 24-residue synthetic atrial natriuretic factor was infused for 30 minutes, followed by a 1-hour recovery period. Mean arterial pressure fell significantly during infusion (control, 125 +/- 4; infusion, 108 +/- 5; recovery, 125 +/- 9 mm Hg; p less than 0.05) and was accompanied by a slight but significant bradycardia (control, 144 +/- 7; infusion, 134 +/- 5; recovery, 145 +/- 7 beats/min; p less than 0.05). Significant reductions in cardiac output (control, 2.66 +/- 0.60; infusion, 2.18 +/- 0.60; recovery, 2.74 +/- 0.60 L/min; p less than 0.05), stroke volume (control, 18.4 +/- 3.9; infusion, 16.0 +/- 4.2; recovery, 19.0 +/- 3.7 ml/beat; p less than 0.05), and maximum increase in rate of change of left ventricular systolic pressure (control, 2475 +/- 200; infusion, 2088 +/- 216; recovery, 2487 +/- 243 mm Hg/sec; p less than 0.05) were also observed during infusion. No significant changes in total peripheral resistance or central venous pressure were noted, although the latter tended to fall during infusion. A similar pattern was observed in six pentobarbital-anesthetized dogs, except that infusion of atrial natriuretic factor did not induce bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acceleration of recombinant tissue-type plasminogen activator-induced reperfusion and prevention of reocclusion by recombinant antistasin, a selective factor Xa inhibitor, in a canine model of femoral arterial thrombosis.

Antistasin is a 119-amino acid protein initially isolated from salivary glands of the Mexican leech, Haementeria officinalis, that exhibits potent anticoagulant properties resulting from selective inhibition of blood coagulation factor Xa. The comparative antithrombotic efficacies of recombinant antistasin (rATS), standard heparin (Hep), and aspirin (ASA) administered adjunctly with recombinant tissue-type plasminogen activator (tPA) on thrombolytic reperfusion and reocclusion were determined in a canine model of femoral arterial thrombosis. An occlusive thrombus was formed by insertion of a thrombogenic copper coil into the femoral artery, and blood flow velocity was monitored directly and continuously by Doppler flowmetry. Sixty minutes after occlusion, dogs received an intravenous infusion of either saline (vehicle) or rATS (0.31, 1.25, or 2.5 micrograms/kg/min), intravenous boluses of Hep (100 units/kg + 50 units/kg/hr or 200 units/kg + 150 units/kg/hr), or a single intravenous bolus of ASA (2.0 mg/kg), followed 45 minutes later by tPA (0.8 mg/kg i.v. over 90 minutes). The saline and rATS infusions were discontinued 60 minutes after termination of tPA, and the last Hep boluses were given 105 minutes after termination of tPA. All dogs achieved reperfusion. The time to reperfusion in the ASA group was similar to that in the vehicle group (50 +/- 9 versus 50 +/- 6 minutes, respectively). Reperfusion times were slightly decreased by the low and high doses of Hep (34 +/- 6 and 31 +/- 4 minutes, respectively) and the rATS doses of 0.31 and 1.25 micrograms/kg/min (37 +/- 4 and 36 +/- 5 minutes, respectively). However, the time to reperfusion was dramatically reduced with the 2.5 micrograms/kg/min rATS dose (15 +/- 3 minutes, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary thrombolysis in dogs with intravenously administered human pro-urokinase

Coronary thrombolysis was induced by infusion of highly purified human pro-urokinase isolated from a transformed kidney cell line (ACHN) or by infusion of urokinase of urinary origin in anesthetized dogs with 1-hr-old clots in the left anterior descending coronary artery. The clots were induced with a copper coil and thrombolysis was detected by repeat coronary angiography. Intravenous infusion of pro-urokinase at a rate of 10 micrograms/kg/min for 30 min in two dogs did not induce thrombolysis, which was only obtained after 8 and 15 min of its subsequent intracoronary administration. Intravenous infusion of pro-urokinase at a rate of 20 micrograms/kg/min for 30 min in four dogs induced coronary thrombolysis within 23 +/- 2 min (mean +/- SEM). This was not associated with systemic fibrinolytic activation because the alpha 2-antiplasmin and fibrinogen levels did not decrease. Intravenous infusion of urokinase at a rate of 10 micrograms/kg/min for 30 min elicited thrombolysis in four of seven dogs within an average of 19 +/- 2 min. In the other three dogs thrombolysis was only obtained within 11 +/- 3 min of its subsequent intracoronary infusion. Administration of urokinase was associated with systemic fibrinolytic activation as evidenced by a decrease of alpha 2-antiplasmin to about 10% and of fibrinogen to 43 +/- 13% of the preinfusion value. It is concluded that intravenous infusion of pro-urokinase at a sufficiently high rate produces coronary thrombolysis without systemic fibrinolysis in dogs.     

Synergistic combinations of recombinant human tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. Effect on thrombolysis and reocclusion in a canine coronary artery thrombosis model with high-grade stenosis

The synergistic effects of recombinant human tissue-type plasminogen activator (rt-PA) and single-chain urokinase-type plasminogen activator (scu-PA) on coronary arterial thrombolysis were investigated in open-chest dogs with thrombosis of the left anterior descending coronary artery and a superimposed high-grade stenosis. A 90% stenosis was generated by external constriction, reducing blood flow to 40 +/- 10% of baseline. Localized thrombosis was produced by endothelial cell injury and instillation of thrombin and fresh blood. Intravenous infusion for 60 minutes of either 30 micrograms/kg/min rt-PA alone or 10 micrograms/kg/min scu-PA alone consistently produced coronary artery recanalization (six of eight dogs and five of five dogs, respectively) but was almost always associated with reocclusion during or shortly after the end of the infusion (four of six dogs and five of five dogs, respectively). Infusion of either 15 micrograms/kg/min rt-PA or 5 micrograms/kg/min scu-PA for 60 minutes did not cause coronary artery recanalization (none of four dogs in each group). Combined infusion of 7.5 micrograms/kg/min rt-PA and 2.5 micrograms/kg/min scu-PA for 60 minutes (one fourth of the minimum thrombolytic dose of each agent) induced coronary artery recanalization (six of six dogs) but was also associated with early reocclusion (six of six dogs). Combined infusion of 3.75 micrograms/kg/min rt-PA and 1.25 micrograms/kg/min scu-PA for 60 minutes did not consistently cause recanalization (one of four dogs). Combined infusion of 15 micrograms/kg/min rt-PA and 5 micrograms/kg/min scu-PA for 60 minutes caused recanalization in all of six dogs but was associated with reocclusion in all six.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective dopamine DA1 stimulation with fenoldopam in cirrhotic patients with ascites: a systemic, splanchnic and renal hemodynamic study.

We studied the effects of fenoldopam, a selective dopamine DA1 agonist on systemic and splanchnic hemodynamics, renal blood flow and sodium excretion in 12 patients with alcoholic cirrhosis and ascites. Hepatic, azygos and renal veins were catheterized before and after intravenous administration of fenoldopam, 0.05 micrograms/kg/min for 1 hr and increased to 0.1 micrograms/kg/min for another hour. Mean arterial pressure progressively decreased (from 83 +/- 7 to a minimum of 77 +/- 8 mm Hg 100 min after starting the infusion) but returned to baseline level at 120 min. Plasma norepinephrine and renin activity increased (respectively from 567 +/- 297 to 919 +/- 375 pg/ml, p less than 0.05, and from 17 +/- 14 to 23 +/- 15 ng/ml/hr, p less than 0.05). Renal blood flow, urine output or sodium excretion did not change. Sodium output decreased at 1 hr from 6.9 mumol/min to 4.0 mumol/min, p less than 0.05. Both hepatic venous pressure gradient and azygos blood flow significantly increased by 21%. We conclude that the acute administration of fenoldopam did not improve renal hemodynamics or function in patients with cirrhosis and ascites. In addition, dopamine DA1 agonism caused further increases in norepinephrine concentration and plasma renin activity. Portal pressure also increased, probably because of an increase in mesenteric blood flow. These results question the renal benefit and raise concern about the use of dopamine agonists in patients with cirrhosis and ascites.     

Effect of diltiazem on norepinephrine-induced acute left ventricular dysfunction.

The present study has examined the role of diltiazem as a protective agent in a canine model of norepinephrine cardiotoxicity. Effects of diltiazem, 20 micrograms/kg/min x 5 min pretreatment followed by 10 micrograms/kg/min x 90 min, or saline infusion were examined at baseline and 1 h after infusion of norepinephrine, 4 micrograms/kg/min for 90 min, in closed-chest anesthetized dogs. Left ventricular function was assessed by equilibrium radionuclide angiogram and two-dimensional echocardiogram. In 7 saline experiments, hypotension and increased heart rate were observed at 1 h post infusion. In the diltiazem-treated group (n = 7), mean arterial pressure and heart rate were unchanged. In the saline group, left ventricular ejection fraction fell from 0.50 +/- 0.04 to 0.28 +/- 0.04. Left ventricular ejection fraction was unchanged in the diltiazem-treated group: 0.52 +/- 0.03 to 0.55 +/- 0.07. Left ventricular end-diastolic volume was increased at 1 h post infusion in saline controls but not in the diltiazem-treated group. Measurement of fractional shortening from two-dimensional echocardiograms also indicated left ventricular dysfunction in the saline but not diltiazem-treated groups. Left ventricular end-systolic wall stress following norepinephrine infusion was significantly increased in the saline but not diltiazem-treated groups: 122.7 +/- 18.7 vs 67.6 +/- 19.7 g/cm2, respectively. In dogs receiving saline without norepinephrine infusion, no significant changes occurred over the course of the experiment. Histologic examination showed mild contraction band necrosis in saline controls but not in sham saline dogs. Diltiazem showed intermediate histologic evidence of injury, which was not further quantified. This study suggests that effects of norepinephrine on left ventricular function in the canine model of norepinephrine cardiotoxicity may be largely due to increased wall stress following a prolonged increase in afterload. Diltiazem pretreatment afforded significant protection of left ventricular function.     

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.