Hemodynamic effects of intra-arterial infusions of catecholamines on the canine gastric circulation.

The effects of intra-arterial infusions of epinephrine, norepinephrine, and isoproterenol upon right and left gastric blood flow were studied in anesthetized dogs. Blood flow was measured electromagnetically before and after adrenergic blockade. Infusion of epinephrine (0.05 mug Kg.(-1) min.(-1)) resulted in vasoconstriction (-50 +/- 6 ml. min.(-1)) with autoregulatory escape in the right gastric artery (RGA) and constriction (-41 +/- 8 ml. min.(-1)) followed by significant dilation (+ 56 +/- 10 ml. min.(-1)) in the left gastric artery (LGA). Alpha adrenergic blockade with phenoxybenzamine produced only a dilator response in both RGA and LGA to epinephrine infusion and beta adrenergic blockade resulted in a constrictor response with no autoregulatory escape. Norepinephrine infusions produced a constrictor response of similar magnitude as epinephrine but with little evidence of autoregulatory escape in either RGA and LGA. Alpha adrenergic blockade significantly attenuated this response in both circulations. Isoproterenol is a dilator in both circulations and its response is attenuated only by beta adrenergic blockade. This study demonstrates that the canine stomach has two regionally distinct circulations with the fundus and body exhibiting a greater dilator response than the antrum and pylorus.

Opiate receptors and endorphins in the pathophysiology of hemorrhagic shock.

We investigated the hypothesis that endorphins released by stress act on opiate receptors to depress cardiovascular function during hemorrhagic shock. Anesthetized adult mongrel dogs were bled into a heparinized reservoir to achieve a mean arterial pressure (MAP) of 45 mm Hg. The reservoir was adjusted to maintain MAP for 1 hour and then clamped for 1 hour, at the end of which time the shed blood was reinfused. While the reservoir was clamped we treated the animals with an intravenous bolus followed by 3-hour infusion of either 0.9% NaCl (as control) or the specific opiate receptor antagonist naloxone at three dose regimens (0.5, 1, or 2 mg/kg plus 0.5, 1, or 2 mg/kg . hr). Naloxone produced dose-dependent increases in MAP, cardiac output, stroke volume, and left ventricular contractility. Survival at 72 hours was related to the dose of naloxone used. None of six dogs treated at 0 mg/kg . hr survived, one of six survived at 0.5 mg/kg . hr, four of five at 1 mg/kg . hr, and five of five at 2 mg/kg . hr. Since naloxone has minimal effect on cardiovascular function in nonshocked dogs, these results implicate opiate receptors and perhaps endorphins in the cardiovascular pathophysiology of hemorrhagic shock.

Adrenergic mechanisms in the hindlimb circulation of baboons.

The effects of the adrenergic agonists norepinephrine, epinephrine, isoproterenol, and phenylephrine upon femoral arterial blood flow were measured in baboons before and after alpha (phenoxybenzamine) and beta (propranolol) adrenergic receptor blockade. Flow was measured with an electromagnetic flowmeter. Arterial and venous pressures were recorded simultaneously. Femoral vascular resistance was calculated from these data. Catecholamines were injected intra-arterially (10(-3)--10(0) mug, base, kg.(-1) and intravenously (1.0 mug kg.(-1) in a randomized sequence. All four adrenergic amines were vasodilators at low dose (10(-3) mug kg.(-1), intra-arterially) and this effect was abolished during beta adrenergic receptor blockade. Intra-arterial isoproterenol elicited dose-dependent increases in femoral flow; the other amines were vasoconstrictors at high doses. Alpha adrenergic blockade "reversed" the vasoconstrictor effects of these three amines. At the same dose isoproterenol increased flow more through the intra-arterial than the intravenous route. Conversely, norepinephrine and epinephrine were potent femoral vasodilators when injected intravenously. The findings indicate that the classical adrenergic amines are all vasodilators of the subhuman primate hindlimb at low doses due to their interaction with beta receptor sites. The fact that epinephrine and norepinephrine exert a greater increase in flow when given intravenously than when given intra-arterially is presumably secondary to increased arterial pressure, in turn due to the vasoconstrictor effects of these agents on other regional circulations.

Adrenergic mechanisms in the hepatic arterial circulation of baboons.

The effects of intra-arterial injections and infusions of three adrenergic amines upon hepatic arterial blood flow were measured in anesthetized baboons before and after alpha and beta adrenergic blockade with intravenous phenoxybenzamine and propranolol. Injections of norepinephrine or epinephrine caused dose-dependent decreases in hepatic arterial blood flow. These responses were attenuated by alpha adrenergic blockade and were unchanged by beta adrenergic blockade. Injections of isoproterenol caused dose-dependent increases in hepatic arterial flow. These increases were relatively small and were reversed to constriction at low doses and attenuated at high doses of the agonist by beta adrenergic blockade. Intrahepatic arterial infusions of constrictors were unaccompanied by autoregulatory excape. The degree of constriction was attenuated by alpha adrenergic blockade but was not potentiated by beta adrenergic blockade. Intrahepatic arterial infusion of a relatively large dose of isoproterenol was required to evoke a relatively modest, but sustained, increase in hepatic arterial blood flow. This response was not potentiated by alpha adrenergic antagonism, but was attenuated by beta adrenergic blockade. These observations suggest an apparent and relative decrease in beta adrenergic receptor activity in the hepatic arterial bed of the baboon when compared to other regional circulations such as the mesenteric and femoral beds. These beta receptors are relatively resistant to both stimulation and blockade.

Alteration of lymphocyte function due to anesthesia: in vivo and in vitro suppression of mitogen-induced blastogenesis by sodium pentobarbital.

The mechanism of decreased lymphocyte responsiveness after major surgery is unclear. Because sodium pentobarbital, and intermediately long-acting barbiturate, will reproducibly induce anesthesia in experimental animals, we utilized a canine model to investigate its effect on lymphocyte proliferation induced by the mitogenic lectins erythroagglutinating phytohemagglutinin (E-PHA) and leukoagglutinating phytohemagglutinin (L-PHA). Although no effect was observed at 10 minutes or 1 hour after an anesthetic dose of sodium pentobarbital, after 1 and 3 hours of anesthesia, canine lymphocytes were significantly suppressed, as demonstrated by decreased responsiveness to E-PHA and L-PHA mitogen stimulation. After 3-hours the majority of animals had mitogenesis values of less than 50% of the preanesthetic control values. Recovery, as measured by a return to at least 70% of the preanesthetic mitogenesis value, was noted in the majority of animals at 24, 48, and 72 hours. In order to investigate the machanisms of the in vivo capability of sodium pentobarbital to induce immunosuppression of lymphocyte transformation, in vitro studies were carried out. Sodium pentobarbital was found to significantly inhibit mitogen-induced canine mononuclear cell blastogenesis at anesthetic (1.5 to 3.0 mg%) drug concentrations in vitro. Lymphocytes pretreated with barbiturate and washed prior to plating did not show this inhibiting effect. Our findings suggest that depression of the immune response reported in patients after operation could result from short-acting barbiturates administered during the induction phase of clinical anesthesia. Furthermore, the suppression may involve in vivo metabolism of pentobarbital, hormones or other in vivo factors, since washed lymphocytes from the in vivo but not the in vitro experiments demonstrated suppression. These results indicate that anesthesia may be an important factor in the immunosuppression reported after major surgery.

Failure of immunosuppression to prolong venous allograft survival.

The role of allograft veins in vascular reconstruction remains ill defined. The present experiment was undertaken to evaluate the role of immunosuppression in maintaining allograft patency in the canine femoral venous circulation. Twenty-seven mongrel dogs had segments of both femoral veins excised and each dog received one allograft and one autograft. The dogs were randomly assigned to a control group or to one of three treatment regimens of azathioprine. Low doses of azathioprine were of no benefit in improving patency of venous alografts. Microscopic evaluation of these grafts suggests that substantial intimal repopulation by host cells occurs by six to eight weeks in the canine model. Other methods of preserving patency until intimal repopulation occurs deserve further investigation.

Effects of opiate receptor drugs injected intracerebrally into the normovolemic and hypovolemic monkey.

Systemic injection of naloxone (NAL), an opioid-receptor antagonist, significantly elevates systolic blood pressure (SBP) in anesthetized hypovolemic monkeys, providing indirect evidence that endogenous opioids contribute to cardiovascular depression during shock. The purpose of this study was to identify specific centrally located opioid receptor sites that participate in SBP regulation under normovolemic and hypovolemic conditions. In 6 monkeys, bilateral guide cannulae were stereotaxically implanted above areas ranging from the diencephalon to the lower medulla. Microinjections (1 microliter) of D- Ala2-Met-enkephalinamide (DAME) (3.4-27.2 nM) into normovolemic unanesthetized monkeys reduced SBP by 10-65 mm Hg in a dose-related fashion. Subsequent injection of NAL (12.2 nM) attenuated this hypotensive response. Heart rate fell 20-40 bpm with DAME, but not in response to dose. In the anesthetized animal rendered hypotensive (SBP = 45 mm Hg) by hemorrhage. NAL injected into predetermined DAME-sensitive sites failed to increase SBP more than 5 mm Hg. Even consecutive injections into multiple sites elevated SBP only 20 mm Hg. We conclude that the centrally located opioid-sensitive sites tested exert only a mild influence in mediating hemorrhagic hypotension.

Autonomic effects of central injections of D-Ala2-Met-enkephalinamide (DAME) in the conscious monkey.

The use of naloxone (NAL), an opioid receptor antagonist, has provided indirect evidence that endogenous opioids contribute to cardiovascular depression during shock. To determine if endogenous opioids act centrally to influence cardiovascular function, injections of D-Ala2-Met-enkephalinamide (DAME), a potent Met-enkephalin analog, were made into the 3rd cerebral ventricle (ICV) of 5 conscious cynomulgus monkeys restrained in primate chairs. Systolic blood pressure (SBP) and heart rate (HR) were determined every 10 min during a 30-60 min control period and for up to 5 hr post-injection. Colonic temperature (Tc) was monitored continuously. SBP declined from baseline values with 50 and 100 micrograms (85.2 and 170.4 nM) doses but was significant (p less than 0.001) for only the 100 micrograms dose between 15-125 min post-injection. HR also decreased but did not exhibit any significant variation with time. However, when averaged across time, HR fell significantly (p less than 0.001) from baseline: -9.1 +/- 2.3 and -15.0 +/- 2.1 b/min for 50 and 100 micrograms DAME, respectively. Tc displayed a nonsignificant, delayed (greater than 2 hr) rise in Tc with the 50 micrograms dose, whereas the 100 micrograms dose caused a significant (p less than 0.001) decline in Tc (from 65-125 min post-injection). NAL injected ICV attenuated the effects of DAME but had no effect on SBP, HR or Tc when injected alone. Systemic injection of DAME (300 micrograms) in one monkey produced a transient decline in SBP (26 mmHg within 2 min) which returned to baseline values 4 min post-injection. HR and Tc were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic changes following corticosteroid and naloxone infusion in dogs subjected to hypovolemic shock without resuscitation.

B-endorphin, which is released concomitantly with ACTH from the pituitary during stress, may also alter cardiac performance in hemorrhagic shock. In this study of 36 dogs subjected to hemorrhagic shock without resuscitation, we demonstrate the interaction of high doses of dexamethasone (DEX) or methylprednisolone (M) and opiate receptor blockade with naloxone (NAL). NAL, when given alone, resulted in the most hemodynamic improvement and the longest survival time while those animals receiving DEX or M, even in combination with NAL, did not do as well. These data suggest that corticosteroids block the NAL effect following hemorrhagic shock.

The therapeutic efficacy of opiate antagonists in hemorrhagic shock.

The endogenous opioids have been implicated as contributing factors to the cardiovascular dysfunction of shock. Opiate receptor antagonists improve cardiovascular function and long-term survival in laboratory animal models of shock. In this communication, evidence of the therapeutic efficacy of opiate antagonists in canine and primate hemorrhagic shock is presented. The animals were hemorrhaged into a reservoir to lower MAP to 45 mmHg and that pressure was maintained for 1 h at which time the reservoir was clamped and treatment initiated. The "shed blood" was returned at t = 120 min and treatment continued until t = 180 min. Opiate antagonists employed included naloxone, naltrexone and the mixed agonist/antagonist agent, nalbuphine. Both naloxone and naltrexone improved cardiac function at doses of 1 and 2 mg/kg. Animal survival was significantly enhanced in the high dose format. Nalbuphine also improved cardiovascular performance at doses from 1 to 4 mg/kg but at higher doses it depressed cardiac performance. The efficacy of the antagonists is attenuated by acidosis and hypothermia. Opiate antagonists may induce cardiac arrhythmias in combination with beta-adrenergic blocking drugs and the efficacy is reduced in animals that received high dose steroid therapy. Thus the use of opiate antagonists would be contraindicated in patients that received drugs such as propranolol or methylprednisolone. There have been no controlled clinical trials of opiate antagonists in human hemorrhagic shock; these are needed for final clarification.

Hemodynamics of experimental portal venous occlusion in dogs.

The effects of graded occlusion of the portal vein upon hepatic arterial blood flow were studied in anesthetized dogs to evaluate the so-called "reciprocal relationship" between portal venous flow and hepatic arterial flow in maintaining oxygenation of the liver. An obstruction that increased portal venous pressure to 20 mm Hg was accompanied by a transient increase in hepatic arterial blood flow without changing the other hemodynamic parameters. Release of portal venous occlusion was accompanied by a transient fall in hepatic arterial blood flow in this group of experiments. Increasing portal venous pressure to 30 mm Hg caused a gradual but progressive fall in arterial pressure accompanied by a significant fall in hepatic arterial blood flow. With complete obstruction of the portal vein there is a reduction in arterial pressure to the same level of portal venous pressure and a significant and sustained diminution in hepatic arterial blood flow. These observations conflict with previously described theories of a relationship between diminution in portal venous flow and increases in hepatic arterial blood flow.

Pancreatitis induced renal vasoconstriction.

The etiology of renal vasoconstriction in acute pancreatitis remains obscure. The canine model of bile pancreatitis was used to determine whether hypovolemia or increased circulating levels of catecholamines are responsible for this phenomenon. Treatment of the pancreatitis was either with volume loading or alpha adrenergic blockade with Prazosin given both before and after the induction of pancreatitis. Neither pretreatment nor post-treatment with either volume loading or Prazosin protected the kidneys from the standpoint of mitigating renal vasoconstriction. To the contrary, treatment with alpha blockade produced the greatest decreases in renal blood flow.

A magnetically actuated left ventricular assist device.

Over the past 6 years, research has led to development of a small, lightweight, power-efficient, uniquely simple ventricular assist device driven by a magnetic actuator. Magnetic actuation permits total elimination of all mechanical motion converter components used for pusher plate displacement, resulting in a significant reduction in complexity and resultant increase in reliability. Extensive in vitro mock loop development has resulted in a left ventricular assist device (LVAD), the primary design parameters of which for the clinical prototype actuator and pump are 1) an actuator weight of 312 g, 2) actuator size of 32.5 cm3, 3) power requirements of 7.8 to 11.4 watts (60-100 beats per minute [BPM]), and 4) system efficiency of 24% to 34% and average dynamic stroke volume of 65 ml. Initial in vivo tests assessed this LVAD's performance in four sheep under three acute conditions of ventricular dysfunction. The results demonstrate that, at a pump-rate of 100 BPM, mean aortic pressure increased by 45-50 mmHg during 1) beta blockade, 2) coronary ligation, and 3) ventricular fibrillation. Pump flow ranged from 2.71 L/min to a maximum of 4.6 L/min. Acute test periods were arbitrarily set for 6 hours duration. Of the four sheep, two survived, one lived 5 hours, and the fourth lived 4.5 hours. Global fibrillation was the primary cause of failure. This initial in vivo data demonstrates the pump's ability to maintain satisfactory hemodynamic parameters of flow and pressure under three acute conditions of extreme left ventricular dysfunction in an animal model. These initial LVAD performances were encouraging. Further tests will use calves with a greatly expanded performance evaluation protocol.