Use of a Porcine Model to Evaluate the Risks and Benefits of Vasopressors in Propranolol Poisoning.

INTRODUCTION: Vasopressors are a commonly used treatment in beta-blocker poisoning despite evidence they may be ineffective or harmful. The primary objective of the present study is to use previously collected data from two prior studies (high-dose insulin (HDI) versus vasopressin + epinephrine and a placebo-controlled HDI study) to compare survival between vasopressin + epinephrine and placebo. Secondary outcomes included a comparison with HDI as well as comparisons with hemodynamic parameters, including mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), and systemic vascular resistance (SVR). METHODS: Cardiogenic shock was induced in healthy pigs with a bolus of 0.5 mg/kg of intravenous propranolol followed by an infusion of 0.25 mg/kg/minute until the point of toxicity, defined as (0.75 × initial HR × initial MAP), at which point the infusion was reduced to 0.125 mg/kg/minute for 240 (vasopressin + epinephrine or HDI) or 360 minutes (placebo) or until death. RESULTS: Survival was significantly lower in pigs receiving vasopressin + epinephrine (0%, 0/5) than in pigs receiving placebo (50%, 2/4) (p < 0.01). Survival was significantly higher with HDI compared with both groups (100%, 5/5) (p < 0.01). All vasopressin + epinephrine pigs died within 100 minutes after reaching toxicity. Over the course of the resuscitation, we observed a statistically significant steady decrease in CO and HR in the vasopressin + epinephrine group compared with placebo (p < 0.01). In contrast, we observed a statistically significant change in MAP and SVR that followed a parabolic arc, with MAP and SVR rising significantly initially in the vasopressin + epinephrine group then rapidly falling until death (p < 0.01). CONCLUSIONS: Mortality was higher with vasopressors compared with placebo in this porcine model of propranolol poisoning. Further studies are warranted to define the optimal timing and role of vasopressors in beta-blocker poisoning.

Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery.

OBJECTIVE: Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) are associated with vasomotor dysfunction of coronary arterioles in patients with diabetes (DM) undergoing cardiac surgery. We hypothesized that DM may up-regulate vasopressin receptor expression and alter the contractile response of coronary arterioles to vasopressin in the setting of CP/CPB. METHODS: Right atrial tissue samples of patients with DM and without (ND) (n = 8 in each group) undergoing cardiac surgery were harvested before and after CP/CPB. The isolated coronary arterioles (80-150 µm) dissected from the harvested right atrial tissue samples were cannulated and pressurized (40 mm Hg) in a no-flow state. The changes in diameter were measured with video microscopy. The protein expression/localization of vasopressin 1A receptors (V1A) and vasopressin 1B receptors (V1B) in the atrial tissue were measured by immune-blotting and immunohistochemistry. RESULTS: The pre-CP/CPB contractile responses of the coronary arterioles to vasopressin were significantly increased post-CP/CPB in both the ND and DM groups. This effect was more pronounced in the vessels from patients in the DM group than that of vessels from patients in the ND group (P < .05). Vasopressin-induced contractile response of the coronary arterioles was inhibited in the presence of the specific V1A antagonist SR 49059 (10-7 M) in both ND and DM vessels (P < .05). The post-CP/CPB protein levels of V1A were significantly increased compared with pre-CP/CPB values in both the ND and DM groups (P < .05), whereas this increase was greater in DM than that of ND (P < .05). Immunohistochemistry staining further indicates that V1B were mainly expressed in the myocardium but not in vascular smooth muscle. CONCLUSIONS: CP/CPB and DM are both associated with up-regulation in V1 receptor expression/localization in human myocardium. Vasopressin may induce coronary arteriolar constriction via V1A. This alteration may lead to increased coronary arteriolar spasm in patients with DM undergoing CP/CPB and cardiac surgery.

Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors.

Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.

Protein kinase C regulates internal initiation of translation of the GATA-4 mRNA following vasopressin-induced hypertrophy of cardiac myocytes.

GATA-4 is a key member of the GATA family of transcription factors involved in cardiac development and growth as well as in cardiac hypertrophy and heart failure. Our previous studies suggest that GATA-4 protein synthesis may be translationally regulated. We report here that the 518-nt long 5'-untranslated region (5'-UTR) of the GATA-4 mRNA, which is predicted to form stable secondary structures (-65 kcal/mol) such as to be inhibitory to cap-dependent initiation, confers efficient translation to monocistronic reporter mRNAs in cell-free extracts. Moreover, uncapped GATA-4 5'-UTR containing monocistronic reporter mRNAs continue to be well translated while capped reporters are insensitive to the inhibition of initiation by cap-analog, suggesting a cap-independent mechanism of initiation. Utilizing a dicistronic luciferase mRNA reporter containing the GATA-4 5'-UTR within the intercistronic region, we demonstrate that this leader sequence confers functional internal ribosome entry site (IRES) activity. The activity of the GATA-4 IRES is unaffected in trans-differentiating P19CL6 cells, however, is strongly stimulated immediately following arginine-vasopressin exposure of H9c2 ventricular myocytes. IRES activity is then maintained at submaximal levels during hypertrophic growth of these cells. Supraphysiological Ca(2+) levels diminished stimulation of IRES activity immediately following exposure to vasopressin and inhibition of protein kinase C activity utilizing a pseudosubstrate peptide sequence blocked IRES activity during hypertrophy. Thus, our data suggest a mechanism for GATA-4 protein synthesis under conditions of reduced global cap-dependent translation, which is maintained at a submaximal level during hypertrophic growth and point to the regulation of GATA-4 IRES activity by sarco(ER)-reticular Ca(2+) stores and PKC.

Antianginal effects of lercanidipine on the vasopressin or methacholine induced anginal model in rats.

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.

Effects of acupuncture on vasopressin-induced emesis in conscious dogs.

Although acupuncture has a significant clinical benefit, the mechanism of acupuncture remains unclear. Vasopressin, a posterior pituitary hormone, is involved in nausea and vomiting in humans and dogs. To investigate the antiemetic effects of acupuncture on vasopressin-induced emesis, gastroduodenal motor activity and the frequency of retching and vomiting were simultaneously recorded in conscious dogs. In seven dogs, four force transducers were implanted on the serosal surfaces of the gastric body, antrum, pylorus, and duodenum. Gastroduodenal motility was continuously monitored throughout the experiment. Vasopressin was intravenously infused at a dose of 0.1 U x kg(-1) x min(-1) for 20 min. Electroacupuncture (EA, 1-30 Hz) at pericardium-6 (PC6), bladder-21 (BL21), or stomach-36 (ST36) was performed before, during, and after the vasopressin infusion. To investigate whether the opioid pathway is involved in EA-induced antiemetic effects, naloxone (a central and peripheral opioid receptor antagonist) or naloxone methiodide (a peripheral opioid receptor antagonist) was administered before, during, and after EA and vasopressin infusion. Intravenous infusion of vasopressin induced retching and vomiting in all dogs tested. Retrograde peristaltic contractions occurred before the onset of retching and vomiting. EA (10 Hz) at PC6 significantly reduced the number of episodes of retching and vomiting. EA at PC6 also suppressed retrograde peristaltic contractions. In contrast, EA at BL21 or ST36 had no antiemetic effects. The antiemetic effect of EA was abolished by pretreatment with naloxone but not naloxone methiodide. It is suggested that the antiemetic effect of acupuncture is mediated via the central opioid pathway.

Antianginal effects of FR144420, a novel slow nitric oxide-releasing agent.

The aim of this study was to compare the antianginal effects of two compounds that release nitric oxide (NO) spontaneously, i.e. (+/-)-N-[(E)-4-ethyl-3-[(Z-hydroxyimino]-5-nitro-3-hexenyl] -3-pyridinecarboxamide (FR144420) and (+/-)-(E)-ethyl-2-[(E)-hydroxyimino] -5-nitro-3-hexenamide (FK409), in two different rat models of coronary vasospasm. In the rat methacholine-induced coronary vasospasm model, FR144420 suppressed the elevation of the ST segment dose dependently and significantly at 1.0 mg/kg, i.d. 185 min after its administration. FK409 suppressed the ST elevation only 5 min after its administration at 1.0 mg/kg, i.d. FR144420 and FK409 significantly decreased mean blood pressure at all doses tested only 5 min after their intraduodenal administration, but did not change heart rate at any time. Although the suppression of the ST elevation by FK409 had the same duration as its hypotensive effect, the FR144420-induced suppression of the ST elevation lasted longer than its hypotensive effect. In the rat vasopressin-induced coronary vasospasm model, FR144420 (32 mg/kg) significantly inhibited the depression of the ST segment both 60 min and 120 min after oral administration, whereas FK409 (32 mg/kg) significantly inhibited this ST depression only 60 min after oral administration. These data suggest that FR144420 inhibits coronary vasospasm for longer than FK409 does and particularly shows more prolonged antianginal effects than hypotensive effects in the methacholine-induced coronary vasospasm model. Thus FR144420 is expected to be a useful NO releaser for investigating the in vivo actions of NO.

Novel fluoroprostacyclin analogs with modified cycloalkylenyl chains. Highly potent and orally active anti-anginal agents.

Novel fluoroprostacyclin analogs (1a-f) have been synthesized and pharmacologically evaluated. Compounds 1a-c given intravenously or orally showed potent and long-lasting anti-anginal activities in an animal model.

Histamine-independent modulation of the neuropeptide Y-induced pressor response by alpha-trinositol in the pithed rat.

The modulatory effects of alpha-trinositol (D-myo-inositol-1.2.6- trisphosphate; PP 56) on the systemic arterial blood pressor responses induced by neuropeptide Y, preganglionic nerve stimulation, phenylephrine and vasopressin were studied in pithed rats. Intravenous administration (within 2 min.) of alpha-trinositol reduced the neuropeptide Y-induced increase in mean arterial pressure within a defined dose range without altering the heart rate. The influence of alpha-trinositol on the neuropeptide Y-induced pressor response in the presence of non-selective as well as H1- and H2-selective histamine antagonists (diphenhydramine, mepyramine and cimetidine respectively) were investigated. The maximal increase in mean arterial pressure induced by neuropeptide Y as well as the duration of the pressor response was enhanced after nonselective (diphenhydramine) or H1-selective (mepyramine) histamine blockade. The enhancement of the neuropeptide Y-induced pressor response by the H1 specific antagonist mepyramine was significantly more pronounced compared to the H2-selective agent. The exaggerated increase in mean arterial pressure in response to neuropeptide Y after histamine blockade was inhibited by alpha-trinositol to a similar extent as without such pretreatment. We conclude that neuropeptide Y interacts with histamine in the pithed rat and that this action may partially offset the pressor actions of the peptide. The neuropeptide Y-induced pressor responses may be inhibited by alpha-trinositol within a defined dose range indicating that this non-peptide agent may act as a functional inhibitor to neuropeptide Y in vascular tissue.

Toxic effects of catecholamines on skin.

The purpose of this study was to examine the effects of catecholamines on skin necrosis independent of their vasoactive effects. Rat abdominal or human breast skin was excised, pinned flat, and incubated at 37 degrees C for 6 hours in a buffered salt solution containing catecholamine. At 0.1 and 6 hours the lactate dehydrogenase (LDH) released from the skin and appearing in the buffer was determined spectrophotometrically. All groups showed similar LDH levels at 0.1 hour. Rat skin treated with greater than or equal to 10(-7) M epinephrine (33 times less than the 1:200,000 used clinically) or greater than or equal to 10(-5) M norepinephrine showed a significant increase in the LDH released at 6 hours versus controls (18.75 +/- 1.25 versus 13.75 +/- 1.25 and 29.25 +/- 2.96 versus 22.00 +/- 1.96 IV, respectively). Total tissue LDH levels were not significantly different at 0.1 or 6 hours. The toxic effect of epinephrine was eliminated by the addition of propranolol or selective beta 2 blockade, but not by alpha or beta 1 blockade. Therefore, this effect appears to be mediated largely by beta 2 receptors. Similar toxic effects were seen in human breast skin treated with 1:200,000 epinephrine and were blocked with propranolol. Phenylephrine at 1:20,000 demonstrated toxicity, but angiotensin II and vasopressin did not. These studies indicate that addition of catecholamine to ischemic rat or human skin accelerates skin death within 6 hours, but that the toxicity can be reversed with beta blockade.

Effect of a vasopressin antagonist d(CH2)5Tyr(Met)AVP on the development of renal vasospasm induced by estrin plus vasopressin administration in rats.

The authors studied rats pretreated with estrin acetate to determine the renal circulation changes caused by vasopressin and how these changes are influenced by the pressor effect of an antagonist of vasopressin d(CH2)5Tyr(MET)AVP. Abdominal angiography was performed with contrast material administered via a catheter introduced through the common carotid artery up to the aortic arch. After vasopressin administration, a marked spasm occurred in the larger renal arteries, the arteriovenous time increased, and the parenchymal filling became defective. Renal circulation remained undisturbed if the vasopressin antagonist was administered simultaneously. The results suggest that the vasopressin antagonist prevents renal vasospasm after vasopressin administration in rats pretreated with estrin.

Factors involved in the inactivation of vasopressin after intracerebroventricular injection in mice.

Behavioral excitation induced by intracerebroventricularly administered vasopressin in mice is very short-lasting, suggesting a half-life of the injected peptide of only a few minutes. The results of the present study suggest that vasopressin and related peptides are too hydrophilic to penetrate lipid membranes readily by passive diffusion and that passive diffusion from the extracellular space into cells or the bloodstream is an unlikely mechanism of inactivation. Pharmacological desensitization (tachyphylaxis) occurs after higher doses, but does not seem to be the major factor responsible for the short duration of action. Some deaminoanalogs of vasopressin, however, show a prolonged action, suggesting that degradation by (an) aminopeptidase(s) is a major route of inactivation. These results also suggest that vasopressin-degrading aminopeptidases are accessible from the extracellular space.

Small bowel and liver gas tensions during intravenous vasopressin infusion and 60% oxygen ventilation.

Vasopressin has been found to significantly decrease tissue pO2 in the gastrointestinal tract and the liver. The aim of this study was to find out whether 60% oxygen ventilation could prevent the tissue hypoxia. Vasopressin was infused i.v. in ten piglets for 60 min. During the first 30 min they were ventilated by room air and for the following 30 min by 60% oxygen, which did not alter the intestinal tissue pO2, but liver pO2 increased to the normal level. The plasma lactate was significantly decreased by 60% oxygen ventilation. The findings in this experimental study suggest that 60% oxygen ventilation is indicated in the clinical use of vasopressin infusion.

Cyproterone acetate-promoted prevention of renal cortical necrosis following testosterone and vasopressin administration.

Bilateral focal renal cortical necrosis was observed after vasopressin administration in rats pretreated for 10 days with testosterone phenyl propionate. When the androgen-receptor blocking-agent cyproterone acetate was administered together with the testosterone, the subsequent vasopressin treatment did not cause renal cortical necrosis. The results suggest the role of the androgen receptors in the kidney in the induction of the phenomenon.

[Toxicity tests in vasoconstrictor agents added to local anesthetics]. / Toxizitätsprüfungen von Vasokonstriktoren in Lokalanästhetika

The toxicities of adrenalin, nor-adrenalin and vasopressin derivatives were compared on the basis of animal tests, among others. The adrenalin additive is rejected.