Analysis of regional hemodynamic regulation in response to scald injury.

Ultrasonic probes were placed around dog femoral arteries to record blood flow. Hind paw scalding with boiling water (5 s) caused a marked increase in ipsilateral femoral blood flow that persisted for the 2-h observation period. Contralateral femoral blood flow and systemic and pulmonary vascular resistances were unchanged. Compared to scald only animals, methysergide pretreatment diminished and shortened the femoral vasodilator response to scald (109 +/- 14 vs 243 +/- 27 ml/min at 5 min; 59 +/- 14 vs 191 +/- 31 ml/min at 2 h). Pretreatment with ritanserin, BW A1433U83, atropine, ICI 118551, diphenhydramine, ranitidine, meclofenamate, L-nitro-arginine methyl ester, 3-amino-1,2,4-triazine, and U 37883A had no effect on the increased femoral blood flow response to scald, suggesting this vasodilator response is not dependent upon activation of serotonergic2, adenosineA1, muscarinic, beta 2-adrenergic, histaminergic1 or histaminergic2 receptors, on cyclooxygenase products, endothelium-derived relaxing factor derived from nitric oxide (NO) synthase III, NO derived from NO synthase II, or KATP channels, respectively. Methysergide given after burn immediately reduced the augmented femoral blood flow to preburn levels, suggesting the vasodilator response to scald is mediated through continual activation of local serotonergic1-like receptors, which may be target site(s) for therapeutic interventions to influence burn-induced hemodynamic alterations.

Vasodilator activity of human alpha-calcitonin gene-related peptide in the feline mesenteric vascular bed.

Human alpha-calcitonin gene-related peptide (CGRP) is a substance immunohistochemically present in a number of organ systems; however, the biologic significance of this peptide is uncertain. The present study was undertaken to investigate the effects of CGRP in the feline mesenteric vascular bed under conditions of controlled blood flow. Bolus injections of CGRP decreased mesenteric perfusion pressure in a dose-related fashion. When compared with nitroglycerin, CGRP possesses markedly greater vasodilator activity in the intestinal vascular bed of the cat. Because circulating levels of CGRP have been identified, the present data suggest CGRP may play a role in the regulation of systemic vasomotor tone and regional hemodynamics, as well as involve altered calcium metabolism seen with other calcium-regulating hormones in hypertensive states.

L-NAME enhances pulmonary vasoconstriction without inhibiting EDRF-dependent vasodilation.

The purpose of the present study was to determine the influence of NG-nitro-L-arginine methyl ester (L-NAME) on pulmonary vascular responses to endothelium-dependent relaxing factor- (EDRF) dependent and EDRF-independent substances in the pulmonary vascular bed of the anesthetized cat. Because pulmonary blood flow and left atrial pressure were kept constant, changes in lobar arterial pressure directly reflect changes in pulmonary vascular resistance. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of acetylcholine, bradykinin, serotonin, and 5-carboxyamidotryptamine (a serotonin1A receptor agonist) decreased lobar arterial pressure in a dose-related manner. The pulmonary vasodilator response to serotonin, but not to 5-carboxyamidotryptamine, acetylcholine, and bradykinin, was significantly decreased by L-NAME (100 mg/kg i.v.). Administration of ritanserin (0.5 mg/kg i.v.), but not L-arginine (1 g/kg i.v. with 60 mg.kg-1 x min-1 i.v. infusion), reversed the inhibitory effects of L-NAME on the pulmonary vasodilator response to serotonin and abolished the enhanced pulmonary vasoconstrictor response to (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoproprane hydrochloride (a serotonin2 receptor agonist) after L-NAME administration. In conclusion, the present experiments suggest that L-NAME inhibits the pulmonary vasodilator response to serotonin by increasing the sensitivity of serotonin2 receptor-mediated vasoconstriction and not by inhibiting EDRF formation. Because the pulmonary vasodilator responses to bolus administration of acetylcholine and bradykinin were not inhibited by L-NAME, these data suggest that L-NAME does not appear to be an adequate probe to study the role of endogenous EDRF in the adult feline pulmonary vascular bed in vivo.

Methylene blue selectively inhibits pulmonary vasodilator responses in cats.

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30-45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.

Role of G proteins in the vasodilator response to endothelin isopeptides in vivo.

The purpose of the present study was to determine the influence of pertussis toxin (PTX) on the pulmonary and systemic vasodilator responses to endothelin (ET) isopeptides in the intact cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by an intralobar arterial infusion of U-46619, intralobar arterial bolus injections of ET-1, ET-2, and ET-3 decreased lobar arterial pressure and systemic vascular resistance in a dose-related manner. The vasodilator responses to ET-1 and ET-2 in the cat lung were abolished by PTX pretreatment, whereas PTX pretreatment did not alter the pulmonary vasodilator response to ET-3 and cromakalim, a specific ATP-sensitive potassium (KATP) channel activator, and the systemic vasodilator responses to all ET isopeptides studied. Glipizide, an inhibitor of KATP channels, inhibited the pulmonary vasodilator responses to ET-1, ET-2, and ET-3, whereas the systemic vasodilator responses to these isopeptides were not changed. The present data are the first to provide a functional correlate in vivo suggesting the existence of different signal transduction mechanisms for two pulmonary vascular ET receptor subtypes, ETA-like that is PTX sensitive and has greater sensitivity to ET-1 and ET-2 (than to ET-3) and ETc-like that is PTX insensitive and has sensitivity to ET-3 (than to ET-1 and ET-2). However, both ET-receptor subtypes promote vasodilation in the adult pulmonary vascular bed by activating KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Nisoldipine inhibits vasoconstrictor responses in the cat pulmonary vascular bed.

The influence of nisoldipine, a dihydropyridine calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the feline pulmonary vascular bed under conditions of controlled blood flow. The calcium channel blocking agent caused a small reduction in lobar vascular resistance and blocked pulmonary vasoconstrictor responses to BAY K 8644, an agent which promotes calcium entry. The calcium entry blocking agent also reduced pulmonary vasoconstrictor responses to methoxamine and to BHT 933, alpha 1- and alpha 2-adrenoceptor agonists, and to U 46619, an agent which mimics the actions of thromboxane A2. Although there was a marked difference in vasoconstrictor potency in the pulmonary vascular bed, responses to the thromboxane mimic and to the alpha 1- and alpha 2-adrenoceptor agonists were reduced by approximately the same extent. The increases in systemic arterial pressure in response to BAY K 8644, methoxamine, and BHT 933 were also reduced by nisoldipine, and the calcium entry antagonist reduced systemic arterial pressure and systemic vascular resistance. The results of the present study suggest that an extracellular source of calcium is required for the maintenance of vascular tone and for the expression of vasoconstrictor responses, resulting from activation of alpha 1- and postjunctional alpha 2-adrenoceptors and thromboxane receptors in the feline pulmonary vascular bed.

Endothelin produces pulmonary vasoconstriction and systemic vasodilation.

Endothelin is a newly described polypeptide derived from endothelial cells. The effects of porcine endothelin on the pulmonary vascular bed and systemic vascular bed were investigated in the anesthetized, intact-chest cat under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of porcine endothelin (100-1000 ng) produced a mild vasoconstrictor response in the pulmonary vascular bed. The pulmonary vasoconstrictor response to endothelin was not altered when pulmonary vasomotor tone was increased by infusion of U46619. In contrast to this mild pulmonary vasoconstrictor response, endothelin decreased systemic arterial pressure. Moreover, injections of porcine endothelin into the right and left atria produced similar reductions in aortic pressure as well as similar increases in cardiac output and decreases in systemic vascular resistance. The systemic vasodilator response to porcine endothelin was not affected by beta 2-adrenoceptor blockade. The present data suggest that endothelin does not undergo significant first-pass pulmonary metabolism. The pulmonary vasoconstrictor response to bolus injections of porcine endothelin is not altered by changes in pulmonary vasomotor tone. In contrast, endothelin markedly dilated the systemic vascular bed independently of activation of beta 2-adrenoceptors. The present study provides the first report of the activity of endothelin on pulmonary and systemic hemodynamics in vivo. Moreover, the potent vasodilator activity of endothelin in the systemic vascular bed and its weak effect on pulmonary vessels suggest that endothelin may be more important in the regulation of peripheral vasomotor tone than the pulmonary vascular bed.

Pulmonary vasodilation to endothelin isopeptides in vivo is mediated by potassium channel activation.

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1 microgram), ET-2 (1 microgram), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg iv). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms) and cromakalim (10 and 30 micrograms), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 microgram), prostaglandin I2 (0.1 and 0.3 microgram), and isoproterenol (0.03 and 0.1 microgram) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of responses to endothelins in the rabbit pulmonary and systemic vascular beds.

The effects of two isoforms of human endothelin (ET) on the pulmonary and systemic vascular beds were compared in the anesthetized intact-chest rabbit under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of ET-1 (0.1-1 micrograms) and ET-3 (1-3 micrograms) produced modest vasoconstriction in the pulmonary vascular bed, whereas both peptides decreased systemic arterial pressure. The pulmonary vasoconstrictor response to ET-1 and ET-3 was inhibited by intralobar infusion of nitrendipine but was not altered by indomethacin. In contrast to the small effects of ET-1 and ET-3 on intact pulmonary resistance vessels, both peptides markedly contracted isolated pulmonary conductance vessels, with greater activity on venous than on arterial segments. Intravenous bolus injection of ET-1 (0.1-0.3 micrograms) or ET-3 (0.3-1 microgram) decreased systemic arterial pressure, increased cardiac output, and markedly decreased systemic vascular resistance. Higher doses of ET-1 produce a biphasic systemic vascular response with a prominent secondary pressor component. The present data suggest that the pulmonary vasoconstrictor activity of ET-1 is greater than that of ET-3 and their pressor activity depends on an extracellular source of calcium. The pulmonary and systemic hemodynamic effects of ET-1 and ET-3 in the rabbit do not depend on cyclooxygenase products. The systemic vasodilator response to ET-1 is not altered by first-pass lung transit. Furthermore the systemic vasodilator response to both peptides occurs independent of activation of muscarinic, beta 2-adrenergic, and platelet-activating factor receptors. Although ET-1 and ET-3 were initially reported as vasoconstrictor peptides, the present data suggest that, by having unique and potent systemic vasodilator activity, ET-1 and ET-3 act differently in the systemic and pulmonary vascular beds under resting conditions in the rabbit.

Functional evidence for different endothelin receptors in the lung.

The present study was undertaken to compare and contrast the characteristics of the pulmonary and systemic vascular responses to endothelin (ET) isoforms in the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone (PVT) was actively increased by intralobar infusion of U-46619, intralobar arterial bolus injections of 1 microgram ET-1, 1 microgram ET-2, or 3 micrograms ET-3 markedly decreased lobar arterial pressure, systemic arterial pressure, and systemic vascular resistance. After seven repeated injections of ET-1 or ET-2 to separate groups of cats, pulmonary and systemic responses were largely reversed from vasodilation to vasoconstriction. In contrast, the pulmonary vasodilator response to ET-3 remained intact after multiple ET-3 injections, whereas its systemic vasodilator response was lost. Repeated intralobar arterial bolus injections of ET-1, ET-2, or ET-3 also caused the loss of pulmonary vasodilation to subsequent doses of ET-1, ET-2, or sarafotoxin 6b but not to ET-3. The present data suggest that the pulmonary and systemic vasodilator responses to ET-1 and ET-2 undergo tachyphylaxis and cross-tachyphylaxis. In contrast, the pulmonary vasodilator response to ET-3, unlike its systemic vasodilator response, is resistant to tachyphylaxis and cross-tachyphylaxis. The present data provide a functional correlate for the existence of at least two ET receptor subtypes, ETA-like and ETC-like receptors, in the adult pulmonary vascular bed.

L-NAME enhances responses to atrial natriuretic peptide in the pulmonary vascular bed of the cat.

This study investigated the hypothesis that atrial natriuretic peptide (ANP) responses are mediated by particulate guanylate cyclase in the pulmonary vascular bed of the cat. When tone in the pulmonary vascular bed was raised to a high steady level with the thromboxane mimic U-46619, injections of ANP caused dose-related decreases in lobar arterial pressure. After administration of HS-142-1, an ANP-A- and ANP-B-receptor antagonist, vasodilator responses to ANP were reduced. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) enhanced ANP vasodilator responses, suggesting that inhibition of NO modulates ANP responses. L-NAME administration with constant 8-bromo-cGMP infusion attenuated the increased vasodilator response to ANP, suggesting that supersensitivity to ANP occurs upstream to activation of a cGMP-dependent protein kinase. In pulmonary arterial rings, ANP produced concentration-related vasorelaxant responses with and without endothelium. Methylene blue, L-NAME, or N(omega)-monomethyl-L-arginine did not alter ANP vasorelaxant responses. These data show that ANP supersensitivity observed in the intact pulmonary vascular bed is not seen in isolated pulmonary arterial segments, suggesting that it may only occur in resistance vessel elements. These results suggest that ANP responses occur through activation of ANP-A and/or -B receptors in an endothelium-independent manner and are modulated by NO in resistance vessel elements in the pulmonary vascular bed of the cat.

Effects of methysergide administration on edema formation at the site of scald.

Femoral blood flow (Qa), hind paw lymph flow (Qlym), and lymph-to-plasma protein concentration ratio (Clym/Cp) were monitored before and 4 h after 1) 5-s 100 degrees C paw scald, 2) methysergide (1 mg/kg iv) 20 min before scald, 3) methysergide 30 min after scald, and 4) methysergide only. Before experimentation, hind paw venous pressure was elevated and maintained until steady-state Qa, Qlym, and minimal Clym/Cp levels were reached. The reflection coefficient (sigma d) was determined as 1 - minimal Clym/Cp; the filtration coefficient (Kf) was calculated. Methysergide alone caused no changes. Increases in Qa, Qlym, Clym/Cp, and Kf were identified in all scald groups. Compared with scald only animals, pre- and postscald methysergide blunted the increases in Qa, Qlym, Kf, and paw weight gain without an effect on sigma d. These data demonstrate that methysergide reduces edema formation at the site of scald, perhaps by modulating the burn-induced vasodilator response and/or by limiting the burn-induced increase in microvascular surface area.

The influence of indomethacin on vasodilator responses to bradykinin and nitroglycerin in the cat.

The effects of indomethacin, a cyclooxygenase inhibitor, on vasodilator responses to bradykinin and nitroglycerin were investigated in the peripheral vascular bed of the anesthetized cat. Intra-arterial injections of bradykinin and nitroglycerin elicited dose-related decreases in mesenteric and hindquarters vascular resistance. Mesenteric vasodilator responses to nitroglycerin in absolute units were unchanged 30 min after administration of indomethacin whereas responses to bradykinin expressed as an absolute mm Hg decrease in perfusion pressure were increased. Indomethacin was also without effect on vasodilator responses to lower doses of nitroglycerin whereas responses to higher doses of nitroglycerin and bradykinin in absolute units were enhanced in the hindquarters vascular bed. Indomethacin increased vascular resistance in the mesenteric and hindquarters vascular beds and decreased systemic vasodepressor responses to the prostaglandin precursor, arachidonic acid. When the increase in (initial value) vascular resistance was taken into account by expressing vasodilator responses on a percent decrease basis, indomethacin only enhanced the vasodilator response to the highest does of bradykinin studies. Result of the present study suggest that products in the cyclooxygenase pathway may serve to maintain the peripheral vascular bed of the cat in a dilated state but that these metabolites do not mediate vasodilator responses to bradykinin. The present data further suggest that products in the cyclooxygenase pathway may play a minor role in modulating the dilator effects of bradykinin in the mesenteric and hindquarters vascular beds of the cat.

Endothelin produces systemic vasodilation independent of the state of consciousness.

The effects of endothelin, ET-1, on pulmonary and systemic hemodynamics were studied in the open chest dog and changes in systemic arterial pressure in dogs under conscious and anesthetized states were compared. Rapid intravenous (IV) bolus injections of ET-1, 100-1,000 nanograms/kg, significantly decreased systemic arterial pressure, and significantly decreased systemic vascular resistance whereas left atrial pressure and pulmonary vascular resistance were not altered. Reductions in systemic arterial pressure in response to bolus injection of ET-1, 100 and 300 nanograms/kg IV, during conscious state and during anesthesia were similar, respectively. The present data suggest that ET-1 dilates the systemic vascular bed independent of the animal's state of consciousness. The present data also suggest that when compared to the systemic vascular bed, the pulmonary vascular bed is less responsive to bolus administration of ET-1.

Influence of SQ 29,548 on vasoconstrictor responses in the mesenteric vascular bed of the cat.

The effects of SQ 29,548 on vasoconstrictor responses were investigated in the feline mesenteric vascular bed. Injections of the thromboxane (TX) A2 mimics, U46619 and U44069, caused dose-related increases in mesenteric arterial perfusion pressure. After administration of SQ 29,548, 0.5 mg/kg i.v, vasoconstrictor responses to U46619 and U44069 were reduced markedly whereas responses to prostaglandin (PG) F2 alpha, angiotensin II, vasopressin and BAY K 8644, an agent which enhances calcium entry, were not altered. The duration of the TXA2 receptor blockade was greater than 2 h and SQ 29,548 had no significant effect on mesenteric vasodilator responses to PGE2, isoproterenol, nitroglycerin, acetylcholine or bradykinin. SQ 29,548, at a dose of 0.5 mg/kg i.v., significantly reduced the response to TXB2, which had modest vasoconstrictor activity in the mesenteric vascular bed. However, when the dose of SQ 29,548 was reduced to 0.05 mg/kg i.v., responses to TXB2 were not altered, whereas responses to U46619 were significantly decreased. SQ 29,548 had no significant effect on vasoconstrictor responses to norepinephrine or to sympathetic nerve stimulation. The TXA2 receptor antagonist blocked the vasoconstrictor component of the biphasic response to the PG precursor, arachidonic acid, and the endoperoxide, PGH2. The results of these studies suggest that SQ 29,548 is a specific TX receptor antagonist in the mesenteric vascular bed, that the vasoconstrictor component of the biphasic response to arachidonic acid and PGH2 is due to formation of TXA2, and that endogenously formed TXA2 does not modulate adrenergic responses in the mesenteric circulation of the cat.

Endothelin--a new family of endothelium-derived peptides with widespread biological properties.

Endothelin (ET) is a novel family of three isopeptides (ET-1, ET-2, ET-3) each containing twenty-one amino acids and two disulfide bonds. Initially isolated from the supernatant of cultured porcine aortic endothelial cells, ET is stored as a preproform and released through an unusual proteolytic cleavage. In general, ET-1, ET-2, ET-3 differ quantitatively but not qualitatively in their biologic activity. ET have potent contractile activity in a variety of isolated tissues including arteries veins, trachea, duodenum urinary bladder and uterus. In vivo, ET possesses potent vasodilator and vasoconstrictor properties. Although the mechanisms mediating the hemodynamic effects of ET are not entirely clarified, recent evidence indicates a role for endothelium-derived relaxant factor (EDRF), protein kinase C and extracellular calcium. Moreover, ET appears to produce inflammation and bronchoconstriction through the formation of arachidonic acid metabolites via the cyclooxygenase pathway. The presence of ET binding sites in blood vessels and in several organ systems suggests ET may have important regulatory functions, which remain to be determined.

The physiological response to norepinephrine during hypothermia and rewarming.

Our purpose was to determine if core hypothermia influences physiological responses to norepinephrine (NE); and if rewarming reverses these effects. Animals were instrumented to measure mean arterial pressure (MAP) and cardiac output (CO). Core temperature was manipulated from 37.5 degrees C (normothermia), to 30 degrees C (hypothermia) and the back to 37.5 degrees C (rewarming) using an external arterial-venous femoral shunt. At each of these temperatures, baseline CO and MAP were measured. Norepinephrine (NE) was infused at rates to deliver 0.2, 1.0, or 5 microg kg(-1) per h. At each dose CO and MAP was measured again. Systemic vascular resistance (SVR) was calculated using the formula (SVR = (MAP/CO) x 80). Eight animals underwent all three phases of the protocol. The response to NE during normothermia was a significant increase in MAP to doses of 1 microg kg(-1) per min (P < 0.01) and 5 microg kg(-1) per min (P < 0.01) and SVR to doses of 1 microg kg(-1) per min (P < 0.01) and 5 microg kg(-1) per min (P < 0.01). The response to NE during hypothermia was a significant increase in MAP only at doses of 1 microg kg(-1) per min (P = 0.03) and 5 microg kg(-1) per min (P = 0.01). The response to NE after rewarming was a significant increase in MAP only at a dose of 5 microg kg(-1) per min (P = 0.03). This study shows that core hypothermia causes a change in physiological response to NE that rewarming does not reverse.

The effect of prior hypothermia on the physiological response to norepinephrine.

OBJECTIVE: this study determines the effect of prior hypothermia on the cardiovascular responses to norepinephrine (NE) after rewarming. METHODS: the experiment was a 2x2 controlled design with four groups of feline animals. The two variables were the presence or absence of previous cooling, and the use or non-use of NE after rewarming. During the 'cooling' phase, animals were either cooled using an external arterial-venous femoral shunt to 30 degrees C or maintained at 37 degrees C. After 'rewarming' animals were stratified to receive either NE at rates to deliver 0.2, 1.0 or 5 microg/kg per h or normal saline infusions. Animals were instrumented to measure mean arterial pressure (MAP) and cardiac output (CO) and systemic vascular resistance (SVR) was calculated. RESULTS: there were no differences between groups at baseline and low dose NE (0.2 microg/kg per min). At 1.0 microg/kg per min, NE caused a significant increase in CO (P<0.01) and no effect of MAP or SVR in the rewarmed animals when compared with normothermic controls. In rewarmed animals 5.0 microg/kg per min NE caused a significant increase in CO (P<0.01) and no effect on MAP or SVR. In normothermic controls there was a significant increase in SVR (P=0.02) and MAP (P=0.05) and no effect on CO. CONCLUSION: this study shows that the effect of prior hypothermia on cardiovascular responses to moderate and high doses of NE is an improved CO with no affect on SVR and MAP. This could alter the clinical utility of NE in this situation.

Pharmacological regulation of the circulation of bone.

A study was undertaken to investigate the reactivity of the circulation of bone and to pharmacologically characterize the receptor populations that may be present in this poorly described vascular bed. The nutrient artery of the tibia in skeletally mature mongrel dogs was cannulated, under direct vision, through a posterolateral operative approach. An extracorporeal circuit was established so that the nutrient artery of the tibia could be perfused in vivo under conditions of constant blood flow. Diverse vasoactive substances were injected into the perfusion circuit in small volumes as a bolus close to the nutrient artery of the tibia. A range of doses of nitroglycerin, acetylcholine, isoproterenol, methoxamine, U46619 (a thromboxane A2 mimic), dibutyryl cyclic AMP, 8-bromo-cyclic GMP, and endothelin-1 were injected in a randomized sequence for each experiment. The antagonists that were used were atropine (a non-selective muscarinic receptor antagonist), ICI 118551 (a selective beta 2-adrenoceptor antagonist), ONO 3708 (a prostaglandin H2/thromboxane A2 receptor antagonist), and prazosin (an alpha 1-adrenoceptor antagonist). The results of changes in bone-perfusion pressure under conditions of constant blood flow indicated that the vascular bed of bone actively responds to various vasoconstrictor mechanisms, whereas vasodilator mechanisms appear to be considerably less active. Intra-arterial injections of nitroglycerin, acetylcholine, and 8-bromo-cyclic GMP resulted in dose-related decreases in bone-perfusion pressure that were weak relative to concomitant changes in systemic arterial pressure. Intra-arterial administration of methoxamine, U46619, and endothelin-1 resulted in a potent dose-related increase in bone-perfusion pressure. The results of intra-arterial injections of isoproterenol and dibutyryl cyclic AMP were surprising; both substances caused a substantial rise in bone-perfusion pressure. The responses to acetylcholine, methoxamine, and U46619 were blocked in a competitive manner after administration of atropine, prazosin, and ONO 3708, respectively.

Characterization of alpha-adrenoceptor activity in term-newborn piglet mesentery.

For further characterization of neonatal mesenteric alpha 1-adrenoceptor populations, an extracorporeal perfusion circuit was established to control intestinal blood flow in 0-2 day old piglets. Activation of alpha 1-adrenoceptors was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intra-mesenteric arterial injection of methoxamine and noradrenaline. Peripheral intravenous injections of WB 4101 (a competitive alpha 1A-adrenoceptor antagonist), but not clorethylclonidine (CEC, an alpha 1B-adrenoceptor antagonist), significantly (P < 0.05, analysis of variance) blunted mesenteric vasoconstrictor responses to those agonists. That the mesenteric vasoconstrictor response to mesenteric plexus stimulation was unaltered by CEC, but was muted by both WB 4101 and SK&F 104856 (a post-junctional alpha 1- and alpha 2-adrenoceptor antagonist) suggests that pre- and post-junctional alpha 1A-adrenoceptors are present and functional at birth.