The action of histamine on pulmonary vessels of cats and rats

1. The actions of histamine on pulmonary vascular smooth muscle have been studied in isolated cat and rat lungs perfused with blood, lobes of cat lung perfused in vivo and isolated strips of rat, cat and rabbit pulmonary artery. 2. In all the lung preparations histamine caused both dilatation and constriction. In the rat strips it caused both contraction and relaxation. Dilatation was only well shown when the vessels were in a prior constricted state. In any one lung dilatation occurred with smaller doses than constriction. 3. Histamine caused both increases and decreases in pulmonary artery pressure in collapsed lungs. In this condition these effects are unlikely to have been a consequence of changes in airway pressure. 4. From forward and reverse perfusions of lungs in the waterfall state, where changes in postalveolar vessels do not affect pulmonary artery pressure, it appeared that histamine caused both dilatation and constriction on both sides of the point of collapse caused by alveolar pressure. 5. Plots of the relationship between left atrial and pulmonary artery pressure (at constant alveolar pressure and blood flow) showed that histamine caused both increases and decreases in pulmonary vascular resistance and sometimes also increased the "Starling resistor" properties of lung vessels. 6. In plethysmograph experiments histamine caused moderate dilatation and constriction without affecting lung volume but strong vasoconstriction was accompanied by increases in lung volume.     

Glibenclamide-sensitive mechanism is involved in helodermin-produced vasodilatation in rat mesenteric artery

Helodermin-caused vascular relaxation was simultaneously measured with intracellular Ca2+ concentration ([Ca2+]i) in rat mesenteric artery. Helodermin caused concentration-dependent relaxation in the mesenteric artery preconstricted with norepinephrine (NE). Helodermin-caused relaxation was accompanied by decrease in [Ca2+]i, D-cis-Diltiazem, a Ca2+ channel blocker, also lowered the [Ca2+]i and tension increased by NE. However, helodermin relaxed the artery more efficiently than D-cis-diltiazem, suggesting that the peptide decreased myofilament Ca2+ sensitivity. The vascular relaxation and the corresponding decrease in [Ca2+]i induced by helodermin were partly, but significantly attenuated by glibenclamide. Helodermin-induced vascular responses were mimicked by vasoactive intestinal polypeptide (VIP) or forskolin. Furthermore, helodermin increased cAMP contents in the mesenteric artery. These findings show that vasodilatation induced by helodermin is attributable to lowered [Ca2+]i of arterial smooth muscle partly through the activation of glibenclamide-sensitive K+ channels, and to decrease in the myofilament Ca2+ sensitivity. The increase in the cellular cAMP content probably plays a key role in the peptide-induced vasorelaxation.     

Influence of corticotropin-releasing factor on pancreatic and islet blood flow in different regions of the rat pancreas

Corticotropin-releasing factor (CRF) has previously been shown to selectively dilate the mesenteric vascular bed, without affecting other vascular beds. Pancreatic blood flow and islet blood flow were therefore measured separately with a microsphere technique in the two regions of the rat pancreas perfused by the superior mesenteric artery (SMA) or celiac artery (CA) respectively. Intravenous infusion of CRF (0.25 microgram/kg b.w./min) caused an increase in both whole pancreatic blood flow and islet blood flow in the region of the pancreas perfused by the SMA. The fraction of whole pancreatic blood flow diverted through the islets in this part of the pancreas was, however, unaffected by CRF infusion (approximately 10%). CRF did not change either pancreatic or islet blood flow in the CA-perfused part of the pancreas, and did not affect the release of insulin.     

Interaction of Chlamydia pneumoniae and human alveolar macrophages: infection and inflammatory response

Our laboratory developed an isolated perfused superior mesenteric arterial vascular bed preparation to study and correlate vascular smooth-muscle mechanics with associated biochemical events. This preparation provides consistent dose-dependent contractile responses, contains most of the superior mesenteric artery as well as first-, second-, and third-generation arterioles, and has been used for concurrent functional and biochemical analysis of vascular smooth muscle. Preparations isolated from Sprague-Dawley rats produced rapid, dose-related vasoconstrictor responses to norepinephrine (NE) and KCl, while appearing to be unresponsive to periarterial nerve stimulation. Endothelial relaxations to bolus doses of acetylcholine (ACh) in the presence of a constant infusion of NE (10 microM) were limited, producing reductions of perfusion pressures of <25%. Receptor-binding studies conducted to evaluate alpha1-adrenoceptor subtypes revealed high- and low-affinity binding sites composing 91 and 9% of the overall population, respectively. A 60-s time course for contractile response and inositol 1,4,5-triphosphate (IP3) production revealed a significant but transient increase of IP3 that paralleled the contractile response generated by using bolus injections of NE (30 microg). This preparation offers the capacity to conduct perfusion studies investigating vasoconstrictor responses, as well as biochemical studies including receptor-binding and second-messenger assays in the same tissue.     

Heparin inhibits mesenteric vascular hypertrophy in angiotensin II-infusion hypertension in rats

OBJECTIVE: Chronic infusion with angiotensin II increases blood pressure and activates growth mechanisms to produce hypertrophy of the heart and vessels. In order to better understand mechanisms of angiotensin II induced vascular hypertrophy, this study aimed to determine whether heparin, a potent inhibitor of smooth muscle proliferation mechanisms, was able to inhibit vascular hypertrophy. METHODS: Angiotensin II (100, 200 or 300 ng/min/kg s.c.) or a saline vehicle control were infused into rats for 14 days. A separate group of animals were co-infused with heparin (0.3 mg/h/kg i.v.) and angiotensin II (200 ng/min/kg s.c.) to test whether hypertension or hypertrophy were antagonized. Blood pressure was measured by tail cuff method and vessel media cross sectional area was measured by morphometry in aorta and mesenteric arteries. RESULTS: Blood pressure elevation and cardiovascular hypertrophy produced by angiotensin II were strongly dose-dependent. Hypertrophy responses at 14 days of treatment also appeared to be influenced partly by local factors as medial cross sectional area was increased more in mesenteric arteries than in thoracic aorta, and left ventricle weight was least affected. Heparin treatment did not influence the increase of blood pressure in angiotensin II infused animals, but the mesenteric vascular hypertrophy response due to angiotensin II was inhibited by approximately 50%. Inhibition of a modest cardiac hypertrophy and aortic medial hypertrophy did not reach significance. CONCLUSIONS: Angiotensin II infusion produced vascular medial hypertrophy and increased blood pressure, however the inhibitory effect of heparin on hypertrophy in mesenteric arteries was not mediated through angiotensin II induced vasoconstriction or blood pressure elevation. These data suggest that heparin interferes directly with the hypertrophy mechanism in mesenteric arteries, and that heparin-sensitive growth mechanisms are important in mediating angiotensin induced mesenteric vascular hypertrophy.     

Heat acclimation does not alter rat mesenteric artery response to norepinephrine

Previous studies have shown that heat acclimation raises the temperature threshold for heat-induced splanchnic vasoconstriction in the rat (W. Haddad and M. Horowitz. Thermal Balance in Health and Disease, Advances in Pharmacological Sciences. Basel: Birkhauser, 1994, p. 203-208; M. Shochina, W. Haddad, U. Meiri, and M. Horo-witz. J. Therm. Biol. 21: 289-295, 1996). We tested the hypothesis that heat acclimation alters splanchnic resistance artery sensitivity to norepinephrine (NE). Male Sprague-Dawley rats (n = 5) were acclimated to 35 degreesC ambient temperature for 5-8 wk. Control rats (n = 5) were maintained at 22-23 degreesC ambient temperature for 5-7 wk. Small mesenteric artery segments (2- to 3-mm length, 100- to 340-micrometer ID) were isolated, cannulated at both ends, and pressurized to 50 mmHg. Artery luminal diameter was measured in response to cumulative doses of NE (10(-9) to 10(-5) M) by using video microscopy. NE dose response was measured at 37 and 43 degreesC bath temperatures. There were no differences in constriction responses to NE between acclimated and control rat arteries at either 37 or 43 degreesC. We conclude that acclimation does not alter rat mesenteric artery sensitivity to NE.     

Identification of HLA-A2-restricted epitopes of the tumor-associated antigen MUC2 recognized by human cytotoxic T cells

BACKGROUND: Dopexamine is a specific dopaminergic and beta2-adrenergic agonist. Using newborn piglets, we have previously shown that (1) dopexamine increases cardiac output and mesenteric blood flow; (2) indomethacin reduces mesenteric blood flow. METHODS: Ultrasonic blood flow probes were placed around the ascending aorta, cranial mesenteric artery, and a renal artery of 0 to 2-day-old and 2-week-old piglets. Animals of each age were grouped (5 to 8 animals per group) and subjected to one of three experimental protocols: (1) 0.4 mg/kg indomethacin infusion, (2) 10 microg/kg/min dopexamine infusion begun 10 minutes before indomethacin, or (3) no treatment. RESULTS: Control animals demonstrated no significant alterations in mesenteric blood flow. Compared with baseline, indomethacin produced significant (P< .05, analysis of variance) declines in cranial mesenteric artery blood flow in 0 to 2-day old (37.2+/-5.7 mL/min v 17.9+/-3.7 mL/min at 90 min), and 2-week-old (80.2+/-12.5 mL/min v 29.7+/-5.7 mL/min at 90 minutes) piglets. In both animal groups treated with dopexamine before indomethacin, the decreases in cranial mesenteric artery blood flow were eliminated (38.4+/-7.6 mL/min at baseline v 36.5+/-6.8 mL/min at 90 minutes in 0 to 2 day olds; 79.9+/-10.0 mL/min at baseline v 77.5+/-14.7 mL/min in 2 week olds). Indomethacin-induced declines in renal blood flow were similarly abrogated by dopexamine. CONCLUSION: Dopexamine may prove of clinical benefit when a neonate is considered a candidate for indomethacin therapy.     

Prolonged systemic and regional haemodynamic effects of intracerebroventricular angiotensin II in conscious sheep

1. The haemodynamic mechanisms by which infusion of angiotensin II (AngII), either into the lateral cerebral ventricles (i.c.v.) or intravenously (i.v.), increased arterial pressure were studied in conscious sheep. 2. Sheep were previously fitted with flow probes for measurement of cardiac output and coronary, mesenteric, renal and iliac blood flows. 3. Intracerebroventricular AngII (10 nmol/h for 1 h) increased arterial pressure by 11 +/- 4 mmHg (P < 0.001) due to vasoconstriction, predominantly in the mesentric vasculature. These effects developed over 30 min and took 2 h to return to control. Following the infusion renal conductance increased continuously for 3 h, resulting in a parallel increase in renal blood flow (to 75 +/- 18 mL/min above control, P < 0.001). 4. Intracerebroventricular AngII increased plasma vasopressin from 0.8 +/- 0.3 to 7.2 +/- 1.8 pg/mL (P, 0.01), and reduced plasma renin concentration from 0.9 +/- 0.3 to < 0.4 nmol/L/h. 5. The pressor effect of i.v. AngII (5, 10, 25, 50 nmol/h) also depended on peripheral vasoconstriction, but the pattern of responses was different. The greatest degree of vasoconstriction occurred in the renal, followed by the mesentric and iliac vascular beds; these effects were rapid in onset and offset. 6. In conclusion, the pressor responses to both i.c.v. and i.v. angiotensin depended on peripheral vasoconstriction, but there were contrasting regional haemodynamic changes. ICV AngII caused a prolonged pressor response, mainly due to mesentric vasoconstriction possibly partly due to vasopressin release, and following the infusion there was a pronounced, long-lasting renal vasodilatation. In contrast, i.v. AngII caused vasoconstriction preferentially in the renal vascular bed and its effects were short lasting.     

Liver granulomas in schistosomiasis: mast cell-dependent induction of SCF expression in hepatic stellate cells is mediated by TNF-alpha

Abnormalities of vasomotor tone are characteristic of heart failure. This study was designed to assess the effects of chronic heart failure on endothelium-dependent relaxation in both large conduit arteries and small resistance vessels and to determine whether or not impaired nitric oxide (NO) production is involved. Segments of pulmonary artery (PA), abdominal aorta (AA), and small mesenteric artery (MA) were harvested from rats with heart failure resulting from coronary artery ligation and from sham-operated controls. Organ-bath experiments done in the presence of indomethacin to avoid the influence of vasodilatory prostanoids demonstrated that relaxation to acetylcholine (ACh) was impaired in the PA but not the AA or MA of the group with heart failure. Endothelium-independent relaxation to nitroglycerin was not significantly affected by the development of heart failure. Constriction to prostaglandin (PG) F(2alpha) was enhanced in PA but not in AA or MA segments. Preincubation with N(omega)-nitro-L-arginine (NNA) to inhibit the production of NO increased baseline force in vessels from all three beds, but the effect was greatest in the PA. Although relaxation to ACh was significantly diminished by NNA in the PA, it was not completely abolished. Furthermore, ACh-mediated relaxation in the presence of NAA was still impaired in the group with heart failure compared with the sham-operated control group. NNA had only mild effects on ACh-mediated relaxation in MA. These results demonstrate that (a) the mediators of endothelium-dependent relaxation may vary throughout the arterial circulation, (b) the contribution of NO to endothelium-dependent relaxation is substantial in PA and minimal in mesenteric resistance vessels, (c) endothelium-dependent relaxation is not uniformly impaired throughout the arterial bed by the development of heart failure, and (d) although a defect in NO production may account for enchanced vasoconstriction seen in response to PGF(2alpha), it does not account for the diminished vasodilatory response to ACh in this experimental model of heart failure.     

Pharmacodynamics of intracavernously injected drugs and cavernous wall resistance

The volumetric flow rates, mean and pulsatile, in the aorta and its major branches were measured in nonfed, anesthetized rabbits, using a transit time Doppler ultrasonic flowmeter. Anesthesia was maintained with isoflurane, and a vasodilator was applied topically during the measurements to avoid introducing additional flow resistance due to vasoconstriction. The cranial mesenteric and celiac arteries received the bulk of the aortic flow, (mean +/- SD) 29.5 +/- 6.6% and 23.3 +/- 5.8%, respectively, for mean flow. The brachiocephalic artery received as much as 14.7 +/- 3.2%, while each of the other branches received a considerably smaller fraction: 7.1 +/- 2.5% for the left subclavian artery, 6.2 +/- 2.6% and 5.1 +/- 2.2%, respectively, for the right and left renal arteries, and 6.0 +/- 2.5% for each of the two iliac arteries. Flow divisions were nearly the same in paired vessels. Peak pulsatile flow divisions were similar to their steady flow counterparts in the brachiocephalic, left subclavian, celiac, and cranial mesenteric arteries, but were smaller in the renal and iliac arteries, although the difference was not statistically significant. Reverse flow from one or more of the branches back into the aorta occurred in diastole in seven of eight rabbits studied.     

K+ channel-opening action contributes to the preventive effects of nicorandil on U46619-induced vasoconstriction of canine large coronary arteries in vivo

The antispasmogenic effects of nicorandil on epicardial coronary artery vasoconstriction were compared with those of a K+ channel opener, cromakalim, and a nitrovasodilator, nitroglycerin, in open-chest dogs. Intracoronary administration of U46619 (0.5-1.0 micrograms), a stable thromboxane A2 analogue, reduced the external diameter of the left circumflex coronary artery with no marked alternations in systemic hemodynamics. This U46619-induced vasoconstriction of large epicardial coronary arteries was dose-dependently prevented by the intracoronary infusion of nicorandil (1-10 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min). After pretreatment with glibenclamide (3 mg/kg, i.v.), and ATP-sensitive K+ channel blocker, these effects of nicorandil and cromakalim were inhibited significantly, whereas the response to nitroglycerin remained unchanged. Nicorandil (3 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min) increased coronary blood flow. However, the inhibitory effects of each drug on the U46619-induced vasoconstriction were not influenced by the partial occlusion of the left circumflex coronary artery, which kept coronary blood flow constant. This indicates a direct antispasmogenic effect of K+ channel openers, which is independent of that mediated by the response to flow. Furthermore, our results suggest that, by this effect, nicorandil protects large coronary arteries from U46619-induced vasoconstriction.     

Augmented mesenteric and renal vasoconstriction during exercise in senescent Fischer 344 rats

The purpose of this study was to test the hypothesis that vasoconstriction in the mesenteric and renal circulations is greater at both submaximal and maximal exercise intensities with advancing age. Arterial blood pressure, heart rate, and mesenteric, renal, and iliac (hindlimb) artery blood flow velocities were measured before and during graded treadmill exercise in mature (12 mo) and senescent (24 mo) male Fischer 344 rats. During treadmill running at mild, moderate, and maximal exercise intensities (approximately 45, 70, and 100% of maximal oxygen uptake), the increases in arterial pressure were similar in the mature and senescent animals, whereas heart rate rose less in the older group (P < 0.05). Mesenteric and renal flow velocities declined and vascular resistances increased from resting levels in both groups in response to graded exercise; however, the magnitudes of the increases in both mesenteric and renal vascular resistance were significantly augmented in the older rats at the moderate and maximal workloads. Hindlimb blood flow velocity increased and resistance declined from resting levels at each exercise intensity in both groups. In contrast to the visceral and renal adjustments, the magnitudes of the changes in both hindlimb flow and resistance were similar for the two age groups at all exercise intensities. These findings support the hypothesis that mesenteric and renal vasoconstriction is augmented in senescent Fischer 344 rats during exercise at moderate and maximal intensities but not at mild workloads. Despite these regional differences, the maintenance of arterial pressure is not altered at either submaximal or maximal exercise intensities with advancing age.     

Norepinephrine release in the human forearm: effects of epinephrine

It has been postulated that delayed facilitation of norepinephrine release by epinephrine is causally related to the development of hypertension. It has been proposed that a brief increase in epinephrine concentrations results in the uptake of epinephrine into the sympathetic nerve terminal. Subsequent rerelease of epinephrine stimulates presynaptic beta-adrenergic receptors, resulting in a prolonged increase in plasma norepinephrine (NE) concentrations, with amplified sympathetic responses and vasoconstriction. To determine whether such epinephrine-induced, delayed facilitation of NE release occurs in a vascular bed draining resistance vessels and, if it occurs, whether that facilitation differs in hypertension, we used a radioisotope dilution method to measure unstimulated and isoproterenol-stimulated forearm NE spillover before, during, and after a 50 ng/min infusion of epinephrine for 30 minutes directly into the brachial artery. No delayed facilitatory effects of epinephrine on forearm NE spillover were observed in either 6 normotensive (NT) or 8 borderline hypertensive (BHT) subjects (NT unstimulated forearm NE spillover preepinephrine 1.79+/-0.41 ng/min versus postepinephrine 2.36+/-0.65 ng/min, P=.38; BHT preepinephrine 2.24+/-0.70 ng/min versus postepinephrine 1.93+/-0.46 ng/min, P=.51; NT isoproterenol-stimulated forearm NE spillover preepinephrine 4.61+/-1.01 ng/min versus postepinephrine 4.4+/-0.98 ng/min, P=.9; BHT preepinephrine 4.04+/-1.36 ng/min versus postepinephrine 4.69+/-1.49 ng/min P=.5). We conclude that the short-term local infusion of epinephrine does not have a delayed facilitatory effect on forearm NE spillover in NT or BHT subjects. Therefore, the prolonged increase in NE concentrations after epinephrine infusion previously shown systemically, and not seen locally in the forearm, suggests that the delayed facilitatory response to epinephrine may occur in other organs.     

Influence of central command and ergoreceptors on the splanchnic circulation during isometric exercise

The splanchnic circulation can make a major contribution to blood flow changes. However, the role of the splanchnic circulation in the reflex adjustments to the blood pressure increased during isometric exercise is not well documented. The central command and the muscle chemoreflex are the two major mechanisms involved in the blood pressure response to isometric exercise. This study aimed to examine the behaviour of the superior mesenteric artery during isometric handgrip (IHG) at 30% maximal voluntary contraction (MVC). The pulsatility index (PI) of the blood velocity waveform of the superior mesenteric artery was taken as the study parameter. A total of ten healthy subjects [mean age, 21.1 (SEM 0.3) years] performed an IHG at 30% MVC for 90 s. At 5 s prior to the end of the exercise, muscle circulation was arrested for 90 s to study the effect of the muscle chemoreflex (post exercise arterial occlusion, PEAO). The IHG at 30% MVC caused a decrease in superior mesenteric artery PI, from 4.84 (SEM 1.57) at control level to 3.90 (SEM 1.07) (P = 0.015). The PI further decreased to 3.17 (SEM 0.70) (P = 0.01) during PEAO. Our results indicated that ergoreceptors may be involved in the superior mesenteric artery vasodilatation during isometric exercise.     

Relaxing actions of corticotropin-releasing factor on rat resistance arteries

1. Although it well established that corticotropin-releasing factor (CRF) injected i.v. can cause hypotension and vasodilatation, there is no in vitro evidence that CRF acts as a vasodilator. We have therefore tested the hypothesis that the hypotensive effect of i.v. CRF is due to a direct vasodilator action by carrying out experiments in vitro on rat resistance arteries (i.d. 150-300 microns). 2. Initial in vivo experiments confirmed that CRF (1.5 nmol.kg-1) injected i.v. caused hypotension in rats, this being partially antagonized by the CRF analogue CRF9-41. 3. For the in vitro experiments, vessels were taken from the mesenteric, cerebral and femoral vascular beds, and mounted as ring preparations in an isometric myograph. The vessels were pre-contracted with one of 3 agonists (prostaglandin F2 alpha, arginine vasopressin or noradrenaline) or with a high-potassium solution (K+). 4. With maximal concentrations of the agonists, CRF caused relaxation of mesenteric and cerebral vessels with 10 nM, and near complete relaxation with 100 nM. Femoral vessels pre-constricted with agonists and all vessels pre-constricted with K+ were less affected by CRF. In the mesenteric vessels, with sub-maximal levels of pre-constriction, CRF caused substantial relaxation at 1 nM and could cause complete relaxation at 10 nM. 5. The relaxant effect of CRF on contractions of mesenteric vessels was antagonized by 100 nM CRF9-41. Neither tetraethyl ammonium (30 mM) nor glibenclamide (3 microM) antagonized the relaxant effect of CRF. 6. The relaxant effect of CRF on mesenteric small arteries was found to be unaffected by removal of the endothelium. 7. The results indicate that CRF causes an endothelial-independent vasodilatation of rat resistance arteries under in vitro conditions at concentrations which are consistent with this being an important cause of the hypotension observed with i.v. injection of CRF.     

Effects of BQ-123 on systemic and renal hemodynamic responses to endothelin-1 in the rat split hydronephrotic kidney

OBJECTIVE: To assess the site of action of endothelin-1 in vessels of different sizes in the kidney in vivo and investigate the function of endothelin A (ET(A)) receptors in mediating renal and systemic vasoconstriction. DESIGN: The luminal diameters of different vessels were measured and glomerular blood flow in cortical glomeruli was determined by intravital videomicroscopy in the split hydronephrotic kidney of anesthetized female Wistar rats. METHODS: The rats were infused with endothelin-1 (40 pmol/kg per min) with or without pretreatment with the selective ET(A)-receptor antagonist BQ-123 (0.5 mg/kg). Aortic clamping was used to control renal blood pressure during the endothelin-1 infusion. RESULTS: Exogenous endothelin-1 induced a significant rise (30+/-3%) in mean arterial pressure and a marked, long-lasting fall in glomerular blood flow (53+/-3%) related to reduction of the inner diameter of arcuate (-30%), interlobular arteries (-33%) and afferent arterioles (-17%). Aortic clamping to normalize renal blood pressure did not attenuate the vasoconstriction and reduction in glomerular blood flow. Pretreatment with BQ-123 significantly reduced both the endothelin-1-induced rise in mean arterial pressure (12+/-1%) and the fall in glomerular blood flow (-23+/-11%). BQ-123 blunted the response to endothelin-1 in arcuate (-12%), interlobular (-11%) and afferent vessels (-5%). Acetylcholine and nitroprusside completely reversed the vasoconstriction in BQ-123-pretreated animals. CONCLUSIONS: BQ-123 largely prevented the hemodynamic effects of exogenously administered endothelin-1. Our direct in-vivo techniques showed that ET(A) receptors are, at least in part, involved in endothelin-1 -mediated vasoconstriction in the rat kidney, and support the hypothesis that ET(A) receptors may help to control arterial pressure in anesthetized rats.     

Phrenic nerve injury after coronary artery grafting: is it always benign?

BACKGROUND: In humans with coronary artery disease, ACE inhibition attenuates coronary sympathetic vasoconstriction. Whether this is due to removal of angiotensin (Ang) II production or to a reduced bradykinin breakdown, however, is unknown. METHODS AND RESULTS: In eight normotensive patients with angiographic evidence of mild left coronary artery lesions (< or = 50%), mean arterial pressure (MAP, intra-arterial catheter), heart rate (HR, ECG lead), coronary sinus blood flow (CBF, thermodilution method), and coronary vascular resistance (CVR, ratio between MAP and CBF) were measured before and during a 15-minute left intracoronary infusion of Ang II at a dose that had no direct coronary or systemic vasomotor effects. The same measurements were made before and during a 15-minute infusion of saline. A 2-minute cold pressor test (CPT) and a 45-second diving were performed at the end of either infusion period. These maneuvers were used because their coronary vasomotor effects are abolished by phentolamine and thus depend on sympathetic activation. During saline infusion, both CPT and diving caused a marked increase in MAP. HR increased with CPT and fell with diving. CBF increased in parallel to the MAP increase, with little change in CVR. The MAP and HR responses were similar during Ang II infusion, which, however, caused either no change or a reduction in CBF with a consequent marked increase in CVR with both CPT and diving. In four additional patients, the diameter of the stenotic vessels remained unchanged during the CPT performed under saline and Ang II infusion. CONCLUSIONS: Ang II markedly enhances sympathetic influences on coronary circulation in humans, presumably by acting at the arteriolar level. This may explain the blunting effect of ACE inhibition on sympathetic coronary vasoconstriction in patients with coronary artery disease.     

Effects of the stable prostacyclin analogue iloprost on mesenteric blood flow in porcine endotoxic shock

OBJECTIVE: To determine the effects of the stable prostacyclin analog, iloprost, in a porcine model of endotoxin-induced mesenteric ischemia. DESIGN: Prospective, experimental, randomized, controlled study. SETTING: Animal research laboratory at a university medical center. INTERVENTIONS: Pigs were randomized to receive a constant infusion of iloprost (0.18 microg/kg/min) or an equivalent amount of carrier solution (normal saline) 30 mins before being infused with endotoxin (100 microg/kg over 1 hr). The infusion with iloprost or carrier solution was continued for the duration of the experiment. MEASUREMENTS AND MAIN RESULTS: Twelve pigs (six per group), weighing between 20 and 22 kg, underwent laparotomy during which a magnetic flowprobe was placed around the superior mesenteric artery and an ileal tonometer was inserted. Thirty minutes before they were infused with endotoxin, the animals were randomized to receive intravenous iloprost or normal saline. Endotoxin was infused centrally over a 60-min period. Animals received normal saline at a rate of 1.2 mL/kg/min which was begun at the start of the endotoxin infusion. Data were measured at the end of the endotoxin infusion (E60) and 1 hr later (E120). Mean arterial pressure was not affected by the dosage of iloprost used in this experiment. After resuscitation, the cardiac output returned to baseline in the iloprost-treated group but remained decreased in the control group (2.6 +/- 0.5 vs. 1.6 +/- 0.4 L/min). Superior mesenteric blood flow increased 34% above baseline levels in animals pretreated with iloprost (from 363 +/- 85 to 485 +/- 81 mL/min). The superior mesenteric PCO2 was significantly higher (53 +/- 9 vs. 40 +/- 5 torr; 7.1 +/- 1.2 vs. 5.3 +/- 0.7 kPa) and the ileal intramucosal pH was significantly lower (7.07 +/- .28 vs. 7.44 +/- .23) in the control group than in the iloprost-treated group. CONCLUSIONS: Pretreatment with intravenous iloprost effectively increased intestinal blood flow in this model of endotoxin-induced mesenteric ischemia. This action of the drug resulted in an attenuation of ileal intracellular acidosis. Since low-dose iloprost had no effect on mean arterial pressure, it may be a useful adjunct in the treatment of sepsis and septic shock.     

Contractile properties of intralobar pulmonary arteries and veins in the fetal lamb model of congenital diaphragmatic hernia

BACKGROUND/PURPOSE: Pulmonary hypertension plays a significant role in the pathophysiology of congenital diaphragmatic hernia (CDH). Although there has been an intensive research effort directed at mediators that may cause pulmonary vasoconstriction, no single agent has been identified. The authors hypothesize that there may be an alteration in the cGMP-nitric oxide (NO) pathway of vasodilatation contributing to the pulmonary hypertension observed in CDH. The purpose of these studies is to begin to elucidate vasoactive properties of pulmonary vessels with particular attention to the cGMP-NO pathway of vasodilatation in fetal lambs with CDH. METHODS: Fourth-generation pulmonary arteries and pulmonary veins were dissected from both right and left lungs of eight, 139-day gestational fetuses with surgically created CDH. Vessels were studied with standard isolated tissue bath techniques. Experiments examined basal release of NO in endothelium-intact PVs and PAs of both right and left lungs by measuring the contractile force of vessels constricted with norepinephrine (NE) in the presence and absence of the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NA). Concentration-response curves to the vasodilating agents zaprinast and A23187 were also obtained in vessels contracted by NE. RESULTS: Left and right pulmonary artery responses to NE are enhanced over those of historic controls. Pretreatment of left pulmonary arteries with L-NA enhances the vasoconstrictor response to NE, whereas right PAs show no increased response. Relaxation responses to A23187 and zaprinast, in both left and right pulmonary arteries were not different from control lambs. Relaxation responses of both left and right pulmonary veins to A23187 and zaprinast are blunted compared with controls. This blunting is significantly more in left pulmonary veins than right. Further, right but not left pulmonary veins display enhanced vasoconstrictive response to NE after L-NA pretreatment. CONCLUSIONS: The NO-cGMP pathway of vasodilatation is abnormal in the near term, fetal lamb with CDH. These abnormalities were most apparent in pulmonary veins and may reflect abnormal NOS activity or content between left and right lungs of the fetal lamb with CDH. Pulmonary arteries from CDH lambs have basal and stimulated NO release equal to that of historic controls but appear to be hypersensitive to exogenous vasoconstrictors.     

Mesenteric involvement of thromboangiitis obliterans (Buerger's disease) in a woman

Although patients with peripheral arterial occlusive disease due to thromboangiitis obliterans (TAO) have been well characterized and the relationship of this disease to tobacco is stressed, little attention has been focused on its ability to involve the mesenteric vasculature and its ability to affect women. We report a rare case of a known TAO female patient who presented with abdominal pain due to inflammatory changes of the mesenteric vessels. The resulting small bowel ischemic changes and formation of intramural gas were demonstrated on a small bowel follow-through and a plain abdominal film. An angiography finally showed a superior mesenteric artery occlusion.