Coronary Vascular Reactivity Research Articles

Improved Long-Term Preservation of the Coronary Vasculature with University of Wisconsin Solution

Experiments were designed to investigate coronary vascular function after prolonged cold storage of isolated rat hearts, using University of Wisconsin (UW) solution. Hearts perfused with crystalloid cardioplegic solution (Plegisol) were used as controls. After perfusion with 10 ml at 4 degrees C, hearts were stored for 1 or 10 hours in the respective solutions at 4 degrees C. To evaluate coronary vascular function after perfusion and storage, endothelium-dependent vasodilation was induced with 5-hydroxytryptamine (5-HT) and smooth muscle-dependent dilation with nitroglycerin (GTN). After perfusion only, or perfusion plus 1-hour storage, there was no intergroup difference in response to 5-HT and GTN. After 10-hour storage the vasodilatory response to 5-HT was abolished in the Plegisol group and slight vaso-constriction was observed, whereas in the UW group the vasodilatory effect of 5-HT persisted. The findings suggest that UW solution may be more favorable for prolonged cardiac preservation, as the coronary vascular reactivity was less affected.

Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis.

Abnormal vascular reactivity represents a fundamental disturbance in vascular biology with the development of atherosclerosis. Because endothelial vasodilator function plays a pivotal role in controlling vasomotor tone, we hypothesized that atherosclerotic wall thickening might directly interfere with deficient endothelium-mediated dilation and thereby contribute to the abnormal reactivity of atherosclerotic arteries in vivo. In 26 patients without focal stenoses in the left anterior descending coronary artery, acetylcholine (0.036 to 3.6 micrograms/mL) was infused into the artery to evaluate endothelium-mediated vasodilation. Segmental vasomotor responses to acetylcholine were correlated with the local extent of atherosclerotic wall thickening quantitated by intracoronary ultrasound examination. Seventeen of the patients also underwent cold pressor testing to assess the vasoreactivity to sympathetic activation. The response of coronary artery segments to acetylcholine varied from 35% dilation to 52% constriction and demonstrated a segmental pattern, with dilation and constriction observed in different segments of the same artery. The vasomotor response to acetylcholine was closely correlated with the extent of local atherosclerotic wall thickening (r = -.82, P < .0001). Over the entire range of atherosclerotic wall thickening, segments from patients with elevated high-density lipoprotein (HDL) cholesterol serum levels (> 75th percentile) demonstrated a significantly blunted constrictor response to acetylcholine (P < .01 at the maximal acetylcholine concentration) compared with segments from patients with HDL cholesterol < 75th percentile. The degree of constriction or dilation in response to the acetylcholine infusion correlated with the response to cold pressor testing (r = .75, P < .0001). Again, the cold pressor test-induced constrictor response was significantly (P < .05) blunted in segments from patients with elevated HDL cholesterol serum levels compared with those from patients with HDL cholesterol < 75th percentile despite equal degrees of atherosclerotic wall thickening. Coronary vasomotor responses to the endothelium-dependent dilator acetylcholine and to sympathetic stimulation by cold pressor test correlate with local atherosclerotic wall thickening. Thus, the degree of abnormal local vascular reactivity is closely related to the extent of atherosclerotic "plaque load" in human epicardial arteries in vivo. Elevated HDL cholesterol serum levels ameliorate abnormal vasoconstriction at any given extent of atherosclerotic wall thickening, suggesting that HDL cholesterol exerts a beneficial effect on abnormal vascular reactivity, a fundamental functional disturbance associated with coronary atherosclerosis.

Alterations in coronary artery vascular reactivity of hypertensive Ren-2 transgenic rats.

The renin-angiotensin system and endothelium-derived nitric oxide (EDNO) are important regulators of vascular tone. This study was designed to investigate endothelial and vascular smooth muscle function in coronary arteries of Ren-2 transgenic rats. Left anterior descending coronary arteries and aortas were isolated from transgenic rats and Sprague-Dawley control rats at 6 (young) and 12 (adult) weeks of age and examined in myographs or organ chambers for isometric tension recording. Systolic blood pressure was significantly higher in transgenic rats (young, 229 +/- 6 mm Hg; adult, 239 +/- 8 mm Hg) than in control rats (young, 126 +/- 2 mm Hg; adult, 118 +/- 3 mm Hg; P < .005). N omega-Nitro-L-arginine methyl ester (L-NAME, 10(-7) to 10(-4) mol/L) evoked marked endothelium-dependent contractions in coronary arteries (young, 52 +/- 8% of the contraction to 100 mmol/L KCl; adult, 40 +/- 8%) but not aortas (young, 3 +/- 1%; adult, 2 +/- 1%). In coronary arteries, this response was significantly smaller in adult (n = 9) than in young (n = 8, P < .05) control rats. Young transgenic rats (56 +/- 9%, n = 8) showed slightly stronger contractions in response to L-NAME than young control rats (NS), which almost totally disappeared in adult transgenic rats (6 +/- 3%, n = 7; P < .05 versus adult control rats; P < .01 versus young transgenic rats). Endothelium-dependent relaxations in response to acetylcholine (10(-9) to 10(-4) mol/L) were totally blocked by L-NAME (10(-4) mol/L) but were unaffected by the thromboxane receptor antagonist SQ30741 (10(-7) mol/L). This stimulated release of EDNO, endothelium-independent relaxations in response to the nitrovasodilator linsidomine (10(-9) to 10(-5) mol/L), and contractions in response to KCl (100 mmol/L) were comparable in all groups of rats. Ren-2 transgenic rats develop fulminant hypertension that is associated with a selective decrease in endothelium-dependent contractions in response to L-NAME, whereas endothelium-dependent relaxations in response to acetylcholine as well as smooth muscle function remain unaffected.

Testosterone treatment enhances thromboxane A2 mimetic induced coronary artery vasoconstriction in guinea pigs

Thromboxane A2 (TXA2) has been implicated as an important mediator of cardiovascular diseases. There have been several clinical reports of acute myocardial infarctions occurring in young male athletes abusing anabolic steroids. The effects of treatment of male Guinea pigs with testosterone on the responses to U46619, a TXA2 receptor agonist, in the isolated perfused heart were determined. The maximum pressor responses of the isolated perfused Guinea pig heart to U46619 were significantly (P < 0.05) greater in the Guinea pigs treated with testosterone compared to the controls. These results indicate that testosterone can enhance coronary artery vascular reactivity to TXA2.

Vasoconstrictor effects in isolated rabbit heart perfused with bis(3,5-dibromosalicyl)fumarate cross-linked hemoglobin (alpha alpha Hb).

To study the mechanism by which cell-free hemoglobin preparations may alter coronary vascular reactivity, we investigated the effect of human hemoglobin cross-linked between alpha chains with bis(3,5-dibromosalicyl)fumarate (alpha alpha Hb) on the vasomotor response to acetylcholine (ACh) in isolated perfused rabbit hearts. Dose-response curves were generated by monitoring the increase in coronary pressure during serial addition of 0.2-10 microM ACh before, during and after 20 min infusion of three test solutions: a) 0.1 g/dl alpha alpha Hb (62 microM heme); b) 0.1 g/dl alpha alpha Hb plus 60 microM deferoxamine (DFO); c) 50 microM NG-nitro-L-arginine methyl ester (L-NAME), a specific inhibitor of nitric oxide (NO) synthase. We found that the sensitivity to ACh-induced vasoconstriction was significantly potentiated in the presence of alpha alpha Hb and L-NAME. In addition, this response was only partially reversed after removal of alpha alpha Hb, except when DFO was simultaneously infused with the alpha alpha Hb solution. These findings are consistent with the idea that both NO binding to hemoglobin and iron-mediated oxygen free radical generation contribute to an altered coronary vasomotor responsiveness induced by cell-free hemoglobin.

Assessment of coronary conductance and resistance vessel reactivity in response to nitroglycerin, ergonovine and adenosine: In vivo studies with simultaneous intravascular two-dimensional and Doppler ultrasound

Objectives. The aim of this study was to determine the differential effects of nitroglycerin, ergonovine and adenosine on the resistantce vessels in vivo by using a Doppler-tipped guide wire in combination with an ultrasound imaging catheter.Background. Catheter-based two-dimensional intravascular ultrasound yields images of the coronary arteries from which cross-sectional areas can be measured. Intravascular Doppler ultrasound techniques allow measurement of coronary blood flow velocity. The simultaneous use of the two techniques can yield anatomic and physiologic information on conductance and resistance vessels but has not been tried in the coronary arteries.Methods. In 15 dogs, we studied coronary Bow and vascular reactivity in response to pharmacologic agents using two approaches: 1) a 30-MHz, 4.3F imaging catheter placed alongside a 0.018-in. (0.046 cm) Doppler wire in the circumflex or left anterior descending coronary artery (n = 5); 2) the ultrasound imaging catheter introduced directly over a 0.014-in. (0.036 cm) Doppler wire (n = 10). Vasodilator and vasoconstrictor responses were studied by using intracoronary nitroglycerin (50,100 and 200 μg), ergonovine (200 μg) and adenosine (6 mg).Results. Nitroglycerin caused a dose-dependent increase in epicardial coronary artery cross-sectional area and, to a lesser extent, in average peak flow velocity, resulting in an increase in volumetric coronary blood flow of 39% and 59% at the doses of 100 and 200 μg, respectively. With these doses of nitroglycerin, the decrease in diastolic to systolic velocity ratio and the increased change in cross-sectional area from end-diastole to end-systole suggested an enhanced epicardial coronary artery compliance. With ergonovine, a 12% reduction in epicardial coronary artery cross-sectional area was seen, without a significant change in average peak velocity, resulting in a 15% decrease in volumetric coronary blood flow. Adenosine caused a 270% increase in average peak velocity but no change in epicardial coronary artery cross-sectional area, resulting in a 270% increase in volumetric bood flow.Conclusions. This study demonstrates that nitroglycerin and ergonovine predominantly influence coronary conductance arteries whereas adenosine mainly dilates coronary resistance vessels. These findings also demonstrate that the combined use of a two-dimensional and a Doppler ultrasound transducer within one catheter assembly can provide information on the differential effects of vasoactive agents on the epicardial and microvascular coronary circulation.

Effects of infusion of L-arginine into the left anterior descending coronary artery on acetylcholine-induced vasoconstriction of human atheromatous coronary arteries

Hypercholesterolemia and atherosclerosis are conditions associated with impaired endothelium-dependent relaxation. In hypercholesterolemic animals, intravenous administration of L-arginine, the precursor of nitric oxide, normalizes endothelium-dependent vasodilator activity. In the present study, we questioned whether intracoronary administration of L-arginine in patients with coronary artery disease could improve coronary vascular reactivity to acetylcholine. Thirteen hypercholesterolemic patients with diffuse coronary atherosclerosis but nonstenotic lesions of the left anterior descending (LAD) coronary artery were investigated. Quantitative coronary angiography and subselective intracoronary Doppler flow velocity measurements were performed to determine LAD diameters and coronary blood flow. Intracoronary infusion of acetylcholine was performed during 3 consecutive 3-minute periods at incremental rates adjusted to achieve estimated final concentrations of 5 × 10 −7, 10 −6 and 5 × 10 −6 M. After evaluation of the response to acetylcholine, L-arginine was infused into the LAD at the rate of 25 mg/min (10 −3 M) and the same stepwise 3-minute infusions of acetylcholine were repeated during infusion of L-arginine. Infusion of acetylcholine induced a dose-dependent reduction of distal epicardial LAD diameter reaching −48.5 ± 17% at 5 × 10 −6 M (p < 0.01 vs control values). L-arginine alone had no effect on the distal LAD diameter but attenuated acetylcholine-induced vasoconstriction to −21 ± 9% at 5 × 10 −6 M acetylcholine (p < 0.01). Coronary blood flow showed a biphasic response to acetylcholine, increasing by 41 ± 12% at 5 × 10 −7 M (p < 0.01) and decreasing by 21 ± 13% at 5 × 10 −6 M (p < 0.05). Infusion of L-arginine was associated with a 15 ± 11% increase in coronary blood flow (p < 0.01). The simultaneous infusion of acetylcholine resulted in an increase in coronary blood flow of 53 ± 12% (p < 0.01) and of 17 ± 11% (p < 0.05) at 5 × 10 −7 M and 5 × 10 −6 M, respectively. Consequently, in response to 5 × 10 −6 M acetylcholine, coronary resistance increased by 53 ± 17% during control conditions (p < 0.01) whereas it tended to decrease (−8.5 ± 15%) during simultaneous infusion of L-arginine. The results show that, in patients with coronary artery disease, intracoronary infusion of L-arginine alleviates the vasoconstrictor action of acetylcholine, suggesting improvement of endothelium-dependent relaxation in coronary arteries.

Eicosapentaenoic acid inhibits endothelium-dependent relaxation to acetylcholine in guinea pig coronary resistance vessels.

Dietary supplementation with eicosapentaenoic acid (EPA) alters arachidonate metabolism. This study characterizes the effect of dietary EPA on endothelium-dependent vasodilation to acetylcholine (ACH) and ATP in guinea pig coronary resistance vessels. Guinea pigs were fed standard chow (n = 6), standard chow+sesame seed oil (n = 6), or standard chow+menhaden fish oil (17% EPA; n = 6). Coronary vasodilations were examined in the isolated, potassium-arrested heart utilizing a modified Langendorff preparation. Coronary vessels were constricted with prostaglandin F2 alpha and relaxed with ACH (5.5 x 10(-9)-10(-6) moles) or ATP (10(-10)-10(-7) moles). Endothelium-dependent dilations to ACH, but not ATP, were attenuated by dietary supplementation with EPA. To assess the role of the endothelium in modulating vascular responses to agonists following dietary manipulation, the perfusate was stimulated by electrolysis (9 V, 4 Hz, 2 msec) in order to generate free radicals, which we have shown to preferentially damage the endothelium. After endothelial damage, responses to ACH, ATP, and nitroprusside were similar between the dietary groups. In an additional group of standard diet animals (n = 6) experiments were performed to assess the role of prostanoid metabolism in affecting coronary vascular reactivity. Perfusion of hearts with indomethacin (14 microM) reduced endothelium-dependent vasodilations to ACH (5.5 x 10(-9)-10(-6) moles), but not to ATP (10(-10)-10(-7) moles). After endothelial damage, infusion of ACH resulted in vasoconstriction, whereas vasodilation responses to ATP were absent. We conclude that dietary supplementation with EPA inhibits endothelium-dependent dilations to ACH in guinea pig coronary microvessels. These diet-related differences in vascular reactivity may be related to the fish-oil-induced alteration of vasodilator prostaglandin metabolism. In the coronary bed, different endothelial factors appear to mediate relaxation to ACH and ATP.

L-arginine improves endothelium-dependent relaxation of conductance and resistance coronary arteries in coronary artery disease.

To assess the ability of L-arginine to improve endothelium-dependent vasodilation in atheromatous coronary arteries, we determined whether intracoronary infusion of L-arginine could improve coronary vascular reactivity to acetylcholine (ACh) examining both conductance and resistance vessels. Coronary blood flow velocity was assessed by positioning a 3 Fr Doppler catheter into the proximal coronary artery segment (six left anterior descending and one circumflex coronary artery). Computed quantitative angiography allowed the measurement of distal diameters. After baseline measurements, ACh was infused at incremental infusion rates through the Doppler lumen catheter (3 min period each) to obtain the estimated concentrations of 5 x 10(-7), 10(-6), and 5 x 10(-6) M. After returning to baseline, L-arginine was infused at the rate of 25 mg/min (10(-3) M) through the Doppler lumen catheter. Infusion of ACh was then repeated according to the same protocol than in the absence of L-arginine. The heart rate and mean arterial blood pressure did not change at any step of the protocol. Infusion of ACh induced dose-dependent vasoconstriction of coronary distal segments with a reduction in coronary distal segments by 39 +/- 15% at 5 x 10(-6) M (p < 0.01). During infusion of L-arginine, the coronary diameter was reduced by only 16 +/- 10% (p < 0.05) at the highest ACh dose. The coronary blood flow velocity increased by 100 +/- 15% at 5 x 10(-7) M ACh (p < 0.05) but only to 16 +/- 15% at 5 x 10(-6) M ACh (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial cell dysfunction after ischemic arrest and reperfusion: A possible mechanism of myocardial injury during reflow

To determine the mechanism(s) responsible for decreased coronary flow after global cardiac ischemia and reperfusion, we studied 40 isolated rabbit hearts before and after 30 minutes of normothermic ischemic arrest and reperfusion. In the control group (n = 10) we evaluated the time course of recovery of coronary flow, vascular reactivity, and myocardial function. In experimental groups A (n = 10) and B (n = 10), metabolic control of autoregulation was assessed by plots of myocardial oxygen consumption versus coronary flow generated by incremental increases in heart rate. The slope and intercept of these plots suggested that autoregulation of coronary flow was maintained after ischemia. In group B hearts (n = 10) hyperosmolar reperfusion with mannitol decreased myocardial water by 2% (p less than 0.01) but did not increase coronary flow. Endothelium-dependent function was assessed in group C (n = 10) by the administration of an endothelium-dependent vasodilator (serotonin) and a smooth muscle vasodilator (adenosine). Coronary artery smooth muscle function was comparable in hearts before and after ischemia. However, endothelium-dependent increases in coronary flow to serotonin were significantly impaired after ischemia (p less than 0.01), and this was accompanied by a significant decrease in prostacyclin synthesis by the endothelium (p less than 0.001). Global cardiac ischemia and reperfusion damages coronary artery endothelium, causing increased coronary vasomotor tone; this may be an important mechanism of decreased coronary perfusion and subsequent myocardial injury during reflow.

Formation of 13-HODE, 9-HODE and LTB 4 by pig polymorphonuclear leukocytes and their influence on pig coronary vascular reactivity to histamine

Formation of 13-HODE, 9-HODE and LTB 4 by pig polymorphonuclear leukocytes and their influence on pig coronary vascular reactivity to histamine

Maximal coronary vasodilator capacity of orthotopic heart transplants in patients with and without rejection

In cardiac allograft rejection, histopathologic changes suggesting that myocardial ischemia is a component of the rejection process have been documented. To further define the coronary vascular reactivity of human heart transplant, coronary sinus blood flow and coronary resistance were measured before and after intravenous dipyridamole within the first year after transplantation in 8 patients without rejection (group II) and in 5 patients with rejection (group III). All had normal coronary arteriograms. Results were compared to those of 8 control subjects (group I). After dipyridamole, coronary sinus blood flow was increased in groups I, II and III by 303, 212 (p < 0.01 vs group I) and 45%, respectively (p < 0.001 vs groups I and II). Coronary resistance was reduced by 77, 73 (not significant vs group I) and 36%, respectively (p < 0.001 vs groups I and II). Concomitantly, coronary sinus blood oxygen content was increased by 172, 145 (not significant vs group I) and 78%, respectively (p < 0.001 vs group I, not significant vs group II). Thus, the coronary flow reserve evaluated by the dipyridamole/basal coronary sinus blood flow ratio and the coronary resistance reserve evaluated by the basal/dipyridamole coronary resistance ratio were dramatically impaired in group III (1.56 ± 0.09 and 1.63 ± 0.30, respectively, p < 0.001 vs groups I and II). In contrast, they were almost normal in group II (3.11 ± 0.42 vs 4.03 ± 0.52 in group I, p < 0.02, and 3.83 ± 0.78 vs 4.45 ± 0.81 in group I, difference not significant). Thus, the impairment of coronary reserve during heart rejection should be linked to abnormalities of the coronary microvasculature. This emphasizes the important involvement of the coronary circulation in the rejection process.

Role of invading leukocytes in enhanced atrial eicosanoid production following rabbit left ventricular myocardial infarction.

The isolated perfused hearts of rabbits previously subjected to in vivo left ventricular myocardial infarction (LVMI) show a 5-10-fold increase in f-Met-Leu-Phe (FMLP) and bradykinin (BK)-stimulated eicosanoid metabolite production relative to noninfarcted hearts. This exaggerated arachidonate metabolism has been shown to occur primarily in the cardiac atria, a site remote from the zone of injury and to be associated with a 10-15-fold increase in atrial FMLP receptor number in the absence of atrial inflammation. All of these changes were temporally related to leukocyte infiltration into the infarct zone. To determine whether invading leukocytes mediate these responses, acute inflammatory cell influx was suppressed either by inducing leukopenia with nitrogen mustard or by administration of BW-755C, a mixed cyclooxygenase-lipoxygenase inhibitor. Both pharmacological manipulations resulted in a decrease in inflammatory cells in the infarct zone and a marked suppression (50-70%) of ex vivo agonist-stimulated eicosanoid metabolite production from perfused hearts and isolated atria. These manipulations also resulted in reversal of ex vivo FMLP-induced coronary vasoconstriction as well as augmentation of BK-induced coronary vasodilation. Further studies in nitrogen mustard-treated animals revealed a suppression of the LVMI-stimulated increase in atrial FMLP receptor number. These data show that suppression of leukocyte invasion after LVMI attenuates enhanced cardiac and atrial eicosanoid metabolite production, and results in marked changes in coronary vascular reactivity. An additional finding was that basal and stimulated LTB4 production was markedly increased in infarcted hearts. In vivo suppression of the increase in LTB4 production by BW-755C was associated with inhibition of inflammatory cell influx into the infarct zone. It therefore appears that LTB4 may be an important proinflammatory mediator of leukocyte invasion after LVMI.

Effect of diabetes on metabolic coronary dilatation in the rat.

There is increasing evidence that patients with diabetes mellitus are prone to ischaemic heart disease. This study examined cardiac hyperactivity and its consequent metabolically induced coronary dilatation in isolated, perfused, electrically paced rat hearts from control and spontaneously diabetic Bio-Breeding (BB) rats. Cardiostimulation produced by noradrenaline, calcium, or by tachycardia elicited increases in coronary flow that were significantly lower in diabetic hearts. However, the inotropic responses to noradrenaline and calcium in diabetic preparations were comparable to control. When coronary vascular reactivity was tested with sodium nitroprusside and adenosine, a decreased dilator response was observed with adenosine in diabetic hearts while no difference was observed with sodium nitroprusside. It is suggested that failure in the adaptive coronary flow response to cardiac hyperactivity in diabetes may, in part, be responsible for the higher incidence of ischaemic heart disease in the diabetic population.

Silent myocardial ischemia. I. Pathophysiology, frequency of occurrence, and approaches toward detection

Recent methodologic advances have led to important clinical insights regarding the pathophysiology of myocardial ischemia. Chief among these advances has been the development of accurate ambulatory ECG monitoring of the ST segment. With the use of this new technology, investigators have found that patients with coronary artery disease have frequent episodes of painless myocardial ischemia during daily activity,‘-* a phenomenon that has been termed “silent ischemia.” Silent ischemia frequently occurs at relatively low heart rates and in the absence of exercise.3-7 Investigators are now using a wide variety of techniques to study the pathophysiology of this phenomenon, including ambulatory monitoring, radionuclide imaging, and new means of angiographic assessment, which permit evaluation of coronary vascular endothelial cell function and coronary vascular reactivity. There has also been much recent speculation regarding the potential prognostic implications of silent ischemia. Understandably, there has been little integration of the information regarding this recently studied phenomenon. This article evaluates the current knowledge regarding silent ischemia, with emphasis on potential clinical pitfalls and areas of needed investigation for more adequate characterization of this phenomenon.

Endothelium-dependent relaxation in coronary arteries requires magnesium ions.

A great deal of interest has recently focused upon the mechanism(s) associated with the generation and action of endothelium-derived relaxant factors (EDRFs) in blood vessels. Since we have shown that extracellular magnesium ions ([Mg2+]o) are important in control of coronary vascular tone and reactivity, we wondered whether these divalent cations play any role in the generation or action of EDRF in coronary arterial smooth muscle. Using isolated canine coronary arterial rings, we have now found that removal of [Mg2+]o inhibits the ability of these vascular preparations to relax when challenged with acetylcholine; in the absence of [Mg2+]o, the relaxation concentration-response curves for acetylcholine are shifted markedly to higher concentrations with small maxima. It, thus, appears that [Mg2+]o is an important co-factor for acetylcholine-induced endothelium-dependent relaxation in canine coronary arteries. These findings support our previous hypothesis that dietary deficiency of Mg may be an important factor in aetiology of coronary vasospasm.

Characterisation of humoral trophic factors involved in intestinal adaptation using a 3T3 cell growth factor assay.

Indirect evidence has suggested that circulating trophic factor(s) are involved in intestinal adaptation. A 3T3 fibroblast cell culture system was used to more directly delineate the presence of such factors. Rats were divided into four groups; C-unop, those undergoing no surgery, S, those in which a dorsal slit was made; C-op, those in which the peritoneum was incised; and R, those undergoing 80% intestinal resection. At the time of death at 24 hours, one week and two weeks postoperative, stimulation of DNA synthesis in the 3T3 cells was noted after incubation with platelet free plasma from the C-op and R groups, and simultaneously an increase in ileal DNA specific activity occurred. Characterisation of the plasma fraction with growth factor activity revealed it to have a MW of greater than 6,000 and less than 14,000 d. The factor(s) was resistant to reduction with DTT, and was partially inactivated by heating to 60 degrees C. The use of 3T3 cell growth factor assay system allows further characterisation of circulating factors involved in intestinal adaptation.

Construction and evaluation of a coronary catheter for chronic implantation in dogs.

Construction of a Silastic catheter and the procedure for chronic implantation in a coronary artery in dogs is described. In addition, studies designed to evaluate whether chronic coronary artery catheterization altered coronary vascular reactivity and myocardial function are presented. The results of these studies indicate that chronic implantation of the catheter in a coronary artery of conscious dogs does not significantly interfere with the normal reactivity of the coronary vascular bed, does not compromise regional or global left ventricular function, and does not induce collateral vessel development. This technique will be useful in studies involving the neural and metabolic regulation of the coronary circulation in animals subjected to exercise and/or exercise training.

A method for enriching the cadmium content of cigarette smoke and effect of exposure to this smoke on coronary vascular reactivity in the rat

To study the effect of smoke-borne cadmium on the cardiovascular system, a method was developed to vary the cadmium content in the smoke of Kentucky 2R1 reference cigarettes. 2R1 filler tobacco was sprayed with aqueous solutions of CdSO 4; cigarettes were prepared from this tobacco and smoked through Cambridge filters. These treatments increased the cadmium content of the cigarette smoke from 0.23 ± 0.01 μg Cd 2R1 cigarette to 0.317 ± 0.029, 2.38 ± 0.092, and 4.9 ± 0.1 μg Cd/cigarette for 500 μ m, and 50 m m CdSO 4, respectively. Male Sprague-Dawley rats were exposed for 5 or 23 weeks to smoke from 2R1 reference cigarettes and cigarettes prepared from 2R1 tobacco that was treated with 500 μ m CdSO 4. Following 5 weeks of smoke exposure, neither kidney cadmium amount nor coronary vascular reactivity to angiotensin was altered in either smoke-exposed group compared to cage controls or sham-smoked animals. After 23 weeks of exposure, cadmium amounts in kidneys from animals exposed to cadmium-enriched smoke were significantly greater than quantities observed in any other group. Exposure to either type of cigarette smoke increased coronary vascular reactivity above either control group. Exposure to cadmium-enriched cigarette smoke increased coronary vascular reactivity to angiotensin above the amount observed following exposure to 2R1 cigarette smoke. This finding indicates that smoke-borne cadmium may mediate the observed increases in coronary vascular reactivity following exposure to cigarette smoke.

Chronic administration of water soluble tobacco smoke extract or nicotine fails to influence porcine coronary artery reactivity

To determine if tobacco smoke components directly influence coronary vascular reactivity, we evaluated the contractile effects of prostaglandin (PG)F 2α and hypertonic KCl in porcine isolated left anterior descending coronary arteries derived from animals chronically treated (18 weeks) with either water soluble tobacco smoke extract, nicotine alkaloid, or saline. Dosing protocols for the extract and for nicotine were designed to achieve blood levels of nicotine approximating those attained by consumption of 2 packs/day of University of Kentucky 2Rl reference cigarettes. Histochemical evaluation of the arteries indicated that both the extract and nicotine caused expected increases in the collagen content of the tunica media. Neither the water soluble extract nor pure nicotine significantly altered coronary vascular sensitivity (as expressed by the ED 50) to KCl or PGF 2α. Similarly, neither treatment altered the maximum contractile responses (determined as the tension developed normalized to mg wet wt) evoked by KCl and PGF 2α. These results indicate that prolonged exposure to water soluble components to tobacco smoke, in doses sufficient to elevate the collagen content of the coronary vascular wall, do not have direct effects on coronary reactivity to selected vasoconstrictor stimuli.