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J D Symons

Publications and source records attributed to J D Symons.

At least 19 recordsLinked to original sources
PubMed2001

Effects of red wine, alcohol, and quercetin on coronary resistance and conductance arteries.

Moderate consumption of alcoholic beverages is associated with a reduced risk of coronary heart disease (CHD). Some evidence suggests that red wine is particularly beneficial in this regard and may account in part for the French paradox, although the mechanism of this effect is unknown. We assessed the effects of red wine, ethanol, and quercetin, a major flavonoid constituent of red wine, in coronary resistance vessels (80-150 microm, i.d.) and conductance vessels (300-525 microm, i.d.) of the rabbit. Vessel wall tension was measured in isolated segments maintained in a wire-type myograph (37 degrees C) and preconstricted with 30 mM K+. At an alcohol concentration (14 mM) equivalent to moderate consumption, red wine evoked a small, transient constrictor effect in resistance and conductance vessels (9+/-4%, n = 5; 8+/-1%, n = 7, respectively; p < 0.05). Ethanol alone at this concentration was without effect. Quercetin (5.6, 8, and 30 microM) significantly relaxed resistance (-32+/-4%, n = 10; -47+/-2%, n = 7; -82+/-6%, n = 8, respectively) and conductance (-20+/-3%, n = 8; -32+/-4%, n = 8; -72+/-7%, n = 8, respectively) coronary arteries. Vasorelaxation by quercetin was endothelium-independent and was significantly greater in resistance than in conductance vessels. These data suggest that red wine and ethanol do not evoke relaxation in small coronary arteries at concentrations associated with moderate consumption. Quercetin elicits marked coronary vasorelaxation that is endothelium-independent. However, the concentrations of quercetin necessary to achieve this action are not attained with moderate red wine consumption.

Animals↗
PubMed2001

Volume overload left ventricular hypertrophy: effects on coronary microvascular reactivity in rabbits.

The mechanisms controlling the coronary vascular responses of vessels perfusing the left ventricular (LV) myocardium that is hypertrophied from chronic volume overload are unclear. We hypothesised that endothelial function is compromised, and receptor-mediated contraction is exacerbated, in coronary resistance vessels from rabbits with LV hypertrophy compared to controls. The mitral valve of 10 rabbits was damaged surgically to cause mitral regurgitation and chronic volume overload, resulting in LV hypertrophy (LV hypertrophy rabbits). Echocardiographic assessment at 12 weeks verified that mitral regurgitation was present in LV hypertrophy but not sham-operated, weight- and age-matched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 +/- 7 % vs. 2 +/- 8 %), LV volume (47 +/- 14 % vs. 7 +/- 10 %) and LV mass (27 +/- 4 % vs. 3 +/- 6 %), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (approximately 130 microm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10(-8)-10(-5) M) and -independent (i.e. sodium nitroprusside, 10(-9)-10(-4) M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10(-11)-10(-7) M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (10(-6) M N (G)-monomethyl-L-arginine) was greater (P < 0.05) in LV hypertrophy compared to control rabbits. These results indicate that while coronary resistance vessel function is similar between groups, our estimate of basal nitric oxide production is greater in vessels from LV hypertrophy than control rabbits.

Acetylcholine↗
PubMed2001

Effects of nitric oxide synthase inhibition on vascular conductance during high speed treadmill exercise in rats.

To determine the functional role of nitric oxide (NO) in regulating vascular conductance during high intensity dynamic exercise in skeletal muscles composed of all major fibre types, female Wistar rats (277 +/- 4 g; n = 7) were run on a motor-driven treadmill at a speed and gradient (60 m min(-1), 10 % gradient) established to yield maximal oxygen uptake (V(O2,max)). Vascular conductance (ml min(-1) (100 g)(-1) mmHg(-1)), defined as blood flow normalised to mean arterial pressure (MAP), was determined using radiolabelled microspheres during exercise before and after NO synthase (NOS) inhibition with N (G)-nitro-L-arginine methyl ester (L-NAME; 10 mg kg(-1), I.A.). The administration of L-NAME increased MAP from pre-L-NAME baseline values, demonstrating that NOS activity is reduced. The administration of L-NAME also reduced vascular conductance in 20 of the 28 individual hindlimb muscles or muscle parts examined during high speed treadmill exercise. These reductions in vascular conductance correlated linearly with the estimated sum of the percentage of slow twitch oxidative (SO) and fast twitch oxidative glycolytic (FOG) types of fibres in each muscle (Deltaconductance = -0.0082(%SO + %FOG) - 0.0105; r = 0.66; P < 0.001). However, if the reduction in vascular conductance found in the individual hindquarter muscles or muscle parts was expressed as a percentage decrease from the pre-L-NAME value (%Delta = (pre-L-NAME conductance - post-L-NAME conductance)/ pre-L-NAME conductance x 100), then the reduction in vascular conductance was similar in all muscles examined (average %Delta = -23 +/- 2 %). These results suggest that NO contributes substantially to the regulation of vascular conductance within and among muscles of the rat hindquarter during high intensity exercise. When expressed in absolute terms, the results suggest that the contribution of NO to the regulation of vascular conductance during high intensity exercise is greater in muscles that possess a high oxidative capacity. In contrast, if results are expressed in relative terms, then the contribution of NO to the regulation of vascular conductance during high intensity exercise is similar across the different locomotor muscles located in the rat hindlimb and independent of the fibre type composition.

Animals↗
PubMed2001

Na(+)/H(+) exchange subtype 1 inhibition reduces endothelial dysfunction in vessels from stunned myocardium.

Myocardial ischemia and reperfusion cause myocyte and vascular dysfunction, frequently termed "stunning." We hypothesized that inhibiting the Na(+)/H(+) exchanger subtype 1 isoform (NHE(1)) during ischemia and reperfusion limits myocardial and coronary microvascular stunning. Anesthetized rats completed 2 x 10-min coronary artery occlusions separated by 5-min of reperfusion, followed by 15 or 60 min of reperfusion. Vehicle (saline) or the NHE(1) inhibitor cariporide (HOE-642) was administered 15 min before ischemia and was continued throughout each protocol. After reperfusion, hearts were excised, and the reactivity of resistance arteries (internal diameter, approximately 120 microm) was assessed. The first derivative of left ventricular (LV) pressure, LV developed pressure, and LV systolic wall thickening were depressed (P < 0.05) similarly in vehicle- and cariporide-treated rats during ischemia and after 15 or 60 min of reperfusion compared with sham-operated animals that were not exposed to ischemia (i.e., controls). In vessels obtained after 15 min of reperfusion, the maximal response to acetylcholine-induced relaxation (10(-8)-10(-4) M) was blunted (P < 0.05) in vessels from vehicle- (approximately 35%) and cariporide-treated rats (approximately 55%) compared with controls (approximately 85%). However, the percent relaxation to acetylcholine was greater (P < 0.05) in cariporide-treated rats compared with vehicle-treated rats. Maximal contractile responses to endothelin-1 (10(-11)-10(-7) M) were increased (P < 0.05) similarly in vehicle- and cariporide-treated rats compared with controls. Relaxation to sodium nitroprusside (10(-4) M) was not different among groups. Results were similar in vessels obtained from animals after 60 min of reperfusion. These findings suggest that NHE(1) inhibition before coronary occlusion lessens ischemia-induced microvascular dysfunction for 15-60 min after reperfusion but does not alter myocardial contractile function in the area at risk.

Acetylcholine↗
PubMed2000

Microvascular and myocardial contractile responses to ischemia: influence of exercise training.

We hypothesized that exercise training preserves endothelium-dependent relaxation, lessens receptor-mediated constriction of coronary resistance arteries, and reduces myocardial contractile dysfunction in response to ischemia. After 10 wk of treadmill running or cage confinement, regional and global indexes of left ventricular contractile function were not different between trained and sedentary animals in response to three 15-min periods of ischemia (long-term; n = 17), one 5-min bout of ischemia (short-term; n = 18), or no ischemia (sham-operated; n = 24). Subsequently, coronary resistance vessels ( approximately 106 +/- 4 microm ID) were isolated and studied using wire myographs. Maximal ACh-evoked relaxation was approximately 25, 40, and 60% of KCl-induced preconstriction after the long-term, short-term, and sham-operated protocols, respectively, and was similar between groups. Maximal sodium nitroprusside-evoked relaxation also was similar between groups among all protocols, and vasoconstrictor responses to endothelin-1 and U-46619 were not different in trained and sedentary rats after short-term ischemia or sham operation. We did observe that, after long-term ischemia, maximal tension development in response to endothelin-1 and U-46619 was blunted (P < 0.05) in trained animals by approximately 70 and approximately 160%, respectively. These results support our hypothesis that exercise training lessens receptor-mediated vasoconstriction of coronary resistance vessels after ischemia and reperfusion. However, training did not preserve endothelial function of coronary resistance vessels, or myocardial contractile function, after ischemia and reperfusion.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Perflubron emulsion improves tolerance to low-flow ischemia in isolated rabbit hearts.

The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen delivery, tissue oxygenation, high-energy phosphates (HEPs), and myocardial function was investigated during low-flow ischemia. Perfusion rate, oxygen tensions, and cardiac function were measured during stabilization (5 min), controlled-flow (22 ml/min x 20 min), and low-flow (0.22 ml/min x 120 min) periods in isolated rabbit hearts. Hearts were perfused with Krebs-Henseleit (KH) solution (Control), or 10 or 20% PFC (vol/vol; n = 8 per group) 5 min before and throughout the low-flow period. Myocardial tissue was then frozen for biochemical and metabolic measurements. Myocardial oxygenation was measured at incremental flow rates by using 20% PFC (n = 4) or KH (n = 6). In PFC hearts, oxygen delivery and intramyocardial tissue Po2 were improved at all evaluated time points and flow rates, respectively (p < 0.05). In Control hearts, left ventricular end-diastolic pressure was elevated at 60, 90, and 120 min of low-flow ischemia (p < 0.05). Tissue lactate was higher (p < 0.05) and HEPs lower (p < 0.05) in Control hearts during low-flow ischemia. These results indicate that PFC treatment improves myocardial oxygenation, maintains HEPs, prevents ischemic contracture, and may increase the margin of safety during low-flow ischemia in isolated rabbit hearts.

Adenosine Diphosphate↗
PubMed1999

Regional blood flow responses to acute ANG II infusion: effects of nitric oxide synthase inhibition.

We hypothesized that nitric oxide (NO) opposes regional vasoconstriction caused by acute angiotensin II (ANG II) infusion in conscious rats. Mean arterial pressure (MAP), blood flow, and vascular conductance (regional blood flow/ MAP; ml/min/100 g/mm Hg) were measured and/or calculated before and at 2 min of ANG II infusion (0.05 or 1 microg/kg/min, i.a.) in the absence and presence of NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME), 0.25 or 1 mg/kg, i.a.]. ANG II reduced stomach and hindlimb conductance only after NOS inhibition. For example, whereas 0.05 microg/kg/min ANG II did not attenuate conductance in the stomach (i.e., 1.04+/-0.08 to 0.93+/-0.12 ml/min/100 g/mm Hg), this variable was reduced (i.e., 0.57+/-0.14 to 0.34-/+0.05 ml/min/100 g/mm Hg; p < 0.05) when ANG II was infused after 0.25 mg/kg L-NAME. In addition, whereas hindlimb conductance was similar before and after administering 1 microg/kg/min ANG II (i.e., 0.13+/-0.01 and 0.09+/-0.02, respectively), this variable was reduced (i.e., 0.07+/-0.01 and 0.02+/-0.00, respectively; p < 0.05) when ANG II was infused after 1 mg/kg L-NAME. These findings indicate that NO opposes ANG II-induced vasoconstriction in the stomach and hindlimb. In contrast, whereas both doses of ANG II decreased (p < 0.05) vascular conductance in the kidneys and small and large intestine regardless of whether NOS inhibition was present, absolute vascular conductance was lower (p < 0.05) after L-NAME. For example, 1 microg/kg ANG II reduced renal conductance from 3.34+/-0.31 to 1.22+/-0.14 (p < 0.05). After 1 mg/kg L-NAME, renal conductance decreased from 1.39+/-0.18 to 0.72+/-0.16 (p < 0.05) during ANG II administration. Therefore the constrictor effects of NOS inhibition and ANG II are additive in these circulations. Taken together, our results indicate that the ability of NO to oppose ANG II-induced constriction is not homogeneous among regional circulations.

Angiotensin II↗
PubMed1999

Activation of visceral afferents by bradykinin and ischemia: independent roles of PKC and prostaglandins.

We have shown that the cyclooxygenase (COX) and protein kinase C (PKC) systems both contribute to afferent activation in response to bradykinin (BK) and abdominal ischemia. Because the contribution from PKC to C fiber activation may depend, in part, on prostaglandin production, we hypothesized that an intact COX system is required for PKC-induced activation of ischemically sensitive abdominal visceral afferents by BK and abdominal ischemia. Single-unit activity of abdominal visceral C fibers was recorded from the right thoracic sympathetic chain of anesthetized cats. Three repeated injections of BK (1-2 micrograms/kg ia) produced similar increases in afferent activity from the baseline of 1.32 +/- 0.24, 1.37 +/- 0.32, and 1.41 +/- 0.24 impulses/s (n = 5). In another group of animals (n = 5), the second and third BK injections were performed after COX inhibition (indomethacin; 5 mg/kg iv) and then combined COX + PKC inhibition [PKC-(19-36), 20 micrograms/kg iv], respectively. Inhibition of COX reduced (P < 0.05) the afferent response to BK (0.59 +/- 0.12 impulses/s) compared with the unblocked condition (1.14 +/- 0.27 impulses/s), whereas combined COX + PKC inhibition further attenuated the increase from baseline (0.18 +/- 0.09 impulses/s; P < 0.05). Similar results were obtained in a third group of cats when the antagonists were administered in reverse order (n = 7). In a fourth group of cats (n = 9) that were pretreated with indomethacin, ischemia increased afferent activity (0.78 +/- 0.17 impulses/s). However, neural activity was attenuated (0.51 +/- 0.14 impulses/s; P < 0.05) during a second bout of ischemia in the presence of indomethacin + PKC-(19-36). These results suggest that the contribution from PKC to the activation of ischemically sensitive C fibers, particularly by BK, does not require an intact cyclooxygenase system.

Animals↗
PubMed1999

Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats.

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT(1)-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME); 10 mg/kg ia], or 3) ANG II AT(1)-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 +/- 0.31 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased after ANG II AT(1)-receptor blockade (6.53 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.12 +/- 0.20 ml x 100 g(-1) x min(-1) x mmHg(-1)) and combined inhibition (3.96 +/- 0.57 ml x 100 g(-1) x min(-1) x mmHg(-1); all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 +/- 0.66 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased by ANG II AT(1)-receptor blockade (8.48 +/- 0.83 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.68 +/- 0.22 ml x 100 g(-1) x min(-1) x mmHg(-1); both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, L-NAME-induced reductions in conductance, compared with unblocked exercise (P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats. L-NAME-induced increases in arterial pressure during treadmill running were attenuated (P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.

Angiotensin II↗
PubMed1998

Na-H exchange inhibition with cariporide limits functional impairment caused by repetitive ischemia.

Intracellular calcium ([Ca]i) overload on reperfusion may be one of the mechanisms responsible for ischemia-induced regional myocardial dysfunction. Because inhibiting the Na-H exchanger (NHE) limits intracellular sodium ([Na]i) and subsequent [Ca]i accumulation, we hypothesized that NHE inhibition would attenuate regional dysfunction in response to 25 cycles of ischemia (I, 2-min) and reperfusion (R, 8-min) of the left circumflex coronary artery (LCx) in conscious swine. Six animals were instrumented to measure arterial pressure, regional myocardial blood flow (colored microspheres), systolic wall thickening (WTh) in the normally perfused (left anterior descending, LAD) and LCx regions (sonomicrometry), LCx blood flow velocity (Doppler), and to reversibly occlude the LCx (hydraulic occluder). Each animal completed three protocols separated by 7 days: ISC, 25 I/R cycles; CAR, 25 I/R cycles + NHE inhibition (cariporide); and VEH, vehicle administration for 4.2 h. Regional myocardial blood flow was measured during LCx occlusion in the first protocol and 10 min after I/R 25 in all protocols. Systemic hemodynamics were similar among and within each protocol. Blood flow measured during LCx occlusion confirmed that perfusion was reduced (p < 0.05) to this compared with the LAD region. During ISC, LCx WTh was reduced (p < 0.05) after five IR cycles, and a stable reduction (approximately 55% of baseline; p < 0.05) was present after 20 I/R cycles. During CAR, LCx systolic WTh was reduced (p < 0.05) only after 15 and 25 I/R cycles (approximately 80 and 72%, respectively). The decrease in LCx WTh was greater in ISC than in CAR (p < 0.05). LCx WTh was not altered during VEH, while LAD WTh was similar within and among all protocols. Regional blood flow measured after 25 I/R cycles was not different among protocols. Our results indicate that NHE inhibition delays the onset and limits the degree of regional dysfunction in response to repeated bouts of ischemia and reperfusion.

Adenosine↗
PubMed1998

Signal transduction in activation of ischemically sensitive abdominal visceral afferents: role of PKC.

Abdominal ischemia reflexly activates the cardiovascular system by stimulating abdominal visceral afferent nerve endings. Whereas many ischemic metabolites responsible for activating these nerves have been identified (e.g., bradykinin), their precise mechanism of action is unclear. Protein kinase C (PKC) is an important part of the signal transduction process underlying the action of metabolites such as bradykinin and is a regulator of neuronal activity. Therefore, we hypothesized that PKC contributes to stimulation of ischemically sensitive abdominal visceral afferents. Single-unit activity was recorded from the right thoracic sympathetic chain of anesthetized cats. Exogenous activation of PKC using phorbol 12, 13-dibutyrate (PDBu, 5 microg/kg ia) increased the impulse activity of ischemically sensitive C-fiber afferents from 0.04 +/- 0.01 to 0. 67 +/- 0.23 impulses/s (n = 11; P < 0.05). The influence of endogenous activation of PKC also was evaluated during 10 min of mesenteric ischemia. Inhibition of PKC using PKC-(19-36) (20 microg/kg iv) reduced ischemia-induced increases in afferent activity from 0.46 +/- 0.11 to 0.19 +/- 0.08 impulses/s (n = 7, P < 0.05). Moreover, PKC-(19-36) (20 microg/kg iv) reduced the response of ischemically sensitive C fibers to bradykinin (0.5-1.0 microg/kg ia) from 1.18 +/- 0.20 to 0.66 +/- 0.14 impulses/s (n = 13, P < 0. 05). These results indicate that PKC contributes to activation of abdominal visceral afferents during ischemia and specifically to part of the bradykinin-induced activation of these afferents.

Abdomen↗
PubMed1997

Endothelin-1 limits increases in blood flow to native and collateral-dependent myocardium.

We hypothesized that blood flow to collateralized and noncollateralized myocardium is improved by antagonism of endothelin (ET) A receptors. Coronary collateral development was stimulated by placing an ameroid constrictor around the left circumflex coronary artery (LCx; collateralized region) in 11 swine. After 35 +/- 2 days, the left anterior descending coronary artery (LAD; noncollateralized region) was autoperfused at constant pressure using blood from a femoral artery. In group 1 (n = 6) transmural blood flow was measured using radioactive microspheres in the LAD, LCx, and border regions (i.e., area between LAD and LCx) during pacing stress while vehicle (phosphate-buffered saline) was infused into the LAD coronary artery (pace 1). Approximately 55 min later, a second period of pacing (pace 2) was performed in the presence of ETA receptor antagonism (BQ-123; 5 mg.ml-1.min-1 ic). In the time control group (group 2, n = 5) vehicle was infused during both pacing periods. Indexes of myocardial oxygen demand were similar between paces 1 and 2 in each group. Compared with the first pacing period, transmural blood flow (ml.100 g-1.min-1) was higher (P < 0.05) during ETA receptor antagonism (i.e., pace 2) in the LAD (105 +/- 8 vs. 139 +/- 9), border (51 +/- 5 vs. 83 +/- 7), and LCx regions (22 +/- 3 vs. 41 +/- 4, respectively) in group 1. In group 2, while perfusion in the border (98 +/- 17 vs. 103 +/- 16) and LCx regions (19 +/- 4 vs. 27 +/- 6) was similar in paces 1 and 2, LAD transmural flow was greater (134 +/- 9 vs. 160 +/- 13; P < 0.05) during the second pacing period. However, the percent increase in LAD flow comparing pace 1 with 2 was greater (P < 0.05) in group 1 (39 +/- 6%) compared with group 2 (20 +/- 7%). These data suggest that during the stress of pacing blood flow to collateralized and noncollateralized myocardium is improved in the presence of ETA receptor blockade.

Animals↗
PubMed1996

Effects of angiotensin II receptor blockade during exercise: comparison of losartan and saralasin.

Previous studies indicate that angiotensin II (ANG II) plays a minor role in the hemodynamic responses during dynamic exercise. However, nonspecific effects associated with methods used to block its production [e.g., angiotensin-converting enzyme (ACE) inhibitors] or receptors (e.g., saralasin) may have contributed to these findings. Losartan is a nonpeptide ANG II receptor antagonist that is devoid of such nonspecific effects. We hypothesized that the contribution of ANG II to the cardiovascular response to dynamic exercise is characterized more precisely with losartan than with saralasin. On separate days, 6 miniswine performed treadmill running at 80% of their maximal heart rate (HR) reserve (HRR) in the presence of vehicle (0.9% saline), saralasin (10 or 20 micrograms/kg/min intraleft arterially, i.a.), or losartan (15 or 20 mg/kg i.a.). Cardiac output (CO), HR, and myocardial contractility were similar among all exercise conditions. As compared with the vehicle, losartan decreased mean arterial pressure (MAP) and systemic vascular resistance (SVR) during exercise, whereas no differences occurred between the vehicle and saralasin conditions. Both receptor antagonists increased blood flow and/or decreased vascular resistance during exercise in the myocardium, stomach, small intestine, and colon. As compared with that during treadmill running with vehicle infusion, renal blood flow (RBF) was increased by losartan and decreased by saralasin. We conclude that the contribution of ANG II to the cardiovascular response to dynamic exercise is demonstrated more clearly with losartan than with saralasin.

Angiotensin II↗
PubMed1996

Hemodynamic and regional blood flow responses to nicotine at rest and during exercise.

We hypothesized that nicotine compromises cardiovascular responses to dynamic exercise. Hemodynamic variables were measured in conscious miniswine before and at 2 min of nicotine infusion (20 micrograms.kg-1.min-1; i.a.; N = 6) during resting conditions. Mean arterial pressure elevations (MAP; 14%) and plasma nicotine concentrations (49 +/- 7 ng.ml-1) were similar to those elicited by cigarette smoking in humans. In addition, nicotine increased systemic vascular resistance (SVR; 56%), the heart rate x systolic blood pressure product (RPP; 11%), and regional vascular resistance in the left-ventricular, renal, and splanchnic circulations, while cardiac output decreased (CO; 23%) and skeletal muscle blood flow and vascular resistance were unaffected. Plasma norepinephrine and epinephrine increased by approximately 30% and 90%, respectively. On separate days, the same hemodynamic responses were measured before and at 20 min of treadmill running during vehicle or nicotine infusion for the last 2 min of exercise (N = 10). Nicotine increased MAP (6%), SVR (14%), and RPP (3%), and elevated vascular resistance in the proximal colon and pancreas. Moreover, compared to exercise + vehicle, norepinephrine and epinephrine increased by approximately 13% and 24%, respectively, during exercise + nicotine infusion. These findings suggest that the detrimental effects of nicotine observed at rest are minimized during exercise. Nicotine's effects may be reduced during exercise by competition from local vasodilators in the heart and active musculature, and/or by differing activation of sympathetic nerve activity.

Animals↗
PubMed1995

Role of angiotensin II in hemodynamic responses to dynamic exercise in miniswine.

Angiotensin II (ANG II) is a potent vasoconstrictor of splanchnic and renal resistance vessels. Because ANG II increases during exercise and blood flow in the splanchnic and renal circulations decreases, we tested the hypothesis that ANG II plays a role in arterial blood pressure and regional blood flow responses to treadmill running in the miniswine. Consequently, 11 pigs were instrumented with epicardial electrocardiogram leads and left atrial and aortic catheters to assess mean arterial blood pressure (MAP), heart rate (HR), myocardial contractility, cardiac output, and regional blood flow during treadmill running. Each animal exercised for 20 min at 80% of its maximal HR reserve. Exercise was performed in the absence and presence of the ANG II AT1 receptor antagonist losartan (15-20 mg/kg). ANG II AT1 receptor blockade attenuated the MAP and systemic vascular resistance responses to dynamic exercise but had no effect on cardiac output, HR, or myocardial contractility. In addition, blood flow increased and/or regional vascular resistance decreased in the heart, kidneys, stomach, small intestine, and colon, whereas the reverse occurred in the skin and spleen. These data suggest that ANG II contributes to the increase in MAP and redistribution of cardiac output associated with dynamic exercise.

Angiotensin II↗
PubMed1994

Factors associated with vasopressin release in exercising swine.

This study examined the effect of dynamic exercise on vasopressin release in the miniswine and factors that may elicit this response (n = 15). Thus lysine vasopressin (LVP), the catecholamines epinephrine and norepinephrine (EPI and NE), plasma renin activity (PRA), and plasma volume, Na+, and osmolality were measured before and during treadmill running at work intensities of 60, 80, and 100% of each swine's maximal heart rate reserve (HRR). LVP increased in a progressive manner similar to that of humans, ranging from 5.9 +/- 0.4 pg/ml before exercise to 30.1 +/- 4.5 pg/ml during maximal exercise. EPI, NE, and PRA [an index of angiotensin II (ANG II) activity] demonstrated a pattern of response comparable to LVP. Although these hormones can influence the release of LVP, only PRA displayed a strong correlation with LVP (r = 0.84). When ANG II synthesis was blocked (captopril, 1-3 mg/kg, intra-atrial injection) during exercise (80% HRR), plasma LVP was reduced from 9.9 +/- 0.6 to 7.5 +/- 0.6 pg/ml (P < 0.05). In addition, moderate-to-strong correlations were found between plasma concentrations of LVP and plasma osmolality (r = 0.79) and body temperature (r = 0.78). Plasma LVP also correlated with decreases in plasma volume (r = 0.84). These data suggest that the miniswine model is a good one for studying vasopressin effects during exercise and that ANG II appears to be a particularly strong stimulus for the release of this hormone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Limitation of myocardial infarct size in pigs with a dual lipoxygenase-cyclooxygenase blocking agent by inhibition of neutrophil activity without reduction of neutrophil migration.

OBJECTIVES: The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent of myocardial infarction in the pig and to identify the mechanisms of any cardioprotective action of this drug. BACKGROUND: Activated neutrophils contribute to reperfusion injury after myocardial infarction and inhibition of neutrophil function can limit infarct size. METHODS: In 9 control and 10 study pigs pretreated with intravenous BW755C (10 mg/kg body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid-left anterior descending coronary artery, followed by 3 h of reperfusion. Heart rate, arterial pressure, left ventricular end-diastolic pressure, the first derivative of left ventricular pressure (dP/dt) and regional myocardial blood flow were measured during control, occlusion and reperfusion periods. Infarct size was determined by histochemical staining; and myeloperoxidase activity, a marker for tissue neutrophil content, was assessed in normal and infarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by measuring neutrophil degranulation, leukotriene B4 production, superoxide generation and chemotaxis. RESULTS: Hemodynamic function and regional myocardial blood flow were similar in control and BW755C-treated animals. BW755C significantly reduced myocardial infarct size compared with that in control animals, as measured by infarct/risk areas by histochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial myeloperoxidase activity was similar in normal, salvaged and infarcted areas in the control and treated groups, indicating that neutrophil accumulation in injured myocardium was unaltered by BW755C. However, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B4 production (-48%) and superoxide generation (-74%), but there was minimal inhibition of chemotaxis in vitro. CONCLUSIONS: These findings demonstrate that myocardial infarct size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardium.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗