Baseline Coronary Vascular Resistance Research Articles

Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in Kv channels.

Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K+ (Kv) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO2 and potential involvement of Kv channels and whether the benefit of MR blockade involves improved coronary Kv function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.

Relationship between hyperglycemia and coronary vascular resistance in non-diabetic patients

Background Hyperglycemia upon hospital admission in patients with acute myocardial infarction is associated with the no-reflow phenomenon after successful reperfusion, and increased mortality. However, the mechanism underlying this phenomenon remains unclear. Therefore, the aim of this study was to characterize coronary hemodynamics in a homogenous group of non-diabetic patients without coronary artery disease. Methods and Results A total of 104 consecutive non-diabetic patients (mean age, 62 ± 14 years) without coronary artery disease underwent Doppler flow study of the left anterior descending coronary artery. Vascular reactivity was examined by intra-coronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Coronary vascular resistance (CVR) was calculated as the mean arterial pressure divided by coronary blood flow (CBF). Baseline CVR was shown as CVR at control and minimal CVR was shown as CVR with papaverine administration. Fasting plasma glucose (FPG) level had a significant, positive correlation with baseline CVR and minimal CVR ( r = 0.24, p < 0.02 and r = 0.21, p < 0.05, respectively). Hemoglobin A1c (HbA1c) also had a significant, positive correlation with baseline CVR and minimal CVR ( r = 0.31, p < 0.01 and r = 0.32, p < 0.01, respectively). The percent change in CBF induced by Ach was inversely correlated with HbA1c but not with FPG ( r = 0.22, p < 0.05 and r = 0.06, p = 0.57, respectively). By contrast, neither FPG nor HbA1c had significant correlation with coronary flow reserve to papaverine. Conclusion These data demonstrate that elevated glucose levels are associated with increases in baseline and minimal coronary vascular resistance. These changes may contribute to unfavorable coronary hemodynamics in non-diabetic patients without coronary heart disease.

Nitric oxide‐dependent regulation of coronary vascular resistance in hypertension

Hypertension is associated with impaired endothelium dependent relaxations in many vascular beds. Evidence from the coronary vasculature offers conflicting results. The current investigation examined the role of NO in regulating coronary vascular resistance (CVR) in spontaneously hypertensive rats (SHR) and their normotensive counterparts (WKY). Rats were anesthetized, the hearts were removed and the aorta was cannulated to allow for retrograde coronary perfusion using a constant flow Langendorff set‐up. Flow was assigned based on heart weight which was estimated from body weight. SHR had a greater baseline CVR than the WKY (6.72±0.34 vs 4.97±0.62 mmHg/ml/min, p&lt;0.05). Following ET‐1 administration SHR had a greater resistance (9.82±0.75 vs 6.87±0.96 mmHg/ml/min, p&lt;0.05) although the absolute change was not different. There were no differences in maximal reduction in CVR to bradykinin (BK) or sensitivity to BK. Treatment with LNAME caused an increase in resistance in both groups although the change in resistance was not different between the SHR and WKY (3.46±0.41 vs 3.02±0.69 p&gt;0.05). LNAME completely abolished the BK induced reduction in CVR in both the SHR and WKY; the response to sodium nitroprusside was unchanged. Thus, the response to BK is NO dependent in both SHR and WKY. The CVR is elevated in the SHR and inhibition of eNOS increases CVR to a similar extent in both strains.Funded by NSERC &amp; HSFO

Differential coronary hemodynamics and left ventricular contractility in patients with syndrome X

The relationship between coronary hemodynamics and left ventricular contractility was studied in 20 patients with syndrome X. Among them, 10 patients with a resting left ventricular ejection fraction (LVEF, by radionuclide method) equal to or greater than the mean value of the whole group (58%) were defined as having relative increased left ventricular contractility (group H), and another 10 patients with relatively normal contractility (50%≤LVEF<58%) were in group N. Eight subjects with normal contractility, exercise test and coronary angiograms served as the control (group C). Baseline great cardiac venous flow (GCVF) was higher in group N than in group H ( P<0.05) and C ( P<0.05), but similar between group H and C. After dipyridamole infusion (0.56 mg/kg, i.v., for 4 min), maximum GCVF was less in group H than in group N ( P<0.001) and C ( P<0.001), but similar between group N and C. As compared to group C (3.09±0.35), coronary flow reserve was reduced in both group H (2.34±0.55, P=0.004) and N (2.40±0.36, P=0.001). In all syndrome X patients, resting LVEF was negatively correlated to baseline GCVF ( P=0.026) and tended to be positively correlated to baseline coronary vascular resistance ( P=0.057). Thus, coronary hemodynamics was altered with left ventricular contractility in syndrome X patients. In these patients, coronary flow reserve was similarly reduced with different underlying mechanisms. The limited increase of GCVF after dipyridamole infusion suggests impaired coronary microvascular dilation capacity in patients with relatively increased left ventricular contractility and the increase of baseline GCVF in those with normal contractility is more likely due to an altered basal myocardial metabolism.

Effect of Contrast Media on Coronary Vascular Resistance: Contrast-Induced Coronary Vasodilation

To determine if the vasodilatory response to the intracoronary injection of ionic and nonionic contrast media in intact pigs is dependent on nitric oxide (NO). The mechanisms responsible for inducing the increase in coronary blood flow in response to the intracoronary injection of contrast media during angiography are still not entirely understood. There is evidence to suggest that the response could be partially mediated by NO. We studied 14 anesthetized, open-chested pigs receiving ventilation. Changes in coronary blood flow and coronary vascular resistance were measured in response to the coronary artery injection of saline solution (0.5 mol/L, isosmolar with plasma) and three different contrast agents: meglumine sodium ioxaglate (Hexabrix; Mallinckrodt Medical; Point-Claire, Quebec, Canada), a low osmolar ionic contrast agent; iohexol (Omnipaque 300; Sanofi Winthrop; Markham, Ontario, Canada), a nonionic contrast agent; and diatrizoate meglumine 66%, diatrizoate sodium 10% (MD-76; Mallinckrodt Medical), an ionic contrast agent. Measurements were made during three experimental conditions: the coronary artery infusion of (1) saline solution, control; (2) L-nitro-arginine (LNNA; 10(-3) mol/L and 10(-2) mol/L), a competitive inhibitor of NO synthase; and (3)L-arginine 10(-1) mol/L, a substrate for NO synthase. The infusion of LNNA produced an increase in baseline coronary vascular resistance (p < 0.001), but it did not attenuate the vasodilatory response to the infusion of the contrast agents. Both the high and low osmolar ionic and nonionic contrast media caused a decrease in baseline coronary vascular resistance. For all three conditions, MD-76, which has the highest osmolality, produced the greatest decrease in coronary vascular resistance. The vasodilatory response of the coronary vasculature to contrast agents is directly related to osmolality and is not mediated by NO.

Cardiac and coronary vascular effects of chronically administered estrogen in the dog.

The acute administration of conjugated equine estrogen (CEE) to dogs significantly attenuated the severity and incidence of ventricular arrhythmias during ischemia and reperfusion. We hypothesized that one of the cardioprotective mechanisms of estrogen might be the ability to maintain electrical stability of the heart during ischemia. The current study was conducted to determine the effect of chronic administration of estrogen, simulating hormone replacement therapy, on the ventricular arrhythmias of ischemia and reperfusion. Chronically-treated (100 micrograms/kg/week CEE, or vehicle) male beagles were anesthetized and subjected to regional ischemia (20 min) and reperfusion. Although there was a trend towards a lower incidence of arrhythmias during ischemia in estrogen-treated dogs, values did not achieve significance at P < 0.05. Baseline coronary vascular resistance was significantly higher in estrogen-treated dogs (2.3 vs 1.5 mmHg/ml/min/100 g, P < 0.05) indicating an increase in vasomotor tone. There was also an increase in the time it took hyperemic coronary blood flow to reach a peak value upon reperfusion (71 sec in estrogen-treated dogs vs 12 sec in vehicle-treated dogs, P < 0.05). This slower reflow is consistent with increased coronary vascular resistance upon reflow in estrogen-treated dogs. We conclude that the chronic administration of CEE to male dogs increased coronary vascular tone, and impaired the rate of reperfusion, but did not decrease the incidence of ventricular arrhythmias caused by ischemia.

The role of stressor intensity and underlying vasculopathy in altering coronary reactivity in cardiomyopathic hamsters.

Our previous work showed that stress sensitized the vessels of cardiomyopathic hamsters (CMHs), but only hamsters in the lesion-forming period of their life. We hypothesized that we would find an interaction between stressor intensity and microvascular vulnerability. Male CMHs at ages of 1.5, 2.5, and 3.5 months were stressed with supine immobilization for five consecutive days. Stressor intensity was manipulated by immobilizing groups of CMHs at room temperature for 0 minutes, 15 minutes, 30 minutes, 1 hour, or 2 hours. CMHs were anesthetized and sacrificed 5 days after stress, and their hearts were perfused using a modified Langendorff system. Body weight changes and baseline coronary vascular resistance (CVR) were recorded, and CVR was also measured after coronary artery infusion of arginine vasopressin (AVP). Stress produced no effect on coronary vasculature in 1.5-month-old CMHs. In 2.5-month-old CMHs, only the two highest-intensity stressors enhanced coronary reactivity to AVP. In 3.5-month-old CMHs, higher-intensity stressors produced a marginal AVP-induced increase in CVR; but this marginal increase was significantly lower than the increases seen with the two highest-stressor intensities in the 2.5-month-old CMHs. The stress-induced coronary hyperreactivity to AVP seen in 2.5-month-old CMHs diminished when microvascular vulnerability was lower in 3.5-month-old CMHs. For 1.5-month-old CMHs, the resting CVR was extremely high, so that the addition of stress produced no further increase. Thus, stressor intensity interacted with microvascular vulnerability to alter the consequences of stress.

Stress triggers different pathophysiological mechanisms in younger and older cardiomyopathic hamsters

Because cardiomyopathic hamsters (CMHs) in the lesion-forming period of their disease are more susceptible to the lethal effects of stress than older CMHs, we tested the hypothesis that different pathophysiological effects of stress may occur: coronary vasospasm in younger CMHs and congestive heart failure in older ones. CMHs aged 2.5 and 6.5 months were stressed with 2 h supine cold immobilization for 5 consecutive days. Three, 5 and 7 days after stress, the hearts were excised and perfused using a modified Langendorff system. Maximum +/- dP/dt, developed pressure, ventricular relaxation time (Tau) and coronary vascular resistance (CVR) were recorded and CVR was also measured following coronary infusion of arginine vasopressin (AVP). Stress produced ventricular dysfunction (decreased maximum +/- dP/dt, developed pressure, and increased Tau) in older CMHs (P < 0.05) but not in younger CMHs. Baseline CVR in younger CMHs was significantly higher than in older CMHs (P < 0.01) and AVP infusion produced a bigger increase in CVR in younger stressed CMHs than in either younger nonstressed or older stressed CMHs (P < 0.05). The younger CMH heart exhibits greater resting vascular tone and stress produces coronary vasoconstriction that is consistent with coronary spasm. In contrast, the older CMH experiences a decrease in cardiac function which remains 7 days after stress and indicates an exacerbation of CHF from the mild form existing prior to stress. The lethal effects of stress may occur because of the activation of different pathological processes in younger and older CMHs.

F182. Treatment of polycythemia vera with hydroxyurea: Effects on red blood cell filterability and geometry

To determine if the vasodilatory response to the intracoronary injection of ionic and nonionic contrast media in intact pigs is dependent on nitric oxide (NO). The mechanisms responsible for inducing the increase in coronary blood flow in response to the intracoronary injection of contrast media during angiography are still not entirely understood. There is evidence to suggest that the response could be partially mediated by NO.We studied 14 anesthetized, open-chested pigs receiving ventilation.Changes in coronary blood flow and coronary vascular resistance were measured in response to the coronary artery injection of saline solution (0.5 mol/L, isosmolar with plasma) and three different contrast agents: meglumine sodium ioxaglate (Hexabrix; Mallinckrodt Medical; Point-Claire, Quebec, Canada), a low osmolar ionic contrast agent; iohexol (Omnipaque 300; Sanofi Winthrop; Markham, Ontario, Canada), a nonionic contrast agent; and diatrizoate meglumine 66%, diatrizoate sodium 10% (MD-76; Mallinckrodt Medical), an ionic contrast agent. Measurements were made during three experimental conditions: the coronary artery infusion of (1) saline solution, control; (2) L-nitro-arginine (LNNA; 10−3 mol/L and 10−2 mol/L), a competitive inhibitor of NO synthase; and (3)L-arginine 10−1 mol/L, a substrate for NO synthase. The infusion of LNNA produced an increase in baseline coronary vascular resistance (p < 0.001), but it did not attenuate the vasodilatory response to the infusion of the contrast agents. Both the high and low osmolar ionic and nonionic contrast media caused a decrease in baseline coronary vascular resistance. For all three conditions, MD-76, which has the highest osmolality, produced the greatest decrease in coronary vascular resistance.The vasodilatory response of the coronary vasculature to contrast agents is directly related to osmolality and is not mediated by NO.

F183. 5-Fluorouracil and blood viscosity

To determine if the vasodilatory response to the intracoronary injection of ionic and nonionic contrast media in intact pigs is dependent on nitric oxide (NO). The mechanisms responsible for inducing the increase in coronary blood flow in response to the intracoronary injection of contrast media during angiography are still not entirely understood. There is evidence to suggest that the response could be partially mediated by NO.We studied 14 anesthetized, open-chested pigs receiving ventilation.Changes in coronary blood flow and coronary vascular resistance were measured in response to the coronary artery injection of saline solution (0.5 mol/L, isosmolar with plasma) and three different contrast agents: meglumine sodium ioxaglate (Hexabrix; Mallinckrodt Medical; Point-Claire, Quebec, Canada), a low osmolar ionic contrast agent; iohexol (Omnipaque 300; Sanofi Winthrop; Markham, Ontario, Canada), a nonionic contrast agent; and diatrizoate meglumine 66%, diatrizoate sodium 10% (MD-76; Mallinckrodt Medical), an ionic contrast agent. Measurements were made during three experimental conditions: the coronary artery infusion of (1) saline solution, control; (2) L-nitro-arginine (LNNA; 10−3 mol/L and 10−2 mol/L), a competitive inhibitor of NO synthase; and (3)L-arginine 10−1 mol/L, a substrate for NO synthase. The infusion of LNNA produced an increase in baseline coronary vascular resistance (p < 0.001), but it did not attenuate the vasodilatory response to the infusion of the contrast agents. Both the high and low osmolar ionic and nonionic contrast media caused a decrease in baseline coronary vascular resistance. For all three conditions, MD-76, which has the highest osmolality, produced the greatest decrease in coronary vascular resistance.The vasodilatory response of the coronary vasculature to contrast agents is directly related to osmolality and is not mediated by NO.

Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts.

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 inhibitor [CG-42112A (10(-8) M]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.

Enhanced coronary vasoconstriction in the Syrian myopathic hamster supports the microvascular spasm hypothesis

The heart of the young Syrian cardiomyopathic hamster (CMH) displays discrete patches of active myocytolytic necrosis and it has been hypothesised that these lesions are triggered by arteriolar spasm. Accordingly, we tested the theory that the coronary vasoconstrictor response to arginine vasopressin (AVP) infusion is more vigorous in the actively necrotising young (2-3 month old) CMH than in age matched normal hamsters, 5-6 month old CMHs in the histologically quiescent phase of the disease, or 5-6 month old normal hamsters. An isovolumetric isolated heart preparation was used in which the coronary arteries were perfused with Krebs-Henseleit buffer at constant flow by a syringe pump. Coronary vascular resistance was determined by the ratio of measured perfusion pressure to flow rate during extended diastoles. There were no significant differences in baseline coronary vascular resistance among the four groups. The increase in resistance with AVP infusion (0.54 pressor units.min-1) was significantly greater (p < 0.01) in the young CMH [6.66(SEM 4.75) mm Hg.ml-1.min-1] than in the old CMH [1.66(0.78)], the young normal [1.10(1.07)], and the old normal [2.72(1.86)] groups. There is increased vasoconstrictive responsiveness in the young CMH coronary vasculature. The results suggest a broader coronary abnormality in this myopathic model and are consistent with the microvascular spasm hypothesis of myocytolytic lesion formation.

Effects of indomethacin on systemic and coronary hemodynamics in patients with coronary artery disease

The effects and possible mechanisms of actions of indomethacin on systemic and coronary hemodynamics were studied in 17 patients with coronary artery disease. Group I patients (12) were given either indomethacin or placebo in the absence of prior cyclooxygenase inhibition and group II (five) were given indomethacin after prior treatment with 2600 mg of aspirin. In group I, systolic blood pressure rose from a baseline of 136 ± 5 mm Hg to a peak level of 158 ± 8 mm Hg 5 minutes after drug ( p < 0.01). This was associated with a fall in coronary blood flow and a rise in coronary vascular resistance from a baseline of 1.36 ± 0.4 mm Hg/ml/min to 1.99 ± 0.7 mm Hg/ml/min 5 minutes after indomethacin ( p < 0.01). Immunoreactive thromboxane B 2 levels fell from 191 to 1.4 ng/ml. No changes were noted in plasma renin activity, angiotensin II, or catecholamine levels. Immunoreactive thromboxane B 2 levels were undetectable throughout the study period in group II patients and the blood pressure response to indomethacin was attenuated. Baseline coronary blood flow was significantly higher ( p < 0.01) and baseline coronary vascular resistance significantly lower ( p < 0.01) than in group I. At all time points after indomethacin, the fall in coronary blood flow was greater and the increase in coronary vascular resistance less in group II versus group I ( p < 0.001). These findings suggest a dissociation between the effect of indomethacin on systemic and coronary hemodynamics, the former apparently being more prostaglandin-dependent than the latter.

Effects of morphine sulfate on human coronary blood flow

Because morphine causes coronary vasoconstriction in conscious dogs, human coronary blood flow was measured with the thermodilution technique before and after administration of morphine sulfate, 0.2 mg/kg body weight (maximum 15 mg) intravenously, in 10 patients to determine if the canine experience is clinically applicable. Coronary blood flow increased from a baseline value of 104.4 ± 13.4 (mean ± standard error of the mean) to 113.0 ± 17.4 ml/min (difference not significant) 15 minutes after the administration of morphine. Baseline coronary vascular resistance was 1.14 ± 0.19 mm Hg/ml/min; 15 minutes after morphine administration the resistance value was 1.02 ± 0.17 ( P < 0.025). There was no significant change between baseline values and values 15 minutes after morphine administration in systemic mean arterial pressure (98.2 ± 5.3 to 92.8 ± 4.7 mm Hg); heart rate (69.5 ± 3.5 to 72.6 ± 3.4 beats/min), left ventricular ejection time (0.345 ± 0.009 to 0.342 ± 0.007 second) or tension-time index (2,324 ± 128 to 2,291 ± 149 mm Hg/sec per min). The slight coronary vasodilation noted after morphine administration in this study is in marked contrast to the significant coronary vasoconstriction demonstrated in the unanesthetized dog.