Changes In Coronary Resistance Research Articles

Contribution of local metabolic control to coronary pressure-flow autoregulation

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. This study interrogated the local metabolic hypothesis, which proposes that myocardial oxygen tension, indexed by coronary venous PO 2 (CvPO 2 ), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which dobutamine-induced increases in myocardial oxygen consumption (MVO 2 ) under both normoxic and hypoxemic conditions, influences coronary autoregulatory capability. Experiments were performed on open-chest anesthetized swine during 20 mmHg stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg, via servo-controlled roller pump. Measurements were made in 3 conditions: a) normoxia (n = 7); b) normoxia with dobutamine (10 μg/kg/min, iv; n = 7); and c) hypoxemia (PaO 2 36-38 mmHg) plus dobutamine (n = 5). Under control-normoxic conditions, CvPO 2 decreased from 38 ± 2 to 22 ± 1 mmHg and coronary blood flow fell from 0.93 ± 0.15 to 0.32 ± 0.03 ml/min/g as CPP was reduced from 140 to 40 mmHg. Administration of dobutamine significantly increased heart rate (~60%; P < 0.001), but the combination of hypoxemia plus dobutamine did not further influence heart rate. Further, dobutamine with and without hypoxemia significantly increased MVO 2 (P < 0.001); however, CvPO 2 was reduced (P < 0.001) only in the presence of hypoxemia. Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) was unaffected by dobutamine alone but tended to increase when dobutamine infusion was combined with reductions in PaO 2 ≤ 40 mmHg (P = 0.069). Additional analysis of the autoregulatory slope within this same CPP range revealed no differences between groups. However, there was a significant inverse association between Gc and CvPO 2 , measured at CPP of 100 mmHg, in the absence and presence of dobutamine-induced increases in MVO 2 ± hypoxemic conditions (P < 0.001, r = -0.722). The relationship of coronary resistance (CPP range of 120 to 60 mmHg) relative to respective CvPO 2 revealed that decreases in CvPO 2 were not associated with changes in coronary resistance until CvPO 2 fell below a relative threshold of ~ 25 mmHg (r = 0.88). These findings support the interpretation that the sensitivity of coronary autoregulatory behavior is directly coupled with the activation of local metabolic vasodilator pathways below a critical level of myocardial oxygenation. This work was supported by National Institutes of Health grant R01 HL158723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparison of Non‐Invasive Peripheral Vascular Function to Invasive Measures of Coronary Function in Patients with Suspected Coronary Microvascular Dysfunction

IntroductionThe purpose of this study is to compare non‐invasive vascular assessments to invasive gold standard measures of coronary flow and resistance in patients with suspected coronary microvascular dysfunction (CMD), a condition driven by systemic endothelial dysfunction. We hypothesize that non‐invasive measures will be associated with both coronary flow and resistance following pharmacological hyperemia.MethodsForty‐one patients with suspected CMD attended the Cardiovascular Integrative Physiology Clinic at Southlake Regional Health Centre. Patients underwent finger‐based arterial tonometry (RHPAT) to non‐invasively quantify microvascular endothelial function (EndoPAT). A subset of participants (n=15) also concurrently completed flow mediated dilation (FMD) of the brachial artery to assess conduit artery endothelial function. Briefly, a standard blood pressure cuff was positioned on the right arm of patients, distal to the elbow joint. Baseline recordings preceded 5 minutes of forearm ischemia, and was followed by cuff deflation, eliciting reperfusion. Within 4 months, patients underwent coronary reactivity testing using the Doppler guidewire method. Specifically, the coronary flow reserve (CFR), and the index of microvascular resistance (IMR) were calculated during pharmacologically‐induced hyperemia using adenosine, then acetylcholine, then dobutamine. Prior to each stimuli, baseline measures were obtained to ensure hemodynamics results to baseline.ResultsRHPAT was negatively correlated to the IMR during dobutamine (r=−0.39, p=0.04), but not the CFR (r=0.14, p=0.49). FMD was negatively correlated to the IMR during adenosine (r=−0.64, p=0.01), but not the CFR (r=0.29, p=0.30). RHPAT and FMD were not correlated to the IMR or CFR during acetylcholine.ConclusionThese preliminary results suggest that measures of non‐invasive peripheral vascular function can predict pharmacologically induced changes in coronary resistance, but not coronary flow.Support or Funding InformationSt. Jude MedicalThe Heart of Gold Cardiac Research FundYork UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

English

Several studies indicate that some steroid derivatives have inotropic activity; nevertheless, there is scarce information about the effects of the androsterone derivatives at cardiovascular level. Therefore, in this study, the inotropic activity of montelukast-androsterone was evaluated using an isolated rat heart model. In the first stage, the Langendorff technique was used to measure perfusion pressure and coronary resistance changes in isolated rat heart in absence or presence of androsterone and its derivative. In second stage, the inotropic activity of montelukast-androsterone was evaluated by measuring left ventricular pressure (LVP) in absence or presence of the following compounds; flutamide, prazosin, metoprolol, nifedipine and carbachol. The results showed that the montelukast-androsterone derivative significantly increase the perfusion pressure and coronary resistance in comparison with androsterone and control conditions. In addition, other data indicate that montelukast-androsterone derivative increase LVP in a dose-dependent manner [1 × 10-9 to 1 × 10-4 mmol]; nevertheless, this phenomenon was significantly inhibited by flutamide at a dose of 1 × 10-6mmol. Finally, other data indicate that the effect exerted by androsterone derivative [1 × 10-7 to 1 × 10-4 mmol] on LVP was blocked in the presence of carbachol [1 × 10-3 mmol]. All these data suggest that the montelukast-androsterone derivative induces positive inotropic activity through activation of the androgen receptor. In addition, this phenomenon may involvechanges on the cAMP concentration. Key words: Montelukast-androsterone derivative, Langendorff, inotropic activity.

Effect of progesterone-carbachol derivative on perfusion pressure and coronary resistance in isolated rat heart: via activation of the M<sub>2</sub> muscarinic receptor

The present study was designed to investigate the effects of progesterone-carbachol derivative on perfusion pressure and coronary resistance in rats. An additional aim was to identify the molecular mechanisms involved. The Langendorff model was used to measure perfusion pressure and coronary resistance changes in isolated rat heart after progesterone-carbachol derivative alone and after the following compounds; mifepristone (progesterone receptor blocker), yohimbine (α2 adreno-receptor antagonist), ICI 118,551 (selective β2 receptor blocker), atropine (non-selective muscarinic receptor antagonist), methoctramine (antagonist of M2 receptor) and L-NAME (inhibitor of nitric oxide synthase). The results show that progesterone-carbachol derivative [10(-9) mM] significantly decreased perfusion pressure (P=0.005) and coronary resistance (P=0.006) in isolated rat heart. Additionally, the effect of progesterone-carbachol on perfusion pressure [10(-9) to 10(-4) mM] was only blocked in the presence of methoctramine and L-NAME. These data suggest that progesterone derivative exert its effect on perfusion pressure via activation of the M2 muscarinic. In addition, this phenomenon involves stimulation of nitric oxide synthase (NOS).

Design and synthesis of an estradiol derivative and evaluation of its inotropic activity in isolated rat heart

Several studies indicate that some steroid derivatives have inotropic activity; nevertheless, there is scarce information about the effects of the estradiol derivatives at cardiovascular level. Therefore, in this study, estradiol derivative was synthetized with the objective of evaluating its inotropic activity. In this first stage, the Langendorff technique was used to measure perfusion pressure and coronary resistance changes in isolated rat heart in absence or presence of estradiol derivative. In second stage, the inotropic activity of estradiol derivative was evaluated by measuring left ventricular pressure in absence or presence of following compounds; tamoxifen, prazosin, metoprolol, indomethacin and nifedipine. The results showed that the estradiol derivative significantly increase the perfusion pressure and coronary resistance in isolated heart. Additionally, other data indicate that estradiol derivative increaseleft ventricular pressure in a dose-dependent manner [10-9 to 10-4 mmol]; nevertheless, this phenomenon was significantly inhibited by nifedipine at a dose of 1 × 10-6 mmol. In conclusion, these data suggest that the estradiol derivative induces positive inotropic activity through of activation the L-type calcium channel. Key words: Estradiol derivative, Langendorff, inotropic activity.

Vitamin C prevents hyperoxia-mediated coronary vasoconstriction and impairment of myocardial function in healthy subjects.

Supplementary oxygen is commonly administered in current medical practice. Recently it has been suggested that hyperoxia causes acute oxidative stress and produces prompt and substantial changes in coronary resistance in patients with ischemic heart disease. In this report, we examined whether the effects of hyperoxia on coronary blood velocity (CBV) would be associated with a reduction in myocardial function. We were also interested in determining if the postulated changes in left ventricular (LV) function seen with tissue Doppler imaging (TDI) could be reversed with intravenous vitamin C, a potent, acute anti-oxidant. LV function was determined in eight healthy subjects with transthoracic echocardiography and TDI before and after hyperoxia and with and without infusing vitamin C. Hyperoxia compared with room air promptly reduced CBV by 28 ± 3% (from 23.50 ± 2.31 cm/s down to 17.00 ± 1.79 cm/s) and increased relative coronary resistance by 34 ± 5% (from 5.63 ± 0.88 up to 7.32 ± 0.94). Meanwhile, LV myocardial systolic velocity decreased by 11 ± 6% (TDI). These effects on flow and function were eliminated by the infusion of vitamin C, suggesting that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation.

CHANGES INDUCED BY ESTRADIOL-ETHYLENEDIAMINE DERIVATIVE ON PERFUSION PRESSURE AND CORONARY RESISTANCE IN ISOLATED RAT HEART: L-TYPE CALCIUM CHANNEL

The present study was designed to investigate the effects of estradiol-ethylenediamine derivative on perfusion pressure and coronary resistance in rats. An additional aim was to identify the molecular mechanisms involved. The Langendorff model was used to measure perfusion pressure and coronary resistance changes in isolated rat heart after estradiol-ethylenediamine derivative alone and following compounds; tamoxifen (estrogen receptor antagonist), prazosin (alpha1 adrenoreceptor antagonist), metoprolol (selective beta1 receptor blocker), indomethacin (prostanglandin synthesis inhibitor) and nifedipine (L-type calcium-channel inhibitor). The results show that estradiol-ethylenediamine derivative [10(-9) mmol] significantly increased perfusion pressure (p = 0.005) and coronary resistance (p = 0.006) in isolated rat heart. Additionally, the effect of estradiolethylenediamine on perfusion pressure [10(-9) to 10(-4) mmol] was only blocked in the presence of the L-type calcium-channel (nifedipine). These data suggest that the effect of estradiol-ethylenediamine on perfusion pressure and vascular coronary involves activation of the L-type calcium channel through a non-genomic molecular mechanism.

Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease

Pathological formation of reactive oxygen species within the coronary circulation has been hypothesized to mediate some clinical manifestations of ischemic heart disease (IHD) by interfering with physiological regulation of coronary tone. To determine the degree to which coronary tone responds to acute changes in ambient levels of oxidants and antioxidants in vivo in a clinical setting, we measured the effect of an acute oxidative stress (breathing 100% oxygen) on coronary capacitance artery diameter (quantitative angiography) and blood flow velocity through the coronary microcirculation (intracoronary Doppler ultrasonography) before and after treatment with the antioxidant vitamin C (3-g intravenous infusion) in 12 IHD patients undergoing a clinical coronary interventional procedure. Relative to room air breathing, 100% oxygen breathing promptly reduced coronary blood flow velocity by 20% and increased coronary resistance by 23%, without significantly changing the diameter of capacitance arteries. Vitamin C administration promptly restored coronary flow velocity and resistance to a slightly suprabasal level, and it prevented the reinduction of coronary constriction with rechallenge with 100% oxygen. This suggests that acute oxidative stress produces prompt and substantial changes in coronary resistance and blood flow in a clinical setting in patients with IHD, and it suggests that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation. This observation may have relevance for clinical practice.

Changes in Coronary Resistance Related to the Stages of the Female Life Cycle

Estrogen is known to dilate the coronary vascular system mainly through nitric oxide (NO) release. However, it has not been determined whether or not this effect occurs equally throughout all stages of the female life cycle. We examined the changes in coronary flow properties in adolescent, adult and ovariectomized (OVX) female rats using the endothelial NO synthetase blocker, L-N (omega) nitroarginine (L-NNA). Female rats were divided into 3 groups: adolescent (13 weeks, n=6), adult (19 weeks, n=8) and OVX (20 weeks, n=7, 12 weeks after oophorectomy). Coronary effluent was measured using the Langendorff non-working heart model before and 15 min after the use of L-NNA. In OVX rats, coronary effluent was significantly decreased in comparison with adolescent and adult rats (adolescent vs OVX: p<0.001; adult vs OVX: p<0.05). After treatment with L-NNA, coronary effluent was significantly higher in the adolescent group compared with the adult and OVX groups (adolescent vs adult: p<0.01; adolescent vs OVX: p<0.0005). Oophorectomy brought about an increase in coronary vascular resistance. L-NNA exacerbated coronary vascular resistance in relation to maturation. It is suggested that the effect of estrogen on vascular dilatation in adolescents is largely dependent on a non-NO pathway, whereas adults are largely dependent on an NO pathway.

Short-term responses of coronary circulation to cortisol and estrogen in trout ( Oncorhynchus mykiss)

This study was designed to investigate the short-term effects of cortisol and 17-β-estradiol on the intact coronary tree of rainbow trout ( Oncorhynchus mykiss). A non-working, isolated, and perfused heart preparation was used. The coronary pressure was monitored together with the coronary flow in order to calculate the coronary resistance. The drug effects were expressed as percent change in coronary resistance. At concentrations higher than 10 −5 mol l −1, cortisol elicited a significant vasoconstriction ( p<0.001) within 10 min of perfusion. The simultaneous administration of cortisol and adenosine (both at 10 −4 mol l −1) induced a significant reduction ( p<0.001) of the coronary tree response elicited by each drug alone. The perfusion of the intact coronary trout system with 20 ng ml −1 of 17-β-estradiol elicited a significant vasodilative response ( p<0.001) within 5–15 min of perfusion. This vasodilation did not involve nitric oxide, because no significant effect of N ω-nitro- l-arginine ( l-NA, a nitric oxide synthase inhibitor) in presence of the estrogen was observed. 17-β-Estradiol was also able to reduce the vasoconstriction induced by 10 −3 mol l −1 acetylcholine. From these results it is possible to suggest that the steroid hormones, cortisol and 17-β-estradiol, expound their action on the trout coronary tree through a non-genomic mechanism.

Ouabain-induced coronary vasoconstriction in cats is not neurally mediated.

1. Previous reports indirectly implicate a neural mechanism for coronary constriction to centrally administered digitalis. However, autoregulatory changes in coronary resistance due to changes in arterial pressure may have influenced the interpretation of these studies. 2. We tested directly the hypothesis that cardiac sympathetic innervation is responsible for coronary constriction to ouabain by examining the effects of ouabain (intravenous (i.v.) and intracerebroventricular (i.c.v.)) before and after bilateral stellate ganglionectomy. 3. Cats were anaesthetized and instrumented for the measurement of heart rate, blood pressure and coronary blood flow velocity using an epicardial-attached suction Doppler probe. Animals were treated with atenolol and the effects of either i.v. or i.c.v. injections of ouabain were examined. 4. In seven cats treated with atenolol, i.v. ouabain (0.11 mg/kg) produced maximal increases in arterial pressure and coronary vascular resistance index (CVRI) of 66 +/- 7 mmHg and 37 +/- 9%, respectively. Following bilateral stellate ganglionectomy (n = 7), ouabain produced similar increases in arterial pressure (70 +/- 9 mmHg) and CVRI (39 +/- 7%). A higher dose of i.v. ouabain (1.1 mg/kg) produced maximal increases in arterial pressure (115 +/- 4 mmHg) and coronary resistance (86 +/- 14%) in intact cats (n = 6) that were similar to responses seen in cats in which stellate ganglionectomy had been performed (n = 6; arterial pressure 104 +/- 13 mmHg; coronary resistance 114 +/- 6%). The increases in coronary resistance to ouabain at both doses were significantly greater than increases in coronary resistance to passive elevation of arterial pressure during aortic constriction. Thus, autoregulation does not explain fully the coronary constriction to ouabain. 5. To further examine a central mechanism, i.c.v. perfusion with 0.3 mmol/L ouabain was performed in six cats, resulting in increases in arterial pressure (122 +/- 7 mmHg) and coronary resistance (58 +/- 14%). Similar increases in arterial pressure (117 +/- 16%) and coronary resistance (84 +/- 20%) were seen in separate studies (n = 6) following stellate ganglionectomy. 6. These results indicate that coronary constriction to ouabain does not require intact cardiac sympathetic innervation, but probably involves a direct or humorally mediated effect.

ACE-inhibition attenuates cardiac cell damage and preserves release of NO in the postischemic heart

Cardioprotective effects of angiotensin-converting enzyme (ACE) inhibition have been demonstrated in postischemic reperfusion. This occurred via bradykinin and indirect evidence suggested mediation by nitric oxide (NO), which probably acts as a radical scavenger. To test this hypothesis, we measured release of lactate dehydrogenase (LDH) from isolated guinea pig hearts (constant flow perfusion, 37°C) as a marker of cellular damage, before and after global ischemia (15 min), and we investigated the release of NO during reperfusion, both, without and with ACE inhibition. The main catabolites of NO, nitrate and nitrite, were also quantified. Coronary perfusion pressure (CPP) indicated coronary resistance changes. Cilazaprilat (CIL, 10 μM) was used for inhibition of ACE. Marked and protracted cellular damage occurred during reperfusion in the control group, myocardial LDH release rising nearly 10-fold from 1.5 mU/ml (basal level) to 14 mU/ml during acute reperfusion, then declining to 7 mU/ml after 5 min. ACE inhibition mitigated the acute rise of LDH (9 mU/ml), and reduced its release to preischemic values already after 3 min of reperfusion. Postischemic NO release in the 2nd min of reperfusion was about 40% of the preischemic value (approx. 200 nM) in untreated hearts, while there was 70% recovery after ACE inhibition. After 25 min, NO had recovered to 69% in controls vs. 100% with CIL. Coronary venous nitrate+nitrite was not infringed during early reperfusion (2nd min). After 25 min, nitrate+nitrite had decreased in controls (about 75% of preischemic values), but increased to 110% with CIL. In control hearts, CPP rose continuously from the 10th to the 25th min of reperfusion (from 39 to 55 mmHg), indicating progressive vasoconstriction. CIL significantly attenuated this effect. The results suggest that NO might be consumed during early reperfusion in the act of detoxifying radicals. In control hearts, “endothelial stunning” takes place. Concerning NO production and vasodilatory tone, ACE-inhibition augments postischemic NO release and mitigates disturbances caused by ischemia and reperfusion.

Effect of a new nitric oxide donor on the biomechanical performance of the isolated ischaemic rat heart.

The effect of a new nitric oxide (NO) donor, a meso-ionic 3-aryl substituted oxatriazole-5-imine derivative, GEA 3162 was studied on constant flow-perfused ischaemic Langendorff rat heart. The perfusion was kept constant at a rate of 16 mL min-1. Ischaemia was induced by a low flow rate of 0.8 mL min-1 for 30 min, and was followed by a 40-minute reperfusion. In the first set of experiments the effects of GEA 3162-infusion were examined on perfusion pressure, left ventricular pressure, heart rate and left ventricular dP/dt. GEA 3162 infusion did not affect the pre-ischaemic maximum of left ventricular pressure. During reperfusion, maximal left ventricular pressure, maximal and minimal dP/dt values in the GEA 3162-treated group significantly exceeded those of the untreated controls (by 19.3, 36.0 and 18.0%, respectively). During reperfusion, perfusion pressure increased continuously in the control group indicating an increasing coronary resistance, but it was kept at a continuous low level with GEA 3162 treatment. In a second set of experiments bradykinin was infused in order to test the endothelial function before ischaemia and during late reperfusion. Bradykinin elicited significant vasodilation in the control group during reperfusion, meanwhile it did not cause further change in coronary resistance in the GEA 3162-infused group. We suggest, that GEA 3162 may have a protective effect on isolated rat heart in ischaemia and reperfusion, that results in an improved cardiac performance compared with untreated hearts.

Rate of coronary flow adaptation in response to changes in heart rate before and during anesthesia for coronary artery surgery.

The rate of adaptation of coronary blood flow in response to stepwise changes in heart rate (HR) has been extensively studied in dogs and goats to improve our understanding of the dynamics of coronary regulation processes and their pathophysiology and to obtain time constants for mathematical modeling of the coronary regulation. However, little is known about the dynamic characteristics of coronary flow adaptation in humans. In patients undergoing coronary artery surgery, we investigated the rate of coronary adaptation in response to stepwise changes in HR, in the awake and anesthetized states. In 11 patients with stable coronary artery disease, arterial blood pressure, right atrial pressure, and coronary sinus blood flow, measured by continuous thermodilution, were calculated per beat. The ratio of beat-averaged arterial blood pressure minus right atrial pressure and coronary sinus blood flow was calculated to obtain an index of coronary resistance. The rate of change of coronary resistance index was quantified by t50, defined as the time required to establish 50% of the total change in coronary resistance index. Responses of coronary resistance index after HR changes, before and after induction of anesthesia, were compared. The anesthesia technique consisted of 100 micrograms.kg-1 fentanyl and 0.1 mg.kg-1 pancuronium bromide in combination with oxygen in air ventilation (FIO2 = 0.5). In the awake situation, t50 values of the dilating and constricting responses, induced by an increase and a decrease in HR were 5.0 +/- 2.1 (SD) s (range 2.6-9.0 s) and 5.7 +/- 1.2 s (range 4.1-7.8 s), respectively. During fentanyl/pancuronium anesthesia, the rate of coronary flow adaptation was significantly slower, with t50 values of 10.2 +/- 2.1 s (range 7.7-13.1 s) after an HR step-up and 9.8 +/- 2.1 s (range 6.6-13.2 s) after an HR step-down. Compared to the awake situation, arterial blood pressure was significantly reduced during anesthesia, but coronary vascular resistance remained unchanged. This implies that the steady-state static regulation of coronary blood flow had not changed. These preliminary data suggest that, in patients with coronary artery disease, the rate of change in coronary vascular resistance in response to pacing-induced changes in HR is mitigated by fentanyl/pancuronium anesthesia during positive pressure ventilation. A further qualification of our findings in a larger number of patients is warranted.

Sympathetically mediated effects of mental stress on the cardiac microcirculation of patients with coronary artery disease

Mental stress often causes myocardial ischemia in patients with coronary artery disease (CAD). There is increasing evidence mat the coronary microcirculation of patients with atherosclerosis may be dysfunctional, with the potential of contributing to myocardial ischemia. This study investigated sympathetically mediated coronary microcirculatory and regional noradrenergic effects of mental stress. We measured left anterior descending coronary artery blood flow and norepinephrine kinetics at rest and during a 10-minute video game in 10 CAD patients with nonsignificant atherosclerosis of this artery and in 5 patients with normal coronary angiograms (NCA). The 2 groups did not differ in their responses of systemic and cardiac norepinephrine spillovers, heart rate, and blood pressure during mental stress. Patients with NCA had microvascular dilation during mental stress (26 ± 9% [mean ± SD] decline in coronary vascular resistance from baseline, p < 0.01), whereas patients with CAD did not (9 ± 20% decline, p = 0.11). Six patients with CAD then received intracoronary hentolamine (1.7 ng/kg/min for 5 minutes, followed by 0.17 μg/kg/min) and played the video game again. In contrast to nonsignificant changes in coronary resistance during the initial video game (6 ± 15% decline, p = 0.20), coronary vascular resistance decreased significantly during the repeat video game (25 ± 19% decline, p = 0.02). Vasomotor responses of epicardial coronary artery segments did not differ between the 2 video game studies. Five other patients (4 with CAD, 1 with NCA) repeated the video game during intracoronary administration of 5% dextrose, with systemic and coronary hemodynamic and noradrenergic responses unchanged from those during the initial video game. Thus, the coronary microcirculation of patients with CAD fails to dilate during mental stress, a response likely mediated by α-adrenoceptor activation mat may contribute to myocardial ischemia.

Regulation of coronary diameter by myogenic mechanisms in arterial microvessels greater than 100 microns in diameter

We performed the present study to determine the quantitative significance of transient and steady-state myogenic responses in isolated coronary resistance vessels greater than 100 microns in diameter. Small coronary arteries were isolated from freshly excised porcine hearts (n = 14) and were studied under static conditions in a superfused vessel chamber that allowed internal diameter to be assessed continuously using video microscopic techniques. At a mean distending pressure of 50 mmHg, the passive diameter of resistance arteries following sodium nitroprusside averaged 181 +/- 10 (SE) microns. Upon heating, vessels developed spontaneous tone and constricted to 72 +/- 3% of their maximum diameter. After a 30-mmHg step change in coronary pressure from 50 to 80 mmHg, there was an initial dilation from 131 +/- 9 to 149 +/- 11 microns, followed by myogenic constriction that returned diameter to the initial value over a period of several minutes (134 +/- 10 microns, P = NS). Directionally opposite peak transients were observed during reductions in pressure. Steady-state diameter remained relatively constant over a pressure range from 100 to 20 mmHg. Although these data demonstrate that myogenic responses are present in resistance arteries that are greater than 100 microns in diameter, their contribution to steady-state coronary resistance changes as pressure is varied is small. This suggests that additional mechanisms contribute to the phenomenon of coronary autoregulation in this class of resistance vessel.

Mathematical Analysis of Coronary Autoregulation and Vascular Reserve in Closed-Loop Circulation

The autoregulatory capacity of the coronary circulation has traditionally been studied in open-loop animal models where the coronary circulation was decoupled from the systemic circulation. In the closed-loop circulation, changes in arterial pressure alter coronary flow. Pressure variations can be caused by changes in cardiac contractility, preload, afterload, and heart rate. These changes also affect myocardial oxygen consumption. To maintain equilibrium between oxygen supply and consumption, coronary flow is altered by the autoregulation mechanism. Coronary resistance must change to produce the required change in coronary flow. The direction of change in coronary resistance is not directly predictable. Increased arterial pressure may result in either increased or decreased coronary resistance. To study the changes in coronary resistance in response to changes in arterial pressure that are produced by circulatory parameters, we used mathematical models. Coronary resistance was calculated to obtain equilibrium between ventricular oxygen consumption and supply for different values of contractility, preload, afterload, and heart rate. Maximum coronary resistance, indicating largest coronary vascular reserve and highest efficiency of arterial pressure generation, was defined as an optimal condition. The model predicted that the optimal value of cardiac contractility is its resting value. Minimizing end-diastolic volume and heart rate and maximizing peripheral resistance were shown to improve ventricular coronary vascular reserve. These observations suggest that afterload reduction therapy may not be beneficial for improving myocardial oxygen balance while venous vasodilatation and heart rate reduction result in greater coronary reserve.

Chronic Administration of Nicardipine Attenuates Myocardial Stunning in Isolated Rabbit Hearts

The purpose of this study was to evaluate the effects of the chronic administration of a calcium channel blocker, nicardipine, on systolic and diastolic alterations occurring during myocardial stunning in isolated rabbit hearts. Rabbits were presented with nicardipine 20 mg (O.I.D.) for 30 days. Then hearts were isolated (group II) and compared with control hearts (group I) in their response to 20 min of global ischemia and 30 min of reperfusion. Coronary flow and heart rate were kept constant. Left ventricular isovolumic developed pressure (LVDP), its first derivative (dP/dt), and end diastolic pressure (LVEDP) were measured. After isolation, no statistically significant changes were detected in LVDP, + dP/dtmax, LVEDP, or coronary resistance in hearts of rabbits with or without the pharmacological intervention. Early after the onset of reperfusion, LVDP and + dP/dtmax partially recovered in a similar way in groups I and II. Late in reperfusion LVDP stabilized at 48 ± 7% in group I and 71 ± 6% in group II (P < 0.05) and + dP/dtmax stabilized at 56 ± 7% and 79 ± 6% (P < 0.05), respectively. Diastolic dysfunction was manifested by a 217 ± 39% increase in LVEDP (P < 0.05) in group I, and 140 ± 31% in group II (P < 0.05). The isovolumic relaxation time constant (τ, tau) increased from 70 ± 5 to 151 ± 27 ms (P < 0.05) and from 66 ± 6 to 97 ± 10 ms (NS) in groups I and II, respectively at 5 min of reperfusion. This relaxation parameter returned to normal values in the late reperfusion. Pretreating rabbits with nicardipine appears to protect the heart from the systolic and the diastolic dysfunction of stunning without evidence of prior decrease in contractile state or changes in coronary resistance.

Evidence for a systemic defect of resistance-sized arterioles in hypertrophic cardiomyopathy.

To investigate whether the abnormalities of coronary arterioles observed in association with hypertrophic cardiomyopathy represent a generalized phenomenon, both forearm and coronary vasodilator reserve were measured in 12 patients with hypertrophic cardiomyopathy. Forearm vasodilator reserve was evaluated by measuring minimal forearm vascular resistance (Rmin, the ratio of mean intra-arterial pressure to peak forearm blood flow measured by venous plethysmography) under conditions of maximal postocclusive reactive hyperemia. In a subgroup (n = 5) of patients, the intra-arterial infusion of sodium nitroprusside combined with arterial occlusion did not produce additional vasodilation, indicating that the ischemic stimulus was indeed maximal. Coronary reserve was quantitated by measuring left ventricular blood flow (13N-ammonia and positron emission tomography) and coronary resistance at baseline and after intravenous dipyridamole (0.56 mg/kg). Rmin was significantly greater in patients than in a group of age- and sex-matched controls. The percentage change in coronary resistance after dipyridamole was significantly related to Rmin, whereas no correlation was found between change in coronary resistance and individual septal thickness values. Independent of cardiac hypertrophy, systemic and coronary arterioles of patients with hypertrophic cardiomyopathy are affected by an abnormality that may contribute to the clinical evolution of this syndrome.

Respiratory phasic effects of inspiratory loading on left ventricular hemodynamics in vagotomized dogs

Exaggerated inspiratory swings in intrathoracic pressure have been postulated to increase left ventricular (LV) afterload. These predictions are based on measurements of LV afterload by use of esophageal or lateral pleural pressure. Using direct measurements of pericardial pressure, we reexamined respiratory changes in LV afterload. In 11 anesthetized vagotomized dogs, we measured arterial pressure, LV end-systolic (ES) and end-diastolic transmural (TM) pressures, stroke volume (SV), diastolic left anterior descending blood flow (CBF-D), and coronary resistance. Dogs were studied before and while breathing against an inspiratory threshold load of -20 to -25 cmH2O compared with end expiration. Relative to end expiration, SV and LVES TM pressures decreased during inspiration and increased during early expiration, effects exaggerated during inspiratory loading. In all cases, LV afterload (LVES TM pressure) changed in parallel with SV. LV end-diastolic TM pressure did not change. CBF-D paralleled arterial pressure, and there were no changes in coronary resistance. In two dogs, regional LVES segment length paralleled calculated changes in LVES TM pressure. We conclude that 1) LV afterload decreases during early inspiration and increases during early expiration, changes secondary to those in SV; 2) changes in CBF-D are secondary to changes in perfusion pressure during the respiratory cycle; and 3) the use of esophageal or lateral pleural pressure to estimate LV surface pressure overestimates changes in LV TM pressures during respiration.