Increase In Coronary Pressure Research Articles

EFFECT OF ACUTE HYPERTENSION IN THE CORONARY CIRCULATION

In previous studies severe, acute hypertension damaged the endothelium in proximal coronary arteries and selectively potentiated constriction of the artery to serotonin. In the present study we investigated the role of several mechanical factors and of oxygen radicals in this response. To test the role of mechanical factors in the response to acute hypertension, the effect of different magnitudes of elevation of perfusion pressure and the rate of the rise in perfusion pressure were studied. Pharmacologically induced increases in blood pressure were produced by infusion of angiotensin II or phenylephrine. The role of oxygen radicals was tested by measuring responses to serotonin before and after increases in perfusion pressure in dogs treated with a combination of superoxide dismutase and catalase or with deferoxamine. In open-chest anesthetized dogs the diameter of the left anterior descending coronary artery (LADCA) was measured using sonomicrometer crystals, and the LADCA was perfused at a constant pressure of 80 mmHg from a reservoir. Responses to serotonin were measured at this perfusion pressure before and after an abrupt increase in perfusion pressure. Intracoronary serotonin (5 or 50 micrograms/min) produced a dose-dependent constriction of the LADCA while increasing coronary flow. Abruptly increasing the coronary perfusion pressure from 80 to 120, 150 or 200 mmHg augmented the constriction to serotonin twofold, whereas increases in perfusion pressure to 100 mmHg had no effect. Increasing coronary pressure slowly (over a 4-min period) from 80 to 200 mmHg augmented constriction to serotonin. Inducing acute hypertension (coronary pressure 200 mmHg) pharmacologically with angiotensin II also augmented constriction to serotonin, whereas phenylephrine-induced hypertension did not. Superoxide dismutase, a scavenger of superoxide anions and catalase, a scavenger of hydrogen peroxide, prevented the augmented constriction to serotonin following a pressure increase. Deferoxamine, which prevents generation of hydroxyl radicals from superoxide anions and hydrogen peroxide, also prevented the enhanced constriction to serotonin following an acute pressure increase. Moderate physiological increases in pressure, induced either mechanically or pharmacologically, can augment the responses to serotonin. Oxygen-derived free radicals, particularly hydroxyl radicals, might be involved in the abnormal response to serotonin following an abrupt increase in coronary pressure.

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

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

Positive inotropic effects of low concentrations of leukotrienes C4 and D4 in rat heart

We examined the effects of leukotrienes (LT) B4, C4, D4, and E4 (0.010-2.5 ng/ml) on contractile and coronary function in isolated rat hearts. Concentration-dependent effects were examined either by the cumulative addition of LTs or by addition of specific concentrations to individual preparations. Neither LTB4 nor LTE4 produced myocardial or coronary effects at any concentration, irrespective of addition protocol. At 0.010 ng/ml, both LTC4 and LTD4 produced an increase in force that was associated with a 30% elevation in coronary pressure. Further cumulative addition of either leukotriene resulted in a negative inotropic effect and a further increase in coronary pressure. In contrast, following single additions of LTC4 or LTD4 (0.01-0.50 ng/ml) a positive inotropic effect and an increased coronary pressure were observed. LTC4 or LTD4 at 0.5 ng/ml produced a negative inotropic effect in hearts pretreated with 0.01 ng/ml of LTD4 or LTC4, respectively. Reversal of this addition protocol resulted in a negative inotropic effect of either 0.01 ng/ml LTD4 or LTC4. Verapamil and nifedipine significantly attenuated the positive inotropic and coronary constricting effect of 0.5 ng/ml LTC4 and LTD4. The addition of either LT following BAY K 8644 resulted in a negative inotropic effect, in contrast to the positive inotropic influence seen with leukotriene alone. Our results demonstrate a positive inotropic effect of low concentrations of LTC4 and LTD4 concomitant with coronary artery constriction, a phenomenon determined by leukotriene addition protocols and suggestive of LTC4/LTD4 receptor interaction. The effects of calcium channel antagonists and BAY K 8644 on the inotropic response suggest a leukotriene-mediated activation of the calcium channel resulting in increased intracellular calcium concentrations.

Cellular mechanism of the modulation of contractile function by coronary perfusion pressure in ferret hearts.

1. Isovolumic left ventricular pressure was measured at various coronary arterial pressures in Langendorff-perfused ferret hearts. The concentrations of phosphorus-containing metabolites were measured using 31P nuclear magnetic resonance (NMR). Intracellular free calcium concentration ([Ca2+]i), was measured with 19F NMR in a group of hearts that were loaded with the calcium indicator 5F-BAPTA. 2. Developed pressure increased when coronary arterial pressure was raised from the control value of 80 to 100-160 mmHg and decreased when coronary pressure was lowered to 40-70 mmHg. The changes were reversible. 3. Coronary flow varied directly with coronary pressure over the entire range from 40 to 160 mmHg. 4. The concentrations of phosphorus-containing metabolites and the efflux of lactate from the heart remained unchanged at coronary pressures of 60 mmHg or higher. Below 60 mmHg, intracellular pH decreased, while inorganic phosphate concentration and lactate efflux increased. 5. In contrast to the developed pressure during twitch contractions, maximal Ca2+-activated pressure remained constant at coronary pressures of 60-160 mmHg. Only below a coronary pressure of 60 mmHg did maximal Ca2+-activated pressure decline. 6. An increase in coronary pressure produced an increase in developed pressure even in hearts stretched to the peak of the Frank-Starling relation. 7. When coronary pressure was lowered from 80 to 60 mmHg, [Ca2+]i decreased during systole; the opposite effect was apparent when coronary pressure was raised from 80 to 120 mmHg. 8. We conclude that coronary perfusion (pressure or flow) modulates intracellular calcium and, consequently, contractile force. Ischaemia cannot fully explain this phenomenon, nor can changes in sarcomere length.

Effects of hydrodynamic forces on coronary production of prostacyclin and purines.

Prostacyclin and purine efflux rates from the isolated rabbit heart in response to variations of flow rate or perfusion pressure were investigated. Increases in coronary flow by 25, 50, and 100% augmented the effluxes of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and purines equally, by up to four times. Increases in coronary pressure by 25, 50, and 100% augmented the outflow of 6-keto-PGF1 alpha by up to 20 times, whereas the outflow of purines increased no more than 6.5 times. Neither reduction of perfusate Ca2+ by 50% nor administration of quinacrine (1 microM) affected the basal efflux of 6-keto-PGF1 alpha or its response to an increase in coronary pressure. Both interventions did, however, reduce the pressure-induced purine efflux by approximately 50%. Pulsatile flow did not affect either the outflow of 6-keto-PGF1 alpha or that of purines, in comparison to steady flow at the same rate. The data demonstrate that an increase in coronary pressure activates a specific mechanism for prostacyclin production that appears independent of extracellular Ca2+ and of phospholipase activity.

Altered coronary flow responses to vasoactive drugs in the presence of coronary arterial stenosis in the dog

Recent in vitro observations of human coronary arteries have suggested that intraluminal pressure can be a determinant of the resistance to flow through the stenosis. This study examined whether similar pressure-dependent changes in stenotic resistance could be observed and analyzed in an open chest, anesthetized, animal model of coronary arterial stenosis. Without stenosis, intracoronary isoproterenol (1 μg) or nitroglycerin (10 μg) increased flow and decreased coronary resistance, whereas methoxamine (500 μg) or vasopressin (0.2 U) decreased flow and increased coronary resistance. After partial arterial constriction, administration of isoproterenol (1 μg) resulted in a decrease in coronary pressure from 61.2 ± 2.5 to 39.4 ± 2.7 mm Hg (p ≤ 0.05), a 23 percent derease in distal coronary resistance (p ≤ 0.05) and a 22 percent decrease in flow associated with an increase in stenotic resistance of 2.34 ± 0.97 (p ≤ 0.05). Similarly, nitroglycerin caused a decrease in coronary pressure from 55.7 ± 3.1 to 42.1 ± 3.6 mm Hg (p ≤ 0.05), a 29 percent increase in distal coronary resistance and only a 1 percent increase in flow associated with a 38 percent increase in stenotic resistance. Methoxamine caused an increase in coronary pressure from 62.8 ± 2.0 to 73.6 ± 3.4 mm Hg (p ≤ 0.05), an 18 percent increase in distal coronary resistance, an 8 percent decrease in flow and a 10 percent decrease in stenotic resistance. Vasopressin caused an increase in coronary pressure from 61.0 ± 1.5 to 99.2 ± 7.1 mm Hg (p ≤ 0.05), a 239 percent increase in distal coronary resistance but only a 45 percent decrease in flow associated with a decrease in stenotic resistance of 1.33 ± 0.91 (p ≤ 0.05). Passive changes in the stenotic area caused by coronary pressure changes are postulated as part of the mechanism for the observed changes in stenotic resistance. This hypothesis is strengthened by the changes in stenotic resistance and radiographic analysis obtained from an in vitro carotid arterial preparation. The pressure-dependency of stenotic resistance could be an additional factor in the treatment of patients with coronary artery disease.

Drug-induced changes in blood flow in the acutley ischaemic canine myocardium;relationship to subendocardial driving pressure.

SUMMARY 1. The effects of various drugs have been studied on blood flow and oxygen handling (availability, extraction and consumption) in both normal and acutely ischaemic regions of the canine myocardium. Ischaemia was produced by the acute ligation of the anterior descending branch of the left coronary artery. 2. Lidoflazine, like other coronary vasodilator drugs, increases blood flow in the normal myocardium, but does not increase flow through the ischaemic region. Drugs of this type may, in addition, open up ‘shunt’ vessels within the ischaemic region. 3. Of three cardiac stimulants studied, only oxyfedrine consistently increases blood flow through the ischaemic region; isoprenaline and glucagon do not. 4. Noradrenaline causes marked increases in flow through the ischaemic region: its effect is associated with an increase in coronary pressure in the artery distal to the ligature. 5. Evidence is put forward that the critical factor determining flow through ischaemic regions of the myocardium is the transventricular driving pressure. When the effects of various drugs on flow and driving pressure are analysed and compared, the only drugs that increase flow in an ischaemic region are those that increase the pressure gradient across the wall of the left ventricle.