Coronary flow and thus myocardial perfusion is regulated by myogenic, metabolic, humoral and neuro-hormonal factors which closely interact with local autacoids released from the endothelial lining of the coronary bed. In a number of disease states an impaired synthesis and release of autacoids decisively limit the overall capacity of coronary regulation and adaptation of myocardial perfusion to increased metabolic demands. The important factors for these control mechanisms are analyzed and reviewed in this article.

Amino Acid Oxidoreductases↗

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Transmural distribution of myocardial blood flow and of coronary reserve in canine left ventricular hypertrophy.

Left ventricular hypertrophy was induced by banding of the ascending aorta in pupies at the age of 6 weeks. At the age of one year left ventricular weight per body weight was increased by 87% compared to control litter mates. While myocardial perfusion and myocardial oxygen consumption per 100 g were identical in the hypertrophy and control group, there was a significantly diminshed ratio of subendocardial/subepicardial flow in the hypertrophy group during moderate exercise. With maximal coronary dilation subendocardial diastolic resistance (mm Hg/ml-min-1 per 100 g) was 0.16 +/- 0.03 in the control group and 0.26 +/- 0.03 in the hypertrophy group. This diminished coronary reserve indicates an insufficient growth of the vascular bed in these hypertrophied hearts.

Animals↗

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Hemodynamic and myocardial effects of long-lasting venodilation in the conscious dog: analysis of molsidomine in comparison with nitrates.

The effect of molsidomine-induced venodilation on cardiac preload was studied in conscious resting dogs, instrumented to analyze left ventricular function and myocardial perfusion. Direct effects on veins were studied during chloralose anesthesia by measuring regional venous capacitance changes with an induction angiometer. Kinetics of molsidomine-induced effects were compared to those induced by nitroglycerin and isosorbide dinitrate. This comparison was restricted to low i.v. dosages, causing only transient threshold effects on peripheral resistance and heart rate. During molsidomine-induced venous pooling, neither any direct effect on the coronary circulation nor any direct cardiac depressant activity of the drug was detected. 100 microgram/kg molsidomine caused a reduction of left ventricular preload by 5 mm Hg, lasting at least 4 hours. This effect was significantly more pronounced than that induced by 1 microgram/kg nitroglycerin or by 25 microgram/kg isosorbide dinitrate, lasting 2 min or 20 min, respectively. However, in raising regional venous capacitance, these nitrate dosages were equi-effective to 100 microgram/kg molsidomine, the effect of which was persistent and with a greater delay in onset. These results indicate that the lasting persistance of venodilation is a decisive factor for the amount of volume pooled in the capacitance system and, consequently, for the extent of preload reduction obtained. It is concluded, that lasting vasodilation, restricted to the veins, is beneficial for ventricular performance in ischemic heart disease.

Animals↗

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Transmural differences in myocardial blood flow and in coronary dilatory capacity in hemodiluted conscious dogs.

In 16 conscious resting dogs regional myocardial blood flow and the local coronary dilatory capacity were studied with the particle distribution technique during isovolemic hemodilution (hct = 13%). Postischemic peak coronary hyperemia following release of temporary circumflex coronary artery occlusion was used for quantification of regional coronary dilatory capacity. In hemodilution (arterial blood oxygen content less than one third of normal) left ventricular blood flow (LVBF) was 460 +/- 36 ml/100 g - min, subendocardial/subepicardial flow amounted to 1.3 +/- 0.1. During postischemic peak hyperemia LVBF increased by 33% up to 606 +/- 63 ml/100 g - min. This 33% increase in LVBF was distributed mainly to the subepicardial layer, while in the subendocardial layer there was no significant flow increase. It is concluded that the increase in heart rate and systolic coronary vascular compression in addition to the lowered arterial oxygen content lead to exhaustion of the dilatory reserve in the subendocardium during hemodilution. Therefore the remaining overall dilatory capacity is without functional significance.

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The role of endothelium in the control of vascular tone.

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilatations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such varying stimuli as increases in blood flow and hypoxia, as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells, resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented, which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.

Acetylcholine↗

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Ergonovine-induced constrictions of epicardial coronary arteries in conscious dogs: alpha-adrenoceptors are not involved.

The effect of i.v. ergonovine tartrate infusions (0.05-20 micrograms/kg/min, 12 minutes duration) on coronary arteries was studied in 14 conscious dogs instrumented to continuously measure vascular diameter by an ultrasonic dimension gauge using 10-MHz piezoelectric crystals. Ergonovine induced a biphasic coronary response: small, transient dilation during the first minutes of infusion, followed by slowly developing constriction reaching its maximum 5 to 15 minutes after the end of the infusion and persisting at this level for at least 10 minutes. The threshold dosage for significant constriction was 0.05 microgram/kg/min. A dosage of 5 micrograms/kg/min (cumulative 60 micrograms/kg, corresponding to 35 micrograms/kg ergonovine maleate) caused a decline in mean left circumflex artery diameter by 137 +/- 15 micrometers (= 4.6%) without significantly altering heart rate, plasma catecholamines or plasma renin activity. Coronary venous O2 saturation did not decline, indicating the absence of coronary resistance vessel constriction. The epicardial artery constriction was not attenuated by a vasopressin antagonist. Under adrenergic blockade (2 mg/kg phentolamine and 2 mg/kg nadolol) or under ganglionic blockade (5 mg/kg pentolinium tartrate), ergonovine (5 micrograms/kg /min) caused substantial elevation in mean arterial pressure, while the decline in coronary artery diameter was attenuated. When this increase in arterial pressure was prevented by appropriate bleeding, the ergonovine-induced coronary constriction was not diminished by adrenergic or ganglionic blockade. The serotonin antagonist methysergide (0.5 mg/kg) completely abolished the ergonovine-induced coronary artery vasomotion. It is concluded that ergonovine in dogs causes an epicardial coronary artery constriction comparable to the diffuse coronary artery narrowing in men not suffering from variant angina pectoris. These constrictions are not mediated by an adrenergic mechanism.

Adrenergic beta-Antagonists↗

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Increased effective vascular compliance and venous pooling of intravascular volume during sustained venodilation in conscious dogs.

The hemodynamic effects of the long-acting antianginal drug molsidomine were studied in 8 chronically instrumented conscious dogs by measuring the partition of the intravascular volume and the effective compliance of the total vascular bed. The blood volume of the resting dogs was varied by +/- 4 ml/kg in a cycle of blood infusion, withdrawal and reinfusion within 12 minutes. Relating the observed alterations in mean right atrial pressure to the induced changes in intravascular volume, an effective compliance of 2.9 +/- 0.4 ml. mm Hg-1 . kg -1 (mean +/- SD) was found. Heart rate, total peripheral vascular resistance and the local capacity of the distal femoral vein did not change significantly during the cycle of volume alterations. Following 0.1 mg/kg molsidomine i.v., mean right atrial pressure was lowered by 1.6 mm Hg and mean left atrial pressure by 3.4 mm Hg; the effective compliance was elevated to 4.7 +/- 0.6 ml . mm Hg-1. kg -1 (p less than 0.001), and the central blood volume was lowered from 17.8 +/- 3.1 to 14.8 +/0 3.3 ml/kg (p less than 0.01), while the total blood volume remained constant. The decline in stroke volume and the reflexly induced increase in heart rate correlated with the control heart rate. Mean arterial pressure declined from 101 +/- 7 to 91 +/- 14 mm Hg (p less than 0.05) and total peripheral vascular resistance remained unaffected. It is concluded that molsidomine exerts exerts its hypotensive effect by dilation within the vascular low-pressure system and that this dilation can be described quantitatively in conscious animals by the analysis of the total effective vascular compliance.

Animals↗

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Observations on coronary conductance artery vasomotion by induction angiometry and ultrasonic dimensions technique.

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Animals↗

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Endothelial modulation of coronary tone.

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Animals↗

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Endothelial function in different organs.

The endothelial lining represents an organ of 1.5 kg in an adult which is distributed throughout the body and serves multifunctional purposes. It regulates vascular growth processes and adaptations and controls the delicate equilibrium between coagulation-hemostasis and fibrinolysis. The endothelium is not only a simple diffusion barrier between the intravascular and extravascular space of blood and lymph vessels thus regulating permeability (ie, the fluid, metabolite and catabolite exchange), but synthetizes, releases, converts, activates and/or inactivates various vasoactive hormones. Thus, it regulates vascular tone and organ blood supply as well as lymphatic flow and expression of surface receptors for the activation of leukocytes eg, during inflammation. In different organs it has additional, organ specific functions (eg, cerebral endothelial lining/blood brain barrier, endothelium mediated changes in renal, splenic and hepatic function and in skeletal muscle perfusion) by generating various autacoids such as nitric oxide, prostaglandins, endothelins, hyperpolarizing factors, and so on. These autacoids are not only vasoactive compounds but also modulate the activation of transcription factors. The endothelial autacoids exert an important role in vascular homeostasis (eg, by direct inhibition of atherogenesis and by inhibition of proatherogenic genes).

Animals↗