G Losano

NEW INSIGHTS INTO NITRIC OXIDE AND CORONARY CIRCULATION

Since its discovery over 20 years ago as an intercellular messenger, nitric oxide (NO), has been extensively studied with regard to its involvement in the control of the circulation and, more recently, in the prevention of atherosclerosis. The importance of NO in coronary blood flow control has also been recognized. NO-independent vasodilation causes increased shear stress within the blood vessel which, in turn, stimulates endothelial NO synthase activation, NO release and prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and vasodilator effects of acetylcholine and bradykinin are all mediated by NO. Ischemic preconditioning, which protects the myocardium from cellular damage and arrhythmias, is itself linked with NO and both the first and second windows of protection may be due to NO release. Exercise increases NO synthesis via increases in shear stress and pulse pressure and so it is likely that NO is an important blood flow regulatory mechanism in exercise. This phenomenon may account for the beneficial effects of exercise seen in atherosclerotic individuals. Whilst NO plays a protective role in preventing atherosclerosis via superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO release leading the way for endothelial dysfunction and atherosclerotic lesions. Exercise reverses this process by stimulating NO synthesis and release. Other factors impacting on the activity of NO include estrogens, endothelins, adrenomedullin and adenosine, the last appearing to be a compensatory pathway for coronary control in the presence of NO inhibition. These studies reinforce the pivotal role played by the substance in the control of coronary circulation.

THE ROLE OF NITRIC OXIDE IN THE INITIATION AND IN THE DURATION OF SOME VASODILATOR RESPONSES IN THE CORONARY CIRCULATION

In the coronary bed vasodilatation can be mediated by several mechanisms including endothelium-produced nitric oxide. To examine the contribution of nitric oxide, three different techniques to cause vasodilatation in the coronary vessels were used in the anaesthetized dog: intracoronary injection of 1 μg; acetylcholine, sudden reduction of the aortic blood pressure inducing a myogenic response and transient occlusion followed by release of the left circumflex coronary artery causing reactive hyperaemia. Each manoeuvre was performed before and after intracoronary adminstration of 100 mg N-nitro-l-arginine, an inhibitor of the synthesis of nitric oxide. In contrast to previous investigations, the inhibition of nitric oxide synthesis was prevented from causing an increase in blood pressure by the use of a blood-pressure-compensating device. The results observed during each of the three techniques, suggest that the initial cause of the vasodilatation is not the result of the increase of the production of nitric oxide. However, subsequent to the initiation of vasodilatation, an increase in the shear stress can result in an increase in the release of nitric oxide from the vascular endothelium, thus prolonging the vasodilatation obtained using each technique.

The effect of Bitis gabonica (Gaboon viper) snake venom on external iliac and mesenteric arterial circulation in the dog

The effects of Gaboon viper (Bitis gabonica) venom on external iliac and mesenteric arterial blood flow and resistance were investigated in eight anaesthetized, close-chest dogs. Venom doses in the range 0.125-0.5 mg/kg produced a profound fall in external iliac and mesenteric arterial resistance, which recovered to control values after 30 min. After a third dose of venom, the mean arterial blood pressure failed to recover and the animals died after a period of severe hypotension. External iliac arterial blood flow rose concomitantly with the fall in external iliac resistance and decreased to a value significantly below control after 30 min. Paradoxically, mesenteric blood flow fell during the period of vasodilation. The results suggest that widespread vasodilation of muscle vascular beds (of which the external iliac circulation is representative) leads to shunting of blood away from the less-dilated mesenteric circulation. Venom-induced peritoneal haemorrhage caused a fall in blood volume and increase in viscosity. These undoubtedly contributed to the severe haemodynamic deterioration of the preparations after the third injection of the venom.

Systolic coronary flow impediment in the dog: role of ventricular pressure and contractility

The present study was planned to investigate the effect of left ventricular pressure and inotropic state on coronary arterial inflow in systole in the anaesthetized dog. A wide range of left ventricular systolic pressures, including the physiological range, were studied. Experiments were done under conditions of maximal vasodilatation and low perfusion pressure in order to avoid vascular autoregulative interference and to keep the microvascular pressure within the normal range. In five anaesthetized dogs, perfused with extracorporeal circulation system, ventricular volume was changed from 20 to 50 ml in steps of 10 ml by filling an intraventricular latex balloon, and the related changes in left ventricular pressure and coronary flow were measured. The volume was then extended to 70 ml to obtain an overstretch which induced a transient decrease in cardiac contractility. During the period of low cardiac contractility the volume was brought back to 20 ml in steps of 10 ml. Systolic ventricular pressure changed with volume but was lower during the period of low contractility. For systolic pressures below 100 mmHg there was no significant relationship between pressure and coronary systolic flow, but the relationship shifted to higher flows during low contractility. For systolic pressures above 100 mmHg systolic coronary flow decreased significantly when systolic pressure increased. In this case the slopes of the relationships were not significantly different before and after the reduction in contractility. These findings suggest that for systolic pressures less than 100 mmHg (i.e. below the physiological range) the shielding effect of the contracting ventricle prevents the ventricular pressure from being transmitted in the myocardial wall. When systolic pressure exceeds 100 mmHg the shielding effect is overcome and the amplitude of the systolic flow reduction varies with ventricular pressure.

The effect of Gaboon viper (Bitis gabonica) venom on cardiac stroke work in the anaesthetized rabbit

The effect of Bitis gabonica venom administered intravenously in the rabbit at the dose of 0.125 mg/kg (approximately 10% of LD50) has been studied. Venom caused marked changes in cardiovascular parameters principally a precipitous but transient fall in total peripheral resistance and arterial blood pressure. Furthermore in the period occurring between 5 and 30 min after the injection of venom, a transient increase in stroke work was observed as a result of the ejection of an increased stroke volume against a blood pressure which had already returned to normal. Such a transient inotropic effect has also been observed in other small mammals and could be attributed to an adrenergic mechanism.

Ventricular distension and diastolic coronary blood flow in the anaesthetized dog

SummaryThere appears to be no agreement as to whether or not an increase in diastolic left ventricular pressure and/or volume can cause a decrease in diastolic coronary blood flow. We investigated the problem in the anaesthetized dog using a flaccid freely distensible latex balloon inserted into the left ventricle with the animal on extracorporeal circulation and the coronary perfusion pressure constant at about 45 mm Hg. Maximal vasodilatation and suppression of autoregulation in coronary vasculature was obtained by the intracoronary infusion of dipyridamole (10–40 mg/h). Ventricular volume was changed in steps of 10 ml from 10 to 70 ml and back to 10 ml, whilst recording coronary blood flow and left ventricular pressure in the left circumflex coronary artery.Over a range of ventricular volumes from 20 to 50 ml and a concomitant rise in diastolic ventricular pressure to about 20 mm Hg there was no change in the diastolic coronary flow. Only when the ventricular volume was more than two times the control value (i.e. exceeded 50 ml) and left ventricular pressure was more than 20 mm Hg, was there a decrease in coronary flow. During the return of the volume to the control level there was a fall in diastolic flow and ventricular contractility with respect to the values obtained when the volume was increased; these two effects were transient lasting less than 10 min. It was not considered that any of the three models of the coronary circulation, waterfall, intramyocardial pump or varying elastance model could explain our results. The mechanisms suggested for the decrease in contractility are subendocardial ischaemia, a temporary damage of the endocardium or overstretch of the cardiac muscle. The lower contractility during the reduction of ventricular volume to control could explain, via the capacitive component of flow, the reduced diastolic coronary flow. The reduced coronary flow along with the reduced contractility could also result from incomplete recovery of the myocardium from the stress-relaxation where series elastic components are longer, sarcomeres shorter and muscle fibres thicker.

The mechanical effects of rhinoceros horned viper (Bitis nasicornis) venom on the isolated perfused guinea‐pig heart

In the guinea‐pig Langendorff heart preparation, addition of 0.1 mg Bitis nasicornis venom to the perfusion solution caused transient increases in heart rate (HR) and left ventricular systolic pressure (LVSP) with peak increases at 2 min. With higher doses (0.6 and 1.4 mg), these increases were followed by the return of HR to normal, significant decreases in LVSP below control values and marked increases in left ventricular diastolic pressure. Histaminergic blockade with ranitidine reduced the positive responses. The results suggest that a venom component, possibly acting on intracellular calcium movement, could be responsible for both positive and negative effects.

Coronary myogenic responses to abrupt changes in aortic blood pressure in anaesthetized dogs

A transient increase in coronary transmural pressure was produced in anaesthetized dogs by occlusion of the descending thoracic aorta. Aortic blood pressure (ABP), left ventricular pressure and coronary flow were measured; coronary vascular resistance (CVR) was calculated. Results were similar in innervated and denervated hearts. Occlusion for 10 and 20 s resulted in no change in CVR for 15 s, followed by a metabolic dilatation attributable to enhanced oxygen demand; after release the fall in ABP resulted in an immediate increase in CVR, caused by vascular elastic recoil, followed by hyperaemia.

Transient effects of quick changes in myocardial metabolism and perfusion pressure on coronary vasomotor responses

SummaryThe effects of transient changes in coronary transmural pressure on the coronary vasomotor tone was studied in 23 anesthetized dogs. Increases and decreases of the coronary transmural pressure were obtained by constrictions of various duration (2 to 20 s) of the descending thoracic aorta.The maneuvers were performed in animals with intact cardiac innervation, with the vagi sectioned and with vagal section together with β-blockade. In the absence of β-blockade the increase in the transmural pressure caused a transient increase in the coronary vasomotor tone attributable to a myogenic contractile response and the extravascular compression. This contractile response was not observed when the transmural pressure was increased in the presence of high vasomotor tone after β-blockade. In all animals a transient hyperemia was seen with its peak 8 to 12 s after the release of the aortic constriction. Since its timing and amplitude were independent of the duration of the constriction, the metabolic effect of the increased ventricular afterload, although it may have contributed to the decrease of the coronary resistance, cannot be considered entirely responsible for the hyperemia, which was otherwise compatible with a myogenic vasodilatory response triggered by the sudden fall of the transmural pressure at the release of the constriction.It is concluded that, in the coronary circulation of the intact dog, transient changes in transmural pressure can induce vasomotor responses in which myogenic and metabolic mechanisms combine together in regulating the coronary flow. Changes in extravascular compression can also affect the flow when the experimental maneuver implies changes in the diastolic left ventricular pressure and volume. With the present experimental procedure the myogenic responses have been evidenced when the metabolic factors would have been expected to produce opposite changes in the vasomotor tone.

Relationship between hyperaemic response and viscoelastic properties in the coronary circulation of the dog

A sudden reduction in perfusion pressure evokes a transient hyperaemic response in the coronary arteries of anaesthetized dogs; its characteristics depend on the vasomotor tone. A heuristic model, which mimics the vascular bed with a lumped second-order system on the lines of the well-known Windkessel model, but accounting for the blood inertia, is proposed to describe that response and to quantify the viscoelastic properties of the system.