Differences in Direct Effects of Adrenergic Stimuli on Coronary, Cutaneous, and Muscular Vessels

Direct effects of adrenergic stimuli on coronary vessels in dogs were compared with effects on vessels to skin (hind paw) and skeletal muscle (gracilis muscle) after intravenous administration of practolol (2 mg/kg), a selective myocardial beta receptor blocker which minimized indirect effects of myocardial stimulation on coronary vascular resistance. The left circumflex coronary, cranial tibial, and gracilis arteries were perfused separately but simultaneously at constant flow. Perfusion pressures, left ventricular pressure and dP/dt. and heart rate were recorded. Changes in perfusion pressure to each bed reflected changes in vascular resistance.The direct constrictor effects of sympathetic nerve stimulation, norepinephrine and phenylephrine on coronary vessels were minimal compared with effects on cutaneous and muscular vessels. Subsequent blockade of vascular beta receptors did not augment the constrictor responses. Angiotensin, a nonadrenergic stimulus, produced striking coronary vasoconstriction which exceeded that in skin and approximated that in muscle. These results suggests that there is a paucity of alpha adrenergic receptors in coronary vessels compared to cutaneous and muscular vessels.Direct dilator responses to isoproterenol were similar in coronary and cutaneous vessels, but were greater in muscular vessels. Responses to glyceryl trinitrate, a nonadrenergic dilator, also were greater in skeletal muscle. Therefore, differences in effects of isoproterenol on the three beds may reflect differences in reactivity to dilator stimuli rather than differences in the density of beta receptors.In contrast to norepinephrine, the predominant direct effect of epinephrine on coronary vessels was dilatation mediated through activation of vascular beta receptors. A constrictor effect caused by stimulation of alpha receptors was unmasked by propranolol.Finally, the order of potency of agonists in stimulating coronary vascular beta receptors and the demonstration of selective beta receptor blockade with practolol suggest that beta receptors in coronary vessels resemble those in peripheral vessels more than those in myocardium.     

Effects of Catecholamines, Exercise, and Nitroglycerin on the Normal and Ischemic Myocardium in Conscious Dogs

The effects of isoproterenol, norepinephrine, dobutamine, exercise, and nitroglycerin on left ventricular diameter, pressure, velocity of shortening, dP/dt, dP/dt/P, arterial pressure, left circumflex coronary blood flow, and coronary vascular resistance were examined in healthy conscious dogs with normal coronary perfusion and in the same animals after moderate global ischemia had been induced by partial occlusion of the left main coronary artery. In the normal nonischemic heart, all interventions improved left ventricular performance, as evidenced by increases in dP/dt/P and velocity at the same or lower left ventricular end-diastolic diameter. Interventions, which in the normal heart caused large increases in heart rate and myocardial contractility, e.g. isoproterenol and exercise, or which decreased coronary perfusion pressure, e.g. nitroglycerin or isoproterenol, elicited paradoxical responses in moderate global ischemia, i.e., left ventricular enddiastolic diameter and pressure rose, and dP/dt/P and velocity fell substantially. On the other hand, norepinephrine, which increased coronary perfusion pressure along with myocardial contractility but did not increase heart rate, improved left ventricular function. Dobutamine, which did not alter heart rate or arterial pressure substantially while improving myocardial contractility, produced an intermediate response between that of norepinephrine and isoproterenol in the presence of moderate global myocardial ischemia. Thus, interventions that increase myocardial O(2) requirements, by increasing heart rate and myocardial contractility without augmenting coronary perfusion pressure, can produce a paradoxical depression of ventricular function in the presence of global myocardial ischemia.     

Effects of epinephrine, isoproterenol and IPS-339 on sympathetic transmission to the dog heart: evidence against the facilitatory role of presynaptic beta adrenoceptors

The autoregulation of norepinephrine (NE) release mediated by presynaptic alpha and beta adrenoceptors on sympathetic nerve terminals in the heart of pentobarbital-anesthetized dog was studied. NE overflow elicited by left cardiac sympathetic nerve stimulation was determined from the coronary sinus blood, by using high-performance liquid chromatography with electrochemical detection. Intracoronary infusion of epinephrine (1,3 and 10 micrograms/min) into the left circumflex artery increased basal left ventricular dp/dt maximum (LV dp/dt max) and coronary sinus blood flow. The epinephrine infusion decreased coronary sinus output of NE (NE output) during left cardiac sympathetic nerve stimulation. Intracoronary infusion of isoproterenol (0.03, 0.1 and 0.3 microgram/min) increased the basal LV dp/dt max and coronary sinus blood flow, whereas the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow were not altered by its infusions. Intravenous injection of IPS-339 (0.03, 0.1 and 0.3 mg/kg), a selective beta-2 adrenoceptor antagonist, diminished the stimulation-induced increases in LV dp/dt max and coronary sinus blood flow in a dose-dependent manner, whereas it did not decrease the stimulation-induced increase in NE output. Intracoronary infusion of yohimbine (10, 30 and 100 micrograms/min), a preferentially selective alpha-2 adrenoceptor antagonist, facilitated the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow. There was no significant difference in the facilitation of the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow between intracoronary infusion of both isoproterenol (0.1 microgram/min) and yohimbine (100 micrograms/min) and the infusion of yohimbine alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potentiation of the contractile effects of norepinephrine by hypoxia

Hypoxia has been found to depress the concentration response curve of norepinephrine (NE) in isoalted cat papillary muscles. To investigate the effects of hypoxia in intact hearts, a heart-lung preparation was developed and maximum left ventricular dp/dt (max dp/dt) was measured at constant heart rate, preload, and after load. Left main coronary arterial flow (Q(e)) was measured with an electromagnetic flow probe. As arterial P(O2) decreased from 90 mm Hg (96% saturation) to 20-25 mm Hg (40% saturation) at constant P(CO2) and pH, no change in max dp/dt occurred and Q(e) increased 298%. In contrast to cat papillary muscles, the contractile responses to NE were augmented in hypoxia. The NE dose-response curves shifted to the left. No deterioration of contractility occurred after exposure to NE. In contrast, the chronotropic response was unaltered in hypoxia. Dose-response curves to isoproterenol also were shifted to the left in hypoxia, but responses to paired pacing were unchanged. The responses to NE under oxygenated conditions were unaltered by mechanically increased coronary flow or by increased coronary flow with nitroglycerin. Although the mechanisms responsible for these effects are unknown, the results suggest that hypoxia may open previously nonfunctioning vascular channels and thereby allow more extensive exposure of beta adrenergic receptors to circulating catecholamines.     

Specific enhancement of norepinephrine-induced contraction in rat veins after beta adrenergic antagonists.

Propranolol markedly increased the norepinephrine-induced maximal force in circular smooth muscle of the rat portal, mesenteric, renal and, to a lesser extent, femoral veins without affecting aortic or mesenteric artery responses to norepinephrine. Furthermore, two other beta receptor antagonists, practolol and N-isopropylmethoxamine, specifically enhanced maximal venous responses to norepinephrine. Contractions to norepinephrine, but not to serotonin, were increased by propranolol only in veins, even after the vasodilator, papaverine. The ability of propranolol to enhance norepinephrine-induced contraction in these rat veins paralleled the effectiveness of isoproterenol to relax such tissues. In addition, beta receptor antagonists enhanced the response of veins to the field stimulated release of norepinephrine from sympathetic nerves. These data support the conclusion that beta adrenergic stimulation modulates norepinephrine-induced constriction in certain rat veins but not in the aorta or mesenteric artery.     

In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol

Effects of prolonged in vivo infusion of isoproterenol on acute cardiovascular responses to isoproterenol, dopamine and tyramine were studied in pithed rats. Isoproterenol infusion resulted in a significant decrease in control values for maximum left ventricular dP/dt; heart rate and left ventricular systolic blood pressure were not altered. This treatment also depleted both atrial and ventricular stores of norepinephrine and caused cardiac hypertrophy. Isoproterenol infusion resulted in a desensitization of drug-induced cardiovascular responses. The acute in vivo effects of isoproterenol on maximum left ventricular dP/dt, heart rate and left ventricular systolic blood pressure responses to isoproterenol were severely attenuated. The ED50 for maximum left ventricular dP/dt was increased 36-fold and maximal responses were reduced by half; changes in heart rate occurred in a parallel fashion. By contrast, ED50 values for inotropic responses to tyramine and dopamine were increased 14- and 4-fold, respectively, whereas increases in heart rate were blunted. Tyramine and dopamine-mediated increases in heart rate were completely attenuated by desensitization; chronotropic effects were again evident after pretreatment with the selective alpha-1 blocker prazosin. In addition, prazosin blocked the inotropic responses to tyramine and dopamine after desensitization and this antagonism was only slightly enhanced by addition of propranolol (prazosin + propranolol); propranolol alone was ineffective. These results are consistent with the down-regulation of beta adrenoceptors after prolonged exposure to catecholamines and indicate that under such conditions the alpha-mediated cardiovascular responses may be unmasked. Compared to pure beta agonists, agents with a degree of alpha-1 activity might be superior inotropes in heart failure patients who characteristically present with depleted stores of myocardial norepinephrine and minimal beta adrenoceptor reserve.     

Selective beta-1 receptor blockade with oral practolol in man. A dose-related phenomenon.

The purpose of this study was to test the hypothesis that oral administration of a low dose of practolol in man produces selective beta-1 receptor blockade, whereas oral administration of a high dose blocks both beta-1 and beta-2 receptors. Normal men were studied 2-4 h after a single oral dose of practolol (1.5 or 12 mg/kg) and after placebo. Effects on beta-1 receptors were studied by measuring heart rate responses to exercise. Effects on beta-2 receptors were tested by measuring forearm vascular responses to brachial arterial infusions of isoproterenol. Neither dose of practolol altered base-line heart rate, forearm vascular resistance, and arterial pressure, Both low and high doses significantly attenuated heart rate responses to exercise. Forearm vasodilator responses to isoproterenol were attenuated by the high dose, but not the low dose, of practolol. Serum concentrations of practolol 2 h after administration of the drug and at the time of the studies of forearm vascular responses averaged 0.5+/-0.1 (SE) and 5.9+/-1.0 mug/ml for low and high doses of practolol, respectively. The results indicate that the phenomenon of selective beta-1 receptor blockade in man is related to the dose and serum concentration of practolol selectively block beta-1 receptors; a high dose and serum concentrations block both beta-1 and beta-2 receptors.     

Effects of Increasing Heart Rate Induced by Efferent Sympathetic Neuronal Stimulation, Isoproterenol or Cardiac Pacing on Myocardial Function and Oxygen Utilization

The effects of increasing heart rate by six different methods on cardiac /unction were investigated in 17 open-chest anesthetized dogs. Heart rate was increased approximately 30% by (1) right interganglionic nerve stimulation, (2) atrial pacing, (3) ventricular pacing, (4) atriovenfricular sequential pacing, (5) right stellate ganglion stimulntion, and (6) isoproterenoi administration. During heart rate increases induced by atrial pacing left ventricular intramyocardial pressure, coronary Wood flow, oxygen delivery per unit of myocardial oxygen consumption, and myocardial efficiency were unchanged. Ventricular pacing reduced left ventricular cavity and septal intramyocardial pressure, while circumflex coronary flow increased, resulting in reduced oxygen delivery relative to myocardial oxygen consumption. Similarly, atrioventricu-lar sequential pacing increased circumflex coronary artery flow and myocardial oxygen consumption, and decreased septal intramyocardial pressure and oxygen delivery per unit of myocardial oxygen consumption. Right stellate ganglion stimulation and isoproterenol increased left anterior descending and circumflex coronary artery blood flow, intramyocardial pressure, and myocardial oxygen consumption. Estimated myocardial efficiency (left ventricle) was decreased by ventricular pacing and isoproterenol, and was unchanged by atrial pacing and right interganglionic nerve stimulation. Increases in heart rate induced by right interganglionic nerve stimulation did not alter myocardial oxygen consumption, or the index of cardiac efficiency. It is concluded that augmentation of heart rate by either ventricular or atrioventricular pacing impairs myocardial function so that there is a decrease of left ventricular efficiency, and isoproterenol augments chronotropism and myocardial force relative to cardiac external work so there is a reduction in cardiac efficiency. In contrast, atrial pacing or right interganglionic nerve stimulation augments chronotropism such that myocardial oxygen consumption and efficiency are unchanged.     

The effect of sustained stellate ganglion stimulation on left ventricular contractility in the dog

Although a progressive reduction in left ventricular contractility during sustained left stellate ganglion stimulation has been well documented, there have been no reports on the contractile state after nerve stimulation. Left ventricular contractility after cessation of 60 min of electrical (10 V. 10 Hz. 1 msec) left stellate ganglion stimulation has been assessed in open chest dogs. Before and 15 min after stimulation, left ventricular contractility was evaluated by the end-systolic pressure-segment length relationship using ultrasonic crystals during a stepwise aortic constriction to increase left ventricular afterload. Restimulation of the left stellate ganglion was also performed 15 min after cessation of the first stimulation. After sustained left stellate ganglion stimulation, the end-systolic points shifted to the right from the control and the slope of multiple pressure-segment length coordinates significantly decreased (102.5 +/- 16.1 to 76.5 +/- 10.2 mmHg/mm, mean +/- S.E., p less than 0.05, n = 5), indicating a depression of left ventricular contractility. Increased left ventricular dP/dt max and norepinephrine level in the coronary sinus gradually returned to near base line during 60 min of stimulation. These reduced responses lasted for at least 15 min after cessation of stimulation. The myocardial norepinephrine content was reduced to 0.59 +/- 0.08 (mean +/- S.E.) ng/mg wet tissue from 0.90 +/- 0.15 of the control level (p less than 0.05). These data suggested that left ventricular contractility decreased after sustained cardiac sympathetic nerve stimulation, probably due to norepinephrine reduction in the myocardium.     

Spasm of the coronary arteries: causes and consequences (the scientist's viewpoint)

Both beta 1- and alpha 1-adrenoceptors are present on canine coronary arteries, and they are accessible to norepinephrine released from the sympathetic nerves. Under normal conditions, these arteries relax because of the predominance of the beta 1-adrenoceptors, whereas constriction prevails in the presence of beta 1-adrenoceptor antagonists. The coronary arteries also have cholinergic nerves. When activated, these nerves release acetylcholine, which acts on muscarinic receptors on the sympathetic nerve terminals to reduce the output of norepinephrine and thereby lessen the relaxation mediated by beta 1-adrenoceptors. Thus, muscarinic agonists can precipitate coronary artery spasm. If the smooth muscle cells of the coronary arteries become hypoxic, their responsiveness to beta-adrenergic stimulation is lost and constrictor responses are exaggerated. Cardiac glycosides prevent the predominance of the beta-adrenergic effects of norepinephrine. Therefore, after treatment with ouabain, release of norepinephrine from the sympathetic nerves leads not to relaxation but to further contraction of coronary arteries. The endothelium of the coronary arteries inhibits platelet aggregation by the formation and release of prostacyclin, and it reacts to platelet products by causing relaxation of the underlying smooth muscle. In addition, if any thrombin is formed, it also causes endothelium-mediated relaxation. If the endothelium is damaged, these protective mechanisms are lost. Patients with coronary artery spasm usually have morphologic changes in the artery at the site of the spasm. Platelets can aggregate at this site and release vasoactive substances, which--aided by formation of thrombin--cause contraction. Thus, the blood supply to the myocardium is reduced; the ensuing hypoxia augments the constriction. Acute myocardial ischemia caused by coronary vasospasm may precipitate acute cardiac rhythm disturbances and sudden death by ventricular tachycardia or fibrillation.     

Enhancement by yohimbine of nicotine- and dimethylphenylpiperadinium-induced release of norepinephrine from cardiac sympathetic nerves of the dog: interaction of presynaptic alpha and nicotinic receptors

The effect of yohimbine on nicotine- and dimethylphenylpiperadinium (DMPP)-induced release of norepinephrine (NE) from sympathetic cardiac nerves of the dog was examined in order to elucidate the interaction of presynaptic alpha and nicotinic receptors. Intracoronary infusion of nicotine (300 or 500 micrograms/min) or DMPP (100 or 300 micrograms/min) into the left circumflex artery increased coronary sinus output of NE (NE output), left ventricular dp/dt maximum (LV dp/dt max) and coronary sinus blood flow. The nicotine-induced increases in NE output, LV dp/dt max and coronary sinus blood flow were enhanced by simultaneous yohimbine infusion in doses of 10 and 30 micrograms/min into the same artery, and were attenuated by the drug in a dose of 100 micrograms/min. The DMPP-induced increases were enhanced by 10 micrograms/min of yohimbine infusion, but the enhancement was decreased by 30 and 100 micrograms/min. Yohimbine did not modify increases in NE output, LV dp/dt max and coronary sinus blood flow induced by intracoronary infusion of tyramine (100 micrograms/min). We have reported previously that yohimbine in the dose range used enhanced cardiac sympathetic nerve stimulation-induced increases in these parameters in a dose-dependent manner in the same preparation. The enhancement by yohimbine of nicotinic receptor-mediated NE release would be due to the blockade of presynaptic alpha-2 adrenoceptors. Therefore, it is suggested that presynaptic alpha-2 adrenoceptor-mediated feedback control operates on the process of NE release induced by nicotinic receptor activation as well as nerve stimulation. Although the mechanism of loss of the enhancement of the nicotinic effect by the large dose of yohimbine is not known, the possible mechanisms are discussed.     

Pharmacodynamic Studies of Beta Adrenergic Antagonism Induced in Man by Propranolol and Practolol

The pharmacodynamic activities of two beta adrenergic antagonists, propranolol and practolol, were compared in eight hypertensive patients. The activity of each antagonist was established in relation to its blood concentration at maximal and submaximal adrenergic blockade defined by inhibition of exercise tachycardia. Maximal inhibition of exercise tachycardia was comparable with both drugs and averaged 74+/-7% of the control value during drug treatment. This inhibition was achieved with a blood concentration of 2.5+/-0.4 mug/ml practolol and 0.10+/-0.08 mug/ml propranolol. The antagonist activities of these drugs against adrenergic stimulation with isoproterenol infusion indicated a much greater relative potency of propranolol against this stimulus, and in vivo estimates of PA(2) values differed by more than 600-fold. Relative antagonist activity of practolol during isoproterenol stimulation was equivalent both at cardiac (inotropic and chronotropic) and at vascular adrenergic receptors, whereas greater antagonist activity of propranolol was observed at vascular receptors than at cardiac receptors. Thus, the activity of practolol was not limited to cardiac receptors as previously suggested. Practolol did not reduce cardiac output at any dose level and the effect on resting blood pressure was small. Both practolol and propranolol had much greater hypotensive activity during exercise. These studies have defined the differing pharmacodynamic activities on the cardiovascular system of two effective beta adrenergic receptor antagonists and have established the blood levels of these antagonists necessary to achieve effective adrenergic blockade.     

Beta-receptor mechanisms in the superficial limb veins of the dog

The lateral saphenous vein of dogs was perfused at constant flow with autologous arterial blood, and perfusion and femoral vein pressures were monitored; changes in the difference between these pressures were due to changes in venomotor activity. Injection of isoproterenol into the perfusate caused the vein to dilate. The amount of dilatation depended on smooth muscle tension in the wall of the vein before injection. When this was minimal (after sympathectomy), isoproterenol had no effect. During venoconstriction produced by electrical stimulation of the lumbar sympathetic chain or by the infusion of venoconstrictor drugs, the dilating action of 0.1 mg of isoproterenol was measured. Expressed as a percentage of the initial constriction caused by sympathetic stimulation, 5-hydroxytryptamine, or 1 M potassium chloride, the extent of the dilatation was 86.7+/-4.3 (SE of mean), 79.7+/-4.2, and 87.7+/-3.2, respectively. With norepinephrine and epinephrine infusions, the isoproterenol dilatations were less (65.1+/-9.0 and 55.2+/-7.2, respectively), consistent with the stimulant action of these agents on both alpha and beta receptors; such action was confirmed by comparing the responses to nerve stimulation and infusions of norepinephrine and epinephrine before and after betareceptor blockade. The venoconstriction caused by sympathetic stimulation and by infusions of norepinephrine and epinephrine was greatly enhanced by cooling the vein (decreasing perfusate temperature), but the dilating action of isoproterenol appeared to be insensitive to changes in temperature. The data suggest that beta receptors are specific entities and, when maximally stimulated, are capable of causing a venous relaxation that is proportional to the initial degree of tension in the vein wall.     

Neurogenic cholinergic prejunctional inhibition of sympathetic beta adrenergic relaxation in the canine coronary artery

Electrical stimulation of isolated canine coronary arteries causes release of norepinephrine and subsequent relaxation by activation of beta adrenoceptors. The purpose of the present study was to determine if this beta adrenergic relaxation was influenced by a concomitant release of acetylcholine. Rings of epicardial coronary arteries of the dog were studied in organ chambers filled with physiological salt solution. The tetrodotoxin-sensitive, beta adrenergically mediated relaxation induced by electrical stimulation was studied during contractions evoked by prostaglandin F2 alpha. The relaxation to low-frequency stimulation was inhibited and augmented, respectively, by acetylcholine and atropine, suggesting that release of acetylcholine may modulate the beta adrenergic response to sympathetic nerve stimulation. The relaxation caused by high-frequency stimulation was not affected by atropine or removal of the endothelium, indicating that endogenously released acetylcholine does not act directly on the smooth muscle or initiate an endothelium-dependent vasodilator response. In superfused strips of coronary artery preincubated in [3H]norepinephrine, acetylcholine depressed the stimulated overflow of [3H]norepinephrine, indicating prejunctional cholinergic receptors on adrenergic nerve endings. Atropine augmented the overflow, suggesting that endogenous acetylcholine, released during stimulation, inhibits the release of norepinephrine. These observations suggest that prejunctional inhibition of norepinephrine release, which limits the sympathetic beta adrenergic relaxation of the smooth muscle, is the primary neurogenic cholinergic effect in canine epicardial coronary arteries.     

Effect of inhibition of lipolysis on myocardial oxygen consumption in the presence of isoproterenol

The effect of intravenous infusion of isoproterenol on myocardial oxygen consumption (MVo(2)) was studied in 10 intact and anesthetized dogs before and after inhibition of lipolysis. In five dogs lipolysis was inhibited by nicotinic acid or beta pyridyl carbinol and in five other dogs by high plasma glucose concentrations. In spite of similar mechanical responses to isoproterenol, as evidenced by left ventricular pressure, maximal rate of rise of left ventricular pressure (dP/dt), heart rate and cardiac output, augmentation of MVo(2) was larger before (on average 7.6 ml/min.100 g) than after inhibition of lipolysis either by antilipolytic drugs (on average 4.5 ml/min.100 g) (P < 0.005), or by high plasma glucose concentrations (on average 4.3 ml/min.100 g) (P < 0.02). As mechanical responses to isoproterenol were similar before and after inhibition of lipolysis, it is concluded that the additional rise in MVo(2) with intact lipolysis was caused by a metabolic stimulation by high concentrations of free fatty acids.     

Arterial hypoxemia in awake dogs. Role of the sympathetic nervous system in mediating the systemic hemodynamic and regional blood flow responses

The role of the sympathetic nervous system in the systemic hemodynamic and regional blood flow responses to hypoxia was studied in awake dogs by pre-exposing the animals to phentolamine alone (alpha block) or to phentolamine plus propranolol (alpha + beta block). Hypoxia was produced by switching from room air to either an 8% or 5% oxygen-nitrogen mixture. During 8% oxygen breathing, cardiac output, heart rate, left ventricular dP/dt, dP/dt/P, myocardial oxygen consumption, and myocardial blood flow increased, and both total peripheral and coronary vascular resistance fell. These changes were similar in all groups with and without adrenergic blockade. However, during 5% oxygen breathing, the rises in cardiac output, heart rate, left ventricular dP/dt, myocardial oxygen consumption, and myocardial blood flow and the decrease in coronary vascular resistance were less marked in the group given alpha + beta block than the intact animals or group given alpha block. Coronary blood flow correlated with myocardial metabolic demands. Adrenal and skeletal muscle blood flows increased during hypoxia. Breathing 5% oxygen also increased flow to the brain, but renal and splanchnic flows showed only minor changes. These changes in organ vascular resistance were unaffected by the adrenergic blockade. Our results indicate that although the sympathetic nervous system plays an important role in the systemic hemodynamic responses to hypoxia, the dominant local metabolic factors probably are primarily responsible for hypoxic vasodilation in the awake dog.     

Adenosine selectively attenuates H2- and beta-mediated cardiac responses to histamine and norepinephrine: an unmasking of H1- and alpha-mediated responses

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.     

Responses of saphenous and mesenteric veins to administration of dopamine

Others have observed that dopamine (3,4-dihydroxyphenylethylamine) constricts resistance vessels in skin, but dilates these vessels in the mesentery. We studied the effects of dopamine on cutaneous and mesenteric veins of dogs to see if this agent also produced qualitatively different effects on the tone of capacitance vessels (veins) in these vascular beds. The lateral saphenous or the left colic vein was perfused at constant flow with blood from a femoral artery. Pressures at the tip of the perfusion cannula and at the tip of a catheter 15 cm downstream were recorded continuously. Increases in the pressure gradient between these two points indicated venoconstriction; decreases indicated venodilatation. Dopamine and norepinephrine injected into the perfusion tubing caused constriction of both veins. The constriction was antagonized by blockade of alpha receptors. A dilator action of dopamine was not seen, even after alpha receptor blockade or in the presence of increased venous tone produced by serotonin, norepinephrine, or nerve stimulation. Reserpine and cocaine did not alter responses to dopamine in the saphenous vein; this suggests that the venoconstrictor action of dopamine results mainly from a direct effect on alpha receptors and that uptake into sympathetic nerve endings may not be important in regulating the amount of dopamine available to receptors in the saphenous vein.     

Adenosine receptor-mediated alterations in prostacyclin production and cardiac function in the isolated rabbit heart.

The subtype of adenosine receptor linked to cardiac prostacyclin (PGI2) synthesis, measured as immunoreactive 6-keto-PGF1 alpha, was investigated in the rabbit heart perfused with Krebs' buffer at 20 ml/min. Adenosine (6.4-50 nmol) decreased 6-keto-PGF1 alpha synthesis, coronary perfusion pressure (PP) and myocardial contractility (dp/dt max), whereas higher doses (200 nmol) increased 6-keto-PGF1 alpha output and decreased PP, heart rate (HR) and dp/dt max. Injections (3.2-50 nmol) or infusion (0.6 microM) of A1 receptor agonist 1-deaza,2-chloro,N6 cyclopentyladenosine increased 6-keto-PGF1 alpha production and decreased HR and PP without affecting dp/dt max. 1-Deaza,2-chloro,N6 cyclopentyladenosine 100 to 200 nmol produced similar effects as lower doses except that it decreased transiently PP and reduced dp/dt max. 1,3-Dipropyl,8-cyclopentylxanthine (0.06 microM) prevented the effects of 1-deaza,2-chloro,N6 cyclopentyladenosine (50 mumol) and adenosine (10 microM) to increase 6-keto-PGF1 alpha output and decrease HR and minimized the decrease in dp/dt max. A2 receptor agonist 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido-ade nos ine (1.6-12.5 nmol) or 0.6 microM decreased 6-keto-PGF1 alpha output, PP and dp/dt max without changes in HR. 3,7-Dimethyl-1-propargylxanthine prevented 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine-induced decrease in 6-keto-PGF1 alpha output, PP and dp/dt max; HR was not altered by this agent. These data suggest that stimulation of A2 receptors reduce cardiac PGI2 synthesis and PP, but activation of A1 adenosine receptors increased PGI2 synthesis, produced vasoconstriction and decreased HR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extent of Carotid Sinus Regulation of the Myocardial Contractile State in Conscious Dogs

The effects of bilateral carotid artery occlusion (BCO) and carotid sinus nerve stimulation (CSNS) on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (V), rate of change of pressure (dP/dt), and cardiac output were studied in conscious dogs instrumented with ultrasonic diameter gauges, miniature pressure gauges, and aortic electromagnetic flow transducers. The effects of BCO and CSNS were also studied after automatic blockade and were compared to similar alterations in pressure produced by norepinephrine, methoxamine, and nitroglycerin. When heart rate was maintained constant with atrial stimulation, BCO had little effect on ventricular contractility, increasing isolength systolic pressure (LV P(iso)) by 36% while isolength velocity of myocardial shortening (V(iso)) decreased by 12% and (dP/dt)/P fell by 8%. These effects could be explained largely by vasoconstriction, since elevating systolic pressure with methoxamine produced similar results, while norepinephrine increased V(iso) by 36% and (dP/dt)/P by 56%. CSNS produced directionally opposite results from BCO; it decreased P(iso) by 15%, V(iso) increased by 11%, while (dP/dt)/P remained almost constant. These effects may be explained largely by vasodilatation since reducing systolic pressure to the same level with nitroglycerin produced similar results. When peripheral vasoconstriction was minimized by phenoxybenzamine pretreatment. BCO produced a slight positive inotropic effect (P(iso) increased by 8%, V(iso) by 4%, and (dp/dt)/P by 10%), while CSNS produced a slight negative inotropic effect (P(iso) decreased by 3%, V(iso) decreased by 5%, and (dP/dt)/P by 7%).Thus, in the normal, healthy, conscious dog, the carotid sinuses exert relatively little control of the inotropic state of the left ventricle; moreover, this small inotropic action is masked by the more powerful effects on peripheral resistance.