The effect of sulfonylurea drugs on rabbit myocardial contractility, canine purkinje fiber automaticity, and adenyl cyclase activity from rabbit and human hearts

Long-term clinical studies have associated tolbutamide therapy with an increased incidence of cardiovascular deaths. The effects of this and other sulfonylurea drugs on contractility and rate of isolated rabbit atria, automaticity of isolated dog Purkinje fibers, and adenyl cyclase activity in particulate preparations of rabbit and human hearts were studied. At concentrations that are attained clinically, tolbutamide (10 mg/100 ml) increased contractility of driven rabbit atria to 124+/-5% of control, acetohexamide (3.9 mg/100 ml) to 140+/-5%, chlorpropamide (8.3 mg/100 ml) to 139+/-6%, and tolazamide (3.1 mg/100 ml) to 119+/-6%. These effects were accentuated in the presence of 2.5 x 10(-4) M theophylline and were not blocked by 1 x 10(-5) M propranolol. Adenyl cyclase was activated by each of these drugs at concentrations below those which increase contractility. The drugs also increased the rate and slope of phase 4 depolarization in spontaneously beating Purkinje fibers, but did not alter the spontaneous rate of isolated rabbit atria. Since inotropic and chronotropic stimulation can be deleterious in some clinical settings, these findings may be of significance in interpretation of cardiovascular mortality data.     

The influence of ketamine on inotropic and chronotropic responsiveness of heart muscle.

The influence of ketamine on the inotropic and chronotropic responsiveness of heart muscle was examined in spontaneously beating right atrial preparations and in electrically driven left atrial preparations of guinea pigs. Ketamine (2.63 X 10(-5) to 4.2 X 10(-4) M) decreased heart rate of right atria and decreased contractile tension and its maximum rate of increase in both right and left atrial preparations (right atria greater than left atria). Ketamine did not prevent the heart rate increase produced by norepinephrine (NE; 1 X 10(-8) to 1 X 10(-4) M) in right atria; however, the maximum heart rate was consistently lower in ketamine-treated than in control muscles even after exposure to NE. Although contractile tension was decreased by ketamine, the maximum inotropic response to NE was consistently greater in ketamine-treated atria than in control atria. An inhibitor of the slow Ca++ current in heart muscle, D600, depressed the contractile effects of NE but did not prevent the positive inotropic interaction of ketamine and NE. Ketamine similarly enhanced the inotropic responses to norepinephrine (1 X 10(-6) M), epinephrine (1 X 10(-6) M), isoproterenol (1 X 10(-7) M) and dibutyryl cyclic adenosine 3':5'-monophosphate (AMP; 4 X 10(-3) M) in left atria electrically paced at a constant frequency of contraction of 1 Hz; however, ketamine inhibited the positive inotropic response to increased frequency of stimulation (0.1-3.0 Hz) and to ouabain (3 X 10(-7) M). These findings demonstrate that ketamine can exert a selective positive inotropic influence in heart muscle independent of heart rate or direct or reflexogenic autonomic nervous system changes, and suggest that this activity could in some way be associated with an alteration of the intracellular disposition of cyclic AMP.     

A polypeptide (AP-A) from sea anemone (Anthopleura xanthogrammica) with potent positive inotropic action.

Anthopleurin-A (AP-A), a polypeptide with MW ca. 5500 (53 amino acids), isolated from the sea anemone, Anthopleura xanthogrammica (Brandt), elicited a potent positive inotropic effect but without an accompanying chronotropic effect on the isolated cardiac muscles of rat, rabbit, guinea pig and cat. Similarly in dogs and cats in situ, i.p. injections of AP-A increased the contractile force without effect on heart rate or blood pressure. The cardiotonic potency for AP-A was equivalent to that of isoproterenol but much greater than that for ouabain or glucagon on the isolated cardiac muscle. AP-A increased the contractile force (cardiac output) and decreased atrial pressure in dog heart during pentobarbital-induced failure. This inotropic effect was not inhibited by propranolol pretreatment. The Ca++ requirement to restore the contractile force was less in AP-A-treated than in ouabain or isoproterenol-treated tissues. After AP-A treatment, the cardiac contractility was more resistant to hypoxia and to low or high temperature stress than ouabain-treated or control preparations. AP-A at 5 10(-9) M increased the duration of the action potential, its mean rate of rise and conduction in the guinea-pig atria and ventricles. At the maximum effective concentration, AP-A did not inhibit Na+, K+-activated adenosine triphosphatase, phosphodiesterase (high Km and low Km) and cyclic 3',5'-adenosine monophosphate content of guinea-pig heart. AP-A (5 X 10(-8) to 5 X 10(-7) M) neither contracted nor relaxed the isolated vascular smooth muscle. The results suggest that AP-A may be useful in the clinical management of cardiac failure and as an experimental tool to study the pharmacology and physiology of cardiac muscle.     

Effects of cytochalasin-B and phloretin on digitalis inotropy

Phloretin and cytochalasin-B are known to inhibit sugar transport across the cell membrane of many tissues. Both of these agents at concentrations of 100 and 20 microM, respectively, blocked the inotropic effects of ouabain and acetylstrophanthidin (AS) in isolated rabbit atria and papillary muscle preparations. Neither of these agents had any effect of its own on contractile force. Addition of phloretin or cytochalasin-B after the inotropic response to ouabain was fully established did not reverse the effect. The potency of cytochalasin-B was greater in atria than in papillary muscles, 1 microM of cytochalasin caused significant inhibition of the inotropic effect of ouabain in atria without significant effect in papillary muscles. Phloretin but not cytochalasin-B decreased the binding of [3H]ouabain to a semipurified sarcolemmal preparation isolated from canine left ventricular muscle. Neither ouabain nor AS had a substantial positive inotropic effect in atria suspended in substrate-free medium. Substitution of pyruvate (5 mM) for glucose did not fully support their inotropic effect in atria. Papillary muscles behaved differently, in that substrate-free as well as pyruvate media almost fully supported the inotropic effects of ouabain and of low concentrations of AS. Higher concentrations (greater than 250 ng/ml) of As produced a negative inotropic response in substrate-free medium. The possibility that an "active" sugar transport system is required for digitalis inotropy is ruled out by the observation that 2-deoxyglucose also prevents the inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of somatostatin on atrial and ventricular contractile responses in guinea pig heart: influence of pretreatment with islet-activating protein

The effects of somatostatin on the contractile response of guinea pig cardiac preparations were investigated and compared with those of carbachol and adenosine. Somatostatin produced a concentration-dependent negative inotropic effect in the left atria, which was accompanied by a decrease in action potential duration. The maximum decrease in contractility which was obtained at 3 x 10(-6) M was around 40% of the predrug control values and far less than those produced by carbachol and adenosine. Somatostatin failed to produce inotropic effect on the papillary muscle and did not influence the spontaneously beating rate of the right atria. In the papillary muscles, however, somatostatin inhibited the positive inotropic effect of isoproterenol in a concentration-dependent manner as did carbachol and adenosine. In addition, somatostatin caused a significant inhibition of the isoproterenol-induced increase in cyclic AMP levels without affecting the basal level of cyclic AMP. In the papillary muscle, the inhibitory effect of somatostatin on the positive inotropic response to isoproterenol was significantly attenuated by pretreatment with islet-activating protein, and was significantly antagonized by the somatostatin antagonist cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)]. These results suggest that somatostatin receptors in guinea pig ventricular muscles are coupled with adenylate cyclase via islet-activating protein-sensitive GTP-binding protein, whereas the negative inotropic effect of somatostatin in the left atria might be mediated by a subtype of somatostatin receptors which is different from that in the ventricle.     

Cardiotonic action of [8]-gingerol, an activator of the Ca++-pumping adenosine triphosphatase of sarcoplasmic reticulum, in guinea pig atrial muscle

[8]-Gingerol (gingerol), a component of ginger, produced a concentration-dependent positive inotropic effect on guinea pig isolated left atria at concentrations of 1 X 10(-6) to 3 X 10(-5) M. Gingerol also exhibited positive inotropic and chronotropic effects on guinea pig right atria. The gingerol-induced inotropic effect was abolished by ryanodine, but was little affected by propranolol, chlorpheniramine, cimetidine, tetrodotoxin, diltiazem or reserpine. The time to peak tension and relaxation time within a single contraction were shortened by gingerol (1 X 10(-5) M) as well as isoproterenol, whereas they were prolonged by BAY K 8644. In guinea pig isolated atrial cells, gingerol (3 X 10(-6) M) caused an increase in the degree and the rate of longitudinal contractions. In guinea pig left atria, gingerol (1 X 10(-6) to 3 X 10(-5) M) gave little influence on the action potential, although it increased the contractile force of the atria. The whole-cell patch-clamp experiments showed that the slow inward current was little affected by gingerol (1 X 10(-6) to 3 X 10(-5) M) in voltage-clamped guinea pig cardiac myocytes. The measurement of extravesicular Ca++ concentration using a Ca++ electrode indicated that gingerol (3 X 10(-6) to 3 X 10(-5) M) accelerated the Ca++ uptake of fragmented sarcoplasmic reticulum (SR) prepared from canine cardiac muscle in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the cyclic GMP lowering agent LY83583 on the interaction of carbachol with forskolin in rabbit isolated cardiac preparations

Cyclic GMP (cGMP) has been proposed to be involved in mediating negative inotropic responses to muscarinic agonists in the presence of cyclic AMP (cAMP)-generating agents in the heart. In order to investigate this hypothesis, the effects of the novel cGMP lowering agent, LY83583, on carbachol-induced increases in cGMP levels and decreases in tension were measured in rabbit isolated left atria and right ventricular papillary muscles, in the presence and absence of the adenylate cyclase activator, forskolin. In vehicle-treated preparations, negative inotropic responses to 3 microM carbachol in the presence of 3 microM forskolin were accompanied by significant increases in cGMP levels. Carbachol had no significant effect on forskolin-induced increases in cAMP levels. LY83583 (10 microM) reduced basal tension and basal cGMP levels, and completely abolished carbachol-induced increases in cGMP both in left atria and in papillary muscles. The LY83583 significantly reduced the magnitude of the negative inotropic responses of papillary muscles to carbachol in the presence of forskolin, but had no effect on these responses in left atria. Although a causal relationship has not been established, these data suggest that cGMP may be involved in negative inotropic responses to muscarinic stimulation in the presence of cAMP-generating agonists in ventricular muscle, but not in atria.     

Pharmacological analysis of the cardiac actions of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, in guinea pig heart: evidence for involvement of adenylate cyclase system in its cardiac stimulant actions

The pharmacological effects of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, were examined in guinea pig cardiac preparations and compared with those of isoproterenol to assess possible mechanisms of its cardiac stimulant actions. Xamoterol produced a positive inotropic effect in the papillary muscles and a positive chronotropic effect in the spontaneously beating right atria in a concentration-dependent manner. The maximum inotropic and chronotropic effects of xamoterol were about 33 and 35% of those of isoproterenol, respectively. Although xamoterol failed to produce a consistent increase in contractile force in the left atria, the positive inotropic effect of the agent was observed clearly in preparations obtained from reserpine-pretreated animals. The positive inotropic and chronotropic effects of xamoterol were antagonized by atenolol, but not by ICI 118,551. On the other hand, xamoterol antagonized competitively the positive inotropic and chronotropic responses to isoproterenol. In papillary muscles the increases in contractile force induced by xamoterol and isoproterenol were depressed markedly in the presence of carbachol or adenosine. In all of left atria, right atria and papillary muscles obtained from reserpine-pretreated animals, xamoterol caused a significant elevation in cyclic AMP levels, while inhibiting the isoproterenol-induced increase in cyclic AMP levels. Computer-assisted analysis of concentration-response curves for the inhibition by xamoterol of the binding of [125I]iodocyanopindolol in the membranes from guinea pig ventricles showed the existence of the 5'-guanylylimidodiphosphate sensitive, highly affinity site of beta adrenoceptors for xamoterol, suggesting that xamoterol may induce the formation of a ternary complex with the beta adrenoceptor and a stimulatory guanine nucleotide regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of the third complement component (C3) and C3a generation in cardiac anaphylaxis: histamine release and associated inotropic and chronotropic effects

Activation of the complement system with generation of C3a and C5a anaphylatoxins occurs during immediate hypersensitivity reactions; furthermore, the administration of C3a and/or C5a into isolated hearts causes a dysfunction that closely resembles cardiac anaphylaxis. To determine whether complement is activated and anaphylatoxins are generated in the course of immediate hypersensitivity reactions of the heart, we have challenged presensitized isolated guinea pig atria and papillary muscles with the specific antigen in the presence of a source of complement. We have found that the anaphylactic reaction of these cardiac preparations is characterized by complement activation and C3a generation, as well as by histamine release and positive inotropic and chronotropic effects. The amounts of C3a generated and histamine released directly correlated with the extent of C3 consumption. Furthermore, when C3a and C5a inactivation by serum carboxypeptidase N was prevented by DL-2-mercapto-methyl-3-guanidino-ethylthiopropanoic acid, anaphylactic histamine release was enhanced, and chronotropic and inotropic responses were potentiated and prolonged. Notably, the administration of C3a to nonsensitized guinea pig atria and papillary muscles caused positive chronotropic and inotropic effects, which were associated with histamine release and were antagonized by the H2 receptor blocker cimetidine, thereby mimicking the effects of anaphylaxis. Our findings indicate that complement activation and anaphylatoxin generation are typical of cardiac anaphylaxis and suggest that anaphylatoxins function as mediator-modulators of immediate hypersensitivity reactions of the heart.     

Prazosin-sensitive component of the inotropic response to norepinephrine in rabbit heart

Earlier experiments have usually failed to demonstrate a competitively displaceable alpha adrenoceptor blocker-sensitive component in the dose-dependent inotropic response to norepinephrine in mammalian hearts. We reinvestigated if it was possible to reveal this phenomenon by carefully choosing a concentration of the alpha adrenoceptor blocker prazosin that would give a significant displacement while it still was possible to completely surmount the blockade by reasonable concentrations of norepinephrine. Both inotropic and lusitropic dose-dependent responses to norepinephrine in rabbit heart papillary muscles were recorded. In the presence of 3 X 10(-9) M prazosin there was a significant rightward shift of a component corresponding to about 20% of the total inotropic response to norepinephrine. The prazosin-sensitive component was shifted significantly more to the left by 3 X 10(-5) M cocaine than the nonsensitive component. The maximal inotropic response to norepinephrine was increased at lower prazosin-concentrations (3 X 10(-9) M), whereas at 10(-7) M prazosin the maximal response was unchanged compared to the absence of prazosin. The maximal lusitropic response to norepinephrine was increased monophasically and dose-dependently by prazosin. Thus, by carefully considering the relative potencies of the agonist and the antagonist it was possible to demonstrate an alpha adrenoceptor blocker sensitive component in the inotropic response to norepinephrine in rabbit heart. The effect of cocaine upon the prazosin-sensitive component would indicate that the alpha adrenoceptor population in rabbit myocardium is located more closely to the sympathetic nerve endings than the beta adrenoceptor population.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac histamine receptors: differences between left and right atria and right ventricle.

Histamine can stiumulate the heart by directly interacting with cardiac histamine receptors. In the present study we have investigated the cardiac effects of histamine, 4-methylhistamine (a specific H2-receptor agonist) and 2-pyridylethylamine PEA, a specific H1-receptor agonist] on spontaneously beating right atria and electrically driven left atria and right ventricle strips of the guinea pig. Left atria were driven at 1 Hz and right ventricle strips at 2.5 Hz and at twice the threshold voltage. Histamine and PEA produced a dose-dependent positive inotropic effect on the left atria. The dose-response curves were shifted to the right in a parallel fashion by promethazine (3 x 10(-6)M)+... Burimamide did not affect either dose-response curve. Histamine and 4-methylhistamine had a positive chromnotropic effect on right atria and a positive inotropic effect on right ventricle strips.     

Vascular and cardiac effects of a new dihydropyridine derivative, YC-170: a comparison with Bay K 8644

The pharmacological effects of YC-170, a new dihydropyridine derivative, were studied in the rabbit aortic strips and guinea pig cardiac preparations and compared with those of Bay K 8644. In the rabbit aortic strips, YC-170 produced contraction in normal physiological saline solution ([K+]0 = 5.9 mM) in a concentration-dependent manner. Increasing the [K+]0 of the medium to 15 mM enhanced the contractile response. The maximum contraction produced by YC-170 at [K+]0 of 15 mM was comparable to that by Bay K 8644. However, YC-170 induced relaxation when the strip was contracted by 60 mM K+. In guinea pig left atrium, YC-170 produced a positive inotropic effect in a concentration-dependent manner, but its extent was far less than that of Bay K 8644. Like Bay K 8644, however, YC-170 increased the time to peak tension and relaxation time of the isometric tension, and prolonged the action potential duration. YC-170 failed to produce a positive inotropic action in the papillary muscle in which Bay K 8644 was a potent positive inotropic agent. In spontaneously beating right atria, YC-170 caused a negative chronotropic effect, whereas Bay K 8644 a positive one. The positive inotropic and vasoconstrictor effects of YC-170 were antagonized competitively by a Ca++ antagonist nicardipine. When the left atria were depolarized with high-K+ medium, the positive inotropic effect of YC-170 was attenuated progressively with increasing [K+]0 and at 13.2 mM K+ a negative inotropic effect was induced by YC-170.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacology of LY175326: a potent cardiotonic agent with vasodilator activities

Compound LY175326 is one of a series of novel cardiovascular agents with both inotropic and vasodilator activities. In cat papillary muscles, LY175326 increased contractility in a concentration-dependent manner; these actions were not blocked by prazosin, propranolol or cimetidine. Inotropic responses were observed in unpaced, perfused guinea-pig hearts and these effects were associated with modest increases in heart rate and coronary flow. An i.v. dose of 0.1 mg/kg of LY175326 caused 54 and 95% increases in contractility in either the anesthetized cat or dog, respectively; corresponding heart rates were increased by less than 10%. Oral administration of 0.5 mg/kg to dogs was associated with an inotropic response that was maximal between 60 and 90 min and lasted in excess of 3 hr. These effects were not accompanied by increases in heart rate, gross behavioral changes or emesis. The pharmacology of LY175326 was evaluated in a propranolol-induced heart failure model using anesthetized beagle dogs. A bolus injection of 0.15 mg/kg of LY175326 followed by an infusion of 0.4 mg/kg/hr reversed the hemodynamic symptoms of heart failure by increasing left ventricular dP/dt60, cardiac output and stroke volume and reducing left atrial filling pressure and vascular resistance; heart rate was unchanged and calculated myocardial oxygen consumption was reduced. This balance of inotropic:vasodilator activities may provide a means of improving cardiac function while maintaining the myocardial oxygen supply:demand.     

Whether phenylephrine exerts inotropic effects through α- or β-adrenoceptors depends upon the relative receptor populations

Phenylephrine produced concentration-related positive inotropic responses in isolated left atria and papillary muscles of guinea-pigs and rats. In rat tissues, these responses were unaffected by propranolol but antagonized by prazosin and therefore mediated via alpha 1-adrenoceptors. The alpha 1-adrenoceptor agonist methoxamine also exerted positive inotropic effects in these rat tissues. The maximum alpha-adrenoceptor-mediated effect of methoxamine (relative to the isoprenaline maximum) was greater than that of phenylephrine in left atria (in the presence of propranolol), whereas in papillary muscles phenylephrine exerted the greater maximum. In guinea-pig papillary muscles, the response to phenylephrine was unaffected by prazosin but was antagonized by propranolol and therefore caused by stimulation of beta-adrenoceptors. Methoxamine had no effect in guinea-pig papillary muscles. Guinea-pig left atria produced biphasic concentration-response curves for phenylephrine, the lower portion being antagonized by phentolamine and was therefore alpha-adrenoceptor-mediated, while the upper portion was antagonized by propranolol and therefore beta-adrenoceptor-mediated. Methoxamine exerted a small inotropic response, the maximum of which was similar to that of the first component of the phenylephrine response. Phenylephrine was a partial agonist for the cardiac beta-adrenoceptor. The density of rat ventricular alpha-adrenoceptors was 4 times greater than beta-adrenoceptor density, as measured by [3H]-prazosin and [3H]-dihydroalprenolol binding. This explains why the responses of rat papillary muscles were alpha-adrenoceptor-mediated. In contrast, the density of beta-adrenoceptor binding sites in guinea-pig ventricles was 6 times greater than the alpha-adrenoceptor density. This explains why the phenylephrine responses were beta-adrenoceptor-mediated in guinea-pig papillary muscles. In the left atria of guinea-pigs, which displayed both alpha- and beta-adrenoceptor-mediated responses, the densities of alpha- and beta-adrenoceptor binding sites were similar. Thus, phenylephrine exerts positive inotropic effects through alpha- or beta-adrenoceptors depending upon their relative densities.     

Stimulant effects of muscarinic agonists in embryonic chick ventricular muscle. Are the effects mediated by protein kinase C?

Muscarinic agonists at high concentrations produce stimulant effects in the heart. We used the embryonic chick ventricle, in which muscarinic receptor activation markedly increases phosphoinositide (PI) breakdown, to investigate the possibility that receptor-induced PI metabolism mediates the stimulant effects. In preparations paced at 0.5 to 1 Hz, carbachol (CCh; 10(-6) to 10(-3) M) shifted the action potential plateau to more positive potentials and markedly prolonged the action potential duration (APD). These effects were not associated with a change in the resting potential, did not fade with time and could be obtained in the presence of propranolol (3 x 10(-7) M) or tetrodotoxin (10(-6) M). The same effects could be obtained with acetylcholine or oxotremorine (10(-4) M) and could be suppressed with atropine (0.9 x 10(-6) M). The sensitivity of the APD to muscarinic agonists was high during early embryonic stages and declined rapidly with age. At days 3 to 5, the APD was prolonged in the presence of CCh by greater than 80% of its control value. After day 12, CCh had no prolonging effect on the APD. In nonpaced preparations, the agonist depolarized the membrane and/or induced automaticity in quiescent preparations. When automaticity was present, spontaneously or after addition of Ba++, the frequency of the automatic activity was increased by the agonist. These effects on resting potential and automaticity were also less marked in older embryos. CCh (10(-6) to 10(-4) M) evoked an atropine-sensitive positive inotropic effect in paced ventricular tissues in the presence of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of PGD2 on cardiac contractility: a negative inotropism secondary to coronary vasoconstriction conceals a primary positive inotropic action

The purpose of this study was to characterize by pharmacological means the inotropic action of prostaglandin D2 (PGD2) in the guinea-pig heart. In the whole heart perfused at constant pressure, PGD2 (0.01-10 micrograms) reduced coronary flow rate and decreased left ventricular contractile force in a dose-dependent manner. When the coronary vasoconstricting effect of PGD2 was antagonized by the PG antagonist sodium p-benzyl-4[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl]phenyl phosphonate (N-0164), by the cyclooxygenase inhibitor indomethacin or by the thromboxane synthetase inhibitor sodium (E)-3-[4-(1-imidazolyl-methyl)phenyl]-2-propanoate (OKY 046), the negative inotropic response to PGD2 was attenuated or completely abolished and a positive inotropic effect was unmasked. In the isolated left atrium or right ventricular papillary muscle preparations, PGD2 induced only a positive inotropic response. The atrial response to PGD2 was unaffected by N-0164, indomethacin or propranolol but was markedly decreased by carbachol or adenosine. Conversely, the response of the papillary muscle to PGD2 was potentiated by papaverine. Thus, these data indicate that PGD2 has a primary positive inotropic effect, which may involve cyclic AMP metabolism. On the other hand, because PGD2 is also a potent coronary vasoconstrictor, the secondary negative inotropic effect of PGD2 predominates.     

Cardiac responsiveness to alpha and beta adrenergic amines: effects of carbachol and hypothyroidism

Previous reports of cardiac beta to alpha adrenoceptor interconversion secondary to hypothyroidism left open the alternative possibility of a functional influence by hypothyroidism on the inotropic and chronotropic effects of adrenergic amines through a different mechanism. To test this possibility, the effects of hypothyroidism (thyroidectomy) were compared with those of acute carbachol pretreatment on the responses of isolated rat atria to the selective beta and alpha adrenoceptor agonists isoproterenol and methoxamine. Both hypothyroidism and acute carbachol pretreatment (3 X 10(-7) -10(-6) M): 1) reduced basal right atrial rates and left atrial tensions; 2) caused an apparent decrease in the inotropic and chronotropic potencies of isoproterenol; 3) reduced the degree of antagonism by propranolol of the responses to isoproterenol; 4) increased the maximum inotropic response of left atria to methoxamine; and 5) converted a lack of response to a positive chronotropic response of right atria to methoxamine. Equivalent reductions of basal rates by hypothermia, or of basal tensions by lowered calcium ion concentrations, did not affect the responses to isoproterenol or methoxamine. The results suggest that both carbachol pretreatment and hypothyroidism functionally antagonize the responses to isoproterenol and enhance the responses to methoxamine by means other than adrenoceptor interconversion.     

Electrophysiologic, inotropic and antiarrhythmic effects of propafenone, 5-hydroxypropafenone and N-depropylpropafenone

We compared the electrophysiologic, inotropic and antiarrhythmic properties of propafenone and two metabolites, 5-hydroxy (5-OH) propafenone and N-depropyl (N-DP) propafenone. In 18 canine Purkinje fibers with normal maximum diastolic potentials, all drugs (1 x 10(-8) to 1 x 10(-5) M) reduced action potential amplitude and duration. However, propafenone and 5-OH propafenone reduced Vmax in a use-dependent fashion at a lower concentration than N-DP propafenone. In 16 Purkinje fibers, slow response action potentials were induced by 22 mM K+ and isoproterenol, 1 x 10(-6) M. Vmax was comparably reduced by all compounds at 1 x 10(-5) M, but action potential amplitude was not affected by 5-OH propafenone. In 16 other Purkinje fibers in which automaticity at low levels of membrane potential was induced by BaCl2 (0.25 mM), only 5-OH propafenone was effective in slowing the automatic rate at therapeutic concentrations (3 micrograms/ml). In 15 guinea pig papillary muscles, all three drugs had negative inotropic effects at concentrations greater than or equal to 1 x 10(-6) M. In conscious dogs with sustained ventricular tachycardia 24 hr after infarction, we injected propafenone or a metabolite through an atrial cannula. At similar plasma levels, neither propafenone (n = 6) nor N-DP propafenone (n = 6) suppressed the arrhythmia, whereas 5-OH propafenone eliminated ventricular tachycardia in four of six dogs, and was more effective against monomorphic than polymorphic ventricular tachycardia. Hence, the two major metabolites of propafenone have important electrophysiologic effects, and 5-OH propafenone is more potent than the parent compound as a antiarrhythmic drug in the 24-hr Harris dog.     

Regional differences in the responses of guinea-pig cardiac tissue to carbachol and their potentiation by hypothermia

The responses of guinea-pig isolated cardiac tissues to carbachol were examined. Tension responses of paced left atria and right ventricular papillary muscles, rate responses of spontaneously beating right atria and working hearts and contractility (+dP/dt) of paced and unpaced working hearts were obtained at 38 degrees C. Carbachol induced negative inotropic and chronotropic responses of atria, abolishing tension and rate at the maxima. The spontaneously beating heart also exhibited negative chronotropy. The papillary muscles displayed partial inhibition of tension but, in tissues from reserpine-pretreated animals, negative inotropy was absent. Similarly, no reduction of contractility of paced working hearts was obtained. It was concluded that muscarinic receptors mediating a direct inhibition of ventricular muscle are virtually absent and that the small response obtained in untreated tissue may be due either to inhibition of endogenous catecholamine release via presynaptic receptors or to antagonism of released norepinephrine. Lowering the temperature to 30 or 25 degrees C affected resting tension, rate and contractility and the magnitude of carbachol responses. The concentration-response curves, when plotted as a percentage of the maximum, were displaced to the left by cooling of the atria and papillary muscles. The papillary muscles now exhibited a response after reserpine pretreatment. In working hearts, the concentration-response curves for the fall in spontaneous rate were also shifted to the left, but this was not significant, probably because the temperature could be reduced to only 30 degrees C, below which contractions ceased. Cooling of guinea-pig isolated cardiac preparations therefore induced supersensitivity to the muscarinic effects of carbachol.     

Cardiac angiotensin receptors: effects of selective angiotensin II receptor antagonists, DUP 753 and PD 121981, in rabbit heart.

Angiotensin II (AII) elicits a positive inotropic response in cardiac muscle preparations from several species including humans. The purpose of this study was to characterize the AII binding sites and inotropic responses in rabbit ventricle using the selective AII receptor antagonists/ligands, DuP 753 (AT1) and PD 121981 (AT2). Biphasic displacement of specific 125I-Sar1,Ile8-AII binding was observed with both DuP 753 and PD 121981, suggesting the presence of two AII binding sites. The high affinity site for DuP 753 (29 nM) was a low affinity site for PD 121981 (91 microM), and the high affinity site for PD 121981 (78 nM) was a low affinity site for DuP 753 (81 microM). Of the specific AII binding, 70% was DuP 753 (AT1)-sensitive sites. Positive inotropic responses to AII in isolated papillary muscles from rabbit heart were antagonized competitively by both DuP 753 and PD 121981. The potencies of DuP 753 (pA2 = 7.99) and PD 121981 (pA2 = 4.28) to antagonize AII inotropic responses were similar to their potencies to displace 125I-Sar1,Ile8-AII from AT1 sites. There was no apparent functional consequence of AII interaction with AT2 site. Inotropic responses to isoproterenol were unaffected by DuP 753 and PD 121981. Therefore, there are two binding sites for AII in rabbit ventricle; however, only one site, AT1, participates in the inotropic response to AII. The roles of these receptor subtypes in other cardiac responses to AII have yet to be determined. Also, DuP 753 and PD 121981 are useful tools to study these two AII binding sites in cardiac preparations.