The role of H1 and H2-receptors in the coronary vascular response to histamine of isolated perfused hearts of guinea-pigs and rabbits.

1. The effects of histamine on the isolated perfused hearts of guinea-pigs and rabbits were examined. Records of contractile force, heart rate and coronary perfusion pressure were obtained. 2. Histamine exerted positive inotropic and chronotropic effects which were antagonized by burimamide and attributed to stimulation of H2-receptors. 3. The coronary vascular response to histamine differed between guinea-pigs and rabbits. In guinea-pig hearts, three phases were apparent: (a) An initial vasodilatation preceding any effects on heart force and rate was antagonized by mepyramine and therefore mediated by histamine H1-receptors in the coronary circulation. (b) A secondary vasoconstriction was attributed to the increased myocardial compression during the positive inotropic and chronotropic responses. (c) The final, more predominant, component was a prolonged vasodilatation probably associated with the increased metabolic activity of the heart. 4. The latter two components were abolished together with the myocardial responses by burimamide. The remaining coronary vascular response was biphasic, consisting of a vasodilatation immediately followed by vasoconstriction. Both were antagonized by mepyramine and therefore mediated by H1-receptors. 5. The coronary vascular response of rabbit hearts was similar but no direct vasodilatation was observed and it was concluded that histamine receptors in the coronary vasculature involve only vasoconstriction.     

Anaphylaxis in the guinea-pig isolated heart: Selective inhibition by burimamide of the positive inotropic and chronotropic effects of released histamine

1. Anaphylaxis was induced in the isolated heart of the guinea-pig in the presence of burimamide at concentrations of 4 x 10(-5)M and 2.7 x 10(-4)M.2. Burimamide did not affect the immunological release of histamine; however, it selectively antagonized the positive inotropic and chronotropic effects of released histamine. The antagonism of the positive chronotropic effect was concentration-dependent.3. Neither the negative dromotropic effect nor the decrease in coronary flow rate occurring during anaphylaxis were inhibited by burimamide.4. The results are in agreement with the double histamine receptor theory and suggest that, in the heart of the guinea-pig, H(2)-receptors are involved in the positive inotropic and chronotropic effects of released histamine, and H(1)-receptors in the negative dromotropic effect.     

Investigations into the cardiac effects of tolazoline in guinea pig atria and ventricular strips.

The positive inotropic, chronotropic and cyclic AMP producing effects of tolazoline were studied on atrial and ventricular preparations obtained from guinea pig heart. (1) The direct positive inotropic effects of tolazoline on the paced left atrial preparation from the guinea pig hearts was blocked by promethazine, but not by burimamide. Tolazoline did not elevate cyclic AMP levels in this preparation. (2) Tolazoline produced a positive chronotropic effect which was blocked by burimamide and not by promethazine and caused a 2-3 fold elevation of cyclic AMP in spontaneously beating right atria. (3) Burimamide antagonized the inotropic and cyclic AMP increasing effects of tolazoline on electrically driven ventricular strips. (4) The effects of tolazoline were unchanged by reserpine pretreatment of the guinea pigs or by prior exposure to phentolamine or propranolol. (5) These results suggest that tolazoline can activate both H1 and H2 receptors in the guinea pig heart. Furthermore the data suggests that H2 receptors are present in right atria and ventricle and that such receptors are associated with cyclic AMP. H1 receptors are present in the left atria and are not associated with the cyclic nucleotide.     

Inotropic effects of histamine in human myocardium: differentiation between positive and negative components

Histamine is known to enhance the contractility of the human myocardium in vitro. We have observed that when the H2-receptor antagonist cimetidine (or ranitidine) blocks the positive inotropic effect of histamine in spontaneously beating pectinate muscles isolated from human right atrial appendage, a negative inotropic effect is unmasked. This decrease in contractility is independent of changes in rate, as it occurs in preparations paced at constant rate, is mimicked by the H1-receptor agonist 2-(2-thiazolyl)-ethylamine (ThEA) and is abolished by the H1-antagonist pyrilamine. Thus, the negative inotropic effect of histamine appears to be mediated by H1-receptors. Our data indicate that the inotropic response of the human myocardium to histamine consists of two opposing components: an increase in contraction, mediated by H2-receptors, and a decrease in contraction, mediated by H1-receptors. Given the widespread use of H2-blockers and the multitude of clinical conditions in which histamine is released, there may well be circumstances in which an H1-response predominates. This could result in a decrease in myocardial contractility.     

Selectivity of 4-methylhistamine at H1- and H2-receptors in the guinea-pig isolated ileum

The selectivity of 4-methylhistamine (4-MH) as an agonist at histamine H1- and H2-receptors has been evaluated in the guinea-pig isolated ileum. The EC50 values of 4-MH on H1- and H2-receptors that mediate contractile responses were determined. The EC50 at H1-receptors was estimated after selective blockade of H2-receptors by tiotidine and the EC50 at H2-receptors estimated after selective blockade of H1-receptors by mepyramine. The -log EC50 values at H1- and at H2-receptors were 4.57 and 5.23, respectively. The dissociation constants for the interaction of 4-MH with H1- and H2-receptors were determined. The -log KD values at H1- and H2-receptors were 3.55 and 4.27, respectively. These results suggest that 4-MH is only about 5 times as potent at H2- as it is at H1-receptors in the guinea-pig ileum and that 4-MH should be used with caution to discriminate between H1- and H2-receptors.     

The antianaphylactic action of histamine H2-receptor agonists in the guinea-pig isolated heart.

The effects of histamine and of H1- and H2-receptor agonists on the response to specific antigen were studied in isolated hearts taken from actively sensitized guinea-pigs. Histamine and H2-receptor agonists (dimaprit, impromidine) dose-dependently decrease the positive chronotropic and inotropic effects, and the severity of arrhythmias evoked by the challenge of sensitized hearts with specific antigen. Nordimaprit and the selective H1-receptor agonist 2-pyridyl-ethyl-amine (2-PEA) did not modify the patterns of cardiac anaphylaxis. The positive inotropic and chronotropic responses of the isolated heart to exogenous histamine appear to be partly reduced in the presence of dimaprit. The H2-receptor agonists decrease the amount of histamine released during cardiac anaphylaxis which is increased by cimetidine, while nordimaprit and PEA were ineffective, indicating an inhibitory function afforded by H2-receptors in cardiac anaphylaxis.     

Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atria

The direct positive inotropic effect of histamine was studied on paced left atrial preparations from guinea pigs. Histamine (10^?8 to 10^?4 M) increased the maximum tension developed in left atria incubated at 35°C and driven at 2 Hz. The maximum increase in tension was 60% of that observed with norepinephrine. Metiamide (3 × 10^?5 M; a specific H₂-receptor antagonist) did not alter the inotropic response of left atria to histamine. However, tripelennamine (a typical H₁-receptor antagonist) competitively shifted the histamine inotropic dose—response curve to the right at concentrations from 10^?8 to 10^?7 M. Higher concentrations (3 × 10^?7 and 10^?6 M) caused little further additional shift to the right. The positive chronotropic effect of histamine on spontaneously beating atria was competitively antagonized by metiamide (10^?6 and 3 × 10^?6 M). These results demonstrate that in guinea-pig atria histamine increases myocardial contractility by an interaction with receptors closely related to classical H₁-receptors while its chronotropic effects is mediated by interaction with H₂-receptors.     

Effect of domperidone on the contractility of isolated guinea-pig atria

This study was undertaken to investigate whether or not dopamine receptors are responsible for the cardiac action of domperidone and to gain a better understanding of the mechanism of the cardiac effects of this compound. In isolated electrically driven guinea-pig atria, domperidone (0.1-30 microM) produced a negative inotropic effect (-56.7 +/- 4.9% at 30 microM) and at a concentration of 0.1 microM significantly decreased the positive inotropic response to histamine (0.5-271 microM). In spontaneously beating guinea-pig atria, domperidone failed to modify the chronotropic responses elicited by dopamine and noradrenaline. In the isolated guinea-pig ileum, domperidone alone did not produce any effect, but produced a right-ward displacement of the contractile dose-response curve to histamine. At concentrations of 0.01, 0.1 and 1 microM, domperidone also depressed the maximum response to histamine. The results obtained suggest that the negative inotropic effect of domperidone is not due to dopamine or adrenergic receptor antagonism. This cardiac effect of domperidone can be partially explained by its influence on the effects of histamine acting on H1-receptors, although other mechanisms may be involved.     

Liberation of histamine by compound 48/80, tolazoline, betahistine and burimamide from isolated spontaneously beating guinea pig and rabbit atrial pairs.

Tolazoline, betahistine, burimamide and compound 48/80 release histamine from isolated guinea pig atria resulting in histamine concentrations that stimulate H2-receptors. Tolazoline, burimamide and 48/80 also release histamine from rabbit atria but do not result in histamine concentrations that will stimulate either H1- or H2-receptors. However, betahistine (which does not release histamine from rabbit atria) and tolazoline stimulate the rabbit atrial chronotropic response by releasing catecholamines.     

Cardiovascular effects of histamine mediated by H1- and H2-receptors

Histamine was found to suppress the myocardial contractile function, to decrease systemic arterial blood pressure and to exert a positive chronotropic effect in unanesthetized dogs. A preliminary blockade of H1-receptors prevented the hypotensive effect of histamine, blockade of H2-receptors prevented the development of the positive chronotropic effect.     

The effect of reserpine treatment on the chronotropic and inotropic sensitivities of the perfused guinea-pig heart to norepinephrine and calcium

The chronotropic and inotropic responses of the isolated perfused guinea-pig heart to norepinephrine and calcium were measured in preparations obtained from untreated and reserpinetreated animals. Dose-response curves were obtained in spontaneously beating as well as electrically paced perfused hearts. The dose-response curve for the chronotropic effect of both norepinephrine and calcium was shifted to the left of control in spontaneously beating preparations from animals pretreated with reserpine (0.1 mg/kg/day) for seven days. However, in these same preparations the dose-response curve for the inotropic effect of only norepinephrine was shifted to the left. This may be reflection of the enhanced sensitivity to the chronotropic action of the agonist since a changing rate is known to influence inotropic response. This conclusion is supported by the finding that, in electrically paced perfused hearts, no postjunctional supersensitivity to the inotropic effects of norepinephrine was demonstrable. Since no supersensitivity was observed to the inotropic effects of calcium, it is concuded that true postjunctional supersensitivity develops to the chronotropic but not to the inotropic effects of drugs.     

The effects of cimetidine on histamine atrial chronotropic receptor activity

Clinically useful histamine antagonists have been reported to be specific for H1- or H2-receptors. However, data is accumulating that the specificity of those agents may be relative. This study was undertaken in an attempt to clarify this point. Histamine stimulates the chronotropic responses of rabbit atria by acting on both H1- and H2-receptors. Cimetidine (H2-antagonist) and diphenhydramine (H1-antagonist) both cause some inhibition of the histamine response, but there is no evidence of competitive blockade with these antagonists given separately or in combination. 4-Methylhistamine (H2-agonist) stimulates chronotropic activity, and both H1- and H2-antagonists reduce this response to some degree. 2-Methylhistamine (H1-agonist) is a less effective agonist (perhaps rabbit atria contain fewer H1-receptors), but the response is also decreased by either H1-or H2-antagonists. These two "specific" agonists were combined to stimulate the histamine responses, and the antagonists were given simultaneously. The results were qualitatively similar to those obtained with histamine. The question remains: (1) are these agonists and antagonists specific or (2) are the rabbit atrial chronotropic receptors not typical of the H1- and H2-type receptor?     

Differential effects of histamine mediated by histamine H1- and H2-receptors on contractility, spontaneous rate and cyclic nucleotides in the rabbit heart

The effects of histamine on the contractile force, spontaneous rate of contraction, and cyclic AMP and cyclic GMP content were investigated in isolated rabbit cardiac preparations. Histamine had a positive inotropic effect in the left atrium and papillary muscle, and a positive chronotropic effect in the right atrium. Both effects were produced in a concentration-dependent manner. Impromidine also induced the same effect in the left and right atrium as histamine did. The effects produced by histamine and impromidine were antagonized by cimetidine and tiotidine. On the other hand, the positive inotropic response of papillary muscle to histamine was antagonized by mepyramine and chlorpheniramine and was mimicked by 2-(2-pyridyl)ethylamine. Impromidine at a high concentration induced a small increase in the contractile force, an effect which was antagonized by cimetidine. Histamine significantly increased the cyclic AMP levels in both atria but not in papillary muscles. The increase in cyclic AMP was abolished by cimetidine. Histamine also increased cyclic GMP levels in all of the preparations. The increase in cyclic GMP was abolished by chlorpheniramine. The results suggest that both H1- and H2-receptors exist in all parts of the rabbit heart. However, the positive inotropic and chronotropic effects induced by histamine in left and right atrium are mediated predominantly via H2-receptors, whereas the positive inotropic effect in papillary muscle is predominantly mediated via H1 receptors.     

Inhibition by the tetramine disulphide, benextramine, of cardiac chronotropic histamine H2-receptor-mediated effects

1 Benextramine (N,N1-bis[o-methoxybenzylamino)-n-hexyl]cystamine), which irreversibly blocks alpha-adrenoceptors and does not inhibit the H1-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the H1-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competitive H2-receptor blocking drug cimetidine had a additive blocking effect, benextramine appears to act directly on the chronotropic H2-receptor.     

Synthesis and pharmacologic action of substituted imidazolyl- and thiazolylmethylthioethylguanidine

Starting with diphenyl N-benzoyl-carbonimidate impromidine analogues characterized by various substituted imidazole or thiazole groups instead of the 5-methylimidazole part have been synthesized and tested for H2-agonistic and H1-antagonistic activity as well. The most potent substances 6h,i are 20-30 times more active than histamine at the H2-receptors in the isolated spontaneously beating guinea-pig right atrium. In isolated perfused guinea-pig hearts 6h,i were found to predominantly stimulate heart rate, whereas the increase in LVdp/dtmax was about 40% of impromidine's maximal response.     

Cardiovascular studies with impromidine (SK&F 92676), a new very potent and specific histamine H2-receptor agonist.

Impromidine (SK & F 92676) has recently been identified as a potent and specific histamine H2-receptor agonist. The present paper describes some cardiovascular studies with the drug. Impromidine lowers blood pressure in cats and rats by interaction with H2-receptors. During continuous intravenous infusions of impromidine, the fall in blood pressure is due to a reduction in total peripheral resistance; cardiac output increases during hypotension. The responses to impromidine are similar to responses to histamine in mepyramine-treated cats. Impromidine administered intra-arterially also causes vasodilatation in the femoral and mesenteric vasculature by interaction with H2-receptors. Impromidine stimulates all measured parameters including coronary flow in the isolated working heart of the guinea-pig. Dose-response curves to impromidine were displaced to the right in the presence of cimetidine.     

Positive inotropic and chronotropic effects and coronary vasodilation in vitro by two antiasthmatic xanthines with different abilities to antagonize adenosine

The direct actions and the ability to antagonize adenosine of theophylline (1,3-dimethylxanthine) and enprofylline (3-propylxanthine) were examined in isolated guinea pig heart preparations. Enprofylline was approximately six times as potent as theophylline in reducing coronary perfusion pressure, and between three and five times more potent in increasing rate and force of contraction in isolated perfused hearts, spontaneously beating right atrias, and electrically stimulated left atrias. Adenosine reduced the coronary perfusion pressure and had negative inotropic and chronotropic actions. Theophylline (5-75 microM) concentration-dependently antagonized the coronary vasodilation and the negative chronotropic and inotropic actions of adenosine, whereas enprofylline (2.5-75 microM) did not antagonize adenosine. Since adenosine may be a protective autacoid in the heart under select stress conditions, the possibility that adenosine nonblocking xanthines, like enprofylline, may offer therapeutic advantages over theophylline should be investigated.     

Identification and characterization of histamine H1- and H2-receptors in guinea-pig left atrial membranes by [3H]-mepyramine and [3H]-tiotidine binding.

1. Histamine receptors in the membranes prepared from guinea-pig left atria were characterized with [3H]-mepyramine and [3H]-tiotidine binding. 2. The binding of the H1-antagonist, [3H]-mepyramine, was saturable and of high affinity with a maximum binding capacity of 307 +/- 27 fmol mg-1 protein (n = 14) and with an equilibrium dissociation constant (KD) of 1.5 +/- 0.2 nM (n = 14). The binding was rapid and readily reversible. 3. The competition curve for [3H]-mepyramine binding by histamine was biphasic and revealed high and low affinity states of binding. The addition of 5'-guanylylimidodiphosphate (GppNHp) (100 microM) converted this heterogeneous binding into homogeneous binding of low affinity. 4. The competition curves of H1-antagonists with [3H]-mepyramine had Hill coefficients not significantly different from unity, consistent with competition with [3H]-mepyramine at a single site. GppNHp did not shift the competition curves. 5. Dissociation constants for H1-antagonists determined from inhibition of [3H]-mepyramine binding correlated well with the constants derived from inhibition of the positive inotropic response of guinea-pig left atria to histamine. 6. The H2-antagonist, [3H]-tiotidine, labelled an apparently homogeneous population of recognition sites with a maximum binding capacity of 41 +/- 8 fmol mg-1 protein (n = 6) and a KD of 10.8 +/- 1.2 nM (n = 6). 7. Although histamine competed for [3H]-tiotidine binding in a concentration-dependent manner, the curve was monophasic and was not shifted by GppNHp. 8. It is concluded that both H1- and H2-receptors exist in guinea-pig left atria. H1-receptors probably couple to intracellular effector(s) through a guanine nucleotide-dependent transducing mechanism. (ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for a prostacyclin-mediated chronotropic effect of angiotensin II in the isolated cat right atria

The positive chronotropic effect of angiotensin II was studied on the isolated spontaneously beating cat right atria. Angiotensin II and prostacyclin produced similar positive chronotropic and inotropic effects which were not affected by beta-adrenoceptor and histamine H2-receptor blockers. [Sar1,Ile8] angiotensin II, however, inhibited the positive chronotropic and inotropic responses to angiotensin II without altering that to prostacyclin, noradrenaline and histamine. Nicotine completely abolished the positive chronotropic action of angiontensin II without altering its positive inotropic effect. Nicotine failed to abolish the effects of prostacyclin, noradrenaline and histamine on the rate and contractility. These results were taken as evidence that the angiotensin II-induced increase in heart rate is probably mediated through the increase of prostacyclin biosynthesis in the isolated cat right atria.     

Effect of Ni2+ on the multiphasic positive inotropic responses to histamine mediated by H1-receptors in left atria of guinea pigs

Effects of calcium antagonists and Ni2+ on the positive inotropic responses to histamine mediated by H1-receptors were investigated in left atria of guinea pigs. The preparations were electrically driven at 0.5 Hz in Krebs-Henseleit solution at a temperature of 30 degrees C unless stated otherwise. Histamine in low concentrations of 10 and 100 nmol/1 produced a monophasic positive inotropic effect, whereas in concentrations higher than 1 mumol/1 it exerted a multiphasic inotropic response composed of an initial increasing phase (initial component) and a second and late developing, greater positive inotropic phase (second component). These two components were sometimes separated by a transient decrease in developed tension. Both positive inotropic components caused by 3 mumol/1 histamine were inhibited by the H1-antagonists mepyramine, D-chlorpheniramine and diphenhydramine in a concentration-dependent manner, but not by the H2-antagonist cimetidine. Pretreatment with Ni2+ in concentrations of 0.2 and 0.5 mmol/1 preferentially suppressed the second component of the inotropic effect produced by 3 mumol/1 histamine without significantly affecting the initial component. On the other hand, the monophasic positive inotropic effect of 30 nmol/1 histamine was almost unaffected by this cation. The concentration-response curves for the positive inotropic effect of histamine were hardly influenced by Ni2+ in the range of lower concentrations of histamine, but significantly suppressed in the range of higher concentrations of the agonist.(ABSTRACT TRUNCATED AT 250 WORDS)