The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

Abstract

This review addresses pharmacological, structural and functional relationships among H₂-histamine receptors and H₁-histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H₂-histamine-receptors in cardiac diseases will be examined. The use of H₂-histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H₂-histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H₂-histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H₂-histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H₂-histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H₂-histamine receptors in cardiac disease and whether cardiomyocyte specific H₂-histamine receptor agonists and antagonists should be developed.

Keywords: H2 histamine receptor; arrhythmias; contractil effect; heart failure; ischemia - reperfusion.

FIGURE 1

(A) Scheme: putative mechanism(s) of signal transduction of cardiac H₂-histamine receptors stimulated by histamine and antagonized by cimetidine. H₂-histamine receptors (H₂R) can activate adenylyl cyclases (AC) via stimulatory GTP binding proteins (G_s), which would enhance the 3′, 5′-cyclic adenosine-phosphate (cAMP)-levels in central compartments of the cardiomyocyte. This cAMP can activate cAMP-dependent protein kinase (PKA), which would increase the phosphorylation state and thereby, the activity of several regulatory proteins in the cardiomyocyte. For instance, PKA-stimulated phosphorylation increases the current through the L-type Ca²⁺ channel (LTCC) and/or the release of Ca²⁺ from the sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RYR). This process is thought to initiate cardiac contraction. In diastole, Ca²⁺ is pumped via the SR-Ca²⁺-ATPase (SERCA) from the cytosol into the SR. Activity of SERCA is increased when PKA phosphorylates phospholamban (PLB). PKA also phosphorylates the inhibitory subunit of troponin (TnI). The phosphorylation of TnI reduces the sensitivity of the myofilaments for Ca²⁺ and thus the muscle will relax faster in diastole. The latter effect might also follow from inhibition of PP2A (a serine/threonine phosphatase: PP) activity by MAP kinases (mitogen activated protein kinases) and subsequent increased phosphorylation state and thus activation of I-1 (a specific inhibitory protein of PP1 [serine threonine protein phosphatase 1]), which will lead to decreased activity of PP1. PKA can also phosphorylate and thus activate the cAMP-dependent transcription factor (CREB). Alternatively (sometimes called the non-canonical pathway) the phosphorylation state and thus the activity of ERK1/2, JNK (c-jun N terminal kinase), p38 (p38 mitogen activated protein kinase) could be enhanced by pathways acting via arrestins. In the human heart, via H₂-histamine receptor, cAMP-content is increased, PKA is activated, phospholamban and troponin I phosphorylation is enhanced and the open probability of the LTCC is augmented. (B) Scheme: putative mechanism(s) of signal transduction of cardiac H₁-histamine-receptors, stimulated after endogenous agonist binding (histamine) on the receptor which can be abrogated by an exogenous antagonist like mepyramine. Three putative pathways are indicated with Arabic numbers. H₁-histamine receptors (H₁R) via (labeled 1 in the scheme) the α-subunits of the inhibitory GTP-binding proteins (Giα) can inhibit the activity of adenylyl cyclases (AC) which would reduce the 3′-5′cyclic adenosine-phosphate (cAMP)-levels in central compartments of the cardiomyocyte and thus diminish the activity of cAMP-dependent protein kinases (PKA), which eventually leads to a decline in the phosphorylation state of regulatory proteins in the cell. Alternatively (labeled 2 in the scheme) the activity of phospholipase A2 (PLA₂) might be increased leading to formation of arachidonic acid (AA) and finally activation of protein kinase C (PKC) leading to protein phosphorylation and hence increased force generation. Lastly (labeled 3 in the scheme), H₁-histamine-receptors may via GTP binding proteins called G_q or G₁₁ activate phospholipase C (PLC). This would increase the level of diacylglycerol (=DAG) in the cells and thus elevate the activity of PKC. In addition, PLC leads to the formation of inositol trisphosphate (IP₃), which can release Ca²⁺ from storage sites like the sarcoplasmic reticulum (SR), where it binds to calsequestrin (CSQ) is taken up by SR-Ca²⁺ATPAse (SERCA) which is activated when phospholamban (PLB) is phosphorylated by PKA or CaMKII. Ryanodine receptor upon their phosphorylation release Ca²⁺ from the SR which then contributes to force generation. An elevation of cytosolic Ca²⁺ is expected to bind to calmodulin and this can activate a kinase (CaMKII). This kinase can phosphorylate and activate nitric oxide (NO) synthase (NOS). This activation would lead to the enhanced formation of NO which stimulates guanylyl cyclase (GC) thus increases 3′-5′cyclic guanosine-phosphate (cGMP) levels. Elevated cGMP can reduce the activity of phosphodiesterase III (PDE III) or enhance the activity of phosphodiesterase II (PDE II). This would elevate or reduce cAMP, respectively, which would activate or inhibit PKA and eventually increase or decrease force generation. In the human heart, H₁-histamine receptor stimulation increases cGMP- and cAMP-levels, activate PKA and increase force of contraction (Sanders et al., 1996). In contrast, others reported a decrease of force, at least in some patients after H₁-histamine receptor stimulation (Guo et al., 1984; Du et al., 1993).

FIGURE 2

Scheme: putative mechanisms of interaction between H₁- or H₂-histamine receptors and other GTP-binding protein-coupled heptahelical receptors in the sarcolemma of a cardiomyocyte. As delineated in Figure 1A, H₂-histamine receptors after stimulation by endogenous histamine or by the exogenous H₂-histamine receptor selective agonists like dimaprit will elevate via stimulatory GTP-binding proteins (G_s) the activity of sarcolemmal adenylyl cyclases (AC). Thus, more cAMP is formed and cAMP-dependent protein kinases (PKA) are activated. This leads to a subsequent phosphorylation and activation of cardiac regulatory proteins (RP). Their phosphorylation (compare Figure 1A for details) leads to an increase in force of contraction. The same pathway is used by the cardiac 5-HT₄-serotonin receptor stimulated by endogenous serotonin or the β-adrenoceptors (β-AR) stimulated by exogenous isoproterenol to increase cAMP and thereafter force of contraction. The increase of force of contraction induced by histamine by acting on H₂-histamine receptors is abrogated by additionally acting endogenous compounds like adenosine acting on A₁-adenosine receptors or endogenous acetylcholine (or exogenous carbachol) stimulating M₂-muscarinic receptors. Three pathways may be used by M₂-muscarinic receptors and A₁-adenosine receptors. They may inhibit via inhibitory G-proteins (G_i/oα) the activity of AC, thereby reduce cAMP content and thus decrease force of contraction. In addition, A₁-adenosine and M₂-muscarinic receptors can activate sarcolemmal potassium ion channels: this shortens the duration of the action potential; less time is available for trigger Ca²⁺ to enter the cell via L-type Ca²⁺ channels (see Figure 1A), cytosolic Ca²⁺ declines and force falls. Lastly, M₂-muscarinic and A₁-adenosine receptors may directly or indirectly activate protein phosphatases (PP, see Figure 1A) which would reduce the phosphorylation state and subsequently the force in the myocardium. Moreover, as shown in Figure 1B, H₁-histamine receptors, may activate phospholipase A2 (PLA₂), thereby activating cyclooxygenase 2 (COX2) which generates metabolites of arachidonic acid which can elevate force of contraction. Finally, there seems to be a direct interaction whereby the H₂-receptor stimulation can reduce the activity of the H₁-histamine receptor.

FIGURE 3

Comparison of regional H₁-histamine receptor and H₂-histamine receptor signaling in various regions of mammalian hearts. In sinus node cells, H₂-histamine receptors can stimulate cAMP-production, this cAMP binds to HCN (=I_f-currents, hyperpolarization-activated ion channels) which thereafter open more often and tachycardia ensues (see Table 7 for details). Alternatively, H₁-histamine receptors, in sinus node cells can reduce the beating rate via still unknown mechanisms (see Table 7 for details). In atrial muscle cells, H₂-histamine receptors (via cAMP, see Figure 1A) and H₁-histamine receptors (see Figure 1B via, for instance, activation of PLC and thereafter formation of IP3 and/or diacylglycerol and subsequent phosphorylation steps) can both increase atrial force of contraction in some species. In other species, H₁-histamine receptors in atrial muscle cells decrease force of contraction by activation of phosphodiesterase, inhibition of protein kinases and/or activation of phosphatases. In the atrioventricular (AV) node, H₁-histamine receptors in most species inhibit electrical conduction into the ventricle (see Table 7 for details). Likewise, in the ventricular muscle cells, H₂-histamine receptors increase force of contraction by the mechanism depicted in Figure 1A. But also, in some species, ventricular muscle H₁-histamine receptors can increase force of contraction (see Figure 1B), in other species, H₁-histamine receptors lead to a reduction in force of contraction via the hypothetical mechanism depicted: a cGMP-mediated increase in phosphodiesterase II (PDE II) activity. Alternatively, in other species cGMP might inhibit PDE III and thereby increase cAMP and subsequently (See Figure 1B for details) force of contraction.

FIGURE 4

Cardiac conducting system and regional histamine receptor expression in the heart (modified from Stein et al., 1998). Here, one has tried to relate the mechanical information in Figure 2 with anatomically correct location of the receptor. In the sinus node (SA), the H₂-histamine receptor when it is expressed probably also increase chronotropy, that is increases the heart rate. If the H₁-histamine receptor is functional, if can decrease but sometimes also increase the heart rate: this is meant by ↓ and ↑ (see Table 4 for species differences). For simplicity, in the ventricle a negative inotropic effect of H₁-histamine receptor activation is only depicted. However, in some species a positive inotropic effect of H₁-histamine receptor activation has been described (compare Table 4). If a functional H₂-histamine receptor is expressed in the atrium or ventricle it always increases inotropy (Table 4). Also indicated is the proarrhythmic effect of H₂-histamine receptor stimulation in the ventricle by indicating increased automaticity. H₁-histamine receptors, if present in the AV node (AV), always seem to have negative dromotropic effects, that is, they slow the conduction through the AV node (Table 7). Here, also His-bundles (HIS) are shown where a decrease in the conduction time via H₁-histamine receptors can sometimes be measured.

FIGURE 5

Scheme: putative pathophysiological role(s) of cardiac H₂-histamine-receptors (H₂R). H₂R via stimulatory GTP-binding proteins (Gs) can activate adenylyl cyclases (AC) which would enhance the 3′,5′-cyclic adenosine-phosphate (cAMP)-levels in central compartments of the cardiomyocyte and activate cAMP-dependent protein kinases (PKA), which would increase the phosphorylation state and thereby the activity of various regulatory proteins in the cell (see Figure 1A). PKA-stimulated phosphorylation might also increase the current through the L-type Ca²⁺ channel (LTCC) and/or release of Ca²⁺ from the sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RYR), which can occur in a non synchronous way that leads to early (top left) or delayed (top right) afterdepolarizations and thus to arrhythmias. In diastole, Ca²⁺ is pumped via the SR-Ca²⁺-ATPase (SERCA) from the cytosol into the SR. Activity of SERCA is increased by phosphorylation of phospholamban (PLB). PKA can enhance nuclear gene transcription. In this context, the expression of putatively detrimental proteins may be enhanced and that may impair cardiac function by fostering fibrosis and hypertrophy, reduce cardiac contractility and may lead to heart failure. Hypoxia (reduced oxygen partial pressure: pO₂) and ischaemia impair respiration in the mitochondrion and thus formation of ATP in mitochondria or might activate directly hypoxia-inducible transcription factors (HIF). Increased expression or altered function of sarcolemmal ion channels like the sodium cation channel (Na⁺) or the sodium/calcium exchanger (NCX) but also increased expression of H₂-histamine receptors, can lead to supraventricular or ventricular arrhythmias by alteration of Ca²⁺ homeostasis.