The cardiac effects of adenosine

Belardinelli, Luiz; Linden, Joel; Berne, Robert M.

doi:10.1016/0033-0620(89)90015-7

Cited by 718 publications

(305 citation statements)

References 155 publications

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“…Adenosine, which is known to activate mast cells (38), is elevated in ischemia (39). NPY, coreleased with norepinephrine from sympathetic nerve endings, (40), also activates mast cells (41).…”

Section: Discussionmentioning

confidence: 99%

Mast cells: A unique source of renin

Silver

Reid

Mackins

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

175

159

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In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensinconverting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.T raditionally the renin-angiotensin system (RAS) has been viewed as a circulating axis, whereby renin is released into the circulation from the kidneys in response to decreased renal perfusion pressure, decreased delivery of NaCl at the macula densa, and͞or increased renal sympathetic nerve activity (1). The rate-limiting step in the formation of angiotensin II (ANG II) is the proteolytic action of renin, which cleaves angiotensinogen (Aogen) to the intermediate angiotensin I (ANG I). ANG I is then converted to ANG II by angiotensin-converting enzyme (ACE) at the endothelial surface (2, 3).In addition to this conventional pathway, many tissues, including heart and brain, are thought to be capable of local ANG II production via tissue-specific RAS (4, 5). Although Aogen, ANG I, and ACE, have been demonstrated in various organs, the presence of renin of extrarenal origin has been more difficult to prove and remains controversial. In this investigation, experiments were designed to determine whether renin could be detected in native tissue other than kidney. Because ANG II plays such a crucial role in cardiovascular disease, we focused our efforts on heart tissue, which we screened for renin by using an established polyclonal anti-renin Ab made to recombinant human renin (6). We found that cardiac mast cells were immunopositive for renin. In addition, we used a cultured mast cell line to extrapolate our observations from fixed heart slices to living cells.Our findings indicate that ma...

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Section: Discussionmentioning

confidence: 99%

Mast cells: A unique source of renin

Silver

Reid

Mackins

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

175

159

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“…A hypotensive response closely linked to an action of adenosine at the cardiac level has been already reported in the rat (Webb et al (1990)). A variety of evidence demonstrates the presence of adenosinic receptors responsible both for the negative chronotropic and the inotropic and dromotropic e ects on cardiac function; they are mostly described as belonging to the A1 subtype in experiments in di erent mammals including humans (Belardinelli et al, 1989;Pelleg & Belardinelli, 1993;Olsson & Pearson, 1990; Linden, 1991); these receptors represent the basis for the therapeutic use of adenosine in the treatment of supraventricular tachycardia, and for the use of adenosine receptor antagonists in the treatment of bradyarrhythmias (Ralevic & Burnstock, 1998). Thus, the bradycardic e ect of adenosine in our experiments is in agreement with literature where the occurrence of a cardiac block following high doses has already been reported (Belardinelli et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…A variety of evidence demonstrates the presence of adenosinic receptors responsible both for the negative chronotropic and the inotropic and dromotropic e ects on cardiac function; they are mostly described as belonging to the A1 subtype in experiments in di erent mammals including humans (Belardinelli et al, 1989;Pelleg & Belardinelli, 1993;Olsson & Pearson, 1990; Linden, 1991); these receptors represent the basis for the therapeutic use of adenosine in the treatment of supraventricular tachycardia, and for the use of adenosine receptor antagonists in the treatment of bradyarrhythmias (Ralevic & Burnstock, 1998). Thus, the bradycardic e ect of adenosine in our experiments is in agreement with literature where the occurrence of a cardiac block following high doses has already been reported (Belardinelli et al, 1989). In spite of the inhibitory activity on adenosine response by the selective A 1 antagonist DPCPX, in our experiments, the order of potency of the synthetic adenosine agonists (NECA4R-PIA4APNEA=adenosine, Table 2) is not compatible with A 1 receptor subtype stimulation, but rather with an A 2 stimulation (Fredholm et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…As far as the cardiovascular system is concerned, adenosine slows heart rate (HR) and atrioventricular conduction and antagonizes the cardio-stimulatory e ects of catecholamines via cardiac A 1 receptors in di erent mammals (Belardinelli et al, 1989;Olsson & Pearson, 1990). An increase in blood pressure (BP) and HR has been described in rats and in cats via central A 1 receptors (St Lambert et al, 1994; SilvaCarvalho et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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1 Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic e ect at the highest doses. The ®rst phase hypotensive response was signi®cantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2 The A 2a /A 2b agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not signi®cantly modi®ed by the A 2b antagonist enprofylline. 3 The A 2a agonist CGS 21680 did not signi®cantly in¯uence basal HR while induced a hypotensive response antagonized by the A 2a selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4 The A 1 agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A 1 selective antagonist DPCPX signi®cantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5 The A 1 /A 3 agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a signi®cant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6 The selective A 3 agonist IB-MECA revealed a weak hypotensive and bradycardic e ect, but only at the highest doses. 7 In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A 2a -and NO-mediated hypotension, and a bradycardic e ect with a consequent hypotension, via atypical A 1 receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A 3 receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed. IntroductionFour classes of membrane surface adenosine receptors are described, de®ned A 1 , A 2a , A 2b and A 3 , through which the nucleoside in¯uences many functions in humans and other animals (Ralevic & Burnstock, 1998). As far as the cardiovascular system is concerned, adenosine slows heart rate (HR) and atrioventricular conduction and antagonizes the cardio-stimulatory e ects of catecholamines via cardiac A 1 receptors in di erent mammals (Belardinelli et al., 1989;Olsson & Pearson, 1990). An increase in blood pressure (BP) and HR has been described in rats and in cats via central A 1 receptors (St Lambert et al., 1994; SilvaCarvalho et al., 1993). In contrast, a dose-related decrease in BP and HR is observed after microinjection of adenosine into the caudal nucleus of tractus solitarii in the rat (Lo et al., 1998).As regards a direct e ect on blood vessels, A 1 purinoceptors mediate vasodilation in the porcine coronary artery (Merkel et al., 1992) but they are involved, on the contrary, in vasoconstrictor responses, i.e. in the rat kidney (Jackson, 1991), in guinea-pig pulmonary artery and aorta (Biaggioni et al., 1989;Stoggall & Shaw, 1990) and in hamster skin (Stojanov & Proctor, 1990;Proctor & Stojanov, 1991).Moreover, a signi®cant role of A 1 receptors in the regulation of BP also appears to be linked to a prejunction...

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“…In addition, adenosine causes hyperpolarization by activation of K + channels [15] via G proteins [16,17]. These K + channels are the same channels that are stimulated by acetylcholine in the cardiac tissue [18][19][20].…”

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confidence: 99%

Characterization of adenosine receptors in intact cultured heart cells

El-Ani

Shainberg

1994

Biochemical Pharmacology

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Adenosine receptors were studied on heart cells grown in cultures by the radioligand binding technique. We used the hydrophilic A 1 adenosine receptor radioligand [ 3 H]-8-cyclopentyl-1,3-dipropylxanthine ([ 3 H]CPX), to monitor the level of the receptors on intact cardiocytes. The binding showed high affinity (K d = 0.13 nM) and the number of [ 3 H]CPX binding sites (B max ) was 23.1 fmol/dish (21 fmol/mg protein). The K i of the agonists R-N 6 -(2-phenylisopropyl)-adenosine (R-PIA) and S-N 6 -(2-phenylisopropyl)-adenosine (S-PIA), and of the antagonists CPX and theophylline were 3.57, 49.0, 1.63 and 4880 nM, respectively. The number of adenosine receptors was very low during the first days in cultures (5 fmol/dish) and increased gradually until it reached a plateau on days 8-10. Treatment with norepinephrine or isoproterenol which accelerated the rate of contractions, induced up regulation of the receptors. B max increased 2-3-fold by application of norepinephrine for 4 days, while receptor affinity to the radioligand was unaffected. Lactate dehydrogenase (LDH) and creatine kinase (CK) activity increased only by 22 and 38%, respectively. Similarly, 3 days treatment with triiodothyronine (T 3 , 10 −8 M), which also accelerated heart rate, increased the number of adenosine receptors by 56% without a significant change in the affinity of the receptors to [ 3 H]CPX. Carbamylcholine (5 × 10 −6 M), which reduced the rate of heart contractions, caused 26% down regulation while the affinity of the receptors remained unchanged. It is concluded that there is a linkage between the rate of cardiac contractions and the level of adenosine receptors. Thus, the level of adenosine receptors may respond to drug-induced chronic changes in cardiac contractile activity so as to restore conditions to normal (basal) contractions. KeywordsCPX; heart-rate; norepinephrine; thyroid hormones Adenosine modulates a variety of physiological functions in the heart. These actions are mediated by cell surface adenosine receptors, which can be classified into A 1 and A 2 † Corresponding author. Tel. (972)3-5318265; FAX (972)3-5351824. In conditions of stress like hypoxia or ischemia, the concentration of adenosine in the extracellular fluid rises dramatically, mainly through the breakdown of ATP [4]. In these conditions adenosine has therapeutic and protective effects on the heart [5,6]. Adenosine causes negative chronotropic, dromotropic and ionotropic effects on the cardiac tissue via A 1 receptors [7,8]. Adenosine also acts as a coronary vasodilator via A 2 receptors [9]. These effects of adenosine occur also without prior catecholamine treatment [10]. Stimulation that enhances the cAMP content (catecholamines, forskolin, amrinone), makes the heart more sensitive to adenosine [11][12][13][14]. In addition, adenosine causes hyperpolarization by activation of K + channels [15] via G proteins [16, 17]. These K + channels are the same channels that are stimulated by acetylcholine in the cardiac tissue [18][19][20]. HHS Public AccessChron...

show abstract

The cardiac effects of adenosine

Cited by 718 publications

References 155 publications

Mast cells: A unique source of renin

Mast cells: A unique source of renin

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Characterization of adenosine receptors in intact cultured heart cells

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