Evidence for the presence of A₁ adenosine receptors in the aorta of spontaneously hypertensive rats

Abstract

1 Isolated aortic rings (endothelium-intact and -denuded) from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were used in this study to examine the vasoactive e ects of various adenosine analogues. 2 In phenylephrine contracted aortic rings, concentration-response curves were constructed by cumulative additions (10 711 ± 10 75 M) of (2S)-N 6 -[2-endo-Norbornyl] adenosine (ENBA), N 6 -cyclopentyladenosine (CPA), R-N 6 -(2-phenylisopropyl) adenosine (R-PIA), 2-p-(-2-carboxyethyl) phenethylamino-5'-N-thylcarboxamido adenosine (CGS-21680). 3 A non-speci®c adenosine receptor agonist 2-chloroadenosine (CAD) resulted in biphasic response with a small contraction at lower concentrations (10 79 ± 10 78 M) followed by a signi®cant relaxation at higher concentration in endothelium-intact SHR tissues, suggesting presence of both A 1 and A 2 adenosine receptors in SHR aorta. However, only relaxation was observed in WKY. 4 Contractile response in SHR had the following rank order of potency: ENBA4CPA4R-PIA4CAD. The relaxation response in SHR and WKY had the following rank order of potency: CGS 216804CAD4R-PIA4CPA4ENBA. 5 Removal of endothelium abolished the adenosine analogue induced contractions in SHR aorta and attenuated the vasorelaxation responses in the WKY and SHR. 6 The contractile response in SHR was abolished by A 1 adenosine receptor antagonist N 6 -endonorbornan-2-yl-9-methyladenine (N-0861). A 2 adenosine receptor antagonist, 3,7-dimethyl-1-proparglyxanthine (DMPX) did not a ect the contraction response of adenosine analogues. 7 Endothelium-dependent contractions elicited by A 1 receptor agonists were blocked by indomethacin and by free radical scavengers. 8 These data suggest that the contractile response to adenosine analogues in SHR aorta is probably mediated by free radicals which are generated through the increased cyclo-oxygenase activity occurring in the vascular endothelium of SHR but not the WKY rats.

Novel Mitogenic Effect of Adenosine on Coronary Artery Smooth Muscle Cells

“…Although it is too early to conclude that adenosine is involved in the etiology of coronary artery diseases, several aspects of consideration pertaining to adenosine and the A 1 R point to that potential: (1) the A 1 R is upregulated in diabetes, 33 hypertension, 34 and by oxidative stress, 35 all of which contribute to the development of coronary artery disease; (2) the A 1 R has higher affinity for adenosine than A 2 R, and the desensitization of A 1 R is much slower than A 2 R (t 1/2 : Ϸ10 hours versus Ϸ20 minutes), 36 both properties of which could imply a role for A 1 R in chronic effects on CASMC proliferation; and (3) adenosine is directly released from endothelial cells, stressed myocardial cells, and can also accumulate after catabolism of ATP/ADP released from activated platelets and inflammatory cells surrounding CASMCs after arterial injury. 1 From these points of view, together with the fact that VSMC proliferation is involved in the development of hypertension and atherosclerosis as well as restenosis after angioplasty and bypass surgery, 7,8,32 it is conceivable that identification of a novel mitogenic effect of adenosine and defining its receptor mechanism on CASMC will not only change the paradigm of our current view on the role of adenosine in the coronary circulation and disease, but also imply potential clinical applications via pharmacological intervention such as A 1 R antagonism for limiting the abnormal growth of CASMCs under the aforementioned diseases.…”

“…Therefore, although this compound has been used as a highly selective A 2A R antagonist, caution must be taken when used in pig tissues/cells to differentiate the A 1 R versus A 2A R. The fact that our results differ from results of prior work in VSMCs of other sites exemplifies the prediction made by Ross 32 that VSMCs of different embryonic origins could respond differently to stimuli that generate atherosclerotic lesions in an artery segment-dependent manner. Although it is too early to conclude that adenosine is involved in the etiology of coronary artery diseases, several aspects of consideration pertaining to adenosine and the A 1 R point to that potential: (1) the A 1 R is upregulated in diabetes, 33 hypertension, 34 and by oxidative stress, 35 all of which contribute to the development of coronary artery disease; (2) the A 1 R has higher affinity for adenosine than A 2 R, and the desensitization of A 1 R is much slower than A 2 R (t 1/2 : Ϸ10 hours versus Ϸ20 minutes), 36 both properties of which could imply a role for A 1 R in chronic effects on CASMC proliferation; and (3) adenosine is directly released from endothelial Figure 7. Effects of PTX and PD81723 on the DNA synthesis of CASMCs.…”

Angiotensin II stimulation alters vasomotor response to adenosine in mouse mesenteric artery: role for A1 and A2B adenosine receptors

“…Recently, increased adenosine production and activation of A 2B receptors in kidneys of mice were implicated in chronic angiotensin II‐dependent hypertension (Zhang et al, ). Previously, we demonstrated that endothelium‐dependent contractile responses to adenosine analogues in spontaneously hypertensive rat (SHR) aorta are mediated by A 1 receptors and vasodilatation is mediated by A 2 receptors (Fahim and Mustafa, ). Moreover, in SHR aorta, endothelium‐dependent adenosine receptor‐mediated vasodilatation was attenuated (Fahim et al, ).…”

Mechanism of acidic pH‐induced contraction in spontaneously hypertensive rat aorta: role of Ca2+ release from the sarcoplasmic reticulum

“…This Ca 2+ release in WKY aorta has no influence on the level of sustained contraction, but its functional role is to accelerate the development of contraction induced by acidosis. There are numerous differences between the aortas of SHR and WKY including those of the sensitivity to contractile agonists and relaxants (Honda et al 1999, Fahim & Mustafa 2001. In addition to the contractile properties, differences in the morphology and physiology of SR between the two strains have been described.…”