adenosine-5--(n-ethylcarboxamide) and Hypertension

A2A adenosine receptors inhibit neutrophil adhesion and superoxide anion generation. The aim of the present study was to evaluate the effect of antihypertensive treatment with doxazosin or propranolol on the binding and functional parameters of A2A adenosine receptors of lymphocytes and neutrophils in essential hypertensive patients. Two groups of previously untreated, essential hypertensive patients were studied. The mean affinity (K(d)) and density (B(max)) of adenosine receptors, by the A2A selective radioligand [3H]-ZM-241385 binding assays, and EC50, by cAMP assays, were obtained first on no medication and a second time after treatment for up to 13 weeks with doxazosin (13 patients) or propranolol (8 patients). A third group of 15 healthy normotensive volunteers matched by age, sex, and body mass index was used as a control. Binding and functional parameters of the A2A adenosine receptors were significantly higher in the 2 hypertensive groups than in controls (P always <0.0001), both in lymphocyte and neutrophil membranes. After treatment with propranolol, the binding parameters did not change significantly, whereas after treatment with doxazosin, K(d), B(max), and EC50 values returned to control levels. In never-treated essential hypertensive patients, lower affinity, higher density, and impaired function of A2A adenosine receptors are present. The binding and functional parameters of A2A adenosine receptors appear to be normalized after treatment with doxazosin but not with propranolol.

Topics: Adenosine-5'-(N-ethylcarboxamide); Adult; Antihypertensive Agents; Binding, Competitive; Blood Pressure; Body Mass Index; Cyclic AMP; Diastole; Doxazosin; Female; Humans; Hypertension; Lymphocytes; Male; Middle Aged; Neutrophils; Propranolol; Radioligand Assay; Receptor, Adenosine A2A; Receptors, Purinergic P1; Reference Values; Systole; Treatment Outcome; Triazines; Triazoles

The present study had employed in vitro receptor autoradiography with [3H]DPCPX to visualise the presence of adenosine A1 receptors on the rat nodose ganglion, which contains the perikarya of vagal afferent neurons projecting the the nucleus tractus solitarius (NTS). In addition, unilateral vagal ligation resulted in an accumulation of [3H]DPCPX binding adjacent to the ligatures, indication that adenosine A1 receptors are subject to axoplasmic flow along the rat vagus nerve. Radioligand binding assays were utilised to characterise the properties of adenosine A1 receptors in the dorsal vagal complex (NTS, area postrema and dorsal motor nucleus of the vagus) of pup and adult normotensive (Wistar Kyoto, WKY) and hypertensive (spontaneously hypertensive, SHR) rats. Saturation binding indicated that the affinity (KD) of [3H]DPCPX, and the binding site density (Bmax) were not different between the adult WKY and SHR, although the pup SHR had a lower KD value than the pup WKY rat. Competition binding assays revealed complex differences between the two rat strains; however, with respect to hypertension, the affinity of the selective adenosine A1 agonist, cyclohexyladenosine (CHA), was markedly reduced in the membranes from SHR (Ki approximately 93 nM) compared to WKY (approximately 6 nM). Such an observation is consistent with the attenuated responses of SHRs to intra-NTS injections of adenosine.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Autoradiography; Axonal Transport; Binding, Competitive; Hypertension; Male; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Purinergic P1; Reference Values; Solitary Nucleus; Vagus Nerve; Xanthines

Using the telemetry system in spontaneously hypertensive rats (SHR), we evaluated the hemodynamic effects of four adenosine analogs having different selectivity for A1 and A2a adenosine receptor subtypes. The selective A2a agonists, 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA) and 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoaden osi ne (CGS 21680), the selective A1 agonist, 2-chloro-N6-cyclopentyl-adenosine (CCPA) and the nonselective agonist, 5'-N-ethyl-carboxamidoadenosine (NECA), were administered i.p. to conscious spontaneously hypertensive rats. For comparison, the calcium channel blocker, felodipine, was included. CCPA and 2HE-NECA were tested also by the oral route. Systolic and diastolic blood pressure and heart rate were recorded every 5 min for 24 hr after drug administration. Data were analyzed using the curve fitting model recently elaborated. All compounds caused dose-dependent antihypertensive effects. The i.p. dose inducing a decrease of 50 mm Hg (ED50) was calculated for both systolic and diastolic blood pressure. As regards diastolic blood pressure, ED50 values were: CCPA, 0.019 (0.013-0.027) mg/kg, 2HE-NECA, 0.009 (0.002-0.03) mg/kg, CGS 21680, 0.155 (0.084-0.246) mg/kg, NECA, 0.008 (0.004-0.016) mg/kg and felodipine, 5.16 (4.18-7.18) mg/kg. At equiactive doses, the antihypertensive effects of adenosine agonists were shorter lasting [t1/2 for DBP were: CCPA, 54 (44-76) min, 2HE-NECA, 57 (46-71) min, CGS 21680, 45 (21-94) min, NECA, 61(38-97) min] than those of felodipine [t1/2 = 233 (182-274) min]. After oral administration (0.3, 1 and 3 mg/kg), hypotension induced by 2HE-NECA was longer lasting than that of CCPA. 2HE-NECA, CGS 21680 and felodipine caused tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Blood Pressure; Heart Rate; Hemodynamics; Hypertension; Male; Phenethylamines; Rats; Rats, Inbred SHR; Receptors, Purinergic P1; Telemetry; Time Factors

A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain. Some of these changes led to improved A2 affinity and increased selectivity. Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.

Topics: Adenosine; Alkylation; Animals; Antihypertensive Agents; Blood Pressure; Chemical Phenomena; Chemistry; Cyclohexanes; Heart Rate; Hypertension; Male; Molecular Structure; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Purinergic

(-)-N6-(R-phenylisopropyl)-adenosine (R-PIA) depressed tritium overflow and vasoconstriction evoked by electrical stimulation to a similar extent in isolated tail arteries of Wistar rats (WR) preincubated with [3H]noradrenaline. The inhibitory effects of adenosine, 5'-N-ethylcarboxamidoadenosine (NECA) and R-PIA were determined on the constrictor responses of tail arteries obtained from WR, as well as spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY). In WR and WKY, the rank order of agonist potency (R-PIA greater than NECA greater than adenosine) was compatible with the presence of adenosine A1-receptors. Whereas adenosine, NECA and R-PIA were equiactive in WR and WKY, they produced no or only slight changes in SHR. The left renal arteries of some WR were partially occluded to induce hypertension. R-PIA had the same effect in the tail arteries of these animals as in preparations obtained from sham-operated WR. The above results suggest that the subsensitivity of presynaptic A1-receptors in the blood vessels of SHR is genetically determined. This could contribute in vivo to enhanced transmitter release from terminals of perivascular nerves and subsequent increases in vascular resistance.

Topics: Adenosine; Adenosine Triphosphate; Adenosine-5'-(N-ethylcarboxamide); Animals; Blood Pressure; Electric Stimulation; Hypertension; In Vitro Techniques; Muscle, Smooth, Vascular; Norepinephrine; Phenylisopropyladenosine; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Purinergic; Species Specificity; Theophylline; Vasoconstriction