2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Hypertension

The objectives of the present study were to determine functional (i.e., heparin-releasable) and intracellular (i.e., heparin-non-releasable) cardiac lipoprotein lipase (LPL) activity during the development of hypertension in spontaneously hypertensive (SHR) rats.. Male WKY and SHR rats were killed before (7-8 weeks of age) and following (15-16 weeks of age) the development of severe hypertension in SHR rats. LPL activity in coronary perfusates was determined by retrogradely perfusing the hearts with heparin (5 U/ml). Cardiac myocytes were also isolated from the two groups of rats by collagenase digestion, and surface-bound and intracellular LPL activity measured.. With the development of hypertension in SHR rats, there was a concomitant and progressive reduction in the heparin-releasable coronary endothelial LPL activity. Neither insulin action nor cell-associated enzyme activity could explain this low LPL activity in coronary blood vessels. However, acute vasodilation with nifedipine (a Ca2+ influx blocker) or CGS-21680 (A2-purinergic receptor agonist) increased the peak heparin-releasable LPL activity in hearts isolated from SHR rats.. Our results indicate that hypertension per se may play a significant role in regulating cardiac LPL activity, and hence fatty acid supply to the hypertensive SHR rat heart.

Topics: Adenosine; Animals; Calcium Channel Blockers; Heparin; Hypertension; Intracellular Fluid; Lipoprotein Lipase; Male; Myocardium; Nifedipine; Perfusion; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilator Agents

Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.

Topics: Adenosine; Aggression; Animals; Blood Pressure; Brain; Caffeine; Cloning, Molecular; Heart Rate; Humans; Hypertension; Male; Mice; Mice, Knockout; Molecular Sequence Data; Pain; Phenethylamines; Platelet Aggregation; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Restriction Mapping; Sequence Homology, Amino Acid

Lipoprotein lipase (LPL) is an endothelium-bound enzyme that is rate determining for the clearance of triacylglycerol-rich lipoproteins. We assessed cardiac heparin-releasable LPL activity in an acquired model of hypertension, the fructose-hypertensive rat. Fructose feeding (10% solution in drinking water ad libitum) for 2 (short-term) or 4-6 (long-term) weeks induced hypertension, hypertriglyceridemia, and hyperinsulinemia in male Wistar rats. After short- and long-term fructose treatment, LPL activity in coronary perfusates was determined by retrogradely perfusing the hearts with heparin. Short-term fructose treatment did not alter cardiac heparin-releasable LPL activity, whereas a significant decrease in LPL activity was seen in the long-term treated group. Discontinuation of fructose treatment for 2 weeks from the long-term group normalized blood pressure and cardiac heparin-releasable LPL activity. Interestingly, acute vasodilation by in vitro perfusion of coronary vasodilators like nifedipine and CGS-21680 increased cardiac heparin-releasable LPL activity in the long-term group to control levels. These studies demonstrate that long-term fructose-induced hypertension may play a significant role in regulating cardiac LPL activity. Whether or not this altered LPL activity has a role in the regulation of fatty acid supply to the hypertensive heart has yet to be determined.

Topics: Adenosine; Animals; Blood Glucose; Blood Pressure; Coronary Vessels; Fructose; Heparin; Hypertension; In Vitro Techniques; Insulin; Lipoprotein Lipase; Male; Muscle, Smooth, Vascular; Myocardium; Nifedipine; Perfusion; Phenethylamines; Rats; Rats, Wistar; Triglycerides; Vasodilation; Vasodilator Agents

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

Adenosine receptor-binding profiles in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR) of a series of 2-(cycloalkylalkynyl)adenosines (2-CAAs) and their congeners are described. The structure-activity relationship of this series of compounds is discussed, focusing on the length of the alkynyl side chain and bulkiness of the terminal cycloalkyl substituents in terms of binding activity and cardiovascular effects. All the 2-CAAs had a preferential affinity for A2 receptors. Of these derivatives, 2-(3-cyclopentyl-1-propyn-1-yl)adenosine (10b) exhibited the most selective affinity for A2 receptors (Ki ratio: A1/A2 = 70) on the basis of receptor binding. In the C-2 binding region of adenosine, compounds often have potent and/or selective A2 activity from introduction of an acetylenic group at the C-2 position followed by one methylene residue further followed by a hydrophobic substituent such as a cycloalkyl ring at the terminal position of the alkynyl side chain. Intravenous injection of 10b up to 100 micrograms/kg had a potent hypotensive effect without a marked decrease in heart rate in anesthetized SHR. Compounds 10j-s, with a hydroxyl group in the C-3" position of the alkynyl side chain, had a potent affinity for both A1 and A2 receptors, but they were not highly selective for A2 receptors. These compounds caused a marked bradycardia upon intravenous administration in anesthetized SHR. Oral administration of 10b (0.1-1 mg/kg) had a potent and long-lasting antihypertensive effect in conscious SHR.

Topics: Adenosine; Animals; Antihypertensive Agents; Brain; Cell Membrane; Heart Rate; Hypertension; Molecular Structure; Rats; Rats, Inbred SHR; Receptors, Purinergic; Structure-Activity Relationship