9-(tetrahydro-2-furyl)-adenine and Hypertension

We analyse the effect of aldosterone on vasomotor response induced by electrical field stimulation (EFS) in mesenteric arteries from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).. Aldosterone (0.001-1 microM) reduced vasoconstrictor response to EFS in a dose- and time-dependent manner only in SHR. Thus, the rest of experiments were performed only in SHR. Aldosterone did not affect either noradrenaline response or release. Effect of aldosterone (1 microM) on EFS response was not affected by NG-nitro-arginine-methyl esther (100 microM), and was abolished by capsaicin (0.5 microM) and the calcitonin gene-related peptide antagonist (CGRP 8-37, 0.5 microM). Calcitonin gene-related peptide (0.1 nM-0.1 microM) induced a concentration-dependent relaxation, which was enhanced by aldosterone (1 microM). Incubation with either spironolactone (1 microM), glibenclamide (10 microM), RU 486 10 microM, ODQ (10 microM) or cycloheximide (10 microM) significantly reduced the enhancement of CGRP-relaxation produced by aldosterone, while remained unmodified by SQ 22,536.. Aldosterone decreases the vasoconstrictor response to EFS in mesenteric arteries from SHR but not from WKY. This effect is mediated by an increased response to the sensory neurotransmitter CGRP, substantially, through glucocorticoid receptors activation. Furthermore, this effect is mediated by an increase of cGMP synthesis and ATP-dependent potassium channel activation.

Topics: Adenine; Adenosine Triphosphate; Aldosterone; Animals; Anti-Arrhythmia Agents; Calcitonin Gene-Related Peptide; Capsaicin; Cyclic GMP; Electric Stimulation; Enzyme Inhibitors; Glyburide; Hypertension; Male; Mesenteric Arteries; Mineralocorticoid Receptor Antagonists; Neurons; NG-Nitroarginine Methyl Ester; Norepinephrine; Potassium Channels; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Glucocorticoid; Spironolactone; Vasoconstriction; Vasomotor System

Adrenomedullin (ADM) is a vasodilator produced by vascular endothelium and smooth muscle cells. Although plasma ADM levels are increased in patients with hypertension, heart failure, and myocardial infarction, little information exists regarding the microvascular response to ADM in the human heart. In the present study we tested the hypothesis that ADM produces coronary arteriolar dilation in humans and examined the mechanism of this dilation. Human coronary arterioles were dissected and cannulated with micropipettes. Internal diameter was measured by video microscopy. In vessels constricted with ACh, the diameter response to cumulative doses of ADM (10(-12)-10(-7) M) was measured in the presence and absence of human ADM-(22-52), calcitonin gene-related peptide-(8-37), N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (Indo), (1)H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, or KCl (60 mM). ADM dilated human coronary arterioles through specific ADM receptors (maximum dilation = 69 +/- 11%). L-NAME or N-monomethyl-L-arginine attenuated dilation to ADM (for L-NAME, maximum dilation = 66 +/- 7 vs. 41 +/- 13%, P < 0.05). Thus the mechanism of ADM-induced dilation involves generation of nitric oxide. However, neither (1)H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one, SQ-22536, nor Indo alone altered dilation to ADM. High concentrations of KCl blocked dilation to ADM. The magnitude of ADM dilation was reduced in subjects with hypertension. We propose that, in human coronary arterioles, ADM elicits vasodilation in part through production of nitric oxide and in part through activation of K(+) channels, with little contribution from adenylyl cyclase. The former dilator mechanism is independent of the more traditional pathway involving activation of soluble guanylate cyclase.

Topics: Adenine; Adrenomedullin; Aged; Arterioles; Calcitonin Gene-Related Peptide; Coronary Circulation; Coronary Disease; Coronary Vessels; Enzyme Inhibitors; Female; Heart Failure; Humans; Hypertension; In Vitro Techniques; Male; Microcirculation; Middle Aged; Miotics; NG-Nitroarginine Methyl Ester; Nitric Oxide; omega-N-Methylarginine; Peptide Fragments; Potassium Channels; Vasodilation; Vasodilator Agents