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Stimulation of renal A1-adenosine receptors produces vasoconstriction that is maximal when the animal is salt-depleted and is inhibited during salt loading. We postulated that the effect of salt balance on the vasoconstrictor response to A1-adenosine receptor stimulation was due to a change intrinsic to the kidney, perhaps related to a change in responsiveness of the renal A1-adenosine receptor population. We tested this hypothesis by determining the renovascular response to the metabolically stable, selective, A1-adenosine receptor agonist N6-cyclohexyladenosine (CHA) in salt-loaded and salt-depleted rats in vivo and in isolated, perfused kidneys harvested from these rats. CHA was a renal vasoconstrictor in the salt-depleted animals and a renal vasodilator in the salt-loaded rats. In the isolated, perfused kidneys, CHA produced a biphasic response with submicromolar concentrations being vasoconstrictor and higher concentrations being vasodilator. In contrast to the response in vivo CHA was a more potent vasoconstrictor in the isolated, perfused kidneys that had been removed from salt-loaded animals. Indomethacin enhanced the vasoconstrictor response to CHA in the kidneys removed from salt-loaded animals but had no effect on the kidneys from salt-depleted animals. These findings indicate that the inhibition of the renal vasoconstrictor response to CHA in salt-loaded animals is not related to a change within the kidney but that a factor extrinsic to the kidney must be responsible for the change in adenosine responsiveness in vivo.

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The hypothesis that vascular prostacyclin synthesis is stimulated by the oral administration of hydralazine and may account for part of its vascular effect was tested. Eight white patients with mild essential hypertension were studied in a randomized, double-blind design to assess the effects of indomethacin on hydralazine's ability to lower blood pressure, elevate pulse, and alter the vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha) measured by gas chromatography-mass spectrometry. Administration of hydralazine at either 50 mg bid or 100 mg bid for a week, doses commonly administered in clinical settings, was not associated with a statistically significant fall in mean blood pressure, although there was a tendency towards a decrease but did result in an increase in heart rate. Administration of indomethacin had no effect on the hemodynamic parameters secondary to hydralazine. Administration of indomethacin resulted in a slight but significant weight gain compared to placebo, but the addition of hydralazine did not result in a further increase in weight. Neither dose of hydralazine resulted in an increase in the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha. The excretion rate was 85 +/- 16 ng/g of creatinine during placebo, 88 +/- 16 ng/g of creatinine during hydralazine, 50 mg bid, and 65 +/- 8 ng/g of creatinine during hydralazine, 100 mg bid. Administration of indomethacin, 50 mg bid, resulted in a significant decrease in 2,3-dinor-6-keto-PGF1 alpha from 65 +/- 6 ng/g to 37 +/- 8 ng/g of creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)

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We tested the hypothesis that vascular prostacyclin synthesis is increased by propranolol and could account for some of the drug's antihypertensive effect. We studied 10 white patients with mild essential hypertension in a randomized, double-blind design to assess the effects of indomethacin with or without the addition of propranolol on blood pressure and vascular prostacyclin biosynthesis, as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha), F1 alpha (PGF1 alpha), measured by gas chromatography-mass spectrometry. Seven patients responded to propranolol with a lowering of mean arterial blood pressure in both supine and upright postures. The fall in mean arterial blood pressure (-14.1 +/- 2.1 mm Hg sitting; -17.4 +/- 1.7 mm Hg supine) with propranolol alone was significantly greater than that produced when propranolol was given to patients receiving indomethacin (-7.8 +/- 1.9 mm Hg sitting; -7.7 +/- 3.0 mm Hg supine). Our drug-responsive patients demonstrated a significantly lower excretion rate of 2,3-dinor-6-keto-PGF1 alpha than was found in an age and sex-matched group of normal volunteers. With propranolol treatment, drug-responsive patients showed a significant increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha, such that the mean excretion was not significantly different from that in normal volunteers. Indomethacin caused a significant rise in mean arterial blood pressure and a significant fall in 2,3-dinor-6-keto-PGF1 alpha excretion, and it blocked the rise in urinary 2,3-dinor-6-keto-PGF1 alpha associated with propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

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