Studies on the Antihypertensive Mechanism of adrenergic Receptor Antagonist Propranolol : Special Reference to the Role of Vasodilatory Prostaglandins

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西宮, 孝敏 ; Perry V., Halushka (1988)
  • Publisher: 札幌医科大学医学部
  • Journal: 札幌医学雑誌 = The Sapporo medical journal (issn: 0036-472X, vol: 57, pp: 523-533)
  • Subject: Vasodilatory prostaglandin (PGI?, PGE?) | Phospholipase A? | Propranolol (L-, D-, DL-) | Aortic strip | Spontaneously hypertensive rat
    mesheuropmc: lipids (amino acids, peptides, and proteins)

β-adrenergic receptor antagonists are widely used to treat the patients with hypertension. The mechanism of the antihypertensive effect of these drugs was thought to be associated with 1) negative cardiac inotropic and chronotropic action, 2) suppression of renin secretion, and 3) effects on the central nervous system. However, the precise mechanism is still unknown. Long term therapy with β-adrenergic receptor antagonists is also associated with a reduction in the peripheral vascular resistance. Indomethacin and other non-steroidal antiinflammatory drugs have been shown to blunt the antihypertensive effect of propranolol and other β-adrenergic receptor antagonists in patients and laboratory animals. This study was, therefore, designed to determine the effects of DL-, D- or L-propranolol on the synthesis of the vasodilatory prostaglandin, PGI2 and PGE2 in the aorta, renal medulla, and the renal cortex of spontaneously hypertensive rats (SHR). DL-Propranolol and L-propranolol significantly lowered blood pressures from 148±9/113±5mmHg to 112±3/80±3 and from 133±4/100±2mmHg to 121±3/81±3 mmHg, respectively. Comparable treatment of SHR with D-propranolol revealed no lowering effect. Basal immunoreactive 6-keto PGF1α and PGE2 production by isolated thoracic aorta, renal medulla, and renal cortex was measured in the samples with an incubation time of 60 to 90 minutes and showed no difference in the vehicle compared to the DL-propranolol treated rats. Norepinephrine (1 μM)-stimulated synthesis of 6-keto PGF1α and PGE2 in the aorta was significantly enhanced in the DL-propranolol treated group compared to the vehicle treated group. Aortic 6-keto PGF1α, and PGE2 synthesis stimulated by norepinephrine in the L-propranolol treated rats was also significantly higher than that observed in the vehicle and D-propranolol treated groups. DL-propranolol treatment did not alter norepinephrine-stimulated renal cortical or medullary 6-keto PGF1α and PGE2 production. Bradykinin- and angiotensin II- augmented aortic 6-keto PGF1α along with PGE2 production in the chronic treatment with L-propranolol was significantly higher than that in the D-propranolol treated group. However, arachidonic acid-stimulated aortic 6-keto PGF1α and PGE2 production in the chronic treatment with DL-propranolol group was not different from that of the vehicle treated group. Acute in vitro exposure of thoracic aortas from SHR to D-, or L-propranolol (100ng/ml) did not ?augment aortic 6-keto PGF1α and PGE 2 synthesis compared to the vehicle. These data suggest that 1) the antihypertensive effect of propranolol is stereoselective, 2) norepinephrine-, bradykinin-, and angiotensin II-stimulated aortic vasodilatory prostaglandin synthesis are stereoselective, 3) the antihypertensive effect of propranolol may be related to the enhanced synthesis of vasodilatory prostaglandin, PGI2 or PGE2, in the vascular tissue, and 4) chronic DL-propranolol treatment may modulate arachidonic acid metabolism by changing either phospholipase A2 activity or the membrane phospholipids metabolism.
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