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A series of [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acids and their corresponding 1,1-dioxides were synthesized and evaluated for diuretic activity in the acute saline loaded mice (ASLM) and hypotensive activity in the spontaneously hypertensive rat (SHR). A significant number of compounds were found to display potent activity in one or both assays, and preliminary structure-activity relationships with respect to each assay were delineated. Compound 94, the 1,1-dioxide of [(6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetic acid was markedly active in both the ASLM and SHR by oral administration. The combined diuretic/hypotensive profile of this compound was further substantiated by its good saluretic response in water loaded conscious dogs and a moderate to good activity in renal hypertensive rats and sinoaortic-deafferented hypertensive dogs.

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This study was conducted to determine if there is a difference in the calcium handling mechanism of the thoracic and abdominal aortic regions of the rabbit aorta. Isolated segments of aorta from both regions were studied in HEPES buffer at 37 degrees C and bubbled with 100% oxygen using identical procedures. Intracellular calcium levels were determined after segments had been exposed to 45Ca-labeled buffer during experimental procedures and subsequently washed with a 'quench' solution of zero calcium, 2 mM EGTA, and HEPES buffer, maintained at 0 degree C. The results suggest that the thoracic region is capable of taking up more calcium under resting conditions compared to the abdominal aorta. During stimulation with norepinephrine, both regions show significantly increased calcium influx rates after 10 min of exposure to the agonist, but only in the abdominal region is this effect maintained after 60 min of norepinephrine stimulation. Net (summation of calcium influx and efflux) intracellular calcium levels are significantly increased by norepinephrine in the thoracic but not in the abdominal aorta. Taken together, these data suggest that, compared to the thoracic aorta, the abdominal aorta may possess a more effective calcium efflux mechanism which may be able to fully compensate for the norepinephrine-stimulated increase in calcium influx.

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Studies were undertaken to evaluate the rate of loss in beta-adrenergic responsiveness in the kidney, heart and thoracic aorta in aging male rats. The dipsogenic response to isoproterenol (15 micrograms/kg B.W.) was reduced by 53 and 78% in middle-aged (12 to 13 months) and old (24 to 25 months) versus young (4 to 5 month) rats. In contrast, the drinking response to angiotensin I was unaltered with increasing age, indicating that the decline in B-response was not due to an alteration in the processing of or response to angiotensin. The chronotropic response of the heart to isoproterenol (5 micrograms/kg B.W.) was only moderately decreased by middle-age but was reduced by 69% in old versus young rats. Similarly, the isoproterenol-induced relaxation of aortic rings, in vitro was unchanged at 12 to 13 months of age but was severely diminished at 24 to 25 months of age. Thus the decline in beta-adrenergic responsiveness which accompanies the aging process appears to occur at different rates in several peripheral tissues. In vitro, aortic rings exhibited an age-related decline in contractile response to increasing dose of potassium chloride (KCL) and norepinephrine (NE). Maximum contractility in response to KCl was reduced by middle-age and declined further by 24 to 25 months of age. Similarly, the contractile response of aortic rings to low doses of NE (5 X 10(-10) and 1 X 10(-9)M) was significantly reduced at both middle and old age. Thus, both alpha-adrenoceptor mediated as well as non-receptor mediated aortic contractility are reduced progressively with increasing post-maturational age.

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The vascular reactivity to DL-ortho-, meta-, and para-octopamine was tested in vitro in aortic smooth muscle of the rat. When reactivities were compared on a molar basis with L-phenylephrine, an alpha-adrenergic agonist, the potencies of the three isomers were: 0.7500, 0.0075 and 0.0038 times that of phenylephrine for the m-, p- and o-isomer, respectively, Thus, of the three isomers, DL-m-octopamine had the greatest alpha-adrenergic activity in vitro as it did in vivo in earlier studies. Additional studies showed L-phenylephrine to induce about one-third the vascular response induced by L-norepinephrine.

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A length-tension relationship was established for aortic smooth muscle of rats by means of membrane depolarization with KCl. Maximal tension was developed by aortic rings when the preload initial tension was 8--9 g. Two aortic rings (4 mm thick) were removed from segments of the aorta cut 1.5 (upper) and 2.4 cm (lower) below the aortic arch. Upper rings appeared to develop a greater tension than lower rings during depolarization with KCl. However, in spite of this quantitative difference between rings from upper and lower segments of the aorta, there were no qualitative differences observed. Clonidine, an antihypertensive agent, induced a contraction in aortic smooth muscle, apparently by way of alpha-adrenoreceptor stimulation. Clonidine also attenuated significantly the development of active tension by norepinephrine but did not inhibit significantly the development of active tension following membrane depolarization with KCl. This suggests that there is a partial antagonism between norepinephrine and clonidine, presumably at the site of the receptors on smooth muscle, and that clonidine does not interfere with the contractile mechanism, per se.

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