Adenosine, a locally released and rapidly metabolized nucleoside, protects the heart from damage during ischemia by reducing oxygen demand and increasing oxygen supply. The aminothiophene derivative (2-amino-4,5-dimethylthien-3-yl)[3-(trifluoromethyl)phenyl]-met hanone (PD 81,723) has been shown to act as an allosteric enhancer of the adenosine A1 receptor in brain membranes and thyroid cells. The present study investigates the effects of PD 81,723 in spontaneously contracting right atria and electrically stimulated left atria isolated from Sprague-Dawley rats. N6-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, produced concentration-dependent inhibition of heart rate in right atria and contractile parameters in left atria. In the right atrium, 5 microM of PD 81,723 significantly shifted the concentration-response curves for CPA to the left, both in the absence and presence of a nonselective adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT, 10 microM). In the left atrium, PD 81,723 also shifted the concentration-response curves for CPA to the left, but only in the presence of 8-SPT. Potentiation of CPA-induced negative chronotropic and inotropic responses with PD 81,723, although not significant, was also observed in the presence of a selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 1 nM). These results demonstrate that PD 81,723 enhances the direct negative chronotropic and inotropic effects of adenosine A1 receptor activation in rat atria.
Pharmacodynamics and disposition of diltiazem were determined in twelve young (30 to 39 years of age) and twelve elderly (65 to 83 years of age) persons with hypertension after they had received diltiaz,em by rapid intravenous and long-term oral administration. Plasma disappearance half-life of diltiazem increased similarly and significantly in both groups with long-term dosing (young: rapid intravenous, 3.7 ± 0.8 hour; long-term oral, 6.3 ± 1 hour [mean ± SE]; elderly: rapid intravenous, 3.8 ± 0.7 hour; long-term oral, 7.2 ± 2.1 hour; p < 0.01). During long-term therapy both systolic and diastolic blood pressure was significantly lowered from baseline beyond a 12-hour dose interval, with greater decreases in systolic blood pressure in the elderly. Heart rate was decreased with long-term therapy in both groups. Maximal prolongation of PR interval was greater in the young after the intravenous dose (young: 46 ± 28 msec; elderly: 24 ± 11 msec; p < .01), but this effect was not seen with long-term therapy. These data demonstrate that diltiazem administered every 12 hours is an effective antihypertensive agent in both young and elderly patients. (CLIN PHARMACOL THER 1989;45:682-91.) Blood pressure rises with increasing age, and a majority of persons over 65 years of age can be considered hypertensive, depending on the populations examined and the criteria used.' Treatment of the elderly person with hypertension is complicated by concurrent chronic disease states, frequent drug interactions and adverse effects, difficulty in compliance with therapy, and the predominance of systolic hypertension. It has been suggested that calcium entry blockers are particularly beneficial for selected patient populations, such as elderly and black persons with hypertension.' These agents lower peripheral vascular resistance by direct arterial vasodilation, but without reflex sympathetic discharge and activation of the renin-angiotensin-aldosterone axis From the Section
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