Effects of cyclopentyladenosine on isoproterenol response in adult and senescent cardiac tissue from Fischer 344 rats.

To characterize age-related changes in beta-adrenergic responsiveness and to test the hypothesis that an increase in the effects of adenosine contribute to impaired beta-adrenergic responsiveness, Fischer 344 rat right atria (RA), left atria (LA), and left ventricular trabeculae carnae were exposed to the beta-receptor agonist isoproterenol (ISO), followed by four doses of the selective adenosine A(1) receptor agonist cyclopentyladenosine (CPA). Spontaneous contractile rates of adult RA were inhibited more than senescent RA by CPA. Contractility (+dF/dt) of adult LA was reduced more than senescent LA by CPA. Left trabeculae carnae tissue responded weakly to CPA, but senescent tissue was less responsive than adult tissue. Senescent atrial A(1) receptor density was 56% greater than in adult tissue, whereas the density in senescent ventricles was 39% lower than in adult tissue. No significant difference in antagonist affinities (K(d)) of A(1) receptor was observed between adult and senescent atria. In addition, agonist competition curves indicated a significant increase in senescent atrial and a decrease in senescent ventricular tissue in the affinity of agonist for high-affinity A(1) receptors with no difference in dissociation constant (K(i)). No significant age-related differences in atrial or ventricular tissues occurred in either the antagonist affinity (K(d)) or density (B(max)) of the beta-adrenergic receptors. CPA was found to inhibit ISO-stimulated adenylate cyclase activity more in senescent than in adult atrial and ventricular membrane preparations. We conclude that age-related differences in functional response to ISO and CPA, A(1) receptor density, and ISO-stimulated adenylate cyclase activity differ in atrial and ventricular myocardium.

Age-related characterization of atrial adenosine A1 receptor activation: direct effects on chronotropic and inotropic function in the Fischer 344 rat.

Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R-PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation.

Age-related effects in rabbit hearts of N6-R-phenylisopropyladenosine, an adenosine A1 receptor agonist.

Interventions known to increase cytoplasmic Ca2+ appear to amplify age-related impairment of cardiac function. In addition, increased release of interstitial adenosine, an endogenous nucleoside, has been suggested to mediate the diminished beta-adrenergic responsiveness in senescent heart. However, the direct effects of adenosine A1 receptor activation on senescent myocardium have not been investigated thoroughly. Therefore, the effects of N6-R-phenylisopropyladenosine (R-PIA), an A1 agonist, on atrial rate and contractility (+dF/dt) in adult (6-8 months) and senescent (5-7 years) New Zealand White rabbits were compared in spontaneously beating right atria and electrically stimulated isolated right papillary muscles. Although senescent right atria appeared to be more sensitive to the negative chronotropic-effects of R-PIA, the effective concentrations producing 50% of the maximum response (EC50 values) of R-PIA were not significantly different between adult (26 nM, 95% confidence limits: 12-52 nM) and senescent (13 nM; 95% confidence limits: 10-16 nM). However, senescent right ventricular papillary muscles were more sensitive to the negative inotropic effects of R-PIA. For example, at 90 contractions/min, 100 nM R-PIA decreased +dF/dt 25.3 +/- 7.4% and 61.9 +/- 4.8% in adult and senescent papillary muscles, respectively. To investigate whether R-PIA might alter sarcoplasmic reticulum (SR) function as a mechanism of decreased inotropy, we determined the inotropic effects of R-PIA on steady-state and 30-s postrest-potentiated contractions (PRP; an index of SR Ca2+ release) of left atria. R-PIA did not selectively decrease contractility of PRP compared to steady state in either adult or senescent left atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac functional responses to adenosine by PD 81,723, an allosteric enhancer of the adenosine A1 receptor.

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.

Overcoming problems with polypharmacy and drug misuse in the elderly.

Polypharmacy, the inappropriate use of multiple drug regimens, has a significant impact on the health of elderly individuals. Drug use increases with age, but suitability of therapy is sometimes difficult to define. In ambulatory and hospital care, there is some documentation of poor prescribing practices by physicians and drug misuse by patients. Sound data suggest that polypharmacy and drug misuse are highly prevalent in long-term care facilities. Psychotherapeutic agents are the most commonly misused drugs by physicians in this setting. Polypharmacy is associated with factors such as the number and severity of illnesses, hospitalization, number of physicians seen, number of pharmacies used, and possibly increased patient age. Methods to prevent polypharmacy and drug misuse have not been well studied. There is a need for intensive research to define effective methods to strengthen prescribing practice of physicians for elderly patients, to promote cooperation among health care personnel in ensuring optimal drug use by patients, and to enhance the role of patients as responsible partners in drug therapy. The authors are confident, however, that drug misuse and polypharmacy can be reduced in older persons by the use of current knowledge of risk factors associated with polypharmacy and by improved communication between the physician and patient.

Calcium antagonists in geriatric patients: diltiazem in elderly persons with hypertension.

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 diltiazem 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 less than 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 less than .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.

Physiological response to isoproterenol and coupling of beta-adrenergic receptors in young and elderly human subjects.

Diminished adrenergic responsiveness occurs in aged humans. The purpose of this study was to evaluate the coupling of beta-adrenergic receptors from human neutrophil preparations, and to investigate the relationship of this biochemical parameter to heart rate response after isoproterenol administration in young and elderly individuals. Fifteen young (aged 23-39 years) and eleven elderly (aged 59-82 years) volunteers participated in the study. The ratio, KL/KH, representing the ratio of dissociation constants for the low and high affinity state receptors, was calculated to determine coupling in the beta-adrenergic receptor system. An inverse correlation was observed between KL/KH and age. I25HR, representing the amount of isoproterenol required to elevate heart rate by 25 beats per minute, was determined; this parameter increased with age. Multiple regression analysis revealed that I25HR was most dependent upon age, but the changes with age were accompanied by diminution of both beta-adrenergic receptor affinity for agonist and in KL/KH.

Acute and chronic studies of diltiazem in elderly versus young hypertensive patients.

The pharmacodynamics, disposition and hormonal responses to acute intravenous and chronic oral diltiazem treatment were compared in young and elderly hypertensive patients. In elderly patients, supine diastolic blood pressure decreased significantly during the first week of treatment (baseline mean +/- standard error of the mean, 100 +/- 1 to 93 +/- 2 mm Hg) and decreased further during the study to 86 +/- 2 mm Hg at the end of the study. Diastolic blood pressure of the young patients decreased significantly by the third week of treatment (from 104 +/- 2 to 97 +/- 3 mm Hg) and decreased further during the study to 94 +/- 2 mm Hg at the end of the study. Baseline supine systolic blood pressure was greater in elderly than in young patients (167 +/- 5 vs 144 +/- 3 mm Hg; p less than 0.01) and was significantly reduced in the elderly by the fourth week (167 +/- 5 to 154 +/- 3 mm Hg; p less than 0.003), with a significantly reduction sustained throughout the 14-week period. Young patients had little change in systolic blood pressure. Supine heart rate tended to decrease in both groups during the 14-week period. Acute intravenous diltiazem pharmacokinetics determined at the beginning of the study showed that total diltiazem clearance was similar in elderly (13.3 +/- 1.0 ml/min/kg) and young (13.7 +/- 1.9 ml/min/kg) patients as was volume of distribution (4.2 +/- 0.3 vs 4.3 +/- 0.6 liters/kg) and elimination half-life (3.78 +/- 0.19 vs 3.69 +/- 0.23 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

N-monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives.

1 Twelve young (ages 30-39 years) and twelve elderly (ages 65-83 years) hypertensives were administered diltiazem twice daily for 2 weeks at doses up to 240 mg day-1. 2 Plasma was analysed for diltiazem, N-monodesmethyldiltiazem, and desacetyldiltiazem concentrations after a single 10 min intravenous infusion of 21.8 mg diltiazem HCl on day 1 and after the morning oral dose of 120 mg diltiazem base on day 14. 3 N-monodesmethyldiltiazem accumulated to higher plasma concentrations than desacetyldiltiazem at steady state on day 14 in both age groups. 4 Prolongation of plasma diltiazem half-life occurred after 2 weeks of oral diltiazem therapy in both age groups. 5 There were no significant differences between the young and elderly with regard to half-life, area under the curve, and the peak and trough plasma concentrations of diltiazem, N-monodesmethyldiltiazem, and desacetyldiltiazem; systemic clearance and volume of distribution of diltiazem were also similar in both groups.