A nation-wide study on the practice of euthanasia and physician-assisted suicide in community and hospital pharmacies in The Netherlands.

PURPOSE: In recent years the attitudes and practices of euthanasia (E) and physician-assisted suicide (PAS) among health care workers have been evaluated in different countries. There is, however, still an information gap on the role of pharmacists in these matters. The aim of our study was to study the attitudes and practices of E and PAS among pharmacists. METHODOLOGY: We conducted a nation-wide survey into the practice, including adherence to guidelines, of E and PAS in community and hospital pharmacies (CP and HP) in the Netherlands. Furthermore, the attitude of community pharmacists concerning this subject was evaluated. Anonymous questionnaires were sent to a random sample of 50% (n = 755) of all CP and to all (n = 101) HP. RESULTS: The response rates were 52% and 51% for CP and HP, respectively. Most of the CP-respondents (95%) agreed with the concept of E and PAS and would dispense drugs for these purposes. When the data were extrapolated to all pharmacies, there were 1351 and 340 dispensing of drugs for E and PAS per year in CP and HP (94% of all requests), respectively. In most cases the pharmacist had been notified of the condition of the patient (CP: 93%, HP 87%) and a written request was obtained (CP: 74%, HP: 79%). The drugs were often handed personally to the physician (CP: 98%, HP: 86%). Involvement of pharmacy technicians was more common in HP than in CP (31% versus 6%). The most frequently dispensed drugs were muscle relaxants with barbiturates (CP: 47%, HP 71%), barbiturates only (CP: 19%, HP: 6.1%), and muscle relaxants with benzodiazepines (CP: 14%, HP: 7.6%). CONCLUSION: Most pharmacists are supportive of E and PAS and are prepared to fill prescriptions written for these purposes.

Effects of hypercholesterolemia on the contractions to angiotensin II in the isolated aorta and iliac artery of the rabbit: role of arachidonic acid metabolites.

The aim of this study was to investigate the effect of hypercholesterolemia on the angiotensin II-induced contractions in the isolated aorta and iliac artery of the rabbit, with respect to the role of arachidonate metabolites. Furthermore, the effect of the angiotensin-converting enzyme inhibitor ramipril was studied on the responses to angiotensin II in the cholesterol-fed rabbit. After 12 weeks of cholesterol diet (0.3%), endothelium-dependent relaxations to acetylcholine were significantly fewer compared with control (30.2 +/- 5.9% vs. 73.0 +/- 1.7%) in the aorta but not in the iliac artery of the rabbit. The angiotensin II- and methoxamine-induced contractions were also significantly lower compared with control in the aorta (101.4 +/- 6.7% vs. 60.9 +/- 4.2% and 160.2 +/- 5.7% vs. 135.8 +/- 8.0%, respectively) but not in the iliac artery. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) selectively attenuated the angiotensin II-induced contractions in rabbit aortic rings from the control group only in the presence of the endothelium, whereas it had no effect on the responses to angiotensin II in the cholesterol group (with or without endothelium). In the iliac artery, NDGA inhibited the responses to angiotensin II in both the control and cholesterol groups. Treatment with ramipril (0.33 mg/kg/day) significantly improved the maximal angiotensin II-induced contraction in the aorta of rabbits fed a cholesterol diet for 16 weeks to 61.0 +/- 7.3% (vs. 32.7 +/- 9.0% in the cholesterol group). We conclude that hypercholesterolemia leads to a reduction of angiotensin II-induced contractions in the aorta and not in the iliac artery of the rabbit. This reduction might be related to loss of endothelium-dependent lipoxygenase products and is partially reversed by ramipril.

Relative potency and arteriovenous selectivity of nitrovasodilators on human blood vessels: an insight into the targeting of nitric oxide delivery.

The arteriovenous potency of sodium nitroprusside (SNP), linsidomine (SIN-1) and S-nitrosoglutathione (GSNO) was determined in human capacitance (veins) and resistance (arterioles) vessels in vitro and in vivo and compared with the venoselective nitrovasodilator nitroglycerin (GTN). Concentration-response curves were constructed to GTN, SNP, GSNO and SIN-1 (0.001-10 microM) in preconstricted human saphenous vein and to GTN, GSNO and SIN-1 (0.001-10 microM) in omental resistance vessels. In vivo the dilator responses of the dorsal hand vein and the forearm resistance bed were recorded during local infusions of GTN, SNP, GSNO and SIN-1 (1 pmol/min to 160 nmol/min). SNP and SIN-1 had similar arteriovenous profiles to that of GTN. SNP was equipotent with GTN in arterioles and veins but SIN-1 was 10-fold less potent than GTN in vitro and 100-fold less potent in vivo; the potency of SIN-1 was increased after incubation of saphenous vein with superoxide dismutase. GSNO was equipotent with GTN in arterioles but 10-fold less potent in veins in vitro and in vivo. These results demonstrate that most nitrovasodilators are venoselective irrespective of their mechanism of biotransformation to nitric oxide (NO) and suggests that NO itself might be venoselective in vivo. Endogenous carrier molecules, including glutathione, could alter the vascular profile of NO with physiological and therapeutic implications.

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: I. Effect on progression of atherosclerosis and endothelial dysfunction.

This study was designed to compare the effects of a calcium antagonist (isradipine) and a converting enzyme inhibitor (ramipril) on progression and regression of atherosclerosis in hypercholesterolemic rabbits. Sixty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group II received the 0.3% cholesterol diet, group III received cholesterol diet with isradipine (0.33 mg/kg/day), and group IV received cholesterol with ramipril (0.33 mg/kg/day) for 12 more weeks. A group of 20 rabbits received a standard diet throughout the study (group I). After 16 weeks, 10 rabbits were randomly chosen from each group and used in the progression study. The other rabbits were placed on a standard diet and remained on their respective drug regimen for 12 more weeks. In the progression phase of the study, ramipril significantly attenuated the percentage of aortic lesions in group IV (35 +/- 6%) as compared with group II (56 +/- 6%, p < 0.05), whereas isradipine had no effect. Acetylcholine (ACh)-induced maximum endothelium-dependent relaxations (EDR) of aortic rings were significantly reduced by the atherogenic diet to 37 +/- 4 versus 77 +/- 2% in group I (p < 0.05). Treatment with ramipril significantly improved maximum EDR to 53 +/- 3% (p < 0.05 vs. group II). Isradipine had no significant effect on impaired EDR. Aortic rings with endothelium from group II developed supersensitivity to sodium nitroprusside (SNP) and had significantly reduced basal cyclic GMP levels as compared with those of group I. Both drugs prevented development of supersensitivity to SNP and blunted the cholesterol-induced reduction in basal cyclic GMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: II. Effect on regression of atherosclerosis and restoration of endothelial function.

We report the effects of isradipine and ramipril on regression of diet-induced atherosclerosis in rabbits. Regression of diet-induced atherosclerosis was not significantly affected by ramipril, but isradipine significantly retarded regression. Thirty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group IIr received the 0.3% cholesterol diet, group IIIr received the 0.3% cholesterol diet with isradipine (0.33 mg/kg/day), and group IVr received the 0.3% cholesterol diet with ramipril (0.33 mg/kg/day) for 12 more weeks. The rabbits then received a standard diet and remained on their respective drug regimen for 12 more weeks. Group Ir (10 rabbits) received a standard diet for 28 weeks. Acetylcholine (ACh)-induced maximal endothelium-dependent relaxations (EDR) of aortic rings were significantly less in group IIr (22.8 +/- 3.2%) than in group Ir (66.4 +/- 4.0%; p < 0.05). Ramipril and isradipine did not improve EDR as compared with group IIr. Regression of atherosclerosis was accompanied by an improved endothelium-dependent releasing factor (EDRF) release from the endothelium, but ramipril and isradipine did not promote this process. In addition, regression was associated with increasing sensitivity of vascular smooth muscle to EDRF that was significantly retarded by isradipine but not ramipril. Basal cyclic GMP levels were significantly reduced in aortic rings from group IIr as compared with group Ir. Ramipril, but not isradipine, restored basal cyclic GMP levels to control values. Both isradipine and ramipril protect against endothelial degeneration in hypercholesterolemic rabbits. However, isradipine but not ramipril inhibits regression of diet-induced atherosclerosis in rabbits.

Endothelin receptors mediating functional responses in human small arteries and veins.

1. In the present study, responses of human omental small arteries and veins to endothelin-1 and endothelin-3 were characterized by use of the ETB receptor selective agonist, sarafotoxin S6c, the ETA receptor antagonist, BQ123, the ETB receptor antagonist, IRL1038, the NO-synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 300 microM) and indomethacin (10 microM). 2. Small arteries (internal diameter 413 +/- 22 microns) and parallel running veins (646 +/- 35 microns) were mounted in a myograph under a normalized tension equivalent to 90% of a transmural pressure of 100 mmHg and 19 mmHg in vivo, respectively. 3. In small arteries and veins, endothelin-1 caused a concentration-dependent increase in wall tension (Emax = 3.90 +/- 0.56 mN mm-1 and 1.90 m +/- 0.32 mN mm-1 respectively, P < 0.05) and was equipotent (arteries: pD2 = 8.91 +/- 0.11; veins: pD2 = 8.63 +/- 0.08, NS). In endothelium intact arteries, L-NMMA significantly enhanced the sensitivity to endothelin-1 (pD2 control: 8.92 +/- 0.16; pD2 L-NMMA: 9.37 +/- 0.11; P < 0.05). L-NMMA did not affect the sensitivity of veins to endothelin-1. Indomethacin was without effect in arteries and veins. In veins, endothelin-3 was about a hundred times less potent than endothelin-1 and showed a biphasic response curve. Small arteries did not contract to endothelin-3. Neither small arteries nor veins contracted to sarafotoxin S6c. Furthermore, no relaxation to endothelin-1 or sarafotoxin S6c was seen in any precontracted vessels. 4. BQ123 (0.03-3 MicroM) produced a concentration-dependent rightward parallel displacement of the endothelin-l concentration-response curve in small arteries and veins yielding pA2 values of 7.09 and 7.48 respectively. The slope of the Schild plot in arteries and veins was 1.26 +/- 0.24 (NS from unity) and 0.61 +/- 0.13 (P <0.05 compared to unity) respectively. IRL1038 (3 MicroM) did not affect the potency of endothelin-1 in arteries and veins. In veins, the low sensitivity component (pD2 = 7.16 +/- 0.08) of the biphasic response curve to endothelin-3 was completely blocked by BQ123 (3 MicroM), whereas the high sensitivity component (pD2 = 8.66 +/- 0.08) was resistant to BQ123 (3 MicroM) and IRL1038 (3 MicroM).5. These results indicate that contractions of human small vessels to endothelin-l are predominantly mediated by ETA receptors and that nitric oxide modulates the response to endothelin-l in small arteries but not in veins. The different antagonistic potency of BQ123 against endothelin-l and the differential endothelin-1/endothelin-3 potency ratios in arteries and veins provide evidence for the hypothesis that ETA receptors in human small arteries are different from ETA receptors in human small veins. There is no evidence of contractions mediated by 'classical' ETB receptors in these vessels, but small veins appear to contain a functional non ETA/non ETB receptor with a high affinity for endothelin-3.

Modulation by pertussis toxin of salbutamol- and arecoline-induced effects in the isolated heart and aorta of the rat.

The modulatory effects of pertussis toxin pretreatment on responses mediated via beta-adrenoceptors and muscarinic acetylcholine receptors were investigated in isolated rat hearts and aortic rings 4 days after in vivo administration of pertussis toxin. In isolated hearts, pertussis toxin increased heart weight and baseline coronary flow values but did not effect baseline left ventricular pressure values. In unpaced hearts, pertussis toxin inhibited the arecoline-induced cardiac standstill, while in paced hearts, the beta 2-adrenoceptor agonist salbutamol produced a dose-dependent vasodilation with similar characteristics in pertussis toxin and control preparations. Pertussis toxin had no effect on myocardial or aortic cyclic nucleotide levels and the myocardial beta-adrenoceptor density (Bmax) and dissociation constant (Kd). In precontracted aortic rings, pertussis toxin had no effect on the salbutamol or arecoline induced vasorelaxation. In summary, we demonstrated a reduced cholinergic responsiveness in isolated hearts but an intact beta 2-adrenoceptor pathway in isolated hearts as well as in isolated aortic rings after pertussis toxin pretreatment. In aortic rings no change in muscarinic acetylcholine receptor responsiveness occurred.