A randomised, double-blind, placebo-controlled trial of intravenous nimodipine was conducted in 295 patients with acute ischaemic stroke. Nimodipine was given as an intravenous infusion of 1 or 2 mg/h for 5 days followed by an oral dose of 120 mg daily for a total treatment period of 21 days. Patients with a clinical diagnosis of ischaemic stroke in the carotid artery territory within 24 h entered the study at 34 centres, involving 11 European countries: 100 were randomly assigned to placebo, 101 to nimodipine with an initial intravenous dose of 1 mg/h and 94 patients to an initial dose of 2 mg/h. The trial, initially aiming at a patient inclusion of 600, was terminated because of concerns arising from safety monitoring. Primary efficacy variables were neurological outcome according to the Orgogozo scale and functional outcome according to the Barthel scale at day 21. There were apparent differences between the groups in neurological and functional outcome with a better outcome in the placebo group. The differences between the placebo group and the 2-mg/h group were statistically significant (p = 0.0005 for the Orgogozo scale and p = 0.0033 for the Barthel scale). The differences were even more pronounced at the final follow-up at 24 weeks (p = 0.0001 and p = 0.0002, respectively). There were no statistically significant differences in mortality between the groups. There were statistically significant differences between the groups regarding the effect of the first few days of intravenous treatment on systolic and diastolic blood pressure with the most pronounced reduction in the 2-mg/h nimodipine treatment group at day 2 (p = 0.0001). An explorative analysis indicated a correlation between diastolic blood pressure reduction in the nimodipine-treated groups and unfavourable neurological outcome (p = 0.0005). A potential neuroprotective effect of nimodipine by preventing calcium overload in ischaemic neurons may thus have been outweighed by detrimental haemodynamic effects in the ischaemic area.

Relaxant effects of acetylcholine (ACh), histamine, calcitonin gene-related peptide (CGRP) and the calcium ionophore A23187 were examined in rat femoral (phi approximately 0.2 mm), mesenteric (0.2 mm), intrarenal (0.2 mm) and hepatic (0.3 mm) arteries, and aorta (2 mm). Acetylcholine elicited an endothelium-dependent relaxation in all arteries. Histamine induced an endothelium-dependent relaxation in aorta, and mesenteric and intrarenal arteries, whereas a partly endothelium-dependent and mainly endothelium-independent relaxation was observed in hepatic and femoral arteries, respectively. In hepatic, mesenteric and intrarenal arteries, CGRP induced an endothelium-independent relaxation, whereas either small or no relaxation was obtained in aorta and femoral arteries respectively. A23187 induced an endothelium-dependent relaxation in the aorta and hepatic artery, whereas A23187 had no relaxant effect in femoral, mesenteric and intrarenal arteries. N omega-nitro-L-arginine (L-NOARG, 0.3 mM) reduced the maximum ACh-induced relaxation (in the presence of 10 microM indomethacin) by 66% in the aorta, and abolished the relaxation in femoral and intrarenal arteries. A marked L-NOARG/indomethacin-resistant relaxation was obtained in mesenteric and hepatic arteries. Levcromakalim induced a concentration-dependent and almost complete relaxation in all arteries. When contracted by a 60 mM K+ solution, all arteries responded to ACh with a relaxation that was abolished by L-NOARG. These results demonstrate marked regional differences with regard to the vascular effects of ACh, histamine, CGRP and A23187. Whereas nitric oxide appears to mediate endothelium-dependent relaxation regardless of the vascular region, an L-NOARG/indomethacin-resistant relaxation, presumably mediated by an endothelium-deprived hyperpolarizing factor, was observed only in mesenteric and hepatic arteries, and aorta.

The effect of pinacidil on the contractile response to stepwise increases of the extracellular K+ concentration ([K+]o) was investigated in isolated segments of human pial and mesenteric arteries and rabbit basilar and mesenteric arteries. The [K+]o eliciting half maximum contraction (EC50) was lower in human pial (18 mM) and rabbit basilar (27 mM) arteries than in human (33 mM) and rabbit (32 mM) mesenteric arteries, respectively. The alpha-adrenoceptor blocker, prazosin, increased the EC50 value for K+ from 27 to 40 mM and reduced the maximum response in rabbit mesenteric arteries, but had no effect on the K(+)-induced contraction in rabbit basilar arteries, indicating a substantial noradrenergic component of the K+ response in the former arteries. Removal of the endothelium decreased the EC50 value for K+ from 27 to 15 mM in rabbit basilar arteries, whereas the K+ sensitivity was unaffected in rabbit mesenteric arteries. Pinacidil shifted the K+ concentration-response curve to the right in human and rabbit cerebral and mesenteric arteries. In rabbit basilar arteries, but not in mesenteric arteries, the shift was larger in the absence than in the presence of an intact endothelium. When endothelium-denuded rabbit arteries were compared, the inhibitory effect of pinacidil was larger in basilar than in mesenteric arteries. Thus, pinacidil inhibits K(+)-induced contractions in both cerebral and mesenteric arteries, but appears to act preferentially on endothelium-denuded rabbit basilar arteries. Provided that endothelial damage and depolarization-induced vasoconstriction are of pathophysiological importance in cerebrovascular disorders such as stroke and cerebral ischemia secondary to vasospasm after subarachnoid hemorrhage, pinacidil may have a therapeutic potential.

Nitrendipine (BAY e 5009) is a new calcium channel blocker with a marked effect on excitation-contraction coupling in different types of muscle cells. It has many similarities to the established agent, nifedipine. In the present study, nitrendipine was evaluated in a double-blind within-patient comparison. Twelve patients with essential hypertension were given nitrendipine 20 mg or 40 mg orally for three weeks following a 1-week placebo period. After a second 1-week placebo period, there was a crossover to the alternative dosage (20 or 40 mg respectively), and active therapy was again given for 3 weeks. Both doses of nitrendipine caused a significant and equal reduction of arterial pressure, which persisted for at least 24 hours. Only the highest dose caused an increase in heart rate. There were a few reports of headaches, flushing, and palpitation, particularly after the 40 mg dose. There was a significant correlation between the reduction of mean arterial pressure and the log plasma concentration (20 mg: r = -0.88, p less than 0.01; 40 mg: r = -0.94, p less than 0.001). There was a linear relationship between the area under the curve and the oral dose, indicating that liver enzyme saturation had not occurred. There was no accumulation of nitrendipine in plasma during 3 weeks of treatment.

In-vitro vasoreactivity to extracellular potassium (Ko+) was tested in isolated human pial and mesenteric arteries as well as basilar and mesenteric arteries from rabbits and rats. Contractions were induced by stepwise increases in [K+]o and were measured isometrically with a force-displacement transducer, in small-volume organ baths. Significant differences between species as well as between regions were found. The threshold of [K+]o for eliciting contraction in human cerebral arteries in hyperosmotic solutions was 10 mM, in rabbit cerebral arteries 17 mM and in rat cerebral arteries 27 mM. The threshold concentration for contraction in mesenteric arteries was significantly higher compared to cerebral arteries in humans and rabbits, but lower in rats: 20 mM in humans, 26 mM in rabbits and 25 mM in rats. In all species the contractile amplitudes were significantly higher in both cerebral and mesenteric arteries when [K+]o was increased under isotonic conditions in the buffer solution than when hyperosomolality was created. This difference increased with increasing hyperosmolality. In hyperosmotic solutions, the EC50 for [K+]o was lower in cerebral and mesenteric arteries from man than in vessels from rabbit and rat. When the solutions were isotonic, this pattern was seen only in mesenteric arteries. It is concluded that significant species and regional differences in vascular responses to [K+]o exist. Considering that [K+]o is increased in cerebral ischaemia, the observed significantly lower threshold for K+-induced contractions in human cerebral arteries may be of importance, especially in human cerebral ischaemic events.