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The microvascular actions of three calcium channel antagonists were studied in intact spontaneously hypertensive rats (SHR) provided with a dorsal striated muscle microcirculatory chamber. Verapamil and the dihydropyridine derivatives nifedipine and felodipine reduced mean arterial blood pressure (MAP) in a dose-dependent manner. They dilated arterioles of different sizes, with the most pronounced effect being on the smallest precapillary arterioles. Venular diameters were not affected by the calcium antagonists. Approximately 60% of the small arterioles showed a rhythmic pattern of vasodilatation and constriction. This pattern of spontaneous vasomotion was completely blocked by the calcium channel antagonists, especially those of the dihydropyridine type. It is concluded that (a) small precapillary arterioles play an important role in the vasodilator action of calcium channel antagonists, and (b) arteriolar vasomotion depends on vascular smooth muscle cell calcium influx.

Propranolol in doses from 0.01 to 5 mg/kg x day was infused intracerebroventricularly (i.c.v.) in conscious unrestrained spontaneously hypertensive rats during 5 days by using Alzet osmotic minipumps. When given by this route, brain concentrations achieve values that are approximately 100-fold higher than those after s.c. infusion of equal doses, whereas plasma-levels are comparable. In this study we compared the dose needed to lower blood pressure upon i.c.v. infusion with the dose of 5 mg/kg x day dl-propranolol, which we reported earlier to induce a long lasting bradycardia and antihypertensive effect when infused s.c. Vehicle, 0.01 and 0.1 mg/kg x day of dl-propranolol, did not have any effect on mean arterial pressure or heart rate. Infusion (i.c.v.) of 1 mg/kg x day lowered heart rate during the first 4 days of the infusion. On the fifth day, this effect had disappeared. Also, during the first 2 days of the infusion a reduction of mean arterial pressure was observed, but thereafter pressure was at control levels. Infusion of 5 mg/kg x day of dl-propranolol reduced heart rate significantly from the first day of infusion throughout the whole infusion-period. On the other hand, mean arterial pressure was lowered with a delay of 1 day. It remained significantly below control values throughout the rest of the experimental period. d-Propranolol in a dose of 5 mg/kg x day i.c.v. did not have any effects. Since upon i.c.v. infusion the dose needed for a blood pressure lowering effect is the same as that needed for a s.c. infusion, in spite of 100-fold higher brain-levels, it is concluded that the antihypertensive effect of propranolol in spontaneously hypertensive rats is not caused by an action of the drug in the central nervous system.

1. The role of baroreceptors in the cardiovascular mechanism of action of DL-propranolol has been studied by comparing the acute effects of subcutaneous injection of 1 and 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) of this drug in conscious baroreceptor-denervated spontaneously hypertensive (SH) rats with those in sham-operated control SH rats. 2. At 5 mg/kg (16.5 x 10(-6) mol/kg) propranolol caused a small, but significant, increase in blood pressure in sham-operated SH rats, whereas both after 1 and 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) immediate hypotension was observed in baroreceptor-denervated animals. 3. Heart rate dropped rapidly after injection of 1 or 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) propranolol both in the baroreceptor-denervated and sham-operated SH rats. Bradycardia was significantly larger in the baroreceptor-denervated animals after an injection of 5 mg/kg (16.5 x 10(-6) mol/kg). 4. It is concluded that the lack of an early hypotensive effect of propranolol in intact animals is caused by an increased baroreceptor reflex activity as a consequence of the fall in cardiac output.

Stroke is the second leading cause of death with high blood pressure and female gender being the main risk factors. However, only one treatment is available and with many contraindications, which leaves more than 80% of patients untreated. Over a thousand experimental stroke treatments have remained unsuccessful in the clinic. In preclinical research, low reproducibility and publication bias have been suggested as causes of low translatability success. NADPH oxidases might be key players in stroke via their unique role as a major and/or early source of reactive oxygen species (ROS). To clarify the role of the different NOX isoforms (1, 2, 4, and 5) we analysed different KO and KI models. Previous literature claimed a role for NOX2. Using both a meta-analytical and a blinded randomised controlled trial approach, we however find that NOX2 plays only a minor role and publication bias and lack of power perturbed the published literature. We earlier showed a detrimental role of NOX4 in stroke and extend this based on cell-specific KO animals that endothelial but not vascular smooth muscle cells are the major source of NOX4 in stroke. Mice do not express the human NOX5 gene. Using a NOX5 KI model, we show that endothelial NOX5 induces hypertension and increased stroke risk, particularly in females. In human hypertension, NOX5 is upregulated, and women have a higher stroke risk. Thus NOX5 might be a missing link in this context. In conclusion, NOX4 and NOX5, but not NOX2, are promising targets for the development of new neuroprotective therapies for ischemic stroke. A priori power and sample size calculation as well as reporting of also negative data is essential with respect to preclinical validation of therapeutic targets. [ABSTRACT FROM AUTHOR]