Brief bilateral carotid artery ligation in adult spontaneously hypertensive rats (SHR) induced locomotor hyperactivity and lesions of the CA1 region of the hippocampus but had no effect in Wistar normotensive rats. This result suggests that high blood pressure amplifies the consequences of cerebral ischaemia. Treatment for 7 weeks with the calcium entry-blocker isradipine (5 mg/kg per day, subcutaneously) normalized blood pressure and attenuated the behavioural and histological consequences of cerebral ischaemia. Chronic treatment with hydralazine (25 mg/kg per day, subcutaneously) also normalized blood pressure but afforded no protection against the consequences of cerebral ischaemia. This suggests that the protective effect of antihypertensive treatment depends not only on the blood pressure-lowering action but may also be linked to the mechanism of action of the drug used.

Isolated tail arteries removed from spontaneously hypertensive, renovascular hypertensive, or various strains of normotensive rats were perfused/superfused with norepinephrine or potassium, or subjected to electrical field stimulation. Responses in spontaneously hypertensive and outbred normotensive rat tail artery preparations were similar. Tail artery segments from renovascular hypertensive or normotensive rats of the inbred Wistar-Kyoto strain showed smaller responses to all three stimuli. Thus, in certain in vitro arterial preparations, the apparent increase in vascular reactivity observed when comparing spontaneously hypertensive rats with inbred Wistar-Kyoto rats may be due to a decrease in vascular reactivity in the Wistar-Kyoto rat strain.

As chronic hypertension shifts the lower limit of cerebral blood flow (CBF) autoregulation to higher pressure levels, we studied the effects of the angiotensin converting enzyme (ACE) inhibitor, perindopril on mean arterial pressure (mean BP), basal CBF, and CBF autoregulation in awake renovascular hypertensive (2 kidneys, 1 clip model) and spontaneously hypertensive rats (SHR). Blood pressure was measured via a chronically implanted arterial cannula and CBF by hydrogen clearance. Chronic renovascular hypertension, like spontaneous hypertension, caused a marked shift in the lower limit of CBF autoregulation but did not alter basal CBF. In SHR, acute administration of perindopril did not diminish CBF in spite of the fact that BP fell to a level below the lower limit of CBF autoregulation (determined by hypotensive hemorrhage). Chronic treatment of renovascular hypertensive rats with perindopril normalized BP and restored CBF autoregulation.

Three-month-old spontaneously hypertensive rats were treated for 1, 2, or 3 months with daily intraperitoneal injections of naftidrofuryl (30 mg/kg). Systolic arterial pressure was measured. Tail arteries were removed and perfused at a constant flow rate of 2 ml/min. A concentration-response curve for serotonin was prepared. A second curve was then constructed in the presence of naftidrofuryl. Chronic treatment with naftidrofuryl had no effect on blood pressure but produced a decrease in the maximal vasoconstrictor response and the sensitivity to serotonin in vitro. The in vitro sensitivity to naftidrofuryl was unchanged. These studies suggest that chronic treatment with a dose of naftidrofuryl that does not modify blood pressure attenuates the in vitro vascular sensitivity to serotonin.

Vasoconstriction and changes in cytosolic free Ca2+ concentrations (fura 2 with dual wavelength excitation) were measured simultaneously in the perfused tail artery of the rat. Vasoconstrictors (norepinephrine and 5-HT) appear to modulate contraction not only by changing the cytosolic free Ca2+ concentration but also modifying the sensitivity of the contractile proteins to Ca2+.

Global cerebral ischemia (four vessel model) was induced in renovascular hypertensive rats (two kidney, one clip model) chronically treated with intraperitoneal administration of angiotensin I converting enzyme inhibitors, either captopril (100 mg/kg per day) or Wy-44,655 (10 mg/kg per day). Mortality following cerebral ischemia was higher in renovascular hypertensive rats than in normotensive controls. Reduction of blood pressure with captopril or Wy-44,655, lowered mortality. In surviving renovascular hypertensive and normotensive rats cerebral ischemia induced hyperactivity and lesions of the CA1 area of the hippocampus. Prolonged treatment with captopril--but not with Wy-44,655--reduced hyperactivity and the extent of the CA1 lesions. In conclusion, hypertension increases mortality following cerebral ischemia but does not affect the extent of brain injury in survivors. Prior treatment with converting enzyme inhibitors lowers mortality. Treatment with captopril attenuates brain injury in survivors.

Previous investigations have indicated that the detection and quantification ofω3 (peripheral type benzodiazepine) binding sites densities that are associated with reactive astroglia and macrophages could be of widespread applicability in the localization and indirect assessment of neural tissue damage in the central nervous system. In the present study, we analyze the usefulness of this approach in a number of experimental models that are characterized by (or putatively involve) neuronal degeneration. One week after the systemic administration of the excitotoxin, kainate, a marked increase inω3 site densities (as assessed by [3H]PK 11195 binding) was noted, an increase that was most prominent in known regions of selective vulnerability (hippocampus and septum). However, the kainate-inducedω3 site proliferation was not a function of the dose administered, a marked interstudy variation was observed, and the binding increase was prevented by the administration of the anticonvulsant, clonazepam. The densities ofω3 sites were studied, by autoradiography (using [3H]PK 11195 or [3H]PK 14105 as ligands), in 4 groups of Fischer 344 rats aged 3, 12, 22 and 30 months. No age-related changes were noted except in the 30-month-old group in which discrete and focal increases (reflecting tumoral processes) were observed in various brain regions. In spontaneously hypertensive, stroke-prone rats,ω3 binding increases were observed concomitant with the development of stroke-related neurological signs. With autoradiography, theω3 site increase was localized to focal increases in the boundary zones between major cerebral arteries (and corresponding to regions of ischaemic or haemorrhagic infarction). Focal cerebral ischaemia was studied in rats and mice. Subsequent to middle cerebral artery occlusion in normotensive (Wistar/Kyoto) and spontaneously hypertensive rats, the density of ω3 sites in the ipsilateral hemisphere was markedly elevated, the increase being greater in the spontaneously hypertensive rats. The increases inω3 labelling in these two strains matched the absolute volumes of infarctions, determined previously. Middle cerebral artery occlusion in the mouse also increased hemispheric levels ofω3 sites; the maximum values were obtained between 4 and 8 days following the induction of focal ischaemia. These results demonstrate the feasibility of usingω3 sites as a marker of excitotoxic, ischaemic and proliferative damage in the rodent brain. Binding measurement in tissue homogenates is an economic and time-efficient approach, whereas the autoradiographic detection ofω3 sites allows the localization of brain lesions with a macroscopic or microscopic level of anatomical resolution. Despite its indirect nature, the measurement ofω3 sites constitutes a new and powerful tool for the detection and quantification of a variety of neuropathological lesions within the central nervous system.

Increased calcium content of cardiovascular tissues is a phenomenon common to natural aging and various pathological conditions such as hypertension and arteriosclerosis. We investigated an accelerated cardiovascular calcium overload model in young rats produced by treatment with a single dose of vitamin D3 (300,000 IU/kg, i.m.) followed by up to 4 days of twice daily doses of nicotine (25 mg/kg, p.o.). Large increases in the calcium content of the aorta, kidneys, and myocardium but not in the liver or brain were seen. The magnesium content of these tissues was not modified. On the day following the last nicotine injection, there was marked cardiovascular calcium overloading, the aortic calcium level increasing by up to nine times that of controls. The animals had lower body weights, however, and there was a significant degree of mortality (up to 42%). Signs of kidney failure were evident; the blood urea level, for instance, was doubled. If rats were allowed 13 or 180 days to recover, they showed normal growth and kidney function; aortic calcium overload was still pronounced: 16− and 7-fold increases, respectively. Cardiovascular function in recovery animals was characterized by a doubling of pulse pressure. Dose-response curves following noradrenergic stimulation were shifted to the right after 13 (but not after 180) days recovery. Arterial norepinephrine content doubled. The chronic effects of hypervitaminosis D plus nicotine may produce a useful model for the study of the physiological and/or pharmacological consequences of calcium overload.

We studied the changes in calcium-induced vasoconstriction in isolated tail arteries from young (2 months) and old (12 months) normotensive, and young renovascular hypertensive rats (3 months old, with unilateral renal artery clipping at 6 weeks), pretreated with reserpine. The tail artery was removed and perfused/superfused with either a high potassium Krebs depolarizing solution or Krebs solution plus phenylephrine. Concentration-response curves to calcium were produced. Old rats had a low plasma renin activity and their depolarized tail arteries showed a weak vasoconstrictor response to calcium. Renovascular hypertensive rats had a high mean blood pressure and plasma renin activity. Responses of their depolarized tail arteries to calcium were greater. Responses to calcium in tail arteries perfused with phenylephrine were similar in all groups. We conclude that age and renovascular hypertension produce opposite changes in vasoconstriction induced by calcium in depolarized tail arteries.

The Ca2+ antagonistic effects of a potent vasodilator, nicardipine hydrochloride [2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride], were investigated. Both nicardipine and verapamil, neither of which exhibited a significant effect on cellular 45Ca2+ uptake by the rabbit aorta in normal buffer containing 2.68 mM KCl as measured by the “lanthanum method”, inhibited the enhancement of 45Ca2+ uptake induced by equimolar replacement of 120 mM NaCl by KCl. Nicardipine with an ic50 (the concentration required for 50 per cent inhibition) of 10−9 M was sixty-eight times more potent than verapamil in the inhibition of KCl-induced 45Ca2+ uptake. Nicardipine also repressed KCl-induced contraction of the aorta and its ic50 was about 2 × 10−9M, eighty-five times smaller than that of verapamil. These comparative studies on the relation between cellular 45Ca2+ uptake and KCl-induced contraction of the rabbit aorta suggest that nicardipine causes relaxation of smooth muscle mainly by interfering with Ca2+ influx.