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The effects of two centrally acting antihypertensive agents, clonidine (0.1 mg/kg/day s.c.) and flesinoxan (1 mg/kg/day s.c.), on short-term blood pressure variability (BPV) were investigated in conscious spontaneously hypertensive rats (SHRs). The drugs were infused subcutaneously during 24 h and 4 weeks by osmotic minipumps. BPV was characterized by spectral analysis. In conscious SHRs, clonidine significantly and preferentially reduced the low frequency (LF; 0.25-0.75 Hz) oscillations of mean arterial pressure (MAP) in short-term (24 h) and long-term (4 weeks) treatments but significantly decreased MAP level only in short-term treatments. In contrast, flesinoxan significantly reduced MAP level whatever the duration of infusion but decreased LF-MAP only in short-term treatments. These results show that centrally mediated inhibition of sympathetic tone by stimulation of either alpha2-adrenoceptors or 5-HT1A (serotonin) receptors can reduce BPV. This effect is independent of the modifications in BP level. The effects of the drugs on baroreceptors may also contribute to the decrease in BPV. The dual properties of clonidine (alpha2-adrenoceptors and imidazoline receptors) may account for its differential effects on BP level and BPV.

Some epidemiologic and experimental studies have raised the possibility that pulse pressure may be a determinant of vascular structure. In addition, 24-h blood pressure variability has been reported to be more closely related to the severity of target-organ damage than to casual blood pressure in hypertensive patients. These data suggest that when the effects of mechanical stress on the arterial wall are evaluated, it is necessary not only to take into account steady (i.e., mean) parameters but also to consider pulsatile parameters and the variability of steady and pulsatile parameters. Pharmacologic data suggest that reduction of pulse pressure during antihypertensive treatment may be a factor in prevention of altered vascular structure during chronic hypertension. Improving arterial compliance by specific antihypertensive treatment is a way to reduce pulse pressure and therefore to contribute to this prevention. Whether normalization of blood pressure variability by antihypertensive treatment is also a means of preventing altered vascular structure remains to be determined.

Neuropeptide Y (NPY), a potent vasoconstrictor agent reported to be released, in addition to norepinephrine (NE), by sympathetic nerve endings during stress, may contribute to the pressor response to various stimuli. The objectives of this study were to determine (a) whether plasma NPY concentrations are altered during different types of stress (cold pressor test, mental stress, and active orthostatism) and (b) whether clonidine, via its central sympatholytic effect, affects the stress-induced blood pressure, NPY, and/or catecholamine changes. Eighteen untreated patients with mild essential or borderline hypertension participated in an acute randomized, double-blind, parallel study. The blood pressure and heart rate were recorded during three control periods, each followed by either a cold pressor test (CPT), a mental stress test (MS: mental arithmetic), or active orthostatism (AO), performed in a random order. Venous blood samples for catecholamines and NPY determination were taken at the end of each control and test period. This entire procedure was repeated after oral clonidine (150 micrograms) or placebo. Before treatment, a CPT, MS, or AO increased the blood pressure to the same extent. The stress-induced increase in plasma NE was greater during AO (+99 +/- 23%) than during CPT (+35 +/- 8%) and MS (+55 +/- 12%). The stress-induced increase in plasma epinephrine was only significant during MS (+142 +/- 69%). A small but significant increase in NPY (p < 0.05) was observed during AO only (+10 +/- 7%). Compared to placebo, clonidine significantly decreased the basal blood pressure and the pressor response to CPT, but did not change the pressor response to MS and AO.(ABSTRACT TRUNCATED AT 250 WORDS)

The link between arterial caliber and distensibility has been studied extensively, with conflicting results. As have other researchers, we previously showed evidence of an increase in arterial diameter and a decrease in arterial stiffness with use of nitrates at the site of the brachial artery (BA) and the aorta. Whether these results would apply to other large superficial arteries remained to be established. In the present study, by means of an original pulsed ultrasound echo-tracking system based on Doppler shift, we measured internal diastolic diameter and stroke change in diameter of the common carotid artery (CCA), the femoral artery, and the BA in patients with essential hypertension and determined the acute effects of administration of isosorbide dinitrate (ISDN 20 mg). Twenty untreated hypertensive patients entered this randomized, placebo-controlled, double-blind, parallel study. No significant change occurred during placebo. During ISDN therapy, blood pressure (BP) decreased significantly; cross-sectional compliance increased at the site of the CCA, the BA, and the common femoral artery (CFA). The increase in cross-sectional compliance was mainly due to an increase in internal diameter for CCA and to an increase in distensibility coefficient (DC) for BA. The pattern of cross-sectional compliance was intermediate for CFA. During ISDN therapy, the augmentation index of the CCA distension waveform was significantly reduced, whereas no change occurred during placebo, suggesting a reduction in wave reflection by nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of systemic adrenergic blockade on hypertensive brachial arteries was studied in humans with pulsed Doppler flowmetry. Blockade of beta-receptors by the nonselective beta-blocking agent propranolol did not modify the brachial artery diameter, whereas pindolol increased this parameter for the same degree of blood pressure reduction. The beta1-selective blocking agents atenolol and bisoprolol caused similar decreases in blood pressure and a reduction in the diameters of the brachial artery and abdominal aorta, respectively. The combination of alpha- and beta-blockade produced a rapid drop in blood pressure but did not change the brachial arterial diameter. Thus, following beta-blockade, the arterial diameter increased, did not change, or even decreased despite an adequate blood pressure reduction. It is suggested that beta-blockade in some instances resets the pressure-diameter curve and therefore has a direct action on the arterial wall independent of the mechanical effect of blood pressure reduction.

Reduced aortic distensibility and compliance may participate in the genesis of cardiac hypertrophy in hypertension. In patients with borderline hypertension, indices of aortic distensibility are often altered, but are poorly related to the degree of septal hypertrophy, which is considered to be a marker of cardiac hypertrophy in this particular population. In patients with sustained essential hypertension, the degree of cardiac hypertrophy seems to correlate strongly with the increase in aortic rigidity. Dihydralazinelike substances are unable to modify arterial stiffness, whereas calcium-entry blockers and converting-enzyme inhibitors improve arterial stiffness when achieving the same degree of blood pressure reduction. Modifications in aortic rigidity must be considered in order to understand reversion of cardiac hypertrophy as a result of antihypertensive treatment.

Blood pressure, volume distensibility (VD), and cross-sectional area (CSA) of the brachial artery were studied using pulsed Doppler systems in 51 patients with sustained essential hypertension in comparison with 21 normotensive controls of the same age. In hypertensive patients, in baseline conditions, CSA was significantly increased and VD decreased--the two parameters strongly and negatively correlated independent of the blood pressure level. Arteriolar vasodilatation was produced by three pharmacological agents--cadralazine, a dihydralazine-like compound; nicorandil, a nicotinamide derivative; and nitrendipine, a calcium entry blocker. For the same blood pressure reduction, cadralazine significantly reduced CSA, while nicorandil and nitrendipine increased it. Nitrendipine significantly increased VD, which was not modified by cadralazine and nicorandil. For cadralazine and nicorandil, a significant negative correlation was observed between VD and CSA. The relationship was the same as in baseline conditions. With nitrendipine, no significant correlation was observed between the two parameters. At any given CSA, distensibility was higher with nitrendipine than with cadralazine or nicorandil. The study provided evidence that, in men with essential hypertension, in basal conditions, the negative relationship between VD and CSA reflected intrinsic alterations of the arterial wall, while cadralazine, nicorandil, and nitrendipine caused a similar degree of arteriolar dilatation, nicorandil and nitrendipine caused active arterial dilatation as well, and changes in distensibility after drug administration were not directly related to blood pressure level and were mediated either by predominant geometrical modifications (cadralazine, nicorandil) or by the predominant relaxing effect of the drug on arterial smooth muscle tone (nitrendipine), or both.

The central cardiovascular effects of the calcium channel inhibitor (CCI) nifedipine and the calcium channel activator BAY k 8644 (BAY) were studied in pentobarbital-anesthetized and ventilated normotensive Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). Both drugs were administered under a 1.5 microliter volume into the lateral ventricle of the brain (intracerebroventricular, i.c.v.). The injection of vehicle (ethanol) alone did not significantly change mean arterial pressure (MAP) or heart rate (HR). Nifedipine (5 and 50 micrograms/kg) and BAY (5 and 50 micrograms/kg) induced opposite effects on MAP when centrally injected. Nifedipine decreased MAP and HR while BAY increased MAP without significant change in HR. These effects are likely to be of central origin, because they were suppressed by ganglionic blockade with hexamethonium and by reserpine. Previously i.c.v. administered nifedipine (5 micrograms/kg) antagonized pressor response to BAY (5 micrograms/kg i.c.v.). Changes in MAP and HR were significantly more marked in SHR than in WKY. These results indicate that a calcium channel inhibitor and a calcium channel activator can modulate in opposite fashion central mechanisms involved in blood pressure control.

The effects of the dihydropyridine (DHP) calcium channel antagonist, nicardipine, on central cardiovascular regulation were investigated by injecting it into the cisterna magna or directly into the nucleus tractus solitarii (NTS), in anesthetized normotensive or spontaneously hypertensive (SHR) rats. Intracisternal injections of nicardipine (1-10 micrograms/kg) dose-dependently decreased blood pressure in SHR; there was no significant change in cardiovascular parameters in normotensive rats. In SHR, nicardipine (100 ng) microinjected bilaterally into the NTS produced hypotension and bradycardia. The same doses of nicardipine intravenously injected did not change either parameter. Previous administration of the beta-adrenoceptor blocking drug, tertatolol (50 micrograms/kg i.v.), prevented the nicardipine-induced bradycardia and hypotension after injection into the NTS. These data suggest that part of the central cardiovascular effects of nicardipine result from an interaction with DHP sites within the NTS leading to a withdrawal of the sympathetic tone.