Lennard Tang Jespersen

Development of blood pressure in spontaneously hypertensive rats after withdrawal of long-term treatment related to vascular structure.

We have studied the effects of long-term treatment with different antihypertensive drugs on blood pressure and mesenteric resistance vessel structure of spontaneously hypertensive rats (SHR), both during treatment and after withdrawal of treatment. Young SHR were treated from 4 to 24 weeks with five different drugs: perindopril (1.5mg/kg per day), captopril (60mg/kg per day), hydralazine (25mg/kg per day), isradipine (42mg/kg per day) and metoprolol (130mg/kg per day). At 24 weeks, 24-h mean blood pressures (MBP), measured invasively, were 121 mmHg (perindopril), 137mmHg (captopril), 140mmHg (hydralazine), 149mmHg (isradipine) and 146 mmHg (metoprolol), compared to control values of 177 mmHg (SHR) and 132 mmHg (Wistar-Kyoto rats, WKY). Mesenteric resistance vessel structure, measured as media: lumen ratio (m:1), was also reduced to different extents: to WKY-level by perindopril (m:1 = 4.4%), to midway between SHR- and WKY-levels by captopril, hydralazine and isradipine (m: 1 = 5.9%), and not at all by metoprolol (m: 1 = 6.8%). When treatment was discontinued, low MBP (ca 151 mmHg) persisted for 12 weeks in rats treated with the angiotensin converting enzyme inhibitors (perindopril and captopril), but rose rapidly in rats which had received the other treatments. At 3–12 weeks after withdrawal of treatment vascular structure was closely correlated with the blood pressure expected from the SHR- and WKY-control values, as were the left ventricle: body weight ratios. The results suggest that the ability of a drug to control vascular structure during treatment is not in itself a predictor of a persistent effect on blood pressure after withdrawal of treatment. They also pointed to the usual close relationship between vascular structure and blood pressure in the absence of treatment.

Effect of endogenous vasoconstrictors on maternal intramyometrial and fetal stem villous arteries in pre-eclampsia

The contractile responses to various endogenous vasoactive agents were investigated in isolated human uteroplacental arteries from normotensive (NT) patients and patients with pre-eclampsia (PE) undergoing caesarian section. Tissue samples were obtained from the uterine incision and from macroscopically normal cotyledons. Vascular ring preparations of intramyometrial and stem villous arteries (length 1.0-1.3 mm, outer diameter 400-600 microns) were dissected and mounted in organ baths and isometric tension was recorded. Concentration-response relationships for vasopressin (VP), oxytocin (OX), angiotensin II (Ang II), noradrenaline (NA), 5-hydroxytryptamine (5-HT), prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) were assessed. For each compound, the mean maximum contractile effect (Emax) and the drug concentration producing half-maximal response (EC50) were determined. In intramyometrial arteries from NT and PE patients, VP, Ang II, NA, 5-HT and PGF2 alpha induced contraction while OX and PGE2 produced weak or no responses. Preparations from PE patients showed higher Emax values, while no differences in EC50 were found between the two groups. In fetal stem villous arteries, Ang II, 5-HT, PGF2 alpha and PGE2 induced contractions, while VP, NA and OX produced weak responses. No differences in Emax or EC50 values were found between the fetal vessels of PE and NT patients. No qualitative differences were demonstrated in response to the agents tested between the vessels (fetal and maternal) from NT women at term and PE patients. However, the results may reflect quantitative differences, suggesting increased contractility of maternal uteroplacental arteries from women with PE.

Long-term effects of isradipine on blood pressure and renal function

The hemodynamic and renal effects of isradipine were investigated in 10 hypertensive patients treated for 3.5 months and in a further nine patients treated for two years. Both groups achieved significant and sustained reductions in systolic blood pressure/diastolic blood pressure (-15 percent/-12 percent and -15 percent/-20 percent, respectively; p less than 0.001). Renal parameters were investigated two to three hours after the morning dose of isradipine, using a water-loading procedure. After 3.5 months of treatment, the glomerular filtration rate and renal plasma flow showed small increases (+6 percent and +9 percent, respectively, p less than 0.05), whereas, after two years, these changes were no longer present (+4 percent and 0 percent). Clearance of sodium and uric acid was increased by 40 percent (p less than 0.01) and 21 percent (p less than 0.01), respectively, after 3.5 months, and by 45 percent (p less than 0.05) and 23 percent (p less than 0.01), respectively, after two years. Lithium clearance studies revealed the natriuretic effect to be located in the proximal tubule. After 3.5 months, a significant relationship was found between the blood pressure response and the change in sodium excretion, but this relationship also was no longer present after two years. In conclusion, because of a maintained blood pressure-lowering effect while preserving renal function, and sustained natriuretic and uricosuric actions, isradipine can be considered a promising agent in the long-term treatment of arterial hypertension.

The quantitative aspect of photoplethysmography revised

SummaryThe overall transfer function of a photoplethysmograph (PPG) converting changes in intravascular volume to changes in recorder pen deflection was investigated. The specifications of the apparatus working as a red cell densitometer were assessed in vitro, and it was found that PPG output is a logarithmic function of red cell density roughly in accordance with the Lambert-Beer theorem. In an in vivo experiment it was found that PPG output is also a logarithmic function of digital intravascular volume as assessed by means of air plethysmography. It is suggested that the equation for this in vivo function is different because of a dual action of stasis, producing increases in both intravascular volume and haematocrit. Although the relative contributions of the two disparate phenomena are not assessed further, it is concluded that their joint action on PPG output can be described by a monologarithmic function. In the Appendix, sources of non-linearity in the electronics of PPG are pointed out and instructions for the use of an exponential amplifier which will linearize the overall transfer function are given.

Aggressive long-term antihypertensive therapy with pinacidil does not cause regression of cardiovascular hypertrophy in the spontaneously hypertensive rat.

After dosage titration from the age of 1 month to the age of 3 months, spontaneously hypertensive rats (SHR) were treated with pinacidil 10 mg/kg daily until the age of 6 or 12 months. Morphometric data were obtained from the treated SHR as well as from untreated age-matched SHR and normotensive Wistar-Kyoto rats (WKY) at these two developmental stages. Heart:body weight ratios and media:lumen ratios for resistance vessels were determined. Vessels obtained from the mesenteric region were investigated on a myograph. Vessels from heart, kidney and lung were investigated by morphometric analysis of histological sections, only specimens from 12-month-old rats were used. In SHR no effects of either ageing or treatment were detectable, although their blood pressure had been effectively held at normotensive levels throughout the life of the treated animals from the age of 3 months. With the exception of the media index of the pulmonary vessels, which was not statistically different from treated or control SHR, the WKY morphological parameters were significantly lower. In conclusion, pinacidil normalized blood pressure without complications, but this did not affect SHR cardiovascular structure. It is suggested that development of this strain-specific enlargement can only be modified if blood pressure is kept at hypotensive levels, or if the effect of a hitherto unidentified causative factor is antagonized by more-specific pharmacological treatment.

Acute natriuresis induced by inhibition of proximal tubular reabsorption of sodium and water in hypertensives following acute calcium entry blockade with nifedipine.

To elucidate the renal effects and especially the natriuretic properties of calcium entry blockers, we studied the effect of sublingual nifedipine 20 mg in 16 patients with mild to moderate essential hypertension. The lithium clearance technique was utilized and constant infusion technique was employed to measure glomerular filtration rate (GFR) and renal plasma flow (RPF). Nifedipine induced a significant reduction of systolic and diastolic blood pressure and an increase in heart rate. RPF increased and renal vascular resistance fell significantly, whereas GFR was unchanged. A significant increase in diuresis and in clearance of sodium and lithium was seen. The absolute and fractional proximal reabsorption of sodium and water was reduced. The absolute distal reabsorption increased significantly. The results indicate that the natriuretic action of nifedipine in hypertensives is a proximal tubular event.

Effects of nifedipine on contractile responses to potassium, histamine, and 5-hydroxytryptamine in isolated human pulmonary vessels.

Isolated human pulmonary arteries and veins cut to ring preparations responded with maximum contractions to potassium (127 mM: K), histamine (90 μM), and 5-hydroxytryptamine (47 μM: 5-HT). Nifedipine (0.003–3 μ) had a concentration-dependent relaxant effect on contractions induced by K, histamine, or 5-HT. The magnitudes of the relaxant effect of nifedipine were equal in arteries and veins, except in the highest concentrations used, in which case the effect was more pronounced on K-induced contractions in veins than in arteries. The effect of nifedipine was less pronounced on contractions induced by histamine or 5-HT than on K-induced contractions, and was more pronounced on histamine- than on 5-HT-induced contractions. In Ca-free medium, the response to K was nearly abolished in both arteries and veins. When the Ca concentration was increased from 0 to 4 mM without nifedipine, the contractile response to K was completely restored, while in the presence of nifedipine the response to extracellular Ca was nearly abolished in both types of vessel. The results indicate that active tone induced by K in pulmonary vessels is dependent on Ca entry from the extracellular medium. Nifedipine has a relaxant effect on both arteries and veins. In both types of vessel contractions induced by histamine of 5-HT are more resistant to the effect of nifedipine than contractions mediated by depolarization.

Differential effects of isradipine and atenolol on peripheral hemodynamics and arterial compliance

In a double-blind parallel-group randomized study, 28 patients with essential hypertension (World Health Organization class I/II) were allocated in equal numbers to one of two groups for treatment with either isradipine 5 to 20 mg twice daily or atenolol 50 to 100 mg once daily. At the end of the study, 12 patients were evaluable in the isradipine group and nine in the atenolol group. Assessments at baseline and after 20 weeks of treatment included arterial and venous compliance, mean peripheral perfusion pressure, heart rate, and digital vascular resistance using photoplethysmography. Isradipine had a direct relaxing effect on the arterioles, revealed by a significant increase in arterial compliance and a concomitant normalization of the digital vascular resistance. Atenolol had no significant effect on these parameters but, as expected, it lowered the heart rate, which was not affected by isradipine in the long term. The venous compliance remained low in both groups and, since isradipine--unlike atenolol--is known to have venodilating properties in vitro, its lack of effect in vivo is most likely due to reflex activation of sympathetically mediated venous tone. Because of the preference of isradipine for the arterial side of the peripheral vascular tree, the mean peripheral perfusion pressure remained higher in this group than in the atenolol group, although central systemic blood pressure was lowered equally and satisfactorily in both groups.

Can mean arterial pressure be estimated from measurements of systolic and diastolic blood pressure, and vice versa?

We investigated the reliability of calculating the mean blood pressure (MBP) in spontaneously hypertensive rats (SHR) from the systolic and diastolic blood pressures (SBP; DBP), using a form factor, calculated as: (MBP - DBP)/(SBP - DBP). The mean values of this form factor, as determined by blood pressure curve integration, were 0.459 and 0.450 in awake and anaesthetized SHR, respectively. There was no change in the form factor with pulse frequency. When direct femoral artery MBP measurements (x) were compared with MBP values (y) calculated from tail-cuff measurements of SBP and DBP using the form factor, the linear relationship between the two parameters was: y = 0.91x + 1.5 mmHg (r = 0.98). Actually, direct measurements confirmed that the tail artery MBP was 6-7% lower than the femoral artery MBP. In awake Wistar-Kyoto (WKY) rats, the form factor was 0.468. We therefore concluded that an approximate form factor value of 0.46 could be used in rats to estimate the MBP from known values of SBP and DBP. We further suggest that, because pulse pressure in any given rat remains relatively constant with time, SBP and DBP can be estimated in experiments by initially measuring the pulse pressure; thus, only the MBP need be recorded thereafter.

Antitrophic properties of antihypertensive drugs may depend solely on their blood pressure-lowering capability: A comparative study of isradipine, hydralazine, and metoprolol

The objective of this study was to examine the effect of antihypertensive treatment on the structure of intramyocardial resistance vessels in spontaneously hypertensive rats. The rats were divided into four groups: one was used as control and the other three were treated from the age of four to 24 weeks with isradipine, hydralazine, and metoprolol, respectively. Half of the animals in each group were examined at the end of active treatment and the rest were examined three weeks later. The rats were anesthetized and killed during constant flow perfusion with 1 percent glutaraldehyde. The media index was determined by point counting. The media indices of rats treated with isradipine and hydralazine were significantly smaller than those of age-matched spontaneously hypertensive rat controls, whereas the media indices of rats in the metoprolol group did not differ significantly. Three weeks after treatment withdrawal, the media index tended to increase in all three groups, but the values for the isradipine and hydralazine groups were still significantly reduced. Non-invasive blood pressure measurements taken at the same time demonstrated a significant blood pressure reduction in all groups, although differences within each treatment group were evident. All pressures had stabilized on the level of spontaneously hypertensive rats three weeks after withdrawal. Thus, it is evident that both isradipine and hydralazine were able to prevent hypertrophy of intramyocardial vascular structure and continue to do so even after treatment withdrawal. This finding is consistent with previous findings, suggesting a close relationship between the extent of blood pressure reduction and the degree of prevention of vascular hypertrophy.