E. Mikkelsen

Effect of nifedipine on plasma renin, aldosterone and catecholamines in arterial hypertension.

SummaryAcute sublingual administration of nifedipine 10–20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r=0.92, p<0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r=0.80, p<0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30–60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p<0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r=0.74, p<0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.

Acute and chronic effects of nifedipine in arterial hypertension

SummarySublingual administration of nifedipine 10 mg to 11 patients and 20 mg to 6 patients with arterial hypertension caused a rapid and significant decrease in blood pressure in both groups. The average maximal reductions in the two groups were 21/16 mm Hg and 27/21 mm Hg. A concomitant rise in heart rate was found. Forearm blood flow showed a significant increase and the calculated vascular resistance a significant decrease 15–60 min after administration of both the 10 mg and the 20 mg doses. There was a negative correlation between basal vascular resistance and the maximal change of this parameter (r=−0.72, p<0.01). Plasma concentrations of nifedipine showed considerable individual variation, with slow absorption in some patients, which indicated failure of sublingual absorption in them. The difference between the mean plasma concentration in the two dose groups was statistically significant after 45 min. A negative correlation was present between the plasma concentration of nifedipine and the observed change in calculated vascular resistance (r=−0.74 at t=30 min). Treatment of 10 hypertensive patients with nifedipine 30–60 mg daily for 6 weeks reduced mean blood pressure from 175/115 mm Hg to 151/96 mm Hg (p<0.001). Heart rate and forearm blood flow rose, whereas the forearm vascular resistance showed a significant decrease. Side effects of a sensation of heat and reddening of face were noted in some patients. It is suggested that nifedipine may be useful both in the acute and chronic treatment of arterial hypertension.

Relationship between the antihypertensive effect and steady-state plasma concentration of nifedipine given alone or in combination with a beta-adrenoceptor blocking agent

SummaryThe antihypertensive effect of nifedipine (10–20 mg t.i.d.) given alone, or in combination with a beta-adrenoceptor blocking drug, was related to the observed plasma concentration during one dosage interval at steady-state (Pl-Nifss). The study was carried out as a within-patient comparison of treatment with nifedipine or placebo for 4 weeks. A highly significant reduction in blood pressure was obtained during monotherapy, as well as during combined treatment. The blood pressure reduction when nifedipine was added to beta-adrenoceptor blockade was of the same magnitude as that observed on nifedipine monotherapy. A considerable variation in Pl-Nifss was noted (range: 2–70 ng/ml). No significant correlation was found between the percentage reduction in blood pressure and Pl-Nifss in either of the two groups. There was a close relationship between Pl-Nifss and the concentration found 4 h after the morning dose. Side-effects were common during nifedipine monotherapy and were the reason for discontinuation of treatment in 4 of 18 patients. In contrast, none of the 9 patients on combined treatment dropped-out. In neither of the treatment groups was there any evidence for sodium retention and volume expansion during the first 4 weeks expressed as weight gain or signs of cardiac insufficiency. However, in 13 patients who continued on long-term treatment for 3–14 months, a definite need for concomitant diuretic therapy was found. The results indicate that nifedipine is effective in lowering blood pressure in patients with mild to moderate essential hypertension, either when given alone or in addition to beta-adrenoceptor blockade. It appears best tolerated as combination therapy. Long-term treatment requires addition of a diuretic. Pl-Nifss did not seem to be a major determinant of the magnitude of the hypotensive response.

Active, passive and myogenic characteristics of isolated rat intramural coronary resistance arteries

We have investigated the active, passive and myogenic tension-internal circumference relations of rat intramural coronary and, as controls, mesenteric small arteries (internal diameter ca. 200 μm) using an isometric myograph. The active tensions of the vessels (when fully activated with 30 μM serotonin in K-saline) reached a maximum (2.54 N/m, coronary; 3.39 N/m, mesenteric) at an internal circumference, L0, where the passive tensions (measured in Ca-free solution) were 0.80 N/m (coronary) and 0.74 N/m (mesenteric). Below 0.8 L0 and above 1.2 L0 the active tensions fell linearly, the zero tension intercepts being 0.37 L0 and 1.74 L0 (coronary) and 0.40 L0 and 1.72 L0 (mesenteric). The passive wall tensions of the vessels rose exponentially as a function of internal circumference, the wall tension at 1.5 L0 being 10.0 N/m (coronary) and 8.5 N/m (mesenteric). In normal physiological salt solution, the coronary vessels had a Ca2+ dependent myogenic tone which was also dependent on the internal circumference. Maximum myogenic tone (0.54 N/m) was obtained at 1.18 L0. The mesenteric vessels had no such myogenic tone. Histological examination showed that the media/lumen ratios of both vessel types were the same, and that the smooth muscle content of the media was greater in the coronary (81%) than in the mesenteric (72%) vessels. The smaller active tension of the coronary vessels could not therefore be ascribed to a reduced smooth muscle content, but possibly in part to an observed heterogeneous arrangement of the smooth muscle cells in the coronary vessels.

Abrupt withdrawal of beta-blocking agents in patients with arterial hypertension. Effect on blood pressure, heart rate and plasma catecholamines and prolactin

SummaryChronic treatment with beta-blockers was interrupted abruptly in six patients with arterial hypertension. Three patients, who had experienced symptoms during a previous withdrawal, again complained of transient palpitations, tremor, sweating, headache and general malaise. A significant increase in standing blood pressure (BP) and heart rate (HR) was noted after 24 h. The standing HR reached a maximum after 48 h and had decreased significantly on the 7th day (p<0.005). There was a strong tendency to greater increase in standing BP and HR in the patients who experienced symptoms than in those who did not. Plasma concentrations of noradrenaline, adrenaline and prolactin did not change significantly. Thus, beta-blocker withdrawal symptoms are reproducible and are indicative of a transient sympathetic hyperresponse. The increased activity is not likely to be caused by increased production of circulating catecholamines, but rather by increased sensitivity of the beta-receptor.

5-Hydroxytryptamine does not release endothelium-derived relaxing factor in rat isolated coronary arteries

Removal of the endothelium from isolated rat proximal and distal coronary artery segments shifted the 5-HT concentration-response curve to the left without affecting, the maximal contractile response. 5-HT had no relaxing effect in 10(-5) M prostaglandin F2 alpha-precontracted vessels with an intact endothelium in the presence of 10(-5) M ketanserin. The spontaneous myogenic tone increased in both proximal and distal coronary artery segments after the endothelium had been removed. Indomethacin (10(-5) M) reduced the response of the proximal coronary artery segments to 5-HT by 35% but indomethacin had no effect on the 5-HT concentration-response curve of the distal coronary artery segments. Indomethacin relaxed precontracted (40 mM potassium) proximal coronary artery segments independently of the presence of the endothelium, suggesting a non-specific relaxing effect of indomethacin in these arteries. It is concluded that rat coronary artery endothelium is unresponsive to 5-HT because it lacks 5-HT1 receptors. The increased 5-HT sensitivity and spontaneous myogenic tone of endothelium-denuded rat coronary arteries is probably due to the elimination of the relaxing stimulus mediated by spontaneously released endothelium-derived relaxing factor.

Comparison of effects of a new dihydropyridine, Bay K 8644, and nifedipine on spontaneous mechanical activity in rat portal vein

1 In isolated portal veins from rats, Bay K 8644 (methyl‐1, 4‐dihydro‐2, 6‐dimethyl‐3‐nitro‐4 (2‐trifluoromethyl‐phenyl) pyridine‐5‐carboxylate) increased the spontaneous mechanical activity in low but not in high concentrations. 2 The Bay K 8644‐induced increase in spontaneous mechanical activity was abolished in Ca‐free medium and restored by readdition of Ca. 3 Nifedipine abolished the augmenting effect of Bay K 8644 on the spontaneous mechanical activity; this effect of nifedipine could be eliminated by further increasing the concentration of Bay K 8644. 4 The results are consistant with the conclusion that in rat portal vein, Bay K 8644 increases the entry of extracellular Ca by a mechanism antagonistic to that of nifedipine and in high concentration has a Ca‐entry blocking effect.

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.

Distribution, elimination and natriuretic effect of furosemide in patients with severe arterial hypertension

SummaryFurosemide 40 mg was injected intravenously in 7 patients with severe hypertension and vascular complications. A two compartment, open model was used to describe the disappearance of the drug from serum. The mean serum clearance (Cls=1.83 ml/min · kg) was significantly reduced compared to the mean Cls-value of a group of normals (2.96 ml/min · kg). A significant correlation was found between Cls and mean blood pressure, as well as between Cls and renal clearance (mean Clr=0.83 ml/min · kg); extrapolation of the regression line yielded a Cls-value of 50 ml/min for Clr=0. The Clr was also significantly negatively correlated with mean blood pressure. Protein binding of furosemide was normal, except in one patient, who had considerable impairment of renal function. Apparently more than 90% of unchanged furosemide passed in urine was excreted by tubular transport. A highly significant negative correlation was found between Cls and the fraction of furosemide excreted as a glucuronide. During the first two hours, significantly less sodium was excreted by the patients than by a comparable group of normal subjects. The correlation between serum concentration of furosemide and the amount excreted of sodium was not significant, but highly significant correlations were found between the amounts of furosemide and sodium excreted by the kidney in 0–30 and 0–60 min. In all the individual patients an approximately linear relationship with wide variation in the slope was found between the cumulative excretion of furosemide and sodium from 0–30 min to 0–60 and to 0–120 min. After 120 min deviations were observed in the curves from 4 of the patients, which indicated that smaller and smaller additional amounts of sodium were excreted with constant additional amounts of furosemide.

Effects off pyrroloisoquinoline enantiomers ((+)- and (-)-McN-5652-Z) on behavioral and pharmacological serotonergic mechanisms in rats

A behavioral syndrome consisting of 5-hydroxytryptamine (5-HT)-dependent behaviors (e.g. forepaw treading, retropulsion and splayed hindlimbs) as well as hyperthermia occurred after bilateral injection of the (6S, 10bR)-(+)-enantiomer of McN-5652-Z into the cerebral ventricles in pargyline-treated rats. Both the behavioral syndrome and hyperthermia produced by (+)-McN-5652-Z were counteracted by parachlorophenylalanine or ketanserin. The (6R, 10bS)-(-)-enantiomer of McN-5652-Z influenced neither behavior nor body temperature. The enantiomers of McN-5652-Z differed also in their ability to inhibit ex vivo binding of paroxetine in rat frontal cortex and hypothalamus, in vitro uptake of 5-HT in rat blood platelets, and 5-HT-induced contraction of rat vascular smooth muscle, with (+)-McN-5652-Z being most active. No difference was observed between the effects of (+)- and (-)-McN-5652-Z on 5-HT metabolism by rat brain monoamine oxidase. Molecular models of N-protonated enantiomers having a cis B,C-ring juncture and a B-ring chair conformation were differentiated using a hypothetical model of the 5-HT uptake area. The findings indicate that the enantiomers of McN-5652-Z are useful tools for studying the stereoselectivity of behavioral and pharmacological effects exerted by serotonergic neurotransmission.