The centrally acting alpha-adrenergic receptor agonist compounds have been available for treatment of hypertension for more than 25 years. Through studies of these compounds during this time, new knowledge has been made available not only on their mechanisms of antihypertensive action but also on the role of the adrenergic nervous system in essential hypertension. This discussion primarily reviews work from this laboratory on the cardiovascular actions of these compounds but reflects the general information from other quarters. In general, reduction of arterial pressure induced by these agents is associated with a cardiac output that remains relatively unchanged and with organ blood flows that are preserved. As a result of the reduced pressure, cardiac function is improved; and in recent studies, cardiac mass may be reduced. Associated with the reduced arterial pressure is an expanded plasma volume that is associated with a reduced blood viscosity, hematocrit, and plasma renin activity, but which may be at the expense of some return of arterial pressure toward pretreatment levels. The latter usually requires the addition of diuretic therapy. Current studies in our laboratory concern the performance of the heart following regression of ventricular hypertrophy both at reduced as well as increased ventricular afterloads.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Rat platelets activate high molecular weight atrial natriuretic peptides in vitro.

Evidence suggests that the more biologically active low molecular weight forms (less than 10,000) of rat atrial natriuretic peptides are proteolytically derived from a less active precursor of higher molecular weight. Conversion and activation could occur within the myocyte as well as during circulation. The present study found that in vitro rat blood and platelets were capable of converting the high molecular weight atrial natriuretic peptides (greater than 10,000) to low molecular weight atrial natriuretic peptides within minutes and that enhanced biological activity attended the conversion. Rat high molecular weight peptides were partially purified by gel filtration, lyophilized, and reconstituted in Krebs-Ringer bicarbonate buffer. One milliliter of fresh rat blood was incubated with the high molecular weight peptides at 37 degrees C for 2 minutes. After centrifugation, the supernatant was fractionated on Sephadex G-75. Natriuretic activity was determined by bioassay in anesthetized rats. In contrast to the results following incubation of high molecular weight peptides in Krebs-Ringer bicarbonate buffer alone, which showed that 95% of the natriuretic activity remained in the high molecular weight peptide region, the natriuretic activity of the blood-treated high molecular weight peptides eluted almost exclusively in the low molecular weight peptide region, which indicates conversion. Blood was separated into plasma, erythrocytes, lymphocytes, and platelets. Conversion of high to low molecular weight peptides occurred only after incubation with platelets. Compared with control high molecular weight peptides, rat platelet-treated high molecular weight peptides had significantly greater activity in relaxing histamine-contracted rabbit aortic smooth muscle (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Vasorelaxant and natriuretic activities of synthetic atrial peptides.

The vasorelaxant and natriuretic activities of synthetic atrial natriuretic peptides (ANF) were compared by measuring relaxation of histamine-contracted rabbit aortic rings and changes in urinary sodium excretion in anesthetized rats. The peptides studied and their relation to pro-ANF were: atriopeptins (AP) I, II and III (ANF 103-123, 103-125, 103-126), cardionatrin (CN) (ANF 99-126), alpha-human atrial natriuretic polypeptide (alpha-hANP) (human 99-126) and a fragment of the last (hFrag) (human ANF 105-126). The concentration causing 50% relaxation (EC50) in the vasorelaxant assay for API was greater than that of the other peptides (p less than 0.05). The EC50 for hFrag was 20 times greater than that of alpha-hANP, but this difference was not statistically significant. API caused less natriuresis compared with the other peptides (p less than 0.05). The natriuresis induced by CN was significantly greater than that of the other peptides at the 485 pmol dose. These results indicated that, except for API, the peptides studied has similar vasorelaxant and natriuretic activities.

Animals↗

PubMedDate not supplied

Regression of left ventricular hypertrophy in two-kidney, one clip Goldblatt hypertension.

The effect of regression of left ventricular hypertrophy (LVH) on ventricular performance was studied in two-kidney, one clip Goldblatt hypertensive rats (2K1C) treated with methyldopa or by unclipping. Sham operations were performed in a total of 21 rats; 12 and nine were studied after 4 and 6 weeks, respectively. Hypertension was induced in 38 additional rats. Of these, 11 were studied at 4 weeks. Cardiac index was measured by electromagnetic flowmetry under light ether anesthesia, and ventricular performance was assessed by rapid intravenous saline infusion. Of the remaining 27 hypertensive rats at 4 weeks postclipping, 10 were treated with methyldopa (400 mg/kg/day) and nine were unclipped; eight were left untreated as controls. Two weeks thereafter, ventricular performance was determined as described above. When expressed as the relationship between cardiac index and LV end-diastolic pressure, ventricular performance tended to be depressed in 2K1C. Ventricular performance, mean arterial pressure, and LV-to-body weight ratio returned to control in unclipped rats. Whereas methyldopa resulted in regressed LVH, its effect on mean arterial pressure and total peripheral resistance was not as marked as unclipping, both remaining significantly increased (p less than 0.001). The disparate effects of unclipping and methyldopa on systemic hemodynamics indicate that the improved ventricular performance with methyldopa was related more to its effect on LVH, suggesting that in these animals regression of LVH was associated with improved ventricular performance.

Animals↗