Cell biology of vascular hypertrophy in systemic hypertension.

Recent data demonstrate that in addition to its conduit function, the blood vessel is an active synthetic and secretory organ containing several autocrine and paracrine systems that are involved with the local regulation of its own function (i.e., structure and growth).

Evolving concepts of the renin-angiotensin system. Focus on renal and vascular mechanisms.

The traditional concept of the renin-angiotensin system (RAS) is a circulation-borne endocrine system, the components of which are secreted by various organs. The product of this biochemical cascade, angiotensin II, acts on specific receptors on multiple target organs. Activation of this circulating system has been shown to result in vasoconstriction and hypertension.

Molecular biology of the renin-angiotensin system.

This paper reviews the molecular biology of the renin-angiotensin system. The renin gene structure is analyzed in detail, including an examination of the putative regulatory regions. The combined action of these regulatory sequences would result in the complex, tissue-specific expression and regulation observed in vivo.

Evidence for two cellular pathways of renin secretion by the mouse submandibular gland.

The pathway of renin secretion has been defined in the mouse submandibular gland (SMG). Renin is first synthesized as a prorenin, rapidly cleaved to a one-chain renin, and then very slowly processed to a two-chain form which is stored in mature granules. In pulse-labeling experiments of minced SMG, the swift appearance in the culture medium of radiolabeled one-chain renin, before granule formation, suggested that this form was secreted by a constitutive pathway independent of the granules, possibly directly from the Golgi.

Contributions of neuroendocrine and local autocrine-paracrine mechanisms to the pathophysiology and pharmacology of congestive heart failure.

The degree of activation of neurohormonal mechanisms appears to depend on the severity and acuteness of cardiac impairment as well as the status of the extracellular fluid volume. Vasoconstrictive antinatriuretic mechanisms are markedly activated in severe decompensated cardiac failure. These are accompanied by parallel increases in endogenous vasodilatory natriuretic activities that modulate the powerful vasoconstrictive mechanisms.

Circulating versus local renin-angiotensin system in cardiovascular homeostasis.

The renin-angiotensin system has traditionally been viewed as an endocrine system. Recent data demonstrate that renin and angiotensinogen genes and their products are expressed at many local tissue sites. The concept that multiple tissues synthesize angiotensin has changed our understanding of the physiology of the renin-angiotensin system.

Vascular and renal prostaglandins as counter-regulatory systems in heart failure.

Vasoconstrictors and vasodilators are both activated in patients with severe heart failure. Vasodilatory prostaglandins are increased in parallel with the degree of activation of neurohumoral vasoconstrictor systems, and may serve to offset the circulatory effects of systemic and regional vasoconstriction. Enhanced vasoconstrictive and vasodilatory activities appear to be especially important in patients with hyponatraemia.

Responsiveness of atrial natriuretic factor to reduction in right atrial pressure in patients with chronic congestive heart failure.

In patients with congestive heart failure, atrial natriuretic factor may serve as a counter-regulatory hormone, offsetting the vasoconstrictive and volume-retentive effects of the sympathetic nervous system, the renin-angiotensin-aldosterone system and vasopressin. Indeed, the plasma levels of atrial natriuretic factor and the vasoconstrictor hormones are often simultaneously elevated in these patients. It is not known, however, whether atrial natriuretic factor remains responsive to sudden reductions in atrial pressure in patients with chronic heart failure, or is unresponsive like the vasoconstrictor systems.

Vascular renin-angiotensin system in hypertension. New insights into the mechanism of action of angiotensin converting enzyme inhibitors.

Evidence is accumulating that demonstrates the presence of local renin-angiotensin systems, in addition to the established circulating renin-angiotensin system. Renin-like substances, immunoreactive angiotensins, and angiotensin II receptors have been identified throughout the vasculature. Local tissue concentrations of angiotensin converting enzyme (ACE) inhibitors, rather than serum concentrations, may be more important in determining the magnitude and duration of the long-term cardiac and vascular response to this group of drugs.

Cardiac renin-angiotensin system. Molecular and functional aspects.

Current data support the existence of an endogenous renin-angiotensin system in the heart. Vascular angiotensin may contribute to the regulation of coronary vascular tone. Enhanced local angiotensin production in areas of vascular injury or inflammation may result in increased vasoconstriction or vasospasm.

Different secretory pathways of renin from mouse cells transfected with the human renin gene.

Mammalian cells in culture, transfected with human renin gene, can provide a useful tool for studying renin biosynthesis and secretion. We transfected fibroblast cells (mouse L929 and Chinese hamster ovary cells) and pituitary tumor cells (mouse AtT-20) with the human renin gene and a selectable plasmid (pSV2Neo). Transfected fibroblasts synthesize prorenin only.

Regulation of extra-renal renin during ontogeny.

Previous studies demonstrated that the level of renin in the male submandibular gland (SMG) of mouse strains that contain renin genes [e.g. Cr1:CD-1(1CR)BR] increased dramatically at puberty, but a less pronounced response was seen in the C57BL/10J (a strain that has a single renin gene).

Plasma atrial natriuretic factor during chronic thoracic inferior vena caval constriction.

The effects of chronic constriction of the thoracic inferior vena cava (TIVCC) on plasma atrial natriuretic factor (pANF) were studied in conscious dogs (n = 5). TIVCC decreased left and right atrial pressure and led to a decrease in pANF concentration from 199 +/- 12 to 104 +/- 14 pg/ml while plasma renin and vasopressin concentrations increased. These hormonal changes were associated with a significant fall in sodium excretion to less than 5 meg/day.

Mapping of the human renin transcription start site: evidence for a single functional promoter.

The 5' flanking region of the human renin gene contains two putative promoter sequences (TATA boxes), named P1 and P2. These are located in positions -77 to -71 and -29 to -23 respectively, each followed by a possible translational start site (AUG). In order to identify whether these sequences are functional in the kidney, we employed the RNAse protection assay.

Partial purification of a prorenin activating enzyme in the aortic wall.

The presence of a prorenin activating enzyme in the blood vessel wall may have important physiological implications. The putative enzyme may be involved with the endogenous production of active renin (a key enzyme in the vascular renin angiotensin system) or with the activation of circulating prorenin which had been taken up into the vessel wall. This study demonstrates the existence of a putative prorenin activating enzyme in the bovine aorta.

Renin gene expression, biosynthesis, and cellular pathways of secretion.

The molecular biology of the human renin gene is reviewed. This 12.5 kb gene contains 10 exons and 9 introns.

Autocrine-paracrine mechanisms of vascular myocytes in systemic hypertension.

Recent data demonstrate that in addition to its conduit function, the blood vessel is an active synthetic and secretory organ containing several autocrine and paracrine systems that are involved with the local regulation of its own function. The endothelium plays a pivotal role in modulating the balance between thrombogenesis and thrombolysis. In addition, it secretes vasorelaxant and vasoconstrictive substances, growth factors and inflammatory mediators that exert paracrine influences on vascular myocyte function.

The responses of atrial natriuretic factor concentrations to acute volume changes in conscious rats.

A rapid and sensitive radioimmunoassay has been developed for measurements of atrial natriuretic factor (ANF) in rat plasma. The antiserum, raised to rat ANF (99-126), cross-reacts with rat ANF (103-123), ANF (103-125), ANF (103-126) but not with smaller fragments, human ANF (99-126), angiotensin II, bradykinin or vasopressin. The plasma ANF concentration is 181 +/- 24 pg/ml (N = 24) in the unstressed conscious rats (Charles River CD, male).

Human renin biosynthesis and secretion in normal and ischemic kidneys.

The pathway of renin biosynthesis and secretion in normal and ischemic human kidneys has been investigated by pulse-labeling experiments. The results indicate that in normal human kidney, preprorenin is rapidly processed to 47-kDa prorenin. Microradiosequencing showed that this molecule was generated by cleavage between Gly-23 and Leu-24, yielding a 43-amino acid proregion.

Dissociation of the prostaglandin and renin angiotensin systems during captopril therapy for chronic congestive heart failure secondary to coronary artery disease.

Neurohumoral systems are activated as compensatory mechanisms in congestive heart failure (CHF). A close correlation has been reported between the renin angiotensin and prostaglandin systems in CHF. Furthermore, serum sodium concentration provided an excellent index of hormonal status.

Stimulus-response curve of the renal baroreceptor: effect of converting enzyme inhibition and changes in salt intake.

We investigated the effect of converting enzyme inhibition (CEI) on the relationship between renal perfusion pressure (RPP) and steady-state plasma renin activity (PRA) in uninephrectomized conscious dogs on normal-salt (80 meq Na+/day) and low-salt (10 meq Na+/day) diets. Stimulus-response curves for the renal baroreceptor were determined by measuring the steady-state PRA while the RPP was lowered and then held constant by an inflatable cuff placed around the renal artery. On each diet the control stimulus-response curve can be described by two lines intersecting at a threshold pressure; in the higher pressure range PRA is relatively insensitive to changes in RPP, while in the lower pressure range PRA is very responsive to changes in RPP.

Relationship of cardiac chamber volume to baroreflex activity in normal humans.

The objectives of this study were to examine the effect of incremental lower body negative pressure (LBNP) on cardiac chamber volume and assess the relationship between cardiac chamber volume and baroreflex activation of the neurohormonal axis. Accordingly, echocardiographic determination of cardiac chamber volume and neurohormonal responses were studied in 14 normal subjects during incremental LBNP. LBNP -10 mm Hg decreased left atrial diameter and left ventricular systolic volume index, but did not alter heart rate, systolic or pulse pressure, or stroke volume.