Friday, June 28, 2013

The perfect mixer for hypertension .

The perfect mixer for hypertension  .

Andre Willers
28 Jun 2013
Synopsis :
Beetroot juice with alcohol will lower blood pressure .
Discussion :
1.There are lots of systems that increase BP . See Appendices A  , B  ,  D  .
2.ANP (Atrial natriuretic peptide )
 But only one that decreases BP .  Produced mostly in the heart .See Appendix C
3.Most of the vascular damage is not done by alcohol , but by the hangover . See Appendix D
4.Beetroot juice is high in nitrates . See Appendix E. (Think nitroglycerin) .
5.The BP cocktail :
2 Tots of vodka or cane
3 Tots of Beetroot juice.
Top up with ice , soda/water
Quite tasty , actually . 

Watch vascular stress decrease .
Enough of these , and you won’t care , in any case .

Appendix A
Renin-aldosterone axis in ethanol intoxication and hangover.
Linkola J, Fyhrquist F, Nieminen MM, Weber TH, Tontti K.
The renin-aldosterone system was studied in human volunteers during ethanol intoxication and hangover. Plasma renin activity increased more than 100%, when 1.5 - 2.3 g ethanol per kg body weight was ingested over a three hour period. During hangover the increase even exceeded 200%. Plasma aldosterone concentration decreased during ethanol intoxication, but increased greatly during hangover. It is suggested that the stimulation of the renin-aldosterone axis during ethanol intoxication and hangover is due to dehydration and increased activity of the sympathetic nervous system.
PMID: 1261587 [PubMed - indexed for MEDLINE]
Appendix B

Basic Review: The Renin-Angiotensin-Aldosterone Axis

One of the coolest aspects of the renin-angiotensin-aldosterone system (RAAS) is that it involves multiple organ systems: the liver, lung, adrenal gland, kidney, and vasculature are all prominently involved. It never hurts to review basic physiologic principles, right? Listed are the three main components of the RAAS and their main mechanisms of action.

1. Renin is a peptide hormone secreted from the juxtaglomerular cells of the afferent arteriole in response to 3 main stimuli: (a) renal hypoperfusion, (b) decreased distal chloride delivery to the macula densa, and (c) increased sympathetic activity. Renin antagonists such as aliskiren are presently being tested as antihypertensive agenst with thus far promising results.

2. Angiotensinogen--which is synthesized and secreted from the liver--is cleaved by renin in the systemic circulation to form angiotensin I.

Angiotensin I is cleaved to form angiotensin II by angiotensin converting enzyme (ACE), which is found predominantly within lung endothelium. ACE-inhibitors, as their name implies, targets the ACE enzyme and is one of the most potent anti-hypertensives (and GFR-preserving) therapies available.

Angiotensin II has the following physiologic effects, which it carries out via binding to AT1 and AT2 receptors. Drugs which block the ability of angiotensin II to bind to its receptors ("angiotensin receptors blockers", or ARBs) make up another highly successful and renoprotective antihypertensive therapy. Angiotensin II binding to its receptors have the following major effects:

a) angiotensin II acts as a systemic vasoconstrictor.
b) angiotensin II causes renal efferent arterial vasoconstriction. Acutely, efferent vasoconstriction should increase GFR; however, over time the increased glomerular pressure leads to glomerular damage and, ultimately, renal injury.
c) angiotensin II increases secretion of aldosterone from the zona glomerulosa of adrenal cortex.

3. Aldosterone: in cortical collecting duct cells, aldosterone diffuses into the cell and interacts with the mineralocorticoid receptor, which upon binding translocates to the nucleus and increases expression of ENac. The end result of aldosterone action is sodium reabsorption and potassium & hydrogen secretion. In addition to angiotensin II, hyperkalemia can also stimulate aldosterone secretion. The drug spironolactone interferes with aldosterone interacting with its receptors, and can be effective in the treatment of hypertension.

Appendix C

Atrial natriuretic peptide
From Wikipedia, the free encyclopedia
For other uses, see ANP.
Natriuretic peptide A

Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), Cardionatrine, Cardiodilatine (CDD) or atriopeptin, is a powerful vasodilator, and a protein (polypeptide) hormone secreted by heart muscle cells.[1][2][3] It is involved in the homeostatic control of body water, sodium, potassium and fat (adipose tissue). It is released by muscle cells in the upper chambers (atria) of the heart (atrial myocytes) in response to high blood pressure. ANP acts to reduce the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure.[1] ANP has exactly the opposite function of the aldosterone secreted by the zona glomerulosa.[4]
The ANP gene has 3 exons and 2 introns; it codes 151-amino acid preproANP. Cleaving the 25-amino acid N-terminal results in pro-ANP. Corin, a membrane serine protease, cleaves the final ANP, the 28-amino acid C-terminal.
ANP is produced, stored, and released mainly by cardiac myocytes of the atria of the heart. Synthesis of ANP also takes place in the ventricles, brain, suprarenal glands, and renal glands. It is released in response to atrial stretch and a variety of other signals induced by hypervolemia, exercise, or caloric restriction.[1] The hormone is constitutively expressed in the ventricles in response to stress induced by increased afterload (e.g. increased ventricular pressure from aortic stenosis) or injury (e.g. myocardial infarction).
ANP is secreted in response to:
Atrial distention, stretching of the vessel walls[1]
Sympathetic stimulation of β-adrenoceptors
Raised sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion[1]
Endothelin, a potent vasoconstrictor
The atria become distended by high extracellular fluid and blood volume, and atrial fibrillation. Notably, ANP secretion increases in response to immersion of the body in water, which causes atrial stretch due to an altered distribution of intravascular fluid. ANP secretion in response to exercise has also been demonstrated in horses.[6]
ANP is also produced by the placenta in pregnant women. The exact function of this remains unclear. [7]

ANP binds to a specific set of receptors – ANP receptors. Receptor-agonist binding causes a reduction in blood volume and therefore a reduction in cardiac output and systemic blood pressure. Lipolysis is increased and renal sodium reabsorption is decreased. The overall effect of ANP on the body is to counter increases in blood pressure and volume caused by the renin-angiotensin system.
Dilates the afferent glomerular arteriole, constricts the efferent glomerular arteriole, and relaxes the mesangial cells. This increases pressure in the glomerular capillaries, thus increasing the glomerular filtration rate (GFR), resulting in greater excretion of sodium and water.
Increases blood flow through the vasa recta which will wash the solutes (NaCl and urea) out of the medullary interstitium.[10] The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
Decreases sodium reabsorption in the distal convoluted tubule (interaction with NCC)[11] and cortical collecting duct of the nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC
Inhibits renin secretion, thereby inhibiting the renin-angiotensin-aldosterone system.
Reduces aldosterone secretion by the adrenal cortex.
Atrial natriuretic peptide (ANP) increases Na+ excretion by decreasing the amount of Na+ reabsorbed from the inner medullary collecting duct via a decrease in the permeability of the apical membrane of the collecting duct epithelial cells. Less Na+ is able to enter the epithelial cells and therefore, less Na+ is reabsorbed. ANP also increases Na+ excretion by increasing the filtered load of Na+
Relaxes vascular smooth muscle in arterioles and venules by:
Membrane Receptor-mediated elevation of vascular smooth muscle cGMP
Inhibition of the effects of catecholamines
Inhibits maladaptive cardiac hypertrophy
Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly[12]
Re-expression of NPRA rescues the phenotype.
It may be associated with isolated atrial amyloidosis.[13]
Adipose tissue[edit]
Increases the release of free fatty acids from adipose tissue. Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans.
Activates adipocyte plasma membrane type A guanylyl cyclase receptors NPR-A
Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of a cGMP-dependent protein kinase-I (cGK-I)
Does not modulate cAMP production or PKA activity

Regulation of the effects of ANP is achieved through gradual degradation of the peptide by the enzyme neutral endopeptidase (NEP). Recently, NEP inhibitors have been developed; however they have not yet been licensed. They may be clinically useful in treating congestive heart disease.
Other natriuretic factors[edit]

In addition to the mammalian natriuretic peptides (ANP, BNP, CNP), other natriuretic peptides with similar structure and properties have been isolated elsewhere in the animal kingdom. Tervonen (1998) described a salmon natriuretic peptide known as salmon cardiac peptide,[14] while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba, a species of African snake.[15]
Pharmacological modulation[edit]

Neutral endopeptidase (NEP) is the enzyme that metabolizes natriuretic peptides. Several inhibitors of NEP are currently being developed to treat disorders ranging from hypertension to heart failure. Most of them are dual inhibitors. Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns. Other dual inhibitors of NEP with ACE/angiotensin receptor are currently being developed by pharmaceutical companies.[16]
Appendix D

To study the mechanisms of alcohol-induced diuresis, the plasma concentration of immunoreactive atrial natriuretic peptide and arginine vasopressin, serum sodium and osmolality, plasma renin activity and aldosterone, urinary sodium and volume, free water clearance, blood pressure and heart rate were measured in seven healthy men after oral intake of ethanol (1.5 g kg-1 in 6 h). Serum ethanol levels increased to 27 ± 4 mmol 1-l (mean ± SD) in 30 min and remained detectable for 14 h. Serum osmolality rose from 280±10 to 340 ± 4 mosm kg-1 in 2 hours (P < 0.01) and was 300 ± 4 at 14 h (P < 0.01). Formation of hypotonic urine began after the alcohol intake and resulted in a net loss of 0.9 ± 0.1 kg water in 2 h. Free water clearance increased from -3.4 ± 1.4 to 2.8 ± 1.5ml min-l in 2 h (P < 0.01). Plasma immunoreactive arginine vasopressin decreased from 5.7 ± 2.1 to 3.3 ± 1.3 ng 1-1 (P = 0.05) in 30 min and increased to 17 ± 25 and 12±10 ng 1-1 at 6 and 12 h, respectively (P < 0.05 for both). Plasma immunoreactive atrial natriuretic peptide levels decreased from 17 ± 9 to the minimum of 11 ± 3 ng 1-1 in 2 h (P < 0.01) and returned to the initial levels in 6 h. Serum sodium, plasma renin activity and plasma aldosterone increased maximally by 4 ±2, 165 ± 153 and 143 ± 101 % (P < 0.01 each) during 1–6 h. No changes in blood pressure were observed during the ingestion period, but the heart rate rose significantly from 70 min-1 at 6 p.m. to 95 min-1 at 12 p.m.

We conclude that ethanol intake in relation to serum ethanol levels caused in the first phase a rapid increase in osmolality which was associated with a decrease in plasma immunoreactive arginine vasopressin. This caused hypotonic diuresis and increased free water clearance followed by volume contraction which evidently led to decreased plasma immunoreactive atrial natriuretic peptide. Serum osmolality was significantly elevated during the whole experiment and serum sodium 1–2 h after the ethanol intake. This was associated with the return of plasma immunoreactive atrial natriuretic peptide to initial levels after 6 h, the increase in plasma immunoreactive arginine vasopressin levels and reduced diuresis after 2 h. Our results suggest that ANP is not responsible for the diuresis seen after the alcohol intake.
Appendix E
Nitric Oxide Signalling in Vascular Control and Cardiovascular Risk

Annette Schmidt1
[1] Leibniz-Institute of Arteriosclerosis Research at the University of Muenster, Germany
1. Introduction

Nitric oxide – a free radical molecule – has been known for many decades, but only since its recognition as endothelium-derived relaxing factor (EDRF) the interest in the molecule has exponentially increased (Moncada, 1991). At the present time NO is an important messenger that regulates numerous functions and also participates in the pathogenesis of various diseases (Lloyd-Jones & Block, 1996). NO is generated from the conversion of arginine to citrulline in a multistep oxidation process by the NO-synthase (NOS), a NADPH-dependent enzyme that requires Calcium-Calmodulin, Flavinadeninedinucleotide, Flavinmononcleotide and Tetrahydro-L-biopterin as cofactors (Förstermann et al., 1994). Three isoforms of NOS have been identified. All isoenzymes, the neuronal NOS (nNOS), the inducible NOS (iNOS) and the endothelial NOS (eNOS) (Liu & Huang, 2008), are homodimers with subunits of 130 – 160 kDa. As major signalling molecule of the vascular system NO is generated by the constitutively expressed eNOS.


No comments: