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It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α 2 -adrenoceptors ( α 2 -ARs) in skin-lightening experiments in the frog. Now α 2 -ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α 2 -AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α 2 -ARs. In this model system and in the setting of furosemide-induced sodium excretion, α 2 -AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α 2 -AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α 2 -ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α 2 -ARs activate prohypertensive biochemical systems. While investigating the role of α 1 -adrenoceptors ( α 1 -ARs) versus α 2 -ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α 1 -ARs suppress the postjunctional expression of α 2 -ARs. Here, we describe how this finding relates to a broader understanding of the role of α 2 -ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α 2 -AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 William A. Pettinger and Edwin K. Jackson.)

The Hypertension Community has 3 conflicting dilemmas: a goal systolic pressure of 120 mm Hg or less (the SPRINT Trials), 40% of our 60,000,000 hypertensives still sustain blood pressures above 140/90 mm Hg, and our most potent antihypertensive drug minoxidil sits on the sidelines, imprisoned in the Food and Drug Administration's Black Box designation. My solutions to these dilemmas are: (1) review of the facts of our most potent antihypertensive drug minoxidil which is essentially free of toxicity, (2) treatment focus on the fundamental cause of high blood pressure, that is excess dietary sodium and, (3) prevention of, and/or reversal of, the fundamental mechanism of worsening hypertension, arteriolar hypertrophy., Summary: The Hypertension Community has 3 conflicting dilemmas: a goal systolic pressure of 120 mm Hg or less (the SPRINT Trials), 40% of our 60,000,000 hypertensives still sustain blood pressures above 140/90 mm Hg, and our most potent antihypertensive drug minoxidil sits on the sidelines, imprisoned in the Food and Drug Administration's Black Box designation. My solutions to these dilemmas are: (1) review of the facts of our most potent antihypertensive drug minoxidil which is essentially free of toxicity, (2) treatment focus on the fundamental cause of high blood pressure (HBP) and excess dietary sodium and, (3) prevention of, and/or reversal of, the fundamental mechanism of worsening hypertension, arteriolar hypertrophy. My focus at UT Southwestern in Dallas was on extremely severely hypertensive patients with a quantifiable, measurable complication of HBP, progression of nephrosclerotic damage to kidneys. This model had the greatest likelihood of exposing fundamental disregulatory mechanisms in hypertensive patients (which it did) and the potential for study of the most relevant antihypertensive drug interactions to achieve optimal blood pressure control (which it did). By maintaining diastolic pressures at 80 mm Hg or less in the first National Institutes of Health-supported, long-term randomized clinical trial to save the kidneys, the bases for a fundamental blood pressure support mechanism (arteriolar hypertrophy) was illuminated but not fully described until now. This fundamental hypertensinogenic mechanism results from HBP but with time and severity, becomes its own raison d'être. I am now aged 84 years. As a result of a stroke 20 years ago, which caused permanent double vision, and because of poor blood pressure control with triple therapy, I started using minoxidil 5 mg/d along with atenolol and occasional furosemide. Now, along with some dietary salt restriction, my resting blood pressure is 110/65-125/75 and, despite >30 years history of HBP, I have no retinal arteriolar hypertrophy nor arcus senilis (Dr. Schwartz-U. of Miami) which is almost universally present at this age. Yes, prevention of, or reversal of, arteriolar hypertrophy should be a central focus of HBP treatment. I simply wish to share a bit of accumulated wisdom that might be of use to others.

We report the clinical, pathologic, and immunohistochemical features of a severe hypertensive patient with recurrent migraine-induced hypotension. The patient died of migraine-induced vasomotor paralysis despite prompt institutions of fluid and sympathomimetic and parasympatholytic agents. Postmortem study revealed autonomic ganglionitis and neuritis.

Male Dahl salt-sensitive hypertensive (S) rats develop hypertension faster than females. We measured renal alpha2-adrenergic receptor density of inbred Dahl salt-sensitive (SS/JR) and salt-resistant (SR/JR) rats, using [3H]-rauwolscine saturation binding studies. Male and female SS/JR rats were gonadectomized or sham-operated at 6 weeks of age and fed a high salt diet for 4 weeks. Additional intact SS/JR and SR/JR rats of both sexes were fed the high salt diet for a longer period of time (7 weeks instead of 4 weeks). Both blood pressure and renal alpha2-adrenergic receptor density were significantly higher in male than female SS/JR rats on high salt diet for 4 weeks. Gonadectomy did not change blood pressure nor did it change renal alpha2-adrenergic receptor density measured at the 4th week of high salt feeding in either male or female SS/JR rats. When the SS/JR rats were fed high salt diet for a longer period (for 7 weeks), blood pressure of female SS/JR reached the level of males, but the density of renal alpha2-adrenergic receptors was still significantly lower than that of males. Both renal alpha2-adrenergic receptor density and blood pressure were higher in male than female SR/JR. We conclude that higher blood pressure in male Dahl SS/JR and SR/JR rats is associated with higher renal alpha2-adrenergic receptor density compared with their female counterparts.

Hypertensive nephrosclerosis is a progressive renal disease and the leading cause of end-stage renal disease (ESRD) in blacks in the United States. It is generally believed that hypertensive renal injury is responsible for progressive renal failure; however, it is not known whether pharmacologic lowering of blood pressure to any level prevents progression of renal disease. Accordingly, we performed a long-term prospective randomized trial to determine whether "strict" [diastolic blood pressure (DBP) 65 to 80 mm Hg] versus "conventional" (DBP 85 to 95 mm Hg) blood pressure control is associated with a slower rate of decline in glomerular filtration rate. Eighty-seven non-diabetic patients (age 25 to 73; 68 black, 58 male) with long-standing hypertension (DBP > or = 95 mm Hg), chronic renal insufficiency (GFR < or = 70 m/min/1.73 m2) and a normal urine sediment were studied. DBP was pharmacologically lowered to < or = 80 mm Hg (3 of 4 consecutive measurements at 1 to 4 weeks intervals) after which patients were randomized. DBP and GFR (renal clearance of 125I-iothalamate) were measured at baseline, at three months and every six months post-randomization. The rate of decline in GFR (GFR slope, in ml/min/1.73 m2/year), estimated by the method of maximum likelihood in a mixed effects model, was the primary outcome variable. In a secondary analysis, 50% reduction in GFR (or a doubling of serum creatinine) from baseline, ESRD and death were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens regulate blood pressure and renal alpha 2-adrenergic receptors in a parallel fashion in the spontaneously hypertensive rat (SHR). The present studies investigated whether this regulation of renal alpha 2B-adrenergic receptors occurs at the mRNA level. Male and female SHR were gonadectomized at 4 weeks of age. The gonadectomized rats were implanted with or without testosterone propionate. Sham-gonadectomized rats served as controls. Total kidney RNA was purified, and alpha 2B-adrenergic receptor mRNA was quantified with a reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The assay uses a mimic RNA added at known concentrations to the sample RNA. The mimic was constructed from the target sequence in the alpha 2B-adrenergic receptor mRNA plus a 20-bp insertion of a random nucleotide sequence. The amount of alpha 2B-adrenergic receptor mRNA present in each sample was obtained by determining the equivalence point between the amount of RT-PCR product formed in the target band versus the mimic band, which were resolved by gel electrophoresis. Intact males had more than two times as much alpha 2B-adrenergic receptor mRNA as intact females. Castration of males reduced the male-female difference by more than 60%. Ovariectomy slightly increased the alpha 2B-adrenergic receptor mRNA level compared with that of intact females. Treatment with testosterone elevated alpha 2B-adrenergic receptor mRNA levels of gonadectomized males and females to the level of intact males. The alpha 2B-adrenergic receptor mRNA levels correlated remarkably well with renal alpha 2-adrenergic receptor density. We conclude that testosterone regulates renal alpha 2B-adrenergic receptor gene expression at the mRNA level in the SHR.

Using the restriction endonuclease, BgI I, Samani et al. found a restriction fragment length polymorphism (RFLP) for the renin gene in spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats. This RFLP was confirmed in our laboratory in SHR and WKY rats using a rat renin cDNA probe. The correlation of blood pressure and the renin RFLP was examined in 106 F2 rats produced from F1 rats, the offspring of a cross between SHR males and WKY females. Systolic blood pressure was measured by the tail cuff method at 12 weeks of age. Mean arterial blood pressure of anesthetized rats was measured by cannulation of the femoral artery prior to sacrifice. The frequency of renin genotype showed a typical 1:2:1 Mendelian ratio in F2 rats of SHR and WKY cross. The mean arterial blood pressure of F2 rats homozygous with the SHR allele was significantly higher than F2 rats that were heterozygous or homozygous for the WKY allele. No significant difference in systolic blood pressure was observed in these F2 rats. Thus, the renin gene RFLP cosegregates with an increase in mean arterial blood pressure in the F2 rats of SHR and WKY cross.

Over the past two decades the incidence of stroke and myocardial infarction in hypertensive populations has decreased, yet the incidence of end-stage renal disease attributed to hypertension has increased. This apparent paradox has raised questions about the adequacy of blood pressure control in hypertensive patients with renal disease. Chronic renal failure is commonly associated with hypertension, and is often severe and difficult to control, particularly in patients with hypertensive nephrosclerosis. The optimal level of blood pressure control in these patients has not been established. Long-term diastolic blood pressure control to a level lower than 90 mm Hg is associated with stable or improving renal function in hypertensive nephrosclerosis and with slowing of the deterioration in renal function from other causes of renal failure. Moreover, recent studies indicate that when blood pressure control is achieved and maintained at a level of about 130/86 mm Hg (systolic/diastolic), deterioration in renal function can be halted even in black patients with hypertensive nephrosclerosis. Therefore, in hypertensive nephrosclerosis we attempt to control diastolic blood pressure at 80 to 85 mm Hg. Newer antihypertensive agents such as calcium channel blockers and angiotensin-converting enzyme inhibitors contribute to lowering blood pressure and preserving renal function. However, they have yet to be proven superior to conventional agents in double-blind randomized clinical trials in humans with hypertensive nephrosclerosis. Importantly, minoxidil is still relied on for aggressive control of blood pressure in many patients with hypertensive nephrosclerosis.

Male spontaneously hypertensive rats (SHR) have higher blood pressure than females. We compared renal alpha 2-adrenergic receptor density among intact SHR and Wistar-Kyoto (WKY) rats of both sexes, male and female SHR gonadectomized at 4 weeks of age, and gonadectomized SHR supplemented with testosterone. Additional groups of SHR were treated with enalapril (30 mg/kg per day), an angiotensin-converting enzyme inhibitor, from 5 to 14 weeks of age. Renal alpha 2-adrenergic receptor density was higher in males than females in both SHR and WKY rats. Female SHR and WKY rats had identical low renal alpha 2-adrenergic receptor density. Castration of male SHR reduced the male-female differences in blood pressure and renal alpha 2-adrenergic receptor density by 60%. Treatment with testosterone raised blood pressure and renal alpha 2-adrenergic receptor density to the intact male levels in both gonadectomized males and females. Treatment with enalapril decreased blood pressure but not renal alpha 2-adrenergic receptor density in both male and female SHR. We conclude that (1) both renal alpha 2-adrenergic receptor density and blood pressure are influenced by sex in SHR and WKY, (2) renal alpha 2-adrenergic receptor density like blood pressure is regulated by androgens, and (3) increased renal alpha 2-adrenergic receptor density is not a consequence of high blood pressure in male SHR.

The Doppler RI, measured in a blinded fashion, was correlated with RBF, RVR, and GFR calculated by simultaneous clearance measurements. Nine hypertensive patients were studied weekly while receiving increasing doses of the vasodilator minoxidil. In 36 studies, RI was significantly correlated with RBF (r = -0.42) but not with RVR or GFR. When RI values were adjusted for ERV, correlations strikingly improved and were further improved by adjustment for pulse pressure. The ARI allowed semiquantitative predictions of RBF and RVR more accurately than blood urea nitrogen or serum creatinine levels. Correlation with GFR was weak.

Using the restriction endonuclease, Bgl I, Samani et al. found a restriction fragment length polymorphism (RFLP) for the renin gene in spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats (1). This RFLP was confirmed in our laboratory in SHR and WKY rats using a rat renin cDNA probe. The correlation of blood pressure and the renin RFLP was examined in 106 F2 rats produced from F1 rats, the offspring of a cross between SHR males and WKY females. Systolic blood pressure was measured by the tail cuff method at 12 weeks of age. Mean arterial blood pressure of anesthetized rats was measured by cannulation of the femoral artery prior to sacrifice. The frequency of renin genotype showed a typical 1:2:1 Mendelian ratio in F2 rats of SHR and WKY cross. The mean arterial blood pressure of F2 rats homozygous with the SHR allele was significantly higher than F2 rats that were heterozygous or homozygous for the WKY allele. No significant difference in systolic blood pressure was observed in F2 rats with different genotypes. Thus, the renin gene RFLP cosegregates with an increase in mean arterial blood pressure in the F2 rats of SHR and WKY cross.

Mesenteric artery rings from Wistar and Wistar-Furth rats subcutaneously treated with deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water were used to measure endothelial modulation of contractile sensitivity and vasopressin receptor function and affinity. DOCA-salt hypertension reduced contractile sensitivity to arginine vasopressin (AVP) and did not affect contractile sensitivity to norepinephrine in arteries from Wistar rats. Endothelial removal caused a threefold increase in contractile sensitivity to AVP and norepinephrine in DOCA-salt hypertensive Wistar rats. In Wistar-Furth rats, DOCA-salt treatment did not affect contractile sensitivity to AVP, lysine vasopressin, oxytocin, and norepinephrine or the affinity of the vasopressin receptor for agonists or antagonists. Removal of endothelium did not affect vasopressin contractile sensitivity but caused a 15-fold increase in contractile sensitivity to norepinephrine in untreated or DOCA-salt-treated Wistar-Furth rats. These data show that reduced vasopressin receptor function and increased endothelial function that compensate for increased contractile sensitivity in arteries from DOCA-salt hypertensive Wistar rats are not the cause of resistance of DOCA-salt-treated Wistar-Furth rats to the development of enhanced contractile sensitivity and hypertension.

Renal glomerular hyperfiltration has been proposed as an important contributing factor to the progression of hypertensive nephrosclerosis in rats with reduced renal mass. However, no clinical studies have assessed the role of glomerular hyperfiltration in the pathogenesis of hypertensive nephrosclerosis in humans. In a prospective, randomized, long-term blood pressure control study with up to 3 years follow-up, we showed that good blood pressure control with a mean diastolic blood pressure < or = 95 mm Hg preceded by a 2- to 4-month period of diastolic blood pressure < or = 80 mm Hg improved renal function in hypertensive nephrosclerosis patients. Patients treated with minoxidil, an angiotensin-converting enzyme inhibitor (enalapril), or a calcium entry blocker (nifedipine) had improvement in renal function, as indicated by a positive slope of the reciprocal serum-creatine concentration versus time and an increment in glomerular filtration rate. These results suggested that improvement in renal function occurred with these major types of antihypertensive drug treatment. To assess the renal hemodynamics of minoxidil, enalapril, and nifedipine, eight patients with hypertensive nephrosclerosis were admitted to the General Clinical Research Center for renal clearance studies on each drug while ingesting a fixed-calorie, 12% protein, 40% fat, and 100 mEq Na/d diet. Mean blood pressure, effective renal plasma flow, and renal vascular resistance did not change during the three phases of treatment. However, minoxidil treatment increased the glomerular filtration rate by 48% versus enalapril and by 79% versus nifedipine. Since minoxidil treatment improves renal function while causing a relative hyperfiltration, glomerular hyperfiltration per se is an unlikely mechanism for the progression of hypertensive nephrosclerosis in humans.

In deoxycorticosterone acetate (DOCA)-NaCl hypertension, the effects of vasopressin (VP) in the cortical collecting tubule (CCT) are exaggerated. These include both the biochemical effect of VP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) formation in the CCT and physiological effects of VP-mediated sodium and water retention. In this study, we examined the mechanism of enhanced VP-stimulated cAMP formation in the CCT. We compared cAMP formation in response to activators (following in parentheses) of the VP receptor (VP), of the stimulatory guanine nucleotide binding (Gs) protein [guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S); F-], and of the catalytic subunit of adenylyl cyclase (forskolin, Mn2+) between control and DOCA-NaCl-treated rats. The effects of VP and forskolin were enhanced in CCT of DOCA-NaCl-treated animals by 201 and 139%, respectively, compared with control animals. Other activators, Mn2+ (150%), F- (142%), and GTP gamma S (156%), also caused augmented cAMP formation in the CCT of DOCA-NaCl-treated rats. The DOCA-NaCl-induced increment in cAMP response to VP remained after pretreatment of the rats with pertussis toxin (171 and 169% increase in response in DOCA-NaCl and control rats, respectively), suggesting that altered inhibitory guanine nucleotide binding (Gi) protein function is not the mechanism for the altered response to VP in the CCT. Further evidence that Gi function is intact in DOCA-NaCl animals is that epinephrine (via alpha 2-adrenoceptor stimulation) inhibited VP-stimulated cAMP accumulation to a similar degree in DOCA-NaCl and control rats (86 and 76%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

We have briefly discussed the antihypertensive drug interactions which result in additive or synergistic actions on lowering of blood pressure when they are administered concomitantly. The choice of antihypertensive agents should be individualized based on the patient's age, race, sex, weight prior therapy, coexisting diseases, underlying diseases, and the pathophysiology of the disease. The goal of antihypertensive treatment extends not only to the control of hypertension per se but also to the reduction of side effect profiles, the treatment of co-existing diseases and optimizing quality of life.

Objective: To examine the frequency of distribution of allelic polymorphisms of the alpha 2-adrenoceptor gene in normotensive and hypertensive humans., Design: The frequency of alpha 2-adrenoceptor genotypes was compared in the two groups using the chi 2-test., Setting: The Midwest Hypertension Research Center Outpatient Clinic of Creighton University School of Medicine., Study Participants: History was taken from and physical examination performed on each of the 60 hypertensive and 47 normotensive adults., Methods: DNA was extracted from leukocytes from each participants. Twenty restriction endonucleases were used and one restriction fragment length polymorphism (RFLP) was found using a 950-bp restriction fragment from the coding region of the human platelet alpha 2-adrenoceptor gene (ADRA2R) and Bsu36I restriction endonuclease. This probe and Bsu36I restriction endonuclease, in addition to another restriction endonuclease (Dra I), were then used in the study., Results: Three genotype patterns were found. Homozygotes for the Bsu36I RFLP have either a unique 12-kb or a unique 5.8-kb band. Heterozygotes have both bands. The frequency of this alpha 2-adrenoceptor RFLP was calculated. In hypertensives the frequencies of the 12- and 5.8-kb alleles were 0.52 and 0.48, compared with 0.45 and 0.55, respectively, in normotensive, a difference that was not statistically significant., Conclusions: The frequency of the Bsu36I RFLP involving an alpha 2-adrenoceptor gene in hypertensives did not differ significantly from that in normotensives. A genetic linkage study is now under way to test for an association of the Bsu36I RFLP of the alpha 2-adrenoceptor gene with essential hypertension in families.

Ring segments of superior mesenteric arteries studied in vitro were used to determine the role of the vascular endothelium in regulating vascular contractile and relaxant sensitivity in deoxycorticosterone acetate (DOCA)-salt hypertension. Wistar rats were given DOCA (20 mg/kg s.c. twice per week) and 1% NaCl drinking water for 5 weeks. In ring segments containing endothelium, there was a decrease in contractile sensitivity to arginine vasopressin, no change in contractile sensitivity to norepinephrine and KCl, and no change in relaxant sensitivity to acetylcholine or isoproterenol in arteries from hypertensive rats compared with normotensive controls. Removal of the vascular endothelium by rubbing had no effect on the contractile response to arginine vasopressin and KCl or the relaxant response to isoproterenol in control arteries. In arteries without endothelium, DOCA-salt hypertension caused a threefold increase in contractile sensitivity for arginine vasopressin, norepinephrine, and KCl; a 50% reduction in maximal relaxation to isoproterenol; and a threefold decrease in relaxant sensitivity to sodium nitroprusside. Indomethacin (10 microM) had no effect on contraction or relaxation. However, N-monomethyl L-arginine unmasked altered contractile sensitivity to norepinephrine in arteries from DOCA-salt hypertensive rats. These data show that the endothelium compensates for increased contractile and reduced relaxant responses of vascular muscle in DOCA-salt hypertension by increasing the release of endothelium-derived relaxing factor. These data suggest that altered vascular responsiveness is masked by the endothelium, thus preventing these alterations from contributing to increased peripheral resistance during the development of DOCA-salt hypertension.

Northern blot and ribonuclease protection assay were used to identify alpha 2-adrenoceptor subtypes in human colonic adenocarcinoma (HT29), neuroblastoma x glioma rat-mouse hybrid NG108-15 (NG108) and opossum kidney (OK) cell lines. Radioligand binding studies showed that the alpha 2-adrenoceptor expressed in HT29, NG108 and OK cells represent the pharmacological alpha 2A, alpha 2B and alpha 2C subtypes respectively. In our Northern blot analysis, hybridization of poly(A)+ RNA from HT29, NG108 and OK cells with human kidney alpha 2-adrenoceptor cDNA probe (alpha 2-C4) identified a single band of 4.4, 4.2 and 4.4 kb respectively in each cell line. Hybridization with a human platelet alpha 2-adrenoceptor genomic probe (alpha 2-C10) resulted in two bands for HT29 cells with the size of 4.4 kb and 3.9 kb. No bands were seen for HT29, NG108 and OK cells when hybridized with a third alpha 2-adrenoceptor human genomic DNA probe which is localized in chromosome 2 (alpha 2-C2). For the HT29 cells, the 3.9 kb band was seen only when using the alpha 2-C10 probe. Thus, this band probably represents alpha 2-C10 mRNA. To further characterize the alpha 2-adrenoceptor mRNA expressed in HT29, NG108 and OK cells, the sensitive ribonuclease protection assay was performed. A single band about 900 bp was protected when the poly(A)+ RNA from NG108 and OK cells was hybridized with an alpha 2-C4 RNA probe and digested with RNAases. Hybridization of mRNA from HT29 cells with alpha 2-C10 RNA probe and digestion with RNAases protected a 500 bp fragment.(ABSTRACT TRUNCATED AT 250 WORDS)

The affinity of vascular vasopressin receptors was studied to determine its role in altered vascular contractile sensitivity in deoxycorticosterone acetate (DOCA)-salt hypertension. Ring segments of rat mesenteric arteries were used to study vascular vasopressin receptors. Male Wistar rats were given subcutaneous injections of DOCA and 1% NaCl in the drinking water. Mesenteric arteries from hypertensive rats had a reduced contractile sensitivity to arginine vasopressin (AVP) and lysine vasopressin (LVP). The order of potency of vasopressin receptor agonists (AVP greater than LVP greater than oxytocin) was the same in arteries from hypertensive compared with normotensive animals. The affinity of the vasopressin receptor antagonist [deamino-Pen1,O-Me-Tyr2,Arg8] vasopressin, and the affinities of the vasopressin receptor agonists AVP and LVP were not altered during developing DOCA-salt hypertension. There was no change in contractile sensitivity to norepinephrine and KCl in arteries from hypertensive rats. The reduced vasopressin contractile sensitivity is not due to a change in vasopressin receptor affinity but may be a compensatory response to elevated blood pressure. These data suggest that increased vascular sensitivity does not contribute to elevated blood pressure during the developing stage of DOCA-salt hypertension.

Separate genes for alpha-1A and alpha-1B adrenoceptors have now been identified. Whereas alpha-1 adrenoceptors are known to mediate rat renal vasoconstriction, the relative importance of these alpha-1 adrenoceptor subtypes was unknown. We cannulated the right suprarenal artery of anesthetized male Sprague-Dawley rats to permit administration of the alpha-1A and alpha-1B alkylating antagonists, SZL-49 (SZL) and chloroethylclonidine (CEC), respectively, directly into the right kidney. Treated kidneys were homogenized to identify the doses of SZL and CEC that caused the maximum reductions in Bmax for [3H]prazosin, the relatively nonselective alpha-1 adrenoceptor antagonist. In other rats, a Doppler flow probe was placed around the right renal artery, and dose-peak response curves for boluses of the alpha-1 adrenoceptor agonist phenylephrine (PHE) were generated before and after supramaximal dosages of SZL or CEC. Renal vasoconstriction to PHE was nearly obliterated by SZL. In contrast, CEC caused only a modest rightward shift in the PHE DRC. SZL also abolished the renal vascular response to two other alpha-1 adrenoceptor agonists, cirazoline and methoxamine. Our data support the conclusion that the alpha-1 adrenoceptors at the level of the rat renal resistance vessels are predominantly alpha-1A adrenoceptors.

alpha 2-Adrenoceptor subtype expression was investigated in cultured rat inner medullary collecting duct (IMCD) cells using radioligand binding studies, Northern blot analysis, and adenosine 3',5'-cyclic monophosphate (cAMP) assays. [3H]rauwolscine bound to a single class of alpha 2-adrenoceptors with high affinity [Kd = 1.7 +/- 0.3 nM, maximum binding (Bmax) = 45.2 +/- 10.8 fmol/mg protein]. alpha 2-Adrenoceptor ligands inhibited [3H]rauwolscine binding with a rank order of potency characteristic of interaction with the alpha 2B-adrenoceptor [inhibitory constant (Ki) values (in nM) rauwolscine (1.95) greater than ARC-239 (8.52) greater than prazosin (237) greater than oxymetazoline (30,000)]. Northern blot analysis was performed using poly(A)+ RNA isolated from 90% confluent rat IMCD cells and probes derived from alpha 2-adrenoceptor DNA sequences from the rat nonglycosylated alpha 2B-adrenoceptor and the human alpha 2A-adrenoceptor. The alpha 2B probe hybridized to a 4.2-kb band under high stringency conditions, but the alpha 2A-adrenoceptor probe did not hybridize to this band. In functional studies, the full alpha 2-adrenoceptor agonists epinephrine and UK-14,304 potently inhibited vasopressin-stimulated cAMP accumulation by 50 to 70% [half-maximal response (EC50) (in nM) epinephrine = 11.2, UK-14,304 = 6.4]. Guanabenz and clonidine were partial agonists, inhibiting cAMP accumulation by 30 to 40% and were less potent than the full agonists [EC50 (in nM) 56.0 guanabenz and 94.5 clonidine]. Epinephrine-induced inhibition of cAMP accumulation was blocked by rauwolscine, prazosin, and ARC-239 but not by the alpha 1-adrenoceptor antagonist corynanthine. We conclude that rat IMCD cells in primary culture express functional alpha 2-adrenoceptors of the alpha 2B-subtype.

Objective: To review the incidence of reversible renal insufficiency in patients with hypertensive nephrosclerosis undergoing antihypertensive therapy., Design: Retrospective analysis of 73 patients in a long-term blood pressure control study that compared the effects of an angiotensin converting enzyme (ACE) inhibitor plus conventional antihypertensive agents compared with placebo plus antihypertensive agents., Setting: Hospital-based outpatient treatment center., Interventions: Patients were divided into group 1, which received enalapril plus conventional antihypertensives, and group 2, which received placebo plus conventional antihypertensives., Measurements: Blood pressure and serum creatinine levels were measured, and imaging studies of the main renal arteries were done., Main Results: In group 1, eight of 42 patients (19%, 95% CI, 9% to 34%) developed reversible renal insufficiency, defined as an unexpected increase in serum creatinine of 88 mumol/L or higher. Six episodes of reversible renal insufficiency occurred during July and August when temperatures were 32.2 degrees C to 37.8 degrees C (90 degrees F to 100 degrees F). Renal artery stenosis was excluded by renal arteriogram or ultrasonic duplex scanning. All eight group-1 patients had a significant decrease in mean arterial pressure below their baseline level during reversible renal insufficiency (mean change, -28 +/- 10 mm Hg, P less than 0.001). The increase in the serum creatinine level was inversely correlated with the decrease in the mean arterial pressure (r = -0.68, P less than 0.01). Reversible renal insufficiency was successfully managed by withdrawing or reducing enalapril as well as other antihypertensive agents. Subsequently, enalapril was tolerated by seven of the eight patients without recurrence of renal insufficiency. In contrast, none of 31 (CI, 0% to 11%) patients in group 2 developed reversible renal insufficiency despite the fact that both the incidence of decreases in mean arterial pressure in 6 of 31 patients (19%) and the magnitude of the decreases in mean arterial pressure (mean change, -33 +/- 16 mm Hg) were similar to those observed in group 1., Conclusions: Reversible renal insufficiency in hypertensive nephrosclerosis associated with ACE inhibitor therapy correlates with relative hypotension, is not dependent on renal artery stenosis, and can usually be managed by dose reduction.

alpha 1-Adrenoceptors are expressed in high density in the rat kidney. Recent studies have shown that alpha 1-adrenoceptors are heterogeneous and can be subtyped based on their affinity for the antagonists WB 4101 (alpha 1A greater than alpha 1B) and chloroethylclonidine (alpha 1B-selective). We therefore investigated the distribution of alpha 1-adrenoceptor subtypes using [3H]prazosin binding in membranes prepared from cortex, the outer stripe of the outer medulla (OSOM), the inner stripe of the outer medulla (ISOM) and inner medulla dissected from rat kidney. [3H]Prazosin binding was detectable in each region with the following maximum binding site values for [3H]prazosin (femtomoles per milligram of protein): cortex, 186 +/- 20; OSOM, 76 +/- 14; ISOM, 34 +/- 2; and inner medulla, 8 +/- 2. Pretreatment of membranes with chloroethylclonidine (10 microM for 10 min) reduced maximum binding sites to 41 +/- 4% (75 +/- 9 fmol/mg) of control in cortex, 41 +/- 9% of control in OSOM (29 +/- 8 fmol/mg) and 15 +/- 3% of control in ISOM (5 +/- 1 fmol/mg). In competition studies, WB 4101 labeled both high and low affinity sites in cortex (respective pKi values = 10.01 +/- 0.3 and 8.23 +/- 0.1) and OSOM (pKi values = 9.6 + 0.3 and 8.3 +/- 0.5), but only low affinity sites in ISOM (pKi = 8.41 +/- 0.1). The relative prevalence of high:low affinity sites revealed by WB 4101 was 53:47 for cortex, 52:48 for OSOM and virtually all low affinity for ISOM. Prior treatment with chloroethylclonidine greatly reduced the low affinity component of the WB 4101 competition curve in cortex and OSOM. We conclude that: 1) the density of alpha 1-adrenoceptors is highest in the cortex and decreases from cortex to papilla and 2) the alpha 1A and alpha 1B subtypes are approximately equally distributed in the cortex and OSOM, but the alpha 1B subtype predominates in ISOM.

In previous studies we found that vasopressin stimulation of both cyclic AMP (cAMP) formation in cortical collecting tubules (CCT) and sodium reabsorption in isolated perfused kidneys was markedly exaggerated in rats with mineralocorticoid hypertension. In the present study, we tested the response (cAMP accumulation) of cortical and outer medullary collecting tubules (OMCT) to vasopressin in two rat models that are resistant to deoxycorticosterone acetate (DOCA)-induced hypertension, the Wistar-Furth strain and NaCl-deficient rats. The blood pressure of normal outbred Wistar rats rose to hypertensive levels (systolic pressure more than 165 mm Hg) during a 5-week treatment with DOCA (10 mg/week) and 1% saline to drink. Significant hypertrophy of the heart and kidneys was also observed. Vasopressin (10(-8) M)-induced cAMP formation was enhanced 3.4-fold in the CCT (OMCT unchanged) of hypertensive rats compared with normotensive controls. Significant hypertrophy (as indexed by tubule diameter) of the CCT but not the OMCT was also observed in DOCA-salt hypertensive rats. Restriction of dietary NaCl (0.13% in chow, tap water to drink) completely prevented DOCA-induced hypertension, organ and CCT hypertrophy, and enhancement of vasopressin-stimulated cAMP formation in the CCT. In Wistar-Furth rats, DOCA-salt treatment did not alter blood pressure or cause significant organ hypertrophy. However, DOCA-salt treatment enhanced vasopressin-stimulated cAMP formation by 4.1-fold in CCT of Wistar-Furth rats, with significant tubular hypertrophy in the CCT but not the OMCT. We conclude that DOCA-induced hypertension and changes in CCT function are dependent on excess dietary NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Six patients receiving minoxidil, propranolol, and diuretics had clonidine added in increasing dosage. Five patients received 0.2-0.8 mg/day clonidine and one patient 0.2-0.6 mg. Plasma catecholamines, renin activity, blood pressure, and serum creatinine were measured at each dose level. The patients had a hypernoradrenergic state prior to clonidine [mean +/- SE plasma norepinephrine (PNE), 924 +/- 141 pg/ml]. Administration of clonidine, 0.2-0.8 mg/day, lowered supine PNE (p less than 0.01, p less than 0.02), and clonidine, 0.4-0.8 mg/day, lowered standing PNE (p less than 0.01, p less than 0.02). Maximal suppression of PNE occurred with 0.4 mg/day. Systolic blood pressure correlated with supine PNE (r = 0.055, p less than 0.05) at 0.2-0.8 mg/day clonidine, and standing PNE correlated (r = 0.72, p less than 0.01) at 0.2-0.6 mg/day. Plasma epinephrine concentration, plasma renin activity (PRA), and serum creatinine did not show any significant change. PRA did not correlate with blood pressure changes. Plasma clonidine concentration correlated reciprocally with the change in PNE (r = -0.59, p less than 0.01). These findings indicate that clonidine can return elevated PNE to normal levels in the vasodilator beta-blocker-treated patient and thus remove this abnormality as a contributing factor to pathogenetic mechanisms.

Our subjects were seven severely hypertensive patients with blood pressures (BPs) over 140/90 who were using minoxidil, propranolol, and diuretics. Clonidine followed by prazosin was added to their regimen on an outpatient basis to establish the dose-response for BP and catecholamines. Plasma renin activity (PRA), body weight, and renal function were measured. Clonidine was given in doses of 0.2, 0.4, 0.6, and 0.8 mg/day. Supine and standing systolic BP decreased at all dose levels of clonidine (P less than 0.01, P less than 0.05). Diastolic BP decreased in the standing position with doses of 0.4, 0.6, and 0.8 mg (P less than 0.01, P less than 0.05). Subjects were hypernoradrenergic initially with plasma norepinephrine (PNE) 895 +/- 122 pg/ml. PNE was suppressed by 0.2 to 0.8 mg clonidine (P less than 0.01) with near maximal suppression at 0.4 mg daily. Systolic BP correlated with PNE (r = 0.59, P less than 0.001). Supine and standing PRA decreased after 0.2 mg clonidine (P less than 0.05) but not after higher doses. Our findings suggest the antihypertensive action of clonidine is related to PNE suppression but not to that of PRA. Plasma epinephrine (PE), body weight, and renal function did not change. Prazosin was given after clonidine to the same patients in a dose range of 3 to 40 mg/day. With doses of 6 to 40 mg, systolic and diastolic and supine and standing BP fell (P less than 0.001, P less than 0.01). PNE remained elevated throughout all dose levels and did not correlate with BP. Weight rose with prazosin (P less than 0.02) but PE, PRA, and renal function did not change. Hence, clonidine and prazosin induced additional lowering of BP but had different effects of PNE and weight.

Previous studies in our laboratory demonstrated that alpha 2-adrenoceptor activation reversed arachidonic acid induced diuresis in the rat. However, the site of action was not elucidated. Since prostaglandin E2 is the predominant prostaglandin metabolite of arachidonic acid, we studied the effect of renal alpha 2-adrenoceptor stimulation on prostaglandin E2 (PGE2) induced cAMP formation. The study was done in intact single nephron segments and glomeruli. All incubations were done in the presence of 1-methyl-3-isobutylxanthine (phosphodiesterase inhibitor) and propranolol at 37 degrees C for two minutes. PGE2 increased cellular cAMP levels in the thin descending limb of Henle (tDL), cortical collecting tubule (CCT) and glomerulus. Alpha 2-adrenoceptors were activated with varying concentrations of epinephrine (E). In the tDL, alpha 2-adrenoceptor activation with E (5 X 10(-6)M to 5 X 10(-5)M) suppressed (p less than 0.05) PGE2 stimulated cAMP production by 35%. This suppression by E was inhibited by 5 X 10(-6)M yohimbine but not by 5 X 10(-6)M prazosin confirming alpha 2-adrenoceptor mediation of the effects of E. Conversely, in the CCT and glomerulus, E had no effect on PGE2-stimulated increases in cellular cAMP levels. Thus, the capacity of alpha 2-adrenoceptors to inhibit PGE2-stimulated adenylate cyclase is anatomic site-specific. This effect of alpha 2-adrenoceptors on cAMP in the tDL may explain, at least in part, the effect of alpha 2-adrenoceptors on arachidonic acid induced diuresis in the rat.

The antihypertensive mechanisms of single and combined therapy with a beta-adrenergic antagonist (propranolol) and a vasodilator (hydralazine) were investigated in 9 patients with moderately severe hypertension, who were receiving maintenance diuretic (hydrochlorothiazide) treatment. Hemodynamic and neuroendocrine responses were determined at rest and during lower body negative pressure, and dynamic and static exercise stress after the chronic administration of propranolol and hydralazine, given alone or in combination. All 3 drug regimens, each administered for at least 10 weeks, reduced blood pressure (p less than 0.05) compared with diuretic-only therapy in patients at rest, in both the supine and standing position, and during lower body negative pressure and dynamic exercise. There was a significant additive antihypertensive effect when propranolol and hydralazine were combined. Only combination therapy effectively lowered pressure during static exercise. The regimens produced divergent effects on the supine cardiac output: a decrease with propranolol (p less than 0.05), no change with combination therapy and an increase with hydralazine (p less than 0.05). Both hydralazine and combination therapy significantly reduced supine total peripheral resistance (p less than 0.05), whereas propranolol produced no change. All 3 drug treatments significantly reduced total peripheral resistance during upright rest and dynamic exercise (p less than 0.05), without changing cardiac output or maximal exercise capacity. During exercise, cardiac output was maintained in patients treated with propranolol and in those treated with combined therapy by increases in stroke volume (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The early clinical pharmacologic investigations of saralasin were facilitated by the availability of a highly sensitive and specific radioimmunoassay for this peptide. In these studies, plasma concentrations of saralasin were correlated with inhibition of angiotensin receptors in each of three organ systems: vascular smooth muscle, adrenal cortex, and the renin release control mechanism in the kidney. The biochemical half-life of plasma saralasin was 3.2 min and an infusion time-to-plateau was 12--15 min. Saralasin inhibited adrenal cortical, vascular, and intrarenal (renin release) angiotensin receptors. The time required for manifesting these blocking actions was short(3--10 min) except for the 30--60 min required to suppress plasma aldosterone. Saralasin-induced blood pressure lowering was dependent on previously elevated serum renin activity and volume depletion. Expansion of intravascular volume prevented hypotensive responses to saralasin even in high-renin patients. Saralasin-induced renin release occurred independent of hypotension and could be inhibited by propranolol, a beta-adrenergic blocking agent. Thus, saralasin is a selective angiotensin antagonist which lacks organ specificity. It is a highly useful tool in pharmacologic studies of the renin--angiotensin axis in man and shows promise as a diagnostic tool.

Renal function was monitored in 20 previously refractory hypertensive patients treated for 2--7 years with minoxidil, sympathetic suppressants, and diuretics. Serum creatinine concentration increased by more than 1 mg/dl in 9 of the 20 patients. In 4 of the 9 patients, renal disease progressed to require hemodialysis. Eleven patients had no progression of renal disease (creatinine increased less than or equal to 1 mg/dl). Three of the 11 had had malignant hypertension with renal failure which was reversed during this triple therapy. Neither the quality of blood pressure control nor the duration of minoxidil therapy correlated with increases in serum creatinine concentration. Plasma norepinephrine levels were higher (p less than 0.01) and plasma renin activity lower (p less than 0.02) in the group with progression of renal disease. Serum creatinine at the time when neuroendocrine studies were done correlated with PNE (r = 0.51, p less than 0.05). Addition of clonidine to this triple regimen in 2 patients with advanced renal disease lowered plasma norepinephrine by 63 and 81%. These findings suggest that the high norepinephrine levels are due to excess release of norepinephrine rather than defective renal elimination of this catecholamine. Whether the elevated plasma norepinephrine contributes to or is a result of the underlying disease is not known.

alpha 2-Adrenoceptors were first described pharmacologically ten years ago. Within three years their capacity to inhibit adenylate cyclase had been demonstrated in many tissues. They were demonstrated biochemically in the kidneys in 1981 even before any renal physiological effects of their activation were known. They predominate numerically over alpha 1-adrenoceptors in renal membranes and their density is increased in genetic forms of rat hypertension. alpha 1-Adrenoceptors normally mediate the vasoconstriction and sodium- and water-retaining effects of sympathetic neuronally released norepinephrine. Norepinephrine or epinephrine must be infused to activate alpha 2-adrenoceptors, suggesting that renal alpha 2-adrenoceptors are extrajunctional, whereas alpha 1-adrenoceptors are postjunctional. When alpha 1-adrenoceptors are chronically blocked, renal alpha 2-adrenoceptor density increases and they assume a location at postjunctional sites, the otherwise exclusive domain of alpha 1-adrenoceptors. Results from microdissection studies have established that alpha 2-adrenoceptors are present on most segments of the nephron and that their activation can suppress adenosine 3,'5'-cyclic monophosphate (cAMP) accumulation induced by most renal hormones. However, failure of alpha 2-adrenoceptor activation to suppress cAMP accumulation in some tubular segments induced by certain hormones suggests compartmentalization of adenylate cyclase regulation that is hormone-function specific. In view of the potent inhibitory effects of alpha 2-adrenoceptor stimulation on hormone activated cAMP accumulation in several discrete areas of the nephron, we suggest that alpha 2-adrenoceptors fulfill important regulatory role(s) in renal function. To date, alpha 2-adrenoceptor activation has been shown to reverse vasopressin-induced sodium and water retention, and arachidonic acid- and furosemide-induced cAMP, sodium, and water excretion in the isolated perfused kidney. Thus the effects are qualitatively and quantitatively dependent in these studies on the hormone being infused and are therefore hormone-function specific. Physiological effects of alpha 2-adrenoceptor activation of thyrocalcitonin and on parathyroid hormone-induced effects have not been studied. alpha 2-Adrenoceptor activation can inhibit renin release in some model systems and can activate a sodium-hydrogen antiporter system in proximal tubules. The physiological roles of these actions are unknown.

We investigated the relevance of the selective alpha 1-adrenergic receptor blockade produced by prazosin to its blood pressure-lowering efficacy in man. The hemodynamic and neuroendocrine responses to the acute and chronic oral administration of prazosin and phenoxybenzamine were compared in a randomized, double-blind, placebo-controlled, crossover study of 11 patients with essential hypertension. These responses were also evaluated during lower body negative pressure and dynamic bicycle exercise, which produce potent but diversified activation of the sympathetic nervous system. In the acute studies, arterial blood pressure decreased to similar levels with prazosin or phenoxybenzamine; however, hemodynamic and neuroendocrine responses differed both before and during sympathetic nervous system activation. Prazosin lowered arterial blood pressure by reducing total peripheral resistance (p less than 0.05). In contrast, phenoxybenzamine produced a modest reduction in cardiac output (8%, p less than 0.05) with little change in total peripheral resistance, forearm vascular resistance or forearm blood flow. Additionally, plasma norepinephrine concentration and heart rate rose to significantly higher levels with prazosin (p less than 0.02) than with phenoxybenzamine, a difference that was most evident with lower body negative pressure or dynamic exercise. Baroreceptor control of arterial pressure homeostasis was preserved with both agents, except during marked degrees of cardiovascular stress. With chronic therapy, the circulatory responses adapted to the alpha-adrenergic antagonists, and both drugs produced similar hemodynamic and neuroendocrine profiles. The differences with acute administration may be the result of a more rapid onset of action and a more marked degree of alpha-adrenergic blockage with prazosin than with phenoxybenzamine therapy, rather than to any difference in their alpha 1- and alpha 2-adrenergic receptor blocking properties. Moreover, the findings of the present study suggest that the prejunctional alpha 2-receptor, autoinhibitory to sympathetic neuronal norepinephrine release, is of no functional significance in patients with essential hypertension.

Since substance P is a potent natriuretic, diuretic, and vasodilatory peptide, a radioimmunoassay for substance P was developed, and its levels measured in the plasma of normal subjects and patients with essential hypertension. The plasma substance P levels were 186+/-14 pg/ml in normal subjects and 164+/-3 pg/ml in hypertensive patients. When the sodium content of their diet was reduced to 10 mEq/day, substance P levels failed to change, but plasma renin activity and urinary kallikrein increased. An acute saline infusion also failed to alter plasma substance P levels. Assuming an upright posture increased plasma renin activity, but not substance P, in both groups of subjects. Thus, it appears that substance P is not involved in the control of blood pressure, kallikrein excretion or renin release in man.

We examined the effect of long-term blood pressure control on renal function in 41 patients with refractory hypertension by using minoxidil, sympathetic suppressants, and diuretics continuously for 6 months to 7 1/2 years. In 15 of 32 patients with benign hypertension, the serum creatinine concentration increased by more than 1 mg/dL, with nine of 15 requiring hemodialysis. Analysis of 1/serum creatinine versus time plots indicated that use of minoxidil delayed the onset of end-stage renal failure in some patients for up to 6 years. In the remaining 17 patients with benign hypertension, renal function remained stable with no decreases greater than 2 mg/dL. Four of nine patients presenting with malignant hypertension had marked and sustained improvement in renal function, although three initially required hemodialysis. The mean serum creatinine concentration in these four patients fell from 9.7 to 2.9 mg/dL. Thus, impressive renal functional improvement may occur with minoxidil use in some patients with malignant hypertension.

We investigated the effect of captopril on plasma norepinephrine concentration and blood pressure in two groups of hypertensive patients. One group consisted of five severely hypertensive patients rendered hypernoradrenergic by administration of a minoxidil-propranolol-diuretic regimen. The other group was ten untreated mildly hypertensive patients. Two hours after 12.5mg of captopril, blood pressure was lowered (p less than .05) in four of the five hypernoradrenergic patients from 180 +/- 8/102 +/- 8 to 132 +/- 7/77 +/- 8 mmHg. Chronic administration of 100-150mg of captopril tid caused no further blood pressure reduction. Precaptopril plasma norepinephrine concentration was 925 +/- 206 and two hours after the 12.5mg dose was 807 +/- 80 pg/ml. Three months later having advanced the dose to 300-450 mg/day it was lower (p less than .05) at 752 pg/ml. The acute blood pressure response correlated (r = -0.72, p less than .001) with the precaptopril plasma norepinephrine. Precaptopril blood pressure in the mild hypertensive patients was 146 +/- 4/98 +/- 1, after a 25-100mg dose it was 137 +/- 6/91 +/- 2 (diastolic p less than .05) and at two months with the same captopril dose bid it was 141 +/- 8/88 +/- 4 mmHg (diastolic p less than .01). Corresponding initial PNE was 425 +/- 72, two hours after captopril 405 +/- 47 and 310 +/- 63 pg/ml (p less than .05) with chronic administration. Thus, captopril lowers blood pressure in both hypernoradrenergic and eunoradrenergic hypertensive patients without increasing plasma norepinephrine suggesting some unique dampening effect of this drug on the sympathetic nervous system. Also, addition of captopril to triple therapy lowered blood pressure in proportion to plasma norepinephrine levels suggesting importance to its action on this sympathetic nervous system effector.

The potential role of angiotensin II and its heptapeptide metabolite, des-aspartyl-angiotensin II, was studied in the conscious unanesthetized rat. Aldosterone release was induced by both peptides at physiologic doses (0.72 nanogram per minute). [I-Sarcosyl-8-alanyl]-angiotensin II (P-113 inhibited angiotensin II more effectively than des-aspartyl-angiotensin II (101 percent as compared to 82 percent). These results indicate that angiotensin controls aldosterone release in the rat and that des-aspartyl-angiotensin II (that is, angiotensin III) may be important in this sequence.

We activated three known components of the adenylate cyclase system in renal membranes from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. The basal adenylate cyclase activity and responses to plasma membrane receptor activation by parathyroid hormone, isoproterenol and vasopressin were not different between the two strains. The response to prostaglandin E2 (PGE2), however, was less in the SHR than in the WKY at five, (P less than 0.05), 12 (P less than 0.01) and 16 (P less than 0.01) weeks of age. Activation of either the guanosine-5'-triphosphate (GTP) binding regulatory protein (N) with sodium fluoride (NaF) and guanyl-5'-yl-imidodiphosphate [Gpp(NH)p], or the catalytic unit with manganese chloride (MnCl2) or forskolin were not different between the two groups. When the medullary and cortical plasma membrane adenylate cyclase responses were studied separately, the observed decreased response to PGE2 (of SHR) was found to be entirely in the cortex. Also, the NaF response was reduced in the cortical region of the 12-week-old rats, a finding suggesting a possibility of a post receptor defect. These results show that there is a defective renal adenylate cyclase response specific to prostaglandin E2 in SHR. This defect could be related to the development of hypertension, by changing the natriuretic and/or renal vasodilating effects of these prostaglandins.

The roles of absolute and relative oxygen uptake (VO2 and percent of muscle group specific VO2 max) as determinants of the cardiovascular and ventilatory responses to exercise over a wide range of active muscle mass have not previously been defined. Six healthy men performed four types of dynamic exercise--one-arm curl, one-arm cranking, and one- and two-leg cycling at four different relative work loads--25, 50, 75, and 100% of VO2 max for the corresponding muscle group. VO2 during maximal one-arm curl, one-arm cranking, and one-leg cycling averaged 20, 50, and 75%, respectively, of that for maximal two-leg cycling. Cardiac output was linearly related to VO2 with a similar slope and intercept for each type of exercise. Heart rate at a given %VO2 max was higher with larger active muscle mass. In relation to %VO2 max, systemic resistance was lower and plasma catecholamine levels were higher with larger active muscle mass. The cardiovascular responses to exercise are determined to a large extent by the active muscle mass and the absolute oxygen uptake, with the principal feature appearing to be the tight linkage between systemic oxygen transport and utilization.