Biomedical subjects
Publications and source records attributed to W A Pettinger.
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.
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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.
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.
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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.
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.
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.
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.
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.
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)
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.